Ausgewählte Originalarbeiten 2013/14

Kastner C, Löbler M, Sternberg K, Reske T, Stachs O, Guthoff R, Schmitz KP. Permeability of the anterior lens capsule for large molecules and small drugs. Curr Eye Res.

doi: 10.3109/02713683.2013.803288

PMID: 23885713

Abstract:

Purpose: For developing injectable lenses the retention properties of the capsular bag are important. Therefore the apparent permeability coefficients of sodium fluorescein and fluorescent dextrans of different sizes were determined for the human anterior lens capsule to calculate a molecular weight cutoff from these data. In addition, permeability coefficients of drugs helpful for the suppression of secondary cataract were determined.
Materials and Methods: Capsulorhexis specimens were fixed in a specially designed two compartment diffusion chamber to investigate the permeation of sodium fluorescein and fluorescent dextrans of different sizes (10, 40, 70 and 150 kDa) for 24 h (n >= 3) and of the antiproliferative drugs actinomycin D and methotrexate for 0.5, 24, 48 and 72 h (n >= 3).
Results: The molecular weight cutoff of the anterior lens capsule was found to be 166 +/- 82 kDa. After 0.5 h, no passage of actinomycin D and methotrexate was detectable through the lens capsule. The apparent permeability coefficients for actinomycin D and methotrexate were calculated to 0.71 +/- 0.02 mu m/s and to 0.80 +/- 0.13 mu m/s, respectively.
Conclusions: The capsular bag retains fluorescent dextrans with a molecular weight of >166 kDa. Hence, prepolymers are required to polymerize rapidly to be retained inside of the capsular bag. In addition, low-molecular substances intended as antiproliferative drugs for secondary cataract prevention should be applied within a time frame of five minutes in such a way that cells adjacent to the capsular bag will not be damaged.

Curr Eye Res. 2013 Oct; 38(10):1057-63.

Sternberg K, Voss K, Kastner C, Bernsdorf A, Lurtz C, Stachs O, Guthoff RF, Schmitz KP. Development of an Injectable Polymer-Based Local Drug Delivery System for Subconjunctival Treatment of Glaucoma. Biomed Tech.

doi: 10.1515/bmt-2013-4056

PMID: 24042679

Abstract:

Polymer-based local drug delivery (LDD) systems have found applications in diverse medical fields. Due to implant-induced, undesirable foreign body reactions especially implant-associated LDD systems, such as vascular drug-eluting stents, have achieved an increasing importance in the last decade. Another interesting field of application is the use of polymers as carriers of injectable LDD systems. Therefore, the focus of our research presented in this article is the development of a novel biodegradable LDD system intended for the subconjunctival treatment of glaucoma. Since hyaluronic acid sodium salt (HA) is commonly used in ophthalmology due to its viscoelastic and hydrophilic properties, HA was investigated as one polymeric component. As more hydrophobic second component a biodegradable oligomer based on a functionalized 1,2-ethylene glycol bis(dilactic acid) (ELA-NCO) was studied regarding its potential to act as drug carrier.

Biomed Tech (Berl), 2013. 58(Suppl. 1)

Petersen S, Kaule S, Stein F, Minrath I, Schmitz KP, Kragl U, Sternberg K. Novel paclitaxel-coated angioplasty balloon catheter based on cetylpyridinium salicylate: Preparation, characterization and simulated use... Materials Science and Engineering.

doi: 10.1016/j.msec.2013.06.021

PMID: 23910339

Abstract:

Drug-coated balloons (DCB), which have emerged as therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficiency and safety within a number of clinical studies. In vitro studies elucidating the correlation of coating method and composition with DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this context, we evaluated the applicability of a pipetting, dip-coating, and spray-coating process for the establishment of DCB based on paclitaxel (PTX) and the ionic liquid cetylpyridinium salicylate (Cetpyrsal) as novel innovative additive in three different compositions. Among tested methods and compositions, the pipetting process with 50wt.% PTX resulted in most promising coatings as drug load was less controllable by the other processes and higher PTX contents led to considerable drug crystallization, as visualized by electron microscopy, accelerating PTX loss during short-term elution. Applying these conditions, homogeneous coatings could be applied on balloon catheter, whose simulated use in an in vitro vessel model revealed percental drug losses of 36 and 28% during transit and percental drug transfers of 12 and 40% under expansion for coatings applied in expanded and folded balloon condition, respectively. In comparison to literature values, these results support the high potential of Cetpyrsal as novel DCB matrix regarding low drug loss and efficient drug transfer.

 

Materials Science and Engineering C 33 (2013) 4244–4250.

Bandomir J, Schulz A, Taguchi S, Petersen S, Kragl U, Ohno H, Sternberg K. Poly-Ionic Liquids as New Hydrogel Materials: Synthesis, Characterization and Application. Biomed. Tech.

doi: 10.1515/bmt-2013-4204

PMID: 24042835

Abstract:

New hydrogel materials were successfully synthesized by polymerization of imidazolium-based ionic liquids. These materials were fully characterized to compare chemical and mechanical properties with alginate based gels. The synthesized hydrogels are currently under investigation in vitro to determine drug release behaviour of drug-coated balloons within a vessel-simulating flow-through cell.

Biomed. Tech. (Berl) 2013, 58(S1)

Kaule S, Petersen S, Minrath I, Schmitz K-P, Sternberg K. Establishment of an in vitro evaluation system for drug-coated balloons. Biomed. Tech.

doi: 10.1515/bmt-2013-4083

PMID: 24042676

Abstract:

The drug-coated balloon (DCB) is an emerging device in percutaneous coronary intervention, which has shown promising results by means of an efficient local release of paclitaxel (PTX) without the need of an implant remaining in the patient's body. Safe and efficacy of DCB have been already proven in clinical trials for the treatment of in-stent restenosis and complex coronary de novo lesion subsets, such as small vessel diseases, diabetes, and fuse lesions, where stents obtain suboptimal results. However, there is only very few literature data about coating and drug delivery characteristics. In this context, we set up an in vitro evaluation system for DCB including determination of coating morphology, coating thickness, mechanical performance, drug loss and drug application as well as particle release during simulated use. Exemplary data of drug delivery characteristics of an urea-based DCB are provided within the present paper.

Biomed. Tech. (Berl) 2013, 58(S1).

Busch R, Strohbach A , Walz SA, Rethfeldt S, Petersen S, Busch MC, Felix SB Sternberg K. New stent surface materials: the impact of polymer-dependent interactions of human endothelial cells, smooth muscle cells, and platelets. Acta Biomaterialia.

doi: 10.1016/j.actbio.2013.10.015

PMID: 24148751

Abstract:

Despite the development of new coronary stent technologies, in-stent restenosis and stent thrombosis are still clinically relevant. Interactions of blood and tissue cells with the implanted material may represent an important cause of these side effects. We hypothesize material-dependent interaction of blood and tissue cells. The aim of this study is accordingly to investigate the impact of vascular endothelial cells, smooth muscle cells and platelets with various biodegradable polymers to identify a stent coating or platform material that demonstrates excellent endothelial-cell-supportive and non-thrombogenic properties. Human umbilical venous endothelial cells, human coronary arterial endothelial cells and human coronary arterial smooth muscle cells were cultivated on the surfaces of two established biostable polymers used for drug-eluting stents, namely poly(ethylene-co-vinylacetate) (PEVA) and poly(butyl methacrylate) (PBMA). We compared these polymers to new biodegradable polyesters poly(l-lactide) (PLLA), poly(3-hydroxybutyrate) (P(3HB)), poly(4-hydroxybutyrate) (P(4HB)) and a polymeric blend of PLLA/P(4HB) in a ratio of 78/22% (w/w). Biocompatibility tests were performed under static and dynamic conditions. Measurement of cell proliferation, viability, glycocalix width, eNOS and PECAM-1 mRNA expression revealed strong material dependency among the six polymer samples investigated. Only the polymeric blend of PLLA/P(4HB) achieved excellent endothelial markers of biocompatibility. Data show that PLLA and P(4HB) tend to a more thrombotic response, whereas the polymer blend is characterized by a lower thrombotic potential. These data demonstrate material-dependent endothelialization, smooth muscle cell growth and thrombogenicity. Although polymers such as PEVA and PBMA are already commonly used for vascular implants, they did not sufficiently meet the criteria for biocompatibility. The investigated biodegradable polymeric blend PLLA/P(4HB) evidently represents a promising material for vascular stents and stent coatings.

Acta Biomaterialia 2014 Feb;10(2):688-700.

Petersen S, Strohbach A, Busch R, Felix SB, Schmitz KP, Sternberg K. Site-selective immobilization of anti-CD34 antibodies to poly(l-lactide) for endovascular implant surfaces. J Biomed Mater Res B Appl Biomater.

doi: 10.1002/jbm.b.33012

PMID: 24000221

Abstract:

Aiming at a speed up of the re-endothelialization process of biodegradable endovascular implants, novel approaches for the functionalization of poly(l-lactide) (PLLA) with anti-CD34 antibodies were established. We propose a three-step process involving PLLA surface activation with functional amino groups, attachment of a protein repelling peptide spacer, and covalent random or site-selective immobilization of the antibodies. Obtainable antibody surface densities and antigen binding capacities were thoroughly evaluated by means of enzyme-linked immunosorbent assay. Results indicate that a lower amount of anchoring sites on the antibody favors high coupling efficiency, while localization of the anchoring sites, facing the antigen binding moiety, strongly enhances the antigen capture capacity of the support. Besides minimization of physisorption and cell adhesion exemplarily shown with bovine serum albumin, avidin, and human umbilical vein endothelial cells, respectively, the inclusion of the protein-repelling spacer strengthened this effect, yielding antigen capture capacities exceeding values so far reported in literature. In contrast, the number of amino groups on the PLLA surfaces, which is indeed highly dependent on the applied activation procedure, does not seem to influence antibody coupling efficiency and antigen capture capacity considerably. This allows the choice of surface activation treatment, plasma or wet-chemical, regarding other processing parameters as for instance sterilizability or favored modification depth.

J Biomed Mater Res B Appl Biomater. 2014 Feb;102(2):345-355.

Busch R, Strohbach A, Petersen S, Sternberg K, Felix S. Parameters of Endothelial Function are dependent on Polymeric Surface Material. Biomed Tech (Berl).

doi: 10.1515/bmt-2013-4053

PMID: 24042644

Abstract:

Although the first generation of drug-eluting stents have revolutionized the treatment of coronary artery disease in terms of reduction of in-stent-restenosis, there is increasing evidence that the applied surface polymer coatings could be responsible for adverse effects like delayed healing, late stent-thrombosis, local hypersensitivity reaction and remaining in-stent restenosis. Biodegradable polymers are hence investigated. However, tissue response to these materials in terms of vessel healing, inflammation and bio-compatibility is not described in detail yet. In this context, the present study was designed to investigate endothelial cell function on biodegradable polymers using human endothelial cells applied to an in vitro flow chamber model with laminar shear stress exposure. Our data demonstrate a material dependent endothelial cell function.

Biomed. Tech. (Berl) 2013, 58(S1)

Storm T, Teske M, Wulf K, Löbler M, Schmitz KP, Sternberg K. Enhanced Endothelialization of PCL Through Chemical Activation, Protein Precoating and VEGF Stimulation. Biomed Tech (Berl).

doi: 10.1515/bmt-2013-4092

PMID: 24042693

Abstract:

Controlling the post-implantation tissue response in the cardiovascular system remains a formidable challenge. Of utmost importance is the rapid endothelialisation of the implant surface. To promote endothelial cell attachment to the model polymer PCL, we investigated multiple surface modifications in conjunction with VEGF stimulation. Plasma activation and pre-coating with extracellular matrix proteins proved to be especially useful in this context.

Biomed. Tech. (Berl) 2013, 58(S1)

Pandiyaraj K N, Heeg J, Mewes Ch, Wienecke M, Barfels T, Uthayakumar V, Su P G. Investigation on surface and biological properties of silver containing diamond like carbon films on polyethylene terephthalate foil ... Key Engineering Materials

doi: 10.4028/www.scientific.net/KEM.521.191

Abstract:

Silver containing diamond like carbon films were coated on the surface of polyethylene film (PET) using novel hybrid sputtering method. Polymeric substrates can create soft, flexible, highly absorbent and cost-effective materials by selecting or controlling their molecular structures. The material silver is known to be a potential antibacterial material. The silver containing coating has been potentially recommended for synthesis biomedical materials. In the present work, we discussed the antibacterial activity of the silver containing DLC film coated PET film surfaces which was coated as a function of deposition power level. The surface morphology of the Ag-DLC was analysed by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The atomic concentration and structure of the Ag-DLC was measured by energy dispersive X-ray (EDX) and Raman spectroscopy. The hydrophilicity of the films was measured by contact angle analysis. The antibacterial activity of Ag-DLC films were evaluated by bacterial eradication tests with Escherichia coli at incubation time of one day. In addition, blood compatibility of the Ag-DLC films were studied by in vitro blood compatibility tests. It was found that the surface of the obtained Ag-DLC decreases with increasing the deposition power level. The antibacterial and hemocompatibility of the silver containing DLC film increase gradually with increase of deposition power level. Our results revealed that the Ag-incorporated DLC films are potentially useful as biomedical devices having good antibacterial and hemocompatibility.

 

Key Engineering Materials 521 (2012) 191

Strohbach A, Busch MC, Felix SB, Busch R. The Apelin/APJ-System: Different Pathways and Functions of the Isoforms Apelin-12 and Apelin-13. Clin Res Cardiol.

doi: 10.1007/s00392-013-1100-1

Abstract:

Silver containing diamond like carbon films were coated on the surface of polyethylene film (PET) using novel hybrid sputtering method. Polymeric substrates can create soft, flexible, highly absorbent and cost-effective materials by selecting or controlling their molecular structures. The material silver is known to be a potential antibacterial material. The silver containing coating has been potentially recommended for synthesis biomedical materials. In the present work, we discussed the antibacterial activity of the silver containing DLC film coated PET film surfaces which was coated as a function of deposition power level. The surface morphology of the Ag-DLC was analysed by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The atomic concentration and structure of the Ag-DLC was measured by energy dispersive X-ray (EDX) and Raman spectroscopy. The hydrophilicity of the films was measured by contact angle analysis. The antibacterial activity of Ag-DLC films were evaluated by bacterial eradication tests with Escherichia coli at incubation time of one day. In addition, blood compatibility of the Ag-DLC films were studied by in vitro blood compatibility tests. It was found that the surface of the obtained Ag-DLC decreases with increasing the deposition power level. The antibacterial and hemocompatibility of the silver containing DLC film increase gradually with increase of deposition power level. Our results revealed that the Ag-incorporated DLC films are potentially useful as biomedical devices having good antibacterial and hemocompatibility.

Clin Res Cardiol. 2013 Apr;102 (1).

M. Vehse, S. Petersen, P. Oldorf, R. Peters, F. Bendig, C. Schuster, C. Merschjann, S. Lochbrunner, K.-H. Meiwes-Broer, K. Sternberg, K.-P. Schmitz, H. Seitz. Drug delivery from laser drilled discrete drug depots. BioNanoMaterials

BioNanoMaterials, vol. 14 (suppl. 1), p. 36, 2013

M. Vehse, S. Petersen, K. Sternberg, H. Seitz. Drug delivery from photo polymerized poly(ethylene glycol) diacrylate scaffolds Polym. Adv. Technol.

Polym. Adv. Technol., vol. 24 (suppl. 1), p. 156-157, 2013

C. Schuster, C. Merschjann, N. Rothe, S. Fiedler, R. Irsig, K.-H. Meiwes-Broer, M. Vehse, H. Seitz, V. Senz, K. Sternberg, S. Lochbrunner. Machining of biocompatible polymers with shaped femtosecond laserpulses. BiomedTech

doi: 10.1515/bmt-2013-4085

PMID: 24042687

Abstract:

Using a pulse shaper femtosecond laser pulses with variable length are applied in machining biocompatible polymers. It has been found that efficient material ablation can be achieved resulting in sharp cut edges. Systematic variation of the pulse length shows that the shortest pulses allow working with the lowest pulse energy.

BiomedTech, vol. 58 (suppl. 1), 2013

S. Fiedler, R. Irsig, J. Tiggesbäumker, C. Schuster, C. Merschjann, N. Rothe, S. Lochbrunner, M. Vehse, H. Seitz, E.-D. Klinkenberg, K.-H. Meiwes-Broer: Machining of biocompatible ceramics with femtosecond laser pulses. BiomedTech

doi: 10.1515/bmt-2013-4093

PMID: 24042670

Abstract:

Alumina toughened zirconia (ATZ) ceramic composites have been machined and structured with ultrashort laser pulses. With this approach the fabrication of various cavity patterns on the surface of the material with high precision becomes feasible. The scope of surface manipulation with femtosecond lasers gives opportunity to adopt the ceramic surface to tissue apposition for several different medical applications employing biocompatible ceramics.

BiomedTech, vol.58 (suppl. 1), 2013

Sternberg K, Petersen S, Grabow N, Senz V, Meyer zu Schwabedissen H, Kroemer HK, Schmitz KP. Implant-associated local drug delivery systems based on biodegradable polymers – customized designs for different medical applications. Biomed. Tech. (Berl)

doi: 10.1515/bmt-2012-0049

PMID: 23979120

Abstract:

Implants providing controlled, local release of active substances are of interest in different medical applications. Therefore, the focus of the present article is the development of implant-associated diffusion-or chemically controlled local drug delivery (LDD) systems based on biodegradable polymeric drug carriers. In this context, we provide new data and review our own recently published data concerning the drug release behavior of diffusion-controlled LDD systems in relation to the kind of polymer, drug content, coating mass/thickness, and layer composition. We demonstrate that polymers allow a wide range of control over the drug release characteristics. In this regard, we show that the glass transition temperature of a polymer has an impact on its drug release. Additionally, the blending of hydrophobic, semicrystalline polymers with amorphous polymers leads to an increase in the rate of drug release compared with the pure semicrystalline polymer. Moreover, the percentage loading of the embedded drug has a considerable effect on the rate and duration of drug release. Furthermore, we discuss chemically controlled LDD systems designed for the release of biomolecules, such as growth factors, as well as nanoparticle-mediated LDD systems. With our own published data on drug-eluting stents, microstents, and cochlear implants, we highlight exemplary implant-associated LDD systems designed to improve implant performance through the reduction of undesirable effects such as in-stent restenosis and fibrosis.

Biomed. Tech. (Berl). 2013 Okt; 58(5):417-427

Petersen S, Hussner J, Reske T, Grabow N, Senz V, Begunk R, Arbeiter D, Kroemer HK, Schmitz KP, Meyer zu Schwabedissen HE, Sternberg K. In vitro study of dual drug-eluting stents with locally focused sirolimus and atorvastatin... J Mater Sci: Mater Med

doi: 10.1007/s10856-013-5001-7

PMID: 23846839

Abstract:

Within the context of novel stent designs we developed a dual drug-eluting stent (DDES) with an abluminally focussed release of the potent anti-proliferative drug sirolimus and a luminally focussed release of atorvastatin with stabilizing effect on atherosclerotic deposits and stimulating impact on endothelial function, both from biodegradable poly(L-lactide)-based stent coatings. With this concept we aim at simultaneous inhibition of in-stent restenosis as a result of disproportionally increased smooth muscle cell proliferation and migration as well as thrombosis due to failed or incomplete endothelialisation. The especially adapted spray-coating processes allowed the formation of smooth form-fit polymer coatings at the abluminal and luminal side with 70 % respectively 90 % of the drug/polymer solution being deposited at the intended stent surface. The impacts of tempering, sterilization, and layer composition on drug release are thoroughly discussed making use of a semi-empirical model. While tempering at 80 °C seems to be necessary for the achievement of adequate and sustained drug release, the coating sequence for DDES should be rather abluminal-luminal than luminal-abluminal, as reduction of the amount of sirolimus eluted luminally could then potentially minimize the provocation of endothelial dysfunction. In vitro proliferation and viability assays with smooth muscle and endothelial cells underline the high potential of the developed DDES.

J Mater Sci: Mater Med, 2013.

Wulf K, Petersen S, Schünemann S, Knödler S, Schmitz KP, Sternberg K. Development Of A Tunable Drug Delivery System From Biodegradable Scaffolds Via Layer By Layer Deposition. Biomed. Tech.

doi: 10.1515/bmt-2013-4079

PMID: 24042655

Abstract:

Polyelectrolyte multilayer (PEM) films, built using the layer-by-layer (LbL) technique, are attractive for controlled drug delivery in order to improve the tissue regeneration. Here, the influence of PEM, based on poly(L-lactide), (PLLA) containing different polyanions, like hyaluronic acid (HA), polyacrylic acid (PAA) and chondroitin sulfate (CS) on the release profiles of avidin fluorescein isothiocyanate (avidin-FITC) and vascular endothelial growth factor (VEGF) is demonstrated.

Biomed. Tech. (Berl) 2013 Sep; 58(1).

Minrath I, Petersen S, Schmitz KP, Sternberg K. Continuative Studies for Inserting Stimulus-Responsive Functions in Hydrogels for Local Drug Delivery. Biomed. Tech.

doi: 10.1515/bmt-2013-4080

PMID: 24042690

Abstract:

The insertion of stimulus-responsive functions into hydrogels is a promising modification of local drug delivery (LDD) systems. One approach aiming at these systems with stimulus-induced drug delivery is the use of antibody/antigen combinations as crosslinker within hydrogels. In this context, we investigated systematically the drug permeation through different polyacrylamide (PAAm) gel types as model system. It could be shown that permeation behaviour is hardly dependent on structure (semiinterpenetrating polymer network (semiIPN) versus conventional polymer network) and crosslinking ratio but on gel content. Moreover, first evidence of successful incorporation of stimulus-responsive antibody/antigen crosslinkers (mouse IgG/rabbit anti mouse IgG) within PAAm could be given.

Biomed. Tech. (Berl) 2013 Sep; 58(1).

Petersen S, Wulf K, Schünemann S, Teske M, Schmitz K-P, Sternberg K. Biofunctionalization of Polymer Implant Surfaces: From Drug Delivery to Stable Surface Functionality. Biomed. Tech. (Berl)

doi: 10.1515/bmt-2013-4052

PMID: 24042660

Abstract:

Biofunctionalization strategies can be adapted to allow short-term and long-term biomolecule immobilization. By using different protocols for the modification of poly(L-lactide), we evidenced the possibility of drug release control as well as the provision of stable surface functionality at the example of vascular endothelial growth factors and anti-CD34 antibodies, respectively.

Biomed. Tech. (Berl) 2013 Sep; 58(1).

Semmling B, Nagel S, Sternberg K, Weitschies W, Seidlitz A. Long-term stable hydrogels for biorelevant dissolution testing of drug-eluting stents. J. Pharm. Technol. Drug Res.

doi: 10.7243/2050-120X-2-19

J. Pharm. Technol. Drug Res. 2013 Dez 28; 2(19).

Schlie-Wolter S, Deiwick A, Fadeeva E, Paasche G, Lenarz T, Chichkov B. Topography and coating of platinum improve the electrochemical properties and neuronal guidance. Applied Materials and Interfaces

doi: 10.1021/am3028487

PMID: 23327880

Abstract:

To improve neuronal-electrode interfaces, we analyzed the influence of surface topographies combined with coating on the electrochemistry of platinum and neuronal differentiation of PC-12 cells. Surface structuring on nanoscale was realized by femtosecond laser ablation. Additional coating with laminin (LA), collagen type I (COL) or poly-d-lysine (PDL) did not change the produced topography. We further demonstrated that impedance could be improved in all cases. The pre-requisites of differentiation - viability and attachment - were fulfilled on the topography. Cell attachment of non-differentiated and differentiated cells and their formation of focal adhesion complexes were even enhanced compared to unstructured platinum. However, without the nerve growth factor (NGF) no cellular outgrowth and differentiation were possible. The topography enabled cell elongation and reduced the amount of rounded cells, but less effective than coating. Differentiation was either comparable or increased on the structures when compared with unstructured coatings. For instance, microtubule associated protein (MAP2) was detected most on the topography alone. But a combination of surface structuring and coating had the strongest impact on differentiation: the usage of COL provoked best cell elongation and beta III tubulin expression, PDL best synaptophysin. LA-coating had no noteworthy effect. These findings point out that innovative electronic devices like cochlear implants include two aspects: (a) nanotopography to improve the transmission of electrical signals and neuronal attachment; and (b) an additional coating to stimulate neuronal differentiation.

Applied Materials and Interfaces 2013;5(3):1070-1077

Schlie-Wolter S, Ngezahayo A, Chichkov B. The selective role of extracellular matrix components on cell adhesion, morphology, proliferation and communication in vitro. Exp. Cell Research.

doi: 10.1016/j.yexcr.2013.03.016

PMID: 23588204

Abstract:

Cell binding to the extracellular matrix (ECM) is essential for cell and tissue functions. In this context, each tissue consists of a unique ECM composition, which may be responsible for tissue-specific cell responses. Due to the complexity of ECM-cell interactions-which depend on the interplay of inside-out and outside-in signaling cascades, cell and tissue specificity of ECM-guidance is poorly understood. In this paper, we investigate the role of different ECM components like laminin, fibronectin, and collagen type I with respect to the essential cell behaviour patterns: attachment dynamics such as adhesion kinetic and force, formation of focal adhesion complexes, morphology, proliferation, and intercellular communication. A detailed in vitro comparison of fibroblasts, endothelial cells, osteoblasts, smooth muscle cells, and chondrocytes reveals significant differences in their cell responses to the ECM: cell behaviour follows a cell specific ligand priority ranking, which was independent of the cell type origin. Fibroblasts responded best to fibronectin, chondrocytes best to collagen I, the other cell types best to laminin. This knowledge is essential for optimization of tissue-biomaterial interfaces in all tissue engineering applications and gives insight into tissue-specific cell guidance.

Exp. Cell Research. 2013;319:1553-1561

Schmidt W, Kastner C, Sternberg K, Allemann R, Löbler M, Guthoff R, Schmitz KP. New concepts for glaucoma implants--controlled aqueous humor drainage, encapsulation prevention and local drug delivery. Curr Pharm Biotechnol.

PMID: 23092262

Abstract:

Glaucoma is a common cause of blindness in industrialized countries and is the most frequent cause of irreversible blindness worldwide. Since raised intraocular pressure (IOP) has been implicated as the major risk factor, the main goal of all glaucoma treatment is to reduce IOP sufficiently to prevent continuous irreversible retinal ganglion cell damage and progression of visual field loss. Pharmacological reduction of IOP is first-line therapy, followed by laser treatment of the trabecular meshwork and filtering glaucoma surgery, and cyclophotocoagulation of the ciliary body or allogenic implants. The most important glaucoma implants are presented (MOLTENO, AHMED, BAERVELDT, KRUPIN) together with more recent developments (Ex-Press, Eyepass, iStent, Gold micro shunt). Drainage into the suprachoroidal space is a promising option, but is also limited by scarring of the new created outflow route due to proliferation and adhesion of fibroblasts. A deeper understanding of fibroblasts in the related eye compartments is required. Characterization of scleral, choroidal, and, as a reference, Tenon fibroblast subtypes, is possible based on gene expression patterns. Alongside mitomycin C and 5-fluorouracil, newer drugs to prevent fibrosis have been proposed, offering effects that are more specific and more physiological. Effectors involved in wound healing phases and signaling pathways are potential targets for pharmaceutical intervention. Downregulation of growth factors like TGF-ß and their downstream effectors may suppress proliferation and differentiation of fibroblasts, extracellular matrix deposition, wound contraction, and neovascularization. Furthermore, current approaches to local drug delivery in glaucoma implant technology are briefly summarized.

Curr Pharm Biotechnol. 2013 Jan;14(1):98-111

Allemann R, Stachs O, Falke K, Schmidt W, Siewert S, Sternberg K, Chichkov B, Wree A, Schmitz KP, Guthoff RF. New concepts for pressure-controlled glaucoma implants. Ophthalmologe.

doi: 10.1007/s00347-013-2839-5

PMID: 23887742

Abstract:

In industrialized countries glaucoma is one of the most common causes that leads to blindness. It is also the most common cause of irreversible blindness worldwide. In addition to local treatment of intraocular pressure and filtering glaucoma surgery, alloplastic implants are increasingly being used in glaucoma therapy. As long-term results published in the literature of commonly used implants are unsatisfactory, it seems useful to search for new concepts. In order to avoid the well-known short-term and long-term postoperative complications a pressure-controlled microstent with antiproliferative surface modifications was developed. Additionally, the functionality of such a microstent should be investigated using an animal glaucoma model. This paper describes the concept of a microstent which drains aquous humour from the anterior chamber into the suprachoroidal space. In addition, the glaucoma models described in the literature are discussed. Unfortunately, none of the methods could be reproduced permanently. First results show a correct implantation of a coated microstent with valve where the anti-proliferative effect could be demonstrated histologically. The promising results should lead to further investigations and the final goal will be the testing of the stent in the human eye.

Ophthalmologe. 2013 Aug;110(8):733-9.

Sombetzki M, Löbermann M, Bänsch D, Schmitz KP, Sternberg K, Reisinger EC. New Developments in Device-Associated Bloodstream Infections. Biomed Tech (Berl).

doi: 10.1515/bmt-2013-4054

PMID: 24042669

Abstract:

One of the major drawbacks in the long-term use of biomedical devices is the risk of infection of the surfaces of these implants. We discuss risk-factors, mode of infections and innovative preventive measures to reduce device-associated infections.

Biomed Tech (Berl), 2013. 58(Suppl. 1)

Grabow, N., C. Bünger, S. Kischkel, J.H. Timmermann, T. Reske, D.P. Martin, S.F. Williams, W. Schareck, K. Sternberg and K.P. Schmitz, Development of a sirolimus-eluting poly(L-lactide)/poly(4-hydroxybutyrate) absorbable stent for ... Biomed Tech

doi: 10.1515/bmt-2012-0050

PMID: 23898020

Abstract:

Fully absorbable drug-eluting stent platforms are currently entering the clinical arena for the interventional treatment of coronary artery disease. This new technology also holds potential for application in peripheral vascular settings. Our study reports on the development of a sirolimus- (SIR) eluting absorbable polymer stent made from a blend of poly(l-lactide) and poly(4-hydroxybutyrate) (PLLA/P4HB) for peripheral vascular intervention. Stent prototypes were laser-cut from PLLA/P4HB tubes (I.D.=2.2 mm, t=250 µm), spray-coated with different PLLA/P4HB/SIR solutions, and bench-tested to determine expansion properties, fatigue, trackability and in vitro drug release kinetics. The stent prototypes were expanded with a 5.0 × 20 mm balloon catheter, and exhibited a recoil of 3.6% upon balloon deflation. Stent collapse pressure of 0.4 bar (300 mm Hg) was measured under external pressure load. Sustained scaffolding properties were observed in vitro over 14 weeks of radial fatigue loading (50 ± 25 mm Hg at 1.2 Hz). Trackability was demonstrated in bench tests with an 8 French contralateral introducer sheath. SIR release kinetics were adjusted over a broad range by varying the PLLA/P4HB ratio of the coating matrix. The newly developed absorbable SIR-eluting PLLA/P4HB stent successfully fulfilled the requirements for peripheral vascular intervention under in vitro conditions.

Biomed Tech (Berl), 2013. 58(5): 429-37.

Luderer F, Begerow I, Schmidt W, Martin H, Grabow N, Bünger CM, Schareck W, Schmitz KP, Sternberg K. Enhanced visualization of biodegradable polymeric vascular scaffolds by incorporation of gold, silver and magnetite nanoparticles. J Biomater Appl.

doi: 10.1177/0885328212443393

PMID: 22492201

Abstract:

Due to improved tissue regeneration and the enabling of post-operative minimally invasive interventions in the same vessel segment, biodegradable polymeric scaffolds represent a competitive approach to permanent metallic stents in vascular applications. Despite these advantages some challenges, such as the improvement of the scaffold mechanics and enhancement of scaffold visibility during the implantation procedure, are persisting. Therefore, the scope of our studies was to investigate the potential of gold, silver and magnetite nanoparticles incorporated in a polymeric blend of poly(L-lactide)/poly(4-hydroxybutyrate) for image enhancement in X-ray, magnetic resonance or near-infrared imaging. Their impact on mechanical properties of such modified scaffold materials was also evaluated.

J Biomater Appl. 2013 Aug; 28(2):219-31.

Martin, H., N. Grabow, M. Stiehm, D. Lootz and K.P. Schmitz, Finite element analysis of compliance of stent-vessel-systems. Biomed Tech (Berl)

doi: 10.1515/bmt-2013-4111

PMID: 24042752

Abstract:

In this study structural and fluid mechanical investigations of stented coronary arteries are presented. Stents are tubular, mesh-like metallic or polymeric structures which are used to treat coronary and peripheral artery disease. Stents brace the vascular wall to restore the required blood flow. Finite element investigations of the stent/stenosis system were performed to assess the compliance and the vessel wall contact stress for different stent types in a stenosis model.

Biomed Tech (Berl), 2013. 58(Suppl. 1)

Grabow, N., M. Wentzlaff, V. Senz, A. Seidlitz, C. Harder, K. Sternberg, W. Weitschies and K.P. Schmitz, Feasibility of polymer/drug coating on absorbable and permanent stent platforms - technological challenges. Biomed Tech (Berl)

doi: 10.1515/bmt-2013-4383

PMID: 24043092

Abstract:

Coating of drug-eluting stents demands different technologies depending on the nature of the stent platform, the intended coating design, and the coating materials. In this study, the complementary potentials of a spray-coating technology and a fluidized bed coating technology were assessed. Absorbable polymer stents and permanent metallic stents were coated with polymer/drug matrices based on poly(L-lactide) incorporated with the immunosuppressant sirolimus and the model substances fluorescein sodium, curcumin, and quinine. Process parameters were adjusted to yield optimal coating morphology. While spray-coating could be used to deposit even conversely asymmetric abluminal/luminal coating sandwiches, fluidized bed coating has shown tremendous throughput at a significant coating quality.

Biomed Tech (Berl), 2013. 58(Suppl. 1)

Schümann, K., N. Grabow, H. Martin, U. Röhr, K. Sternberg and K.P. Schmitz, The Impact of Design Modifications on the Mechanical Properties of a Polymeric Slotted Tube Coronary Stent. Biomed Tech (Berl)

doi: 10.1515/bmt-2013-4112

PMID: 24042747

Abstract:

Stents made of biodegradable polymers represent a promising alternative to conventional metallic stent concepts based on their total degradability. Due to inferior biomechanical properties of polymers compared to metallic materials the design of polymeric stents is of overriding importance. In this study, finite element analysis is used to investigate the influence of different stent design parameters on the maximum equivalent stresses (von Mises) and maximum plastic strains, as well as the elastic recoil. It is shown that a decrease of strut width reduces maximum stresses and recoil. Enlargement of the radii also causes a reduction of maximum stresses, but an increase of recoil. For a complete evaluation of the stent designs a 3D-analysis to determine radial strength will succeed.

Biomed Tech (Berl), 2013. 58(Suppl. 1)

Stiehm M, Brede M, Quosdorf D, Leder A. On the creation of wall shear stress by helical flow structures in stented coronary vessels. BioNanoMaterials.

doi: 10.1515/bnm-2013-0003

BioNanoMaterials. Band 14 Heft 1-2. pp. 109–115, 2013

Stiehm M, Brede M, Quosdorf D, Martin H, Leder A. A Sensitivity Analysis of Stent Design Parameters using CFD. Biomedizinische Technik

doi: 10.1515/bmt-2013-4351

PMID: 24043033

Abstract:

It is commonly known that the stent design has a significant influence on the flow topology and therefore on the wall shear stress (WSS) distribution as well. Postoperative complications like in-stent restenosis correlate with alterations in the WSS distribution. In the present computational fluid mechanic study the key design parameters of a generic model stent were investigated and the hemodynamical efficiency was evaluated by calculating the sensitivity. It can be concluded that the strut thickness is the most significant design parameter regarding the occurrence of low wall shear stress.

Biomedizinische Technik 2013, (Suppl. 1)

Quosdorf D, Brede M, Stiehm M, Wolter A, Sakowski J, Leder A. Bestimmung phasengemittelter Wandschubspannungen an koronaren Stents bei pulsatiler Anströmung. Lasermethoden in der Strömungsmesstechnik, 21. GALA Fachtagung

Lasermethoden in der Strömungsmesstechnik, 21. Fachtagung, 3. - 5. September 2013, München; [Tagungsband], Karlsruhe, Dt. Ges. für Laser-Anemometrie GALA e. V pp. 59-1 - 59-9, 2013, ISBN 978-3-9805613-9-6

Stiehm M, Quosdorf D, Brede M, Schmitz KP, Leder A. Numerische Simulation pulsatiler Durchströmung von Koronarstents. 21. GALA Fachtagung

Lasermethoden in der Strömungsmesstechnik, 21. Fachtagung, 3. - 5. September 2013, München ; [Tagungsband], Karlsruhe, Dt. Ges. für Laser-Anemometrie GALA e. V pp. 60-1 - 60-8, 2013, ISBN 978-3-9805613-9-6

Reichard M, Hovakimyan M, Guthoff RF, Stachs O. In vivo visualisation of murine corneal nerve fibre regeneration in response to ciliary neurotrophic factor. Exp Eye Res.

doi: 10.1016/j.exer.2013.12.015

PMID: 24412420

Abstract:

The aim of this study was to examine the murine subbasal nerve fibre plexus (SNP) regeneration altered by surgical dissection. Investigations in the mouse model addressed the regeneration capabilities of the SNP, and the influence of local ciliary neurotrophic factor (CNTF) application on the regeneration process. In preliminary experiments, the healthy mouse cornea was monitored using in vivo confocal laser-scanning microscopy (CLSM) from the age of 8-52 weeks, to reveal and rule out the age-dependent changes in SNP. Nerve fibre density (NFD) was determined with the semi-automatic nerve tracing program NeuronJ. No quantitative or qualitative changes in NFD were detected in untreated animals over time; mean NFD in mice aged 8 weeks (28.30 ± 9.12 mm/mm(2)), 16 weeks (29.23 ± 7.28 mm/mm(2)), 30 weeks (26.31 ± 8.58 mm/mm(2)) and 52 weeks (26.34 ± 6.04 mm/mm(2)) showed no statistically significant differences between time points (p > 0.05). For regeneration studies a circular incision through corneal epithelium and anterior stroma of minimum 60 μm depth was generated with a custom-made guided trephine system to cut the subbasal corneal nerves in adult mice. The corneal nerve pattern was monitored and NFD was measured before and up to 8 weeks after surgery. Animals were divided in three groups each comprising 6 mice. The CNTF group received eye drops containing CNTF (25 ng/ml) 3 times daily for 3 weeks, whereas the control group received no further medication. In the sham group the same treatment schedule was applied as in CNTF group, using vehicle. The regenerating subbasal nerve fibres sprouted out of stromal nerves within the cut and additionally regrew over the scar rim from outside. They showed parallel orientation but were thinner than before incision. Whorl patterning was observed after 4 weeks. All three groups revealed a marked NFD reduction starting at one week after incision, followed by continuous recovery. After 8 weeks the NFD reached 23.5 ± 2.4 mm/mm(2) (78% of baseline), 21.9 ± 1.6 mm/mm(2) (73% of baseline) and 29.2 ± 3.4 mm/mm(2) (93% of baseline) in the control, sham and CNTF group, respectively. By comparison with control and sham group, the CNTF group demonstrated significantly higher NFD at every observation time point. The mouse cornea provides a practicable animal model for in vivo CLSM monitoring of corneal nerve behaviour over time and following injury. Non-penetrating trephination generated a severe reduction in the NFD of the SNP, but murine corneas recovered to pre-injury NFD levels within 8 weeks. Local application of CNTF served merely to temporarily accelerate the recovery of NFD.

Exp Eye Res. 2014 Jan 9; 120C: 20-27.

Falke K, Krüger P, Hosten N, Zimpfer A, Guthoff R, Langner S, Stachs O. Experimental differentiation of intraocular masses using ultrahigh-field magnetic resonance imaging - a case series. PLoS One.

PMID: 24349051

Abstract:

PURPOSE: The case reports presented here were compiled to demonstrate the potential for improved diagnosis and monitoring of disease progress of intraocular lesions using ultrahigh-field magnetic resonance microscopy (MRM) at 7.1 Tesla.
METHODS: High-resolution ex vivo ocular magnetic resonance (MR) images were acquired on an ultrahigh-field MR system (7.1 Tesla, ClinScan, Bruker BioScan, Germany) using a 2-channel coil with 4 coil elements and T2-weighted turbo spin echo (TSE) sequences of human eyes enucleated because of different intraocular lesions. Imaging parameters were: 40×40 mm field of view, 512×512 matrix, and 700 µm slice thickness. The results were correlated with in vivo ultrasound and histology of the enucleated eyes.
RESULTS: Imaging was performed in enucleated eyes with choroidal melanoma, malignant melanoma of iris and ciliary body with scleral perforation, ciliary body melanoma, intraocular metastasis of esophageal cancer, subretinal bleeding in the presence of perforated corneal ulcer, hemorrhagic choroidal detachment, and premature retinopathy with phthisis and ossification of bulbar structures. MR imaging allowed differentiation between solid and cystic tumor components. In case of hemorrhage, fluid-fluid levels were identified. Melanin and calcifications caused significant hypointensity. Microstructural features of eye lesions identified by MRM were confirmed by histology.
CONCLUSION: This study demonstrates the potential of MRM for the visualization and differential diagnosis of intraocular lesions. At present, the narrow bore of the magnet still limits the use of this technology in humans in vivo. Further advances in ultrahigh-field MR imaging will permit visualization of tumor extent and evaluation of nonclassified intraocular structures in the near future.

PLoS One. 2013 Dec 9;8(12):e81284

Walter U, Niendorf T, Graessl A, Rieger J, Krüger PC, Langner S, Guthoff RF, Stachs O. Ultrahigh field magnetic resonance and color Doppler real-time fusion imaging of the orbit – a hybrid tool for assessment of choroidal melanoma. European Radiology

PMID: 24519109

Abstract:

OBJECTIVES: A combination of magnetic resonance images with real-time high-resolution ultrasound known as fusion imaging may improve ophthalmologic examination. This study was undertaken to evaluate the feasibility of orbital high-field magnetic resonance and real-time colour Doppler ultrasound image fusion and navigation.
METHODS: This case study, performed between April and June 2013, included one healthy man (age, 47 years) and two patients (one woman, 57 years; one man, 67 years) with choroidal melanomas. All cases underwent 7.0-T magnetic resonance imaging using a custom-made ocular imaging surface coil. The Digital Imaging and Communications in Medicine volume data set was then loaded into the ultrasound system for manual registration of the live ultrasound image and fusion imaging examination.
RESULTS: Data registration, matching and then volume navigation were feasible in all cases. Fusion imaging provided real-time imaging capabilities and high tissue contrast of choroidal tumour and optic nerve. It also allowed adding a real-time colour Doppler signal on magnetic resonance images for assessment of vasculature of tumour and retrobulbar structures.
CONCLUSIONS: The combination of orbital high-field magnetic resonance and colour Doppler ultrasound image fusion and navigation is feasible. Multimodal fusion imaging promises to foster assessment and monitoring of choroidal melanoma and optic nerve disorders.
KEY POINTS:
• Orbital magnetic resonance and colour Doppler ultrasound real-time fusion imaging is feasible
• Fusion imaging combines the spatial and temporal resolution advantages of each modality
• Magnetic resonance and ultrasound fusion imaging improves assessment of choroidal melanoma vascularisation.

European Radiology 2014 Feb 12. [Epub ahead of print]

Dudkin S, Iaroshenko VO, Tolmachev A, Villinger A, Sosnovskikh VY, Langer P. Synthesis and reactivity of 5-polyfluoroalkyl-5-deazaalloxazines. Org. Biomol. Chem.

doi: 10.1039/c3ob26837c

PMID: 23846251

Abstract:

Reaction of 6-arylamino-1,3-dialkyluracils with anhydrides of polyfluorocarboxylic acids in the presence of pyridine and subsequent cyclization with concentrated H2SO4 gave the corresponding 1,3-dialkyl-5-(polyfluoroalkyl)pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones (5-polyfluoroalkyl-5-deazaalloxazines). The reactivity of these compounds towards nucleophilic reagents, such as sodium cyanoborohydride, acetophenone, nitromethane, potassium cyanide, indole and p-thiocresol, as well as Suzuki and Sonogashira couplings are described. The nucleophilic addition takes place at the 5-position of the 5-deazaalloxazine system and is in many cases irreversible to give 5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione derivatives in good to excellent yields.

Org. Biomol. Chem. 2013, 11: 5351-5361.

Ehlers P, Petrosyan A, Baumgard J, Jopp S, Steinfeld N, Ghochikyan TV, Saghyan AS, Langer P. Synthesis of 2,5-Diarylpyrroles by Ligand-Free Palladium-Catalyzed CH-Activation of Pyrroles in Ionic Liquids. ChemCatChem

doi: 10.1002/cctc.201300099

Abstract:

The palladium-catalyzed CH activation and arylation of N-methylpyrrole and N-phenylpyrrole allowed a convenient synthesis of diarylpyrroles. The reactions were performed by using tetrabutylammonium acetate as an ionic solvent, which allowed for the application of a ligand-free catalytic system by using simple palladium salts or polyvinylpyrrolidone-stabilized palladium nanoparticles as the catalyst.

ChemCatChem 2013, 13: 2504-2511.

Iaroshenko VO, Dudkin S, Sosnovskikh VY, Villinger A, Langer P. (ß-D-Ribofuranosyl)formamidine in the design and synthesis of 2-(ß-D-ribofuranosyl)pyrimidines, including RF-containing derivatives. Eur. J. Org. Chem.

doi: 10.1002/ejoc.201300107

Abstract:

A wide range of novel 2-(beta-D-ribofuranosyl)pyrimidines, including R-F-containing derivatives, have been synthesized by the reaction of (beta-D-ribofuranosyl)formamidine with various dielectrophilic substrates such as 3-alkoxy- and 3-chloro-1-(polyfluoroalkyl)propen-1-ones, 3-nitro- and 3-(phenyl-ethynyl) chromones and heteroaryl acetylenic ketones.

Eur. J. Org. Chem. 2013: 3166–3173.

Kiamehr M, Moghaddam FM, Mkrtchyan S, Semeniuchenko V, Supe L, Villinger A, Langer P, Iaroshenko VO. Tandem dinucleophilic cyclization of cyclohexane-1,3-diones with pyridinium salts. Beilstein J. Org. Chem.

doi: 10.3762/bjoc.9.124

PMID: 23843903

Abstract:

The cyclization of cyclohexane-1,3-diones with various substituted pyridinium salts afforded functionalized 8-oxa-10-aza-tricyclo[7.3.1.0(2,7)]trideca-2(7),11-dienes. The reaction proceeds by regioselective attack of the central carbon atom of the 1,3-dicarbonyl unit to 4-position of the pyridinium salt and subsequent cyclization by base-assisted proton migration and nucleophilic addition of the oxygen atom to the 2-position, as was elucidated by DFT computations. Fairly extensive screening of bases and additives revealed that the presence of potassium cations is essential for formation of the product.

Beilstein J. Org. Chem. 2013, 9: 1119-1126.

Kiamehr M, Moghaddam FM, Semeniuchenko V, Villinger A, Langer P, Iaroshenko VO. Facile Synthesis of Thiochromeno[2,3-b]indol-11(6H)-ones and Pyri-do[3',2':5,6]thiopyrano[2,3-b]indol-5(10H)-ones. Tetrahedron Lett.

doi: 10.1016/j.tetlet.2013.07.012

Abstract:

Indole-2(3H)thiones were cyclized under the action of 2-fluorobenzoyl chlorides to give thiochromeno[2,3-b]indol-11(6H)-ones or under the action of 2-chloronicotinoyl chlorides to give pyrido[3',2':5,6]thiopyrano[2,3-b]indol-5(10H)-ones. The reaction of cyclization proceeds regioselectively in DMF and does not require transition metals for completion. Obtained heterocycles are isosteric analogues of various tetracyclic indole derived alkaloids.

Tetrahedron Lett. 2013, 54: 5018-5021.

Löbler M, Buß D, Kastner C, Mostertz J, Homuth G, Ernst M, Guthoff R, Wree A, Stahnke T, Fuellen G, Voelker U, Schmitz KP. Ocular fibroblast types differ in their mRNA profiles - implications for fibrosis prevention after aqueous shunt... Mol Vis.

PMID: 23805039

Abstract:

PURPOSE: For an aqueous shunt draining from the anterior chamber into the choroidal space, fibroblasts from the choroidea and/or the sclera are most likely responsible for a fibrotic response around the outflow region of such a shunt. The prevention of fibrosis should extend the operating life of the shunt. A detailed characterization of fibroblasts derived from choroidea and sclera should provide information about whether a fibrosis reaction can be inhibited by cell type-specific agents.
METHODS: We generated mRNA profiles of fibroblasts from the choroidea, sclera, and Tenon's space by gene array hybridization to provide a basis on which to search for potential pharmacological targets for fibrosis prevention. Hybridization data were analyzed by the Rosetta Resolver system and Limma to obtain mRNA profiles of the three fibroblast types.
RESULTS: The three fibroblast types investigated shared fibroblast-specific gene expression patterns concerning extracellular matrix proteins as collagens and fibronectin, but also showed distinct mRNA patterns.
CONCLUSIONS: Individual mRNA species overexpressed in one of the fibroblast types might serve as markers for the identification of the fibroblast type in histological analyses. Future in-depth analyses of the gene expression patterns might help identify pharmacological targets for fibrosis prevention.

Mol Vis. 2013;19:1321-1331

Loch C, Bogdahn M, Stein S, Nagel S, Guthoff R, Weitschies W und Seidlitz A: Simulation of drug distribution in the vitreous after local drug application into intact vitreous body and in progress of posterior vitreous detachment. J Pharm Sci.

doi: 10.1002/jps.23808

PMID: 24311438

Abstract:

Intravitreal injections and drug-loaded implants are current approaches to treat diseases of the posterior eye. To investigate the release of active agents and their distribution in the vitreous body, a new test system was developed that enables a realistic simulation of eye motions. It is called the eye movement system (EyeMoS). In combination with a previously developed model containing a polyacrylamide gel as a substitute for the vitreous body, this new system enables the characterization of the influence of eye motions on drug distribution within the vitreous body. In the presented work, the distribution of fluorescence-tagged model drugs of different molecular weight within the simulated vitreous was examined under movement with the EyeMoS and without movement. By replacing a part of the gel in the simulated vitreous body with buffer, the influence of the progress of posterior vitreous detachment (PVD) on the distribution of these model substances was also studied. The results indicate that convective forces may be of predominate influence on initial drug distribution. The impact of these forces on drug transport increases with simulated progression of PVD. Using the EyeMoS, the investigation of release and distribution from intravitreal drug delivery systems becomes feasible under biorelevant conditions.

J Pharm Sci. 2014 Feb;103(2):517-26

Semmling B, Nagel S, Sternberg K, Weitschies W, Seidlitz A. Development of hydro-phobized alginate hydrogels for the vessel-simulating flow-through cell and their usage for biorelevant drug-eluting stent testing. AAPS PharmSciTech.

doi: 10.1208/s12249-013-0011-9

PMID: 23918507

Abstract:

The vessel-simulating flow-through cell (vFTC) has been used to examine release and distribution from drug-eluting stents in an in vitro model adapted to the stent placement in vivo. The aim of this study was to examine the effect of the admixture of different hydrophobic additives to the vessel wall simulating hydrogel compartment on release and distribution from model substance-coated stents. Four alginate-based gel formulations containing reversed-phase column microparticles LiChroprep® RP-18 or medium-chain triglycerides in form of preprocessed oil-in-water emulsions Lipofundin® MCT in different concentrations were successfully developed. Alginate and modified gels were characterized regarding the distribution coefficient for the fluorescent model substances, fluorescein and triamterene, and release as well as distribution of model substances from coated stents were investigated in the vFTC. Distribution coefficients for the hydrophobic model substance triamterene and the hydrophobized gel formulations were up to four times higher than for the reference gel. However, comparison of the obtained release profiles yielded no major differences in dissolution and distribution behavior for both fluorescent model substances (fluorescein, triamterene). Comparison of the test results with mathematically modeled data acquired using finite element methods demonstrated a good agreement between modeled data and experimental results indicating that gel hydrophobicity will only influence release in cases of fast releasing stent coatings.

AAPS PharmSciTech. 2013;14(3):1209-1218.

Vilches-Herrera M, Spannenberg A, Langer P, Iaroshenko VO. Novel and Efficient Synthesis of 4,7-Dihydro-1H-pyrrolo[2,3-b]pyridine Derivatives via One-Pot, Three-Component Approach from N-Substituted 5-Amino-3-cyanopyrroles, Various Carbon-yl... Tetrahedro

doi: 10.1016/j.tet.2013.04.115

Abstract:

An efficient route to novel 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines with incorporated tetrahedral fragment in the position-4 via three-component reaction of N-substituted 5-amino-3-cyanopyrroles, various carbonyl and active methylene compounds has been developed. In the same time, by using developed methods here, the 4,7-dihydro-1H-pyrrolo[2,3-b]pyridines with fused 4-spiro-frameworks were synthesized starting from isatins and a set of 1,2-dicarbonyl compounds. The reactions were carried out under mild conditions using ethanol, acetic acid or 1,4-dioxane as solvent.

Tetrahedron 2013, 69: 5955-5967.

Zahid M, Iaroshenko VO, Saghyan AS, Fischer C, Langer P. Convenient Synthesis of Benzo[b]pyrazolo[5,1-f][1,6]naphthyridines by Silver Triflate Catalyzed Three-Component Reaction of 2-Alkynyl-3-formylquinolines, Tosylhydrazine and Carbonyl... Tetrahedron

doi: 10.1016/j.tet.2013.02.060

Abstract:

Benzo[b]pyrazolo[5,1-f][1,6]naphthyridines were prepared by silver triflate catalyzed one-pot cyclization of tosylhydrazine, carbonyl compounds and 2-alkynyl-3-formylquinolines, which are available by Sonogashira reaction of 2-chloro-3-formylquinoline.

Tetrahedron 2013, 69: 3451-3458.

Rudolph A, Eickner T, Seidlitz A, Weitschies W, Wree A, Schmitz KP, Sternberg K. Investigation of in vitro drug release behavior of drug-eluting stents using a perfusion culture system. Biomed Tech. (Berl)

doi: 10.1515/bmt-2013-4098

PMID: 24042667

Abstract:

The use of coronary drug-eluting stents (DES) for the treatment of coronary heart disease is well established. Since the success of the DES is dependent on the drug, the type of the polymeric carrier, the stent coating design and in this context on the drug release profile, the exact in vitro determination of the drug release characteristics under flow conditions is very important. Hence, a perfusion culture system was used in order to analyse the release behaviour of DES, dilated in arteries, close to in vivo conditions.

Biomed Tech. (Berl) 2013. 58 (Suppl. 1)

Loch C, Stein S, Nagel S, Guthoff R, Weitschies W und Seidlitz A: Simulation of the conjunctival and choroidal blood flow using a new multi-layer diffusion cell. Biomed Tech (Berl)

doi: 10.1515/bmt-2013-4349

PMID: 24043064

Abstract:

Drug-loaded subconjunctival and intrascleral injections and implants are receiving greatest interest as an alternative to the permanent topical administration of eye drops. The purpose of these studies is to develop a system which is capable of simulating the drug release and subsequent distribution from such injections and implants. For this purpose the multi-layer diffusion cell (MDC) was developed. By using the MDC, investigation of such implants under the simulation of the choroidal und conjunctival blood flow becomes feasible. Furthermore, the MDC allows a reproducible determination of diffusion coefficients of drugs in various media.

Biomed Tech (Berl), 2013. 58 (Suppl. 1)

Senz, V., W. Schmidt, N. Grabow, D. Arbeiter, K. Sternberg and K.P. Schmitz, Coating thickness determination on drug-eluting stents using confocal laser-scanning microscopy, spectral reflectometry and preparation of cross sections. Biomed Tech (Berl)

doi: 10.1515/bmt-2013-4082

PMID: 24042740

Abstract:

Different methods for the characterization of drug-eluting stent coatings relevant in process development and quality assurance are scrutinized. The results obtained by optical nondestructive methods as confocal laser scanning microscopy and spectral reflectometry are compared with results obtained by direct microscopic investigation of longitudinal cross sections. Comparison shows close agreement for all three techniques. The methods might thus be relevant for the characterization of other drug-coated medical devices with spectral reflectometry as the most effective.

Biomed Tech (Berl), 2013. 58(Suppl. 1).

Seidlitz, A., N. Kotzan, S. Nagel, T. Reske, N. Grabow, C. Harder, S. Petersen, K. Sternberg and W. Weitschies, In vitro determination of drug transfer from drug-coated balloons. PLoS ONE

doi: 10.1371/journal.pone.0083992

PMID: 24391863

Abstract:

Drug-coated balloons are medical devices designed to locally deliver drug to diseased segments of the vessel wall. For these dosage forms, drug transfer to the vessel wall needs to be examined in detail, since drug released into the blood is cleared from the site. In order to examine drug transfer, a new in vitro setup was developed combining the estimation of drug loss during advancement to the site of application in a model coronary artery pathway with a hydrogel compartment representing, as a very simplified model, the vessel wall. The transfer of fluorescent model substances as well as the drug paclitaxel from coated balloons to the simulated vessel wall was evaluated using this method. The model was suitable to quantify the fractions transferred to the hydrogel and also to qualitatively assess distribution patterns in the hydrogel film. In the case of fluorescein sodium, rhodamin b and paclitaxel, vast amounts of the coated substance were lost during the simulated passage and only very small fractions of about 1% of the total load were transferred to the gel. This must be attributed to good water solubility of the fluorescent substances and the mechanical instability of the paclitaxel coating. Transfer of the hydrophobic model substance triamterene was however nearly unaffected by the preliminary tracking procedure with transferred fractions ranging from 8% to 14%. Analysis of model substance distribution yielded inhomogeneous distributions indicating that the coating was not evenly distributed on the balloon surface and that a great fraction of the coating liquid did not penetrate the folds of the balloon. This finding is contradictory to the generally accepted assumption of a drug depot inside the folds and emphasizes the necessity to thoroughly characterize in vitro performance of drug-coated balloons to support the very promising clinical data.

PLoS ONE, 2013. 12(8): e83992.

Wentzlaff, M., A. Seidlitz, S. Nagel, V. Senz, N. Grabow, C. Harder, K. Sternberg and W. Weitschies, Investigating the Applicability of Fluidized-Bed Technology for High-Throughput Coating of Stents. Biomed Tech (Berl)

doi: 10.1515/bmt-2013-4374

PMID: 24043085

Abstract:

Nowadays coating of stents is associated with high manufacturing costs at least partially caused by the single unit coating process. To overcome this limitation we investigated the applicability of high-throughput stent coating via fluidized-bed technology. On the basis of an exemplary coating process we determined deviation of mass, drug release, coating homogeneity and the distribution of coating thickness of coated goods. The results indicate that the fluidized-bed technology can be utilized to obtain highly uniform stent coatings.

Biomed Tech (Berl), 2013. 58 (Suppl. 1).

Schröder M, Buchholz A, Schmidt W, Brandt C, Schmitz K.-P.: Quasi-continuous particle size characterization during accelerated stent radial fatigue test, Biomed Tech

doi: 10.1515/bmt-2013-4094

PMID: 24042646

Abstract:

Characterisation of particulate matter released during stent radial fatigue testing is of growing importance for stent testing. A method to determine the time course of particulate generation is of notably interest. A new method of quasi-continuous particle counting was developed and validated by measurement of particle recovery. Finally the time-dependent particulate generation of each six DES and BMS was tested. The particle recovery requirements of the FDA were met by the test setup. Stent testing showed a linear increase of particulate matter with increased number of load cycles. The method is suitable to characterize the particle generation during the stent fatigue test.

Biomed Tech 2013; 58 (Suppl. 1)

Kastner C, Löbler M, Guthoff R, Schmitz KP. In Vitro Rabbit Drug Cytotoxicity Model for Fibrosis Prevention in Glaucoma Surgery. Biomed Tech (Berl)

doi: 10.1515/bmt-2013-4376

PMID: 24043089

Abstract:

The aim of this in vitro study was to determine cytotoxicity of mitomycin C and paclitaxel of four different ocular cell types from rabbit (choroideal, scleral, and Tenon fibroblasts, and fibroblasts from orbital fat tissue). The cells were cultured and incubated with 1 x 10(-12) - 1 x 10(-4) mol/l of each drug, and their viability and proliferation measured. Cytotoxicity with viability falling below 70 % of NC is reached at <= 10(-6) mol/l of MitC and at <= 10(-7) mol/l of PTX for all cells, except from choroideal fibroblasts that are one order of magnitude less sensitive.

Biomed Tech (Berl), 2013. 58(Suppl. 1)

Siewert S, Becker C, Schmidt W, Specht O, Hinze U, Chichkov B, Guthoff R, Schmitz KP. Development of a Test Facility for Microfluidic Characterization of Glaucoma Drainage Devices. Biomed Tech (Berl).

doi: 10.1515/bmt-2013-4055

PMID: 24042645

Abstract:

Microfluidic characterization plays an outstanding role in the development of glaucoma drainage devices. Here, we describe the optimization of an existing test facility with regard to measurement of small volumetric flow rates in the range of 1 mu l/min to 40 mu l/min in a minimized testing time. The existing test facility is extended by a flow sensor and validated by microfluidic characterization of glass capillaries. Finally, two micro-mechanical valve prototypes are successfully analysed with regard to opening and closing pressure.

Biomed Tech (Berl), 2013. 58(Suppl. 1)

Gatzioufas Z, Labiris G, Stachs O, Hovakimyan M, Schnaidt A, Viestenz A, Käsmann-Kellner B, Seitz B. Biomechanical profile of the cornea in primary congenital glaucoma. Acta Ophthalmol.

doi: 10.1111/j.1755-3768.2012.02519.x

PMID: 22937759

Abstract:

Purpose: The aim of our study was to investigate the biomechanical properties of the cornea in primary congenital glaucoma (PCG) and to identify the potential ocular determinants, which affect the corneal biomechanical metrics.

Methods: Corneal hysteresis (CH), corneal resistance factor (CRF) and central corneal thickness (CCT) were measured in 26 patients with PCG (40 eyes) with the aid of ocular response analyser. In vivo laser-scanning confocal microscopy was used for the estimation of stromal keratocyte density (KD) and the evaluation of corneal endothelium. Twenty normal subjects (40 eyes) served as controls. Students t-test and Pearsons correlation coefficients were used for statistical analysis. p Values <0.05 were considered statistically significant.

Results: Corneal hysteresis, CRF and CCT were significantly reduced in patients with PCG (all p < 0.05). Corneal hysteresis and CRF negatively correlated with the corneal diameter in both groups (r1 = -0.53, r2 = -0.66, p < 0.001 for CH and r1 = -0.61, r2 = -0.69, p < 0.001 for CRF). Moreover, we identified a significant correlation between CH and CRF with CCT in both groups (r1 = 0.51, r2 = 0.48, p < 0.001 for CH and r1 = 0.45, r2 = 0.44, p < 0.001 for CRF). Mean KD was significantly reduced both in the anterior and posterior corneal stroma in patients with PCG (764 +/- 162 and 362 +/- 112 cells/mm2, respectively) compared with controls (979 +/- 208 and 581 +/- 131 cells/mm2, respectively) (p < 0.001). There was no significant correlation between the keratocyte density in anterior and/or posterior stroma and CH or CRF in any group (r1 = 0.29, r2 = 0.31, p < 0.06). Mean endothelial cell density was also significantly reduced in PCG group (2920 +/- 443 cells/mm2) compared with control group (3421 +/- 360 cells/mm2) (p < 0.001). Pleomorphism and polymegalism were significantly increased in corneal endothelium of patients with PCG.

Conclusions: Our results showed a significant reduction in CH and CRF in PCG. Both CH and CRF were negatively correlated with corneal diameter. A significant correlation of CH and CRF with CCT was identified in both groups. Keratocyte density was decreased in PCG, but did not have a significant impact on CH and CRF. Mean endothelial density was also decreased in PCG. Our results suggest that reduced CCT and increased corneal diameter are major ocular determinants for the modified corneal biomechanical profile in PCG, while cellular alterations in corneal stroma and endothelium have no significant biomechanical impact.

Acta Ophthalmol. 2013 Feb;91(1):e29-34

Sternberg K., Grabow N., Petersen S, Weitschies W, Harder C, Ince, H, Kroemer, H K, Schmitz, K-P. Advances in Coronary Stent Technology - Active Drug-Loaded Stent Surfaces for Prevention of Restenosis and Improvement of Biocompat. Curr Pharm Biotechnol.

PMID: 23092260

Abstract: Beyond their originally sole mechanical function, current drug-eluting stents (DES) implement the concept of local drug delivery for the re-opening of stenotic arterial vessels, and for prevention of in-stent restenosis as one of the major limitations of conventional bare metal stents (BMS). Current DES consist of a permanent metallic stent platform and an active agent being released from a drug-incorporated polymer coating or a porous stent surface. Although DES have impressively demonstrated their capability of reducing in-stent restenosis, their safety remains under debate due to potential risks, such as delayed healing, late thrombosis and hypersensitivity demanding further development. Current advancements in the stent design address the stent platform, the pharmacologically active substance and/or the drug carrier. For instance, novel biocompatible absorbable stent platforms and drug carriers are developed and novel drugs with a differential effect on vascular endothelial and smooth muscle cells, providing efficient inhibition of muscle cells without altering the endothelial cell function, are identified. Moreover, biofunctionalization of the stent's surface with capture molecules for endothelial progenitor cells are under investigation in order to achieve an in situ endothelialization of the implant.

Curr Pharm Biotechno, Volume 14, Number 1, 2013 Pp. 76-90

Seidlitz A, Nagel S, Semmling B, Sternberg K, Kroemer HK, Weitschies W. In Vitro Dissolution Testing of Drug-Eluting Stents. Curr Pharm Biotechnol.

PMID: 23092259

Abstract:  Drug-eluting stents (DES) have revolutionized the treatment of coronary artery blockage by tremendously reducing the rate of in-stent restenosis and the necessity of repeat revascularization compared to bare-metal stents. They are also gaining increasing importance in other medical fields such as the treatment of certain localized tumors and in glaucoma therapy. DES generally contain most potent drugs, e.g. immunosuppressants or cytostatics, which are supposed to be released in a well controlled manner over time spans which are chosen according to disease progression. Typically, this means that fairly small amounts of drug are released over long periods of time. Therefore, quantification of in vivo plasma levels is often not feasible. Due to this limitation and the fact that tissue levels cannot be determined in humans, in vitro dissolution testing is one of the most powerful tools to gain insight into the release behaviour of DES. This article focuses on the methods for in vitro dissolution testing of DES which are available up to date and highlights the specific characteristics of drug release from stents arising from the composition and the in vivo localization of the dosage form. 

Curr Pharm Biotechnol. 14 (2013) 1, 67-75

Prakasam RK, Winter K, Schwiede M, Allgeier S, Zhivov A, Köhler B, Guthoff RF, Stachs O. Characteristic Quantities of Corneal Epithelial Structures in Confocal Laser Scanning Microscopic Volume Data Sets. Cornea.

doi: 10.1097/ICO.0b013e31826247bf

PMID: 23132439

Abstract:

PURPOSE: Fully automated quantification of the morphologic features of different epithelial cell layers in healthy human corneas.

METHODS: In vivo confocal laser scanning microscopy was performed on the unilateral eyes of 6 healthy volunteers. Stacks of 160 images (400 × 400 µm) with an interslice distance of 0.4 µm were used to generate full thickness volume data sets of the epithelium. Size and shape factors of basal (BC) and intermediate cell (IC) layers were quantified using appropriate image analysis algorithms. Evaluated parameters include mean area, compactness, solidity, major and minor diameter, and maximum boundary distance.

RESULTS: Mean area of BC and IC demonstrated a linear increase from 80 to 160 µm². A similar trend was noted with major and minor diameter and maximum boundary distance. Major diameters of BC and IC measured between 13.2 and 17.0 µm, whereas minor diameter of these cells measured between 8.6 and 12.4 µm. The maximum boundary distance of BC and IC ranged from 7.0 to 9.1 µm. Compactness of epithelial cells clustered around 1.45 and 1.5, whereas cell solidity measured between 1.0 and 1.03.

CONCLUSION: Several characteristic morphologic quantities can be calculated using this methodology without manual intervention. Our study demonstrated promising results and suggests that this fully automated morphologic quantification can be successfully applied to assess microstructural changes of the epithelium in normal and various corneal disorders.

Cornea. 2013 May; 32(5), 636-43

Ausgewählte Originalarbeiten 2012

Kopp S., Warkentin M., Ori F., Ottl P., Frerich, B., Section plane selection influences the results of histomorphometric studies: the example of dental implants. Biomed. Tech

doi: 10.1515/bmt-2012-0015

Abstract:

Objectives: This study was designed to determine and statistically analyze bone-to-implant contact (BIC) values for human specimens segmented in at least two different locations.

Materials and methods: Samples of human bone with fractured osseointegrated implants were obtained from six patients. Sections were prepared, dehydrated, and resin infiltrated. Undecalcified bone sections were produced using the thin-section technique according to Donath, ultimately obtaining a section thickness of approximately 20 mu m. Fifteen specimens were available for histomorphometry. The bone sections were digitized and analyzed. The bone-to-metal contact (BMC) parameter was determined histomorphometrically. The BMC was returned in terms of the visibly bone-covered implant surfaces as a percentage of the total implant surface shown.

Results: The values obtained for the six implants were arranged as six maximum-distance pairs and tested for significance using the t-test for dependent samples. The mean difference in BIC was 11.69 +/- 9.79%. The two-sided test showed a significant difference (p=0.033).

Biomed. Tech. 2012; 57 (5): 365-370

M. Wentzlaff, A. Seidlitz, S. Nagel, C. Harder, C. Schnittker, E. Trip, R. Bock, N. Grabow, K. Sternberg, and W. Weitschies, Coating of collars via fluidised-bed process. Biomed Tech

doi: 10.1515/bmt-2012-4167

PMID: 22962158

Abstract: Collars are small cylindrical tubes which serve as drug reservoirs that are fitted directly on the lead tip of a pacemaker electrode to reduce inflammatory response after the implantation. Currently, collars are produced by injection moulding which may be associated with content variability and long manufacturing times. Hence, the goal of this study was to adapt the effective fluidised-bed process for coating of collars. In this study, collars were coated in a fluidised-bed apparatus with Eudragit (R) RS 30D as an aqueous dispersion which contained the water-soluble model substance fluorescein-sodium. The process parameters and the composition of coating liquid were adapted to obtain a smooth coating surface. Throughout this investigation the surface morphology of the coated collars was explored by using different microscopic methods. Additionally, the homogeneity of coating content was determined fluorometrically and by differential weighing. Our findings provide a basis for coating of collars via fluidised-bed technology. The fluidised-bed technology was applicable to produce collars with a microscopic smooth surface and high homogeneity of drug content. Nevertheless, further optimizations of the coating composition are necessary to create a coating which is flexible and robust enough to mount the collar onto the pacemaker lead without causing coating defects.

Biomed Tech. 2012 Sep 6. S. 18-21

A. Seidlitz, S. Nagel, B. Semmling, S. Petersen, T. Reske, W. Schmidt, N. Grabow, K. Sternberg, and W. Weitschies, In vitro estimation of drug loss during the implantation procedure of drug-eluting stents. Biomed Tech.

doi: 10.1515/bmt-2012-4120

PMID: 22962169

Abstract: Drug-eluting stents are drug/device combinatory products designed to physically re-establish the blood flow in arteriosclerotic blood vessels and deliver anti-proliferative drugs to the stented vessel section to prevent neointimal hyperplasia. Drug that is released during the implantation procedure is washed away with the blood flow. It was our aim to estimate this drug loss using stents coated with fluorescent model substances in an in vitro setup. Stents mounted on balloon catheters were introduced into a polymethacrylate coronary artery model (adapted from ASTM standard F 2394-07 intended for measurement of securement of stents on delivery systems) via a guiding catheter. The system was perfused by phosphate buffered saline pH 7.4 at a flow-rate adapted to the blood flow-rate in coronary arteries. The perfusate was collected in fractions and model substance content was determined fluorimetrically. The hydrophilic model substance fluorescein sodium was released very fast resulting in a loss of approximately 64 % of the drug load within the first minute and up to 82 % after 5 minutes. The hydrophobic model substance triamterene was released much slower from the coating. A total loss of 5 % was detected after 5 minutes. Furthermore, commercially available sirolimus-eluting Cypher Select (R) + stents were tested. Release into the media was not detected. Obviously, the drug-free top coating effectively prevented drug release during the simulated passage to the site of implantation. An in vitro test system to estimate drug loss during the implantation procedure of drug-eluting stents was successfully established. First results using fluorescent model substances indicate that vast losses have to be expected when using fast releasing delivery systems. Therefore, the model may also prove valuable for the in vitro testing of drug-eluting balloons. Further adaptations, such as the inclusion of biorelevant media, may be suitable to further improve the predictability of in vivo performance.

Biomed Tech. 2012 Sep 6. S.403-406

Specowius V., Bendrath F., Winterberg M., Ayub K., Langer P., Synthesis of Functionalized Indolizines by Lewis Acid Mediated Cyclocondensation of 3-(Pyridin-2-yl)-propiolates with Enones. Adv. Synth. Catal

doi: 10.1002/adsc.201100795

Abstract: Functionalized indolizines were prepared by Lewis acid-catalyzed cyclizations of 3-(pyridin-2-yl)-propiolates with enones. This new type of reaction provides a convenient and regioselective approach to ester-substituted indolizine derivatives which are not readily available by other methods. Based on density function theory (DFT) calculations, a mechanism of the reaction has been suggested.

Adv. Synth. Catal. 2012, 354: 1163-1169

Iaroshenko V.O., Ostrovskyi D., Milyutina M., Maalik A., Villinger A., Tolmachev A., Volochnyuk D.M., Langer P., Design and Synthesis of Polycyclic Imidazole-Containing N-heterocycles based on C-H Activation / Cyclization Reactions. Adv. Synth. Catal.

doi: 10.1002/adsc.201200221

Abstract: A new strategy for the synthesis of polycyclic imidazole-containing N-heterocycles, based on the two general synthetic ways, namely the Pd(II)-catalyzed intramolecular arylation via CH/C?Hal and CH/CH coupling reactions, was developed. The method proposed here enables the synthesis of many fused N-heterocycles containing purine, 1-deazapurines and benzimidazole structural units.

Adv. Synth. Catal. 2012, 354: 2495-2503

Iaroshenko V.O., Ali I., Mkrtchyan S., Semeniuchenko V., Ostrovskyi D., Langer P., Transition Metal - Catalysed Arylation of 1-Deazapurines via C-H bond activation. Synlett

doi: 10.1055/s-0032-1317329

Abstract: Transition-metal-catalyzed arylation of imidazo[4,5-b] pyridines (known as 1-deazapurines) is reported. 1-Deazapurines were synthesized from 5-aminoimidazoles, generated in situ by the reaction of methyl N-(cyanomethyl)formimidate with primary amines.

Synlett 2012, 23: 2603-2608

Vilches-Herrera M., Knepper I., de Souza N., Villinger A., Sosnovskikh V.Y., Iaroshenko V.O., One-Pot, Three-Component Synthesis of 7-Azaindole Derivatives from N-Substituted 2-Amino-4-cyanopyrroles, Various Aldehydes, and Active Methylen ... ACS Comb. Sc

doi: 10.1021/co300042v

PMID: 22616767

Abstract: An efficient and practical route to 7-azaindole framework has been developed by one-pot, three-component cyclocondensation of N-substituted 2-amino-4-cyanopyrroles, various aldehydes, and active methylene compounds in ethanol or acetic acid at reflux. Reactions involving tetronic acid, indane-1,3-dione, dimedone, and 5-phenylcyclohexane-1,3-dione gave carbocyclic fused 7-azaindoles, whereas Meldrum's acid, benzoylacetonitrile, and malononitrile resulted in the highly substituted 7-azaindole derivatives, making this strategy very useful in diversity-oriented synthesis (DOS).

ACS Comb. Sci. 2012, 14: 434-441.

Iaroshenko V.O., Knepper I., Zahid M., Kuzora R., Dudkin S., Villinger A., Langer P., Efficient [5+1]-strategy for the assembly of 1,8-naphthyridin-4(1H)-ones by domino amination/conjugate addition reactions of ... Org. Biomol. Chem

doi: 10.1039/c2ob07030h

PMID: 22402696

Abstract: A facile synthetic approach for the synthesis of 1,8-naphthyridine-4(1H)-one derivatives via a catalyst free and Pd-supported tandem amination sequence is developed and described. In a case of aliphatic amines reaction proceeds in a catalyst free mode, however anilines demand Pd-supported reaction conditions.

Org. Biomol. Chem. 2012, 10: 2955-2959

Semmling B., Seidlitz A., Trip E., Schnittker C., Reske T., Sternberg K., Examination of steroid release from screw-in pacing leads. Biomed Tech

doi: 10.1515/bmt-2012-4138

PMID: 23096332

Abstract: Although constant progress in pacing lead design and life time of pacemaker battery has contributed to the clinical success of this treatment option, the mechanism of drug release from steroid-eluting pacing leads is not completely understood. Besides, drug concentrations of steroids released into the heart-tissue remain unclear. Therefore, three different dissolution test methods were examined: a non-standardized (reagent tube), a compendial USP (paddle) and a hydrogel method. The experimental results indicate that dissolution from pacing leads is governed by a diffusion-controlled mechanism and occurs over a prolonged time. Furthermore, the integration of a hydrogel compartment seemed to have an impact on drug release leading to a decrease in release rate. Nevertheless, the experimental results emphasize different experimental parameters in dissolution testing may have a distinct influence on drug dissolution.

Biomed Tech 2012, 57 (S1): 273-276

Loch C., Nagel S., Guthoff R., Seidlitz A. und Weitschies W., The Vitreous Model – an new in vitro test method simulating the vitreous body. Biomed Tech

doi: 10.1515/bmt-2012-4106

PMID: 23096337

Abstract: The vitreous body has become an interesting location for the administration of injections or implants in modern ophthalmology. Such intravitreal dosage forms are loaded with active agents which are released over a prolonged period of time. A test method simulating the in vivo situation is needed to observe the release behaviour of these new dosage forms and the distribution of drug substances in the vitreous humor. To simulate this situation the Vitreous Model (VM) was developed. The spherical glass corpus of the VM can be filled with a gel medium which is adapted to the in vivo situation. Gel insertion and sampling can be performed via a vent at the top. To simulate the movement of the eye the VM was placed on an altered orbital shaker. As vitreous substitute a modified polyacrylamide gel (PAA-gel), which consists of a 30% solution of acryl amide and standard Ringer buffer solution, was used. The water content, pH, relative density and refractive index of the PAA-gel were examined and compared to previous reported data for properties of human vitreous humor. For comparison the viscosity of the PAA-gel and porcine vitreous humor was determined experimentally. During a period of 3 hours the distribution behaviour of an injection of fluorescein sodium solution (1.25 mM) in the PAA-gel and in porcine vitreous humor was investigated by using the VM. The water content (99%) and pH (7.4) of the PAA-gel were equal to the values reported for porcine and human vitreous humor. Furthermore, the values obtained for the relative density (1.0013) and refractive index (1.3385) showed good accordances (deviation < 1%). Slight deviations were only found for the viscosity. Also in the distribution study a similar behaviour were detected. Along with the adapted shape of the VM, the new model seems suitable to perform in vitro experiments, which are capable of simulating in vivo conditions. Through the possibility of insertion of intravitreal injections and implants in the VM, biorelevant distribution and release studies may become feasible.

Biomed Tech 2012, 57 (S1): 281-284

Seidlitz A. und Weitschies W., In-vitro dissolution methods for controlled release parenterals and their applicability to drug-eluting stent testing. J Pharm Pharmacol

doi: 10.1111/j.2042-7158.2011.01439.x

PMID: 22686343

Abstract:

Objectives Dissolution testing is a powerful tool for the characterization of dosage form performance in vitro under standardized conditions. In spite of the increasing number of parenterally administered medicinal products, currently there are no compendial dissolution test methods designed especially for these types of dosage forms. In addition to classical drug delivery systems, drug/device combination products, such as drug-eluting stents, are being used increasingly.

Key findings This review describes the current methods that are used most often for in-vitro dissolution testing of parenteral dosage forms, i.e. the sample and separate methods, the dialysis methods, and the flow-through methods, with a special emphasis on whether these methods can be used for drug-eluting stent testing. In the light of current regulatory requirements and with the exploding costs of preclinical and clinical development, test systems that include biorelevant parameters and are predictive of in-vivo performance are increasingly important. Published attempts to take biorelevant conditions into consideration in the design of dissolution test apparatus developed for parenteral dosage forms, including a method that was designed to emulate the embedding and flow-conditions at the site of stent implantation, have been outlined in this review.

Summary In spite of the large quantity of highly potent controlled release parenteral products marketed today, there is still a lack of suitable methods for in vitro dissolution testing for these dosage forms especially with regard to biorelevant testing conditions. For dosage forms implanted into tissues it seems of major importance to reproduce the transport forces which are predominant in vivo (diffusive versus convective) in the in-vitro experimental setup.

J Pharm Pharmacol 2012, 64: 969-985

Loch C., Zakelj, S., Kristl, A., Nagel, S., Guthoff, R., Weitschies, W., Seidlitz, A., Determination of permeability coefficients of ophthalmic drugs through different layers of porcine, rabbit and bovine eyes. Eur J Pharm Sci

doi: 10.1016/j.ejps.2012.05.007

PMID: 22659372

Abstract: To treat ophthalmic diseases like glaucoma or inflammatory disorders topically applied ophthalmic formulations such as eye drops are usually used. In addition, novel ophthalmic implants releasing drug substances locally into different parts of the eye are available today. In the work presented here, the permeability coefficients of selected drugs (ciprofloxacin hydrochloride, lidocaine hydrochloride. timolol maleate) for ophthalmic tissues were determined using side-by-side diffusion chambers (so-called Ussing chambers). Sclera, conjunctiva, cornea, choroidea-retina-complex and a complex of conjunctiva-sclera-choroidea-retina were excised from fresh porcine, rabbit and bovine eyes. In the porcine eye tissues the highest P-app values were obtained for conjunctiva with the exception of lidocaine. Therefore, it can be estimated that a certain amount of drug diffuses or is transported through conjunctiva after application. The P-app values for sclera were also higher than those for cornea and even more, the surface area of sclera which is available for drug absorption is much larger than that of cornea when applying an implant. The obtained permeability coefficients for sclera and conjunctiva indicate that the administration of periocular implants can be an alternative to topically applied formulations. The complexes of the tissues were a significantly (p < 0.01) stronger barrier to the investigated substances than the separated tissues. Distinct differences in permeability coefficients between the investigated animal tissues were observed. Overall the highest P-app values for all mounted tissues were obtained with the rabbit, followed by porcine and bovine eyes. Because of these distinct interspecies differences one must be very careful when selecting the proper animal model for the permeability experiments.

Eur J Pharm Sci 2012, 47 (1): 131-138

Bohl A, Rohm HW, Ceschi P, Paasche G, Hahn A, Barcikowski S, Lenarz T, Stöver T, Pau HW, Schmitz KP, Sternberg K. Development of a specially tailored local drug delivery system for the prevention of fibrosis after insertion of ... J Mater Sci Mater Med

doi: 10.1007/s10856-012-4698-z

PMID: 22706626

Abstract: A cochlear implant (CI)-associated local drug delivery system based on dexamethasone (DMS) was developed with the purpose to inhibit the growth of fibrotic tissue which influences the signal transmission from the CI to the neurons of the inner ear. For the realization of a targeted DMS delivery the following concepts were combined: modification of the silicone-based electrode carrier by incorporation of DMS and a DMS-containing polymeric coating chemically attached on the surface of the electrode carrier. It was demonstrated that the coated CI showed a high coating stability in a simulated implantation procedure. The in vitro drug release studies in a quasi-stationary model revealed a faster DMS release in the initial phase originating from the DMS-containing coatings and then a lower and sustained DMS release originating from the DMS-loaded silicone carrier. The performed in vitro biocompatibility study confirmed that the released DMS was non-toxic for cultured spiral ganglion cells.

J Mater Sci Mater Med. 2012 Sep; 23(9):2151-62

Bozdag-Turan I, Turan RG, Paranskaya L, Arsoy NS, Turan CH, Akin I, Kische S, Ortak J, Schneider H, Ludovicy S, Hermann T, D'Ancona G, Durdu S, Akar AR, Ince H, Nienaber CA. Correlation between the functional impairment of bone marrow... J Transl Med

doi: 10.1186/1479-5876-10-143

PMID: 22776510

Abstract:

Background: Bone marrow-derived circulating progenitor cells (BM-CPCs) in patients with coronary heart disease are impaired with respect to number and functional activity. However, the relation between the functional activity of BM-CPCs and the number of diseased coronary arteries is yet not known. We analyzed the influence of the number of diseased coronary arteries on the functional activity of BM-CPCs in peripheral blood (PB) in patients with ischemic heart disease (IHD).

Methods: The functional activity of BM-CPCs was measured by migration assay and colony forming unit in 120 patients with coronary 1 vessel (IHD1, n = 40), coronary 2 vessel (IHD2, n = 40), coronary 3 vessel disease (IHD3, n = 40) and in a control group of healthy subjects (n = 40). There was no significant difference of the total number of cardiovascular risk factors between IHD groups, beside diabetes mellitus (DM), which was significantly higher in IHD3 group compared to IHD2 and IHD1.

Results: The colony-forming capacity (CFU-E: p < 0.001, CFU-GM: p < 0.001) and migratory response to stromal cell-derived factor 1 (SDF-1: p < 0.001) as well as vascular endothelial growth factor (VEGF: p < 0001) of BM-CPCs were reduced in the group of patients with IHD compared to control group. The functional activity of BM-CPCs was significantly impaired in patients with IHD3 as compared to IHD1 (VEGF: p < 0.01, SDF-1: p < 0.001; CFU-E: p < 0.001, CFU-GM: p < 0.001) and to IHD2 (VEGF: p = 0.003, SDF-1: p = 0.003; CFU-E: p = 0.001, CFU-GM: p = 0.001). No significant differences were observed in functional activity of BM-CPCs between patients with IHD2 and IHD1 (VEGF: p = 0.8, SDF-1: p = 0.9; CFU-E: p = 0.1, CFU-GM: p = 0.1). Interestingly, the levels of haemoglobin Alc (HbAlc) correlated inversely with the functional activity of BM-CPCs (VEGF: p < 0.001, r = -0.8 SDF-1: p < 0.001, r = -0.8; CFU-E: p = 0.001, r = -0.7, CFU-GM: p = 0.001, r = -0.6) in IHD patients with DM.

Conclusions: The functional activity of BM-CPCs in PB is impaired in patients with IHD. This impairment increases with the number of diseased coronary arteries. Moreover, the regenerative capacity of BM-CPCs in ischemic tissue further declines in IHD patients with DM. Furthermore, monitoring the level of BM-CPCs in PB may provide new insights in patients with IHD.

J Transl Med. 2012 Jul 9;10:143

Akin I, Kische S, Paranskaya L, Schneider H, Rehders TC, Trautwein U, Turan G, Bänsch D, Thiele O, Divchev D, Bozdag-Turan I, Ortak J, Kundt G, Nienaber CA, Ince H. Predictive factors for pacemaker requirement after transcatheter ... BMC Cardiovasc Disor

doi: 10.1186/1471-2261-12-87

PMID: 23035864

Abstract:

Background: Transcatheter aortic valve implantation (TAVI) has been established as a treatment option for inoperable patients with symptomatic aortic valve stenosis. However, patients suffer frequently from conduction disturbances after TAVI.

Methods: Baseline, procedural as well as surface and intracardiac ECG parameters were evaluated for patients treated with TAVI and a comparison between patients requiring pacemaker with those not suffering from relevant conduction disorders were done.

Results: TAVI was successfully in all patients (n=45). Baseline surface and intracardiac ECG recording revealed longer PQ (197.1 +/- 51.2 msec versus 154.1 +/- 32.1 msec; p<0.001), longer AH (153.6 +/- 43.4 msec versus 116.1 +/- 31.2 msec; p<0.001) and HV interval (81.7 +/- 17.8 msec versus 56.8 +/- 8.5 msec; p<0.001) in patients with need for a pacemaker (n=23) versus control group (n=22); furthermore, 7-day follow-up analysis showed a higher prevalence of new left bundle branch block (LBBB) (87.0% versus 31.9%; p<0.001). Multivariate analysis revealed that only new LBBB, QRS duration >120 msec and a PQ interval >200 msec immediately (within 60 minutes) after implantation of the aortic valve were predictors for high-grade (type II second-degree and third-degree) AV block. Other clinical parameters as well as baseline electrocardiographic parameters had no impact on critical conduction delay.

Conclusion: Cardiac conduction disturbances are common after TAVI. The need for pacing after TAVI is predictable by surface ECG evaluation immediately (within 60 minutes) after the procedure.

BMC Cardiovasc Disord. 2012 Oct 4;12:87

Krueger PC, Stachs O, Hadlich S, Falke K, Erbersdobler A, Hosten N, Langner S. MR Microscopy of the human eye at 7.1 T and correlation with histopathology-proof of principle. Orbit

doi: 10.3109/01676830.2012.723783

PMID: 23231062

Abstract:

OBJECTIVE: Magnetic resonance imaging (MRI) at 1.5 and 3.0 Tesla with small surface coils is a well-established procedure in the diagnosis of masses of the eye and orbital cavity. Until now histological examination has been required to obtain definitive information on tumor extent or possible infiltration of surrounding structures. With ultra-high-field MRI, however, it is possible to evaluate tumor morphology as well as possible extension into surrounding structures with submillimeter spatial resolution.

Materials and METHODS: We present a female patient with a uveal melanoma who underwent a preoperative MRI at 1.5 T (spatial resolution = 0.9 x 0.9 x 4mm/voxel). Postoperatively, the enucleated specimen was examined in a 7.1 Tesla high-field MRI scanner (slice thickness = 500 m, matrix size = 512 x 512 pixels, spatial resolution = 78 x 78 x 500 m/voxel, acquisition time = 8:20min per plane). Finally, the specimen was examined histologically, and the histological and MRI results were correlated.

RESULTS: Ultra-high-field MRI at 7.1 Tesla visualized the uveal melanoma and anatomical structures of the bulb with high resolution, enabling definitive assessment of tumor morphology and extent. Subsequent histological examination confirmed the MRI findings regarding origin, internal structure, and extent of the tumor.

CONCLUSION: MR microscopy correlates strongly with histology, suggesting that this new imaging modality has the potential for noninvasively assessing tumor morphology, extent, and infiltration of surrounding structures. The examination was performed ex vivo and demonstrates that diagnostic assessment of malignant masses is feasible using high-resolution MR microscopy.

Orbit. 2012 Dec;31(6):390-3

Falke K, Zhivov A, Zimpfer A, Stachs O, Guthoff RF. Diagnosis of conjunctival neoplastic lesions by confocal in-vivo microscopy. Klin Monbl Augenheilkd

doi: 10.1055/s-0031-1299158

PMID: 22389263

Abstract:

Background: There is a wide spectrum of benign and malignant conjunctival neoplastic lesions that are often impossible to distinguish clinically by slit-lamp microscopy. The current study was undertaken to compare in-vivo confocal laser scanning microscopy (CLSM) and histology for the preoperative assessment of benign or malignant status.

Case Reports: We present the clinical details of three patients. In two cases the neoplastic lesions were classified as benign (actinic keratosis). In-vivo CLSM revealed densely layered, sometimes hyperreflective conjunctival epithelial cells, together with multiple inflammatory cells and microcysts. Correlated findings on histology showed keratinisation with inflammatory infiltrates and intracellular oedema formation. In-vivo CLSM images in the third patient revealed interruptions of the layered epithelial structure with regular conjunctival epithelium co-existing with complexes of enlarged cells with polymorphic nuclei. Histology also showed an abrupt transition from regular squamous epithelium to hyperplastic, dysplastic squamous epithelium. In this case the neoplastic lesion was classified as carcinoma in situ.

Discussion: The in-vivo CLSM images correlated positively with histology findings. Although in-vivo CLSM offers the capability to perform non-invasive examinations over time, associated histological assessment (because of its more precise detail and additional staining techniques) remains indispensable for planning further action and determining the prognosis.

Klin Monbl Augenheilkd. 2012 Jul;229(7):724-7

Fritzsche C, Stachs O, Holtfreter MC, Nohr-Luczak C, Guthoff RF, Reisinger EC. Confocal laser scanning microscopy, a new in vivo diagnostic tool for schistosomiasis. PLoS One

doi: 10.1371/journal.pone.0034869

PMID: 22529947

Abstract:

Background: The gold standard for the diagnosis of schistosomiasis is the detection of the parasite's characteristic eggs in urine, stool, or rectal and bladder biopsy specimens. Direct detection of eggs is difficult and not always possible in patients with low egg-shedding rates. Confocal laser scanning microscopy (CLSM) permits non-invasive cell imaging in vivo and is an established way of obtaining high-resolution images and 3-dimensional reconstructions. Recently, CLSM was shown to be a suitable method to visualize Schistosoma mansoni eggs within the mucosa of dissected mouse gut. In this case, we evaluated the suitability of CLSM to detect eggs of Schistosoma haematobium in a patient with urinary schistosomiasis and low egg-shedding rates.

Methodology/Principal Findings: The confocal laser scanning microscope used in this study was based on a scanning laser system for imaging the retina of a living eye, the Heidelberg Retina Tomograph II, in combination with a lens system (image modality). Standard light cystoscopy was performed using a rigid cystoscope under general anaesthesia. The CLSM endoscope was then passed through the working channel of the rigid cystoscope. The mucosal tissue of the bladder was scanned using CLSM. Schistoma haematobium eggs appeared as bright structures, with the characteristic egg shape and typical terminal spine.

Conclusion/Significance: We were able to detect schistosomal eggs in the urothelium of a patient with urinary schistosomiasis. Thus, CLSM may be a suitable tool for the diagnosis of schistosomiasis in humans, especially in cases where standard diagnostic tools are not suitable.

PLoS One. 2012;7(4):e34869

Hovakimyan M, Ramoth T, Löbler M, Schmitz KP, Witt M, Guthoff R, Stachs O. Evaluation of protective effects of trehalose on desiccation of epithelial cells in three dimensional reconstructed human corneal epithelium. Curr Eye Res

doi: 10.3109/02713683.2012.700754

PMID: 22730897

Abstract:

Purpose: Trehalose has been shown to protect epithelial cells from desiccation damage in cell culture and the murine dry eye model. The present study evaluates the protective role of trehalose in reconstructed human corneal epithelium (3D-HCE) during desiccation.

Materials and methods: The morphology of 3D-HCE was examined using in vivo an ex vivo confocal laser-scanning microscopy (CLSM). The 3D-HCE was desiccated with or without pre-treatment with trehalose. Evaluation of protective role of trehalose was conducted using different in vitro cell viability assays and CLSM. Tissue thickness for each condition was determined by optical coherence tomography (OCT).

Results: 3D-HCE tissue revealed similar features with human cornea at histological level. After desiccation the percentage of living cells was only 32% in 3D-HCE tissue without pre-incubation and 98% in trehalose-pre-incubated tissue, as shown by a cell viability assay. These findings were confirmed by using a Live-Dead assay. Also, the confocal immunofluorescence analysis revealed much better preservation of tight junctions in trehalose-pre-treated tissue.

Conclusions: CLSM and an in vitro cell viability assays could be successfully used for the characterization of 3D-HCE tissue. We demonstrated the protective role of trehalose using reconstructed corneal epithelium (3D-HCE), which mimics HCE and has the potential to become a valuable model in ophthalmic research.

Curr Eye Res. 2012 Nov;37(11):982-9

Falke K, Prakasam RK, Guthoff RF, Stachs O. In vivo imaging of limbal epithelium and palisades of vogt. Klin Monbl Augenheilkd

doi: 10.1055/s-0032-1327981

PMID: 23258669

Abstract: Limbal disorders can lead to loss of stem cell population and deficiency in corneal integrity. The aim of this study is to describe the morphological features of this region by using confocal laser scanning microscopy (CLSM) and spectral domain optical coherence tomography (SD-OCT) in healthy subjects, contact lens wearers and in patients with surface disorders. On examination hyper- and hyporeflective finger-like structures were found with numerous basal epithelial cells within and in between crypts. In contrast, detailed imaging of limbal palisades of Vogt was not possible on SD-OCT, the corresponding hyperreflective line was identified. These typical crypts were less pronounced or absent in cases with corneal alterations as has been demonstrated. Additionally morphological changes at the level of intermediate and basal cell layers were discussed. A better understanding of the corneal limbus can provide valuable clues on understanding cell integrity and wound-healing processes. In future, quantitative analyses of limbal epithelium in different corneal disorders will be preferable.

Klin Monbl Augenheilkd. 2012 Dec;229(12):1185-90

Stiehm M, Quosdorf D, Brede M, Schmitz KP, Leder A. Numerische Simulation von nicht-newtonschen Strömungen in Koronarstents. GALA Fachtagung

Abstract: -

GALA Fachtagung “Lasermethoden in der Strömungsmesstechnik” 4. – 6. September 2012, Hrsg.: A. Leder, M. Brede, B. Ruck, D. Dopheide, S. 28-1 bis 28-8, © Gala e.V. 2012 Karlsruhe

Quosdorf D, Stiehm M, Brede M, Sakowski J, Martin H, Schmitz KP, Leder A. Charakterisierung von Stentstrukturen anhand von Wandschubspannungsverläufen unter Nutzung der Micro-Particle-Image-Velocimetry. GALA Fachtagung

Abstract: - 

GALA Fachtagung “Lasermethoden in der Strömungsmesstechnik” 4. – 6. September 2012, Hrsg.: A. Leder, M. Brede, B. Ruck, D. Dopheide, S. 27-1 bis 27-10, © Gala e.V. 2012 Karlsruhe

Stiehm M, Martin H, Quosdorf D, Brede M, Schmitz KP, Leder A. Numerical and Experimental Analysis of Mechanical Loads on Stent-Vessel-Systems. Biomed Tech

doi: 10.1515/bmt-2012-4131

PMID: 22962183

Abstract: Blood vessels as well as the blood flow are significantly influenced by coronary stents. On the one hand the compliance of the vessel wall will increase due to the stiffness of the stent struts. Therefore a structural mechanic analysis is necessary to find a compromise between the elasticity of the stent and the stiffness necessary to brace the vessel wall. On the other hand, the stent struts induce non-physiological flow effects like recirculation zones, which result in alterations of the wall shear stress distribution. Particularly low wall shear stresses are under suspect to increase the risk of an in-stent restenosis. In this paper structural und fluid mechanical methods are presented to analyse the influence of the stent on the wall of the vessel and on the blood flow. It has been proven that coronary stent increases the compliance of the vessel wall. Furthermore recirculation zones have been found upstream and downstream of the stent struts. The acquired results will be used to improve the stent design.

Biomed Tech. 2012 (S1), 14-17

Grabow N, Schmitt L, Pfensig S, Reske T, Rehme H, Senz V, Sternberg K, Schmitz KP, Spray-coating process development, manufacture, quality assessment and drug release behavior of peripheral drug-eluting stents. Biomed Tech

doi: 10.1515/bmt-2012-4298

PMID: 22962185

Abstract: Manufacture of peripheral DES requires development of process technologies to accommodate their geometrical and biomechanical specifics. In this study, a spray-coating process for peripheral DES coatings was developed. Peripheral-size, self-expanding nickel titanium stents (7.0 x 40 mm) were coated with the biodegradable polymer poly(L-lactide) (PLLA) incorporated with the immunosuppressant sirolimus (SIR) in a ratio of 82.5/17.5 % w/w. Coating mass was 3400 mu g. A parameter study was conducted to assess optimum coating parameters. The coated DES were evaluated for coating morphology, thickness, and integrity. Drug release behavior was assessed by HPLC. SEM evaluation confirmed a smooth, defect-free PLLA/SIR coating with complete strut coverage. A coating thickness of 5.5 +/- 0.4 mu m was determined by CLSM. SIR release was traced over up to 430 h, exhibiting an initial burst over 30 h, followed by a steady, retarded drug release. Altogether, the results indicate the technical feasibility of self-expanding, peripheral DES.

Biomed Tech. 2012 57(S1), 867-868

Osipov V, Doskolovich L, Bezus E, Cheng W, Gaiduvicute A, Chichkov B. Fabrication of three-focal diffractive lenses by two-photon polymerization technique. Appl Phys A

doi: 10.1007/s00339-012-6903-9

Abstract: Fabrication of submicron-height relief of three-focal diffractive lenses using two-photon polymerization is studied. Optical properties of the designed lenses are investigated theoretically and experimentally. The proposed design of the combined diffractive-refractive lenses is promising for the realization of three-focal optical ophthalmological implants with predetermined light intensity distribution between the foci. The realized three-focal optical element has a diameter size of 2.7 mm with the focal distances in the range of 27-34 mm.

Appl Phys A (2012) 107:525–529

Minrath I, Petersen S, Schmitz K-P, Sternberg K. Drug permeation studies of hydrogels usable for stimulus-induced local drug delivery systems. Biomed. Tech.

doi: 10.1515/bmt-2012-4367

PMID: 22944938

Abstract: The drug release of well-established local drug delivery (LDD) systems is either diffusion or chemically controlled. However, drugs are released independently of their need, possibly leading to ineffectiveness of the LDD systems at the time of interest. Novel intelligent systems hence foresee an appropriate drug release at an adequate time, exemplarily established by a hydrogel-coating whose swelling property and drug permeability is dictated by the presence of a specific protein. In this context, we systematically investigated the drug permeation though various polyacrylamide-gels as model coating. In order to define this design at the example of polyacrylamide we initially investigated the effect of the monomer-to-crosslinker-ratio (acrylamide (AAm)/N,N'-methylenebisacrylamide (MBAA)) and the gel content on the temporal release of model drugs, such as albumin and myoglobin in a chamber especially designed for these test runs. Among performed experiments, the gel content evidenced the strongest effect on drug permeation. For instance, several test runs using different AAm/MBAA-ratios showed comparable drug permeation, while they all illustrated increasing drug permeability with decreasing gel-content. High gel content seems to be hence afforded for the formation of a stable, impermeable implant coating, whereas the amount of MBAA as crosslinker could be reduced in favor of sensor molecules. The realized studies give evidence of the afforded gel composition, which is a high general content and a low grade of crosslinking to allow integration of sensor molecules, aiming at stimulus-induced LDD systems.

Biomed. Tech. 2012, 57(S1):569-571

Sternberg K, Petersen S, Grabow N, Luderer F, Bohl A, Reske T, Siewert S, Minrath I, Seidlitz A, Weitschies W, Meyer zu Schwabedissen H, Kroemer HK, Schmitz K-P. Implant-associated local drug delivery systems for different medical ... Biomed. Tech.

doi: 10.1515/bmt-2012-4473

PMID: 22962162

Abstract: In recent years novel implants in particular have already proven to contribute substantially to enhanced quality of life, higher efficacy of therapeutic approaches, as well as patient safety. With the purpose to optimize the implant-tissue interaction the focus of efforts is on implants with a controlled, site-selective drug release. Therefore, we develop within the REMEDIS consortium implant-associated local drug delivery (LDD) systems for different medical applications. Engineering and natural scientists together with medical experts from all over Germany work in close collaboration to develop such innovative implants which combine the function as medical device and as LDD system. These include vascular stents and stimulation electrodes for the circulatory system and the ears, glaucoma stents for the eyes as well as auditory tube stents for the ears. Through its efforts to combine a LDD system into the functionality of implants, REMEDIS provides cutting-edge research into such medical technology.

Biomed. Tech. 2012, 57(S1):393-396

Fiedler S, Irsig R, Gieseke M, Vehse M, Senz V, Oniszczuk AW, Tiggesbäumker J, Schuster C, Svanidze AV, Rothe N, Kaierle S, Hustedt M, Haferkamp H, Sternberg K, Schmitz KP, Seitz H, Lochbrunner S, Meiwes-Broer KH. Material Processing with Femtosecond .

doi: 10.1515/bmt-2012-4405

PMID: 22944966

Abstract: Medical implants require functional surfaces in order to ensure biological compatibility. Micrometer-sized surface structures are needed in particular for a successful adaptation on a cellular basis. Pulsed laser light sources with sub-ps pulse durations are promising tools exceeding the precision in material processing of nowadays mechanical methods. Our three-axis-scanner allows arbitrary focus positioning on the sample for material processing. Intense ultrashort near infrared laser pulses with adjustable pulse envelopes and variable focusing conditions are used for the material ablation. Moreover, process parameters like pulse energy, pulse repetition rate and focusing conditions are adjusted to adapt the laser parameters to the specific requirements regarding geometry and materials in use. Prototype drug depots have been machined by laser surface structuring.

Biomed. Tech. 2012; 57 (S1): 603-605

Svanidze AV, Schuster C, Rothe N, Fiedler S, Irsig R, Tiggesbäumker J, Meiwes-Broer KH, Vehse M, Seitz H, Senz V, Lochbrunner S. Material processing with shaped femtosecond laser pulses. Biomed. Tech.

doi: 10.1515/bmt-2012-4037

PMID: 22962184

Abstract: Laser material processing of aluminium and some polymers such as polyamide and low-density polyethylene has been performed using femtosecond pulses with different pulse durations. In order to investigate and optimize the ablation process we have developed an experimental setup with spatial light modulator for phase and amplitude modulation of the pulses. Considerable differences in the integrity of areas surrounding cut edges could be found for cuts of aluminum foil made by 70 fs and 230 fs laser ablation. For shorter pulses less damaged area caused by shock waves and less melting of the material have been observed. No debris was attached to the cut edges. The ablation of polymer surfaces has been carried out in nano-and femtosecond regimes. Strong heat transfer into the target, the consequent melting and even bubbling prevent a precise machining of polymers by nanosecond pulses. In addition femtosecond laser ablation allows creation of the holes on the polymer surface with higher precision. Such structures obtained in laser machining experiments can provide the opportunity for designing medical implants with high precision.

 

Biomed. Tech.  2012; 57 (S1): 894-896.

 

Löbler M, Vehse M, Seitz H, Schmitz KP. Laser structuring of silica surface improves cell adhesion. Biomed. Tech.

doi: 10.1515/bmt-2012-4317

PMID: 22944985

Abstract: When implants are required to develop good contact to surrounding tissue the implant surface has to serve as an adhesion substrate for the appropriate cell type. As silica is nontoxic and biocompatible the question arises whether surface modifications will render a surface amenable to cellular adhesion. The silica surface is micro-structured by laser treatment using a frequency doubled Nd:YAG system. Laser treatment strategy and direct laser parameters were varied in order to generate different surface topographies. To test cellular adhesion of silica samples L929 mouse fibroblasts were seeded onto the surface of silica probes. Samples were incubated for 48 h and cell viability was determined by the CellQuanti-Blue assay. Viable cells attached to the silica surface were stained with calcein and visualized by confocal laser scanning microscopy. The silica materials used in this study do not release toxic substances when incubated in aqueous media. Nevertheless, cells seeded onto such silica surfaces show reduced viability when compared to cells seeded onto polystyrene. Confocal laser scanning microscopy reveals that an untreated silica surface does not provide a good cell adhesion substrate whereas a grid surface structure of about 40 mu m line space allows cell adhesion. To make silica a substrate for cell adhesion physical surface modification could be a first step. As the pattern is in the micrometer range there might be a need to adjust grid size to target cell size. As a conclusion: laser structuring of silica surfaces improves cell adhesion.

 

Biomed. Tech. 2012; 57 (S1): 423-425

Gieseke M, Senz V, Vehse M, Fiedler S, Irsig R, Hustedt M, Sternberg K, Nölke C, Kaierle S, Wesling V, Tiggesbäumker J, Meiwes-Broer KH, Seitz H, Schmitz KP, Haferkamp H. Additive Manufacturing of Drug Delivery Systems. Biomed. Tech.

doi: 10.1515/bmt-2012-4109

PMID: 22962182

Abstract: New Drug Delivery Devices are produced using Selective Laser Micro Melting (SL mu M). In a first approach, hollow micro needles with an inner diameter of 160 mu m were manufactured from 316L stainless steel powder. Afterwards, the hollow micro needles were successfully filled with a test liquid. In a second approach, fully dense micro needles with an outer diameter of 200 mu m were produced. A femtosecond laser setup was used to create discrete drug depots in fully dense micro needles.

Biomed. Tech. 2012; 57 (S1): 398-401

Vehse M, Gieseke M, Fiedler S, Petersen S, Irsig R, Senz V, Löbler M, Hustedt M, Kaierle S, Haferkamp H, Sternberg K, Schmitz KP, Lochbrunner S, Meiwes-Broer KH, Seitz H. Loading method for discrete drug depots on implant surfaces. Biomed. Tech. 2012

doi: 10.1515/bmt-2012-4006

PMID: 22944984

Abstract: Modern biomedical engineering focuses more and more on the development of implant-associated local drug delivery systems for many different applications like stents for the treatment of coronary artery disease. A common method to deposit drugs on implants is their integration within a polymeric coating, which might however be contributor of adverse cardiac events. Moreover, modern implants pursue multimodal and time-controlled approaches, which require more sophisticated drug loading methods. In this context, a loading method based on surface depots that are selectively filled with drugs using a drop-on-demand printhead is investigated. As a first step small drug depots were produced by abrasive or additive laser-based methods on or into the surface of the implant. The range of the depot volumes varies between 1.4x10(5) and 1x10(7) mu m(3). These depots (cavity or tubes) can be filled with pure drugs, drug-polymer-mixtures and/or covered with biodegradable polymers using a piezoelectric drop-on-demand printhead. Therefore, the drugs are dissolved in methanol, ethanol or dimethyl sulfoxide (DMSO). The minimal droplet volume is about 100 pl. The quantity of drug per depot is specified by the number of droplets that are printed into the depots. The proof of principle of the loading method could be demonstrated on stainless steel samples as model implant surface. Drug depots were successfully filled with fluorescein disodium salt, dissolved in a mixture of 50 % DMSO and 50 % ethanol. Further drug depots were loaded with acetylsalicylic acid (ASS), dissolved in pure DMSO. Because of the low volume of a single droplet the depots could be filled very precisely.

Biomed. Tech. 2012; 57 (S1): 1089-1092

Vehse M, Löbler M, Schmitz KP, Seitz H. Laser induced surface structure on stainless steel influences cell viability. Biomed. Tech.

doi: 10.1515/bmt-2012-4007

PMID: 22944970

Abstract: The interaction of cells and tissue with implant surfaces significantly decides about the reaction of the organism in contact with an implant. The interface between implant and surrounding cell media influences the initiated immune response. An initial point to influence the cell-implant-interaction is to structure the surface of the implant. Laser techniques offer many degrees of freedom to generate micro structures on material surfaces. Using a frequency doubled Nd:YAG laser system, the surface of stainless steel (316L) samples was micro-structured. Micro structures in the range of 20-80 mu m line width and 10-50 mu m depth were chosen. Lattice structures, wave structures or nub structures were created on steel plates. L929 mouse fibroblasts were seeded on the plates in order to determine the cell viability and adhesion by confocal laser scanning microscopy. Non-toxic stainless steel (tested in aqueous media) shows significant distinctions in cell adhesion dependent from structure dimensions. Especially surface structures with intersecting square grids with a linewidth near 40 mu m lead to good cell viability. Cells grown on a square pattern with a linewidth of 40 mu m show numerous pseudopodia which is an indication of cell adhesion. In contrast, rectangular patterns with only one dimension below 10 mu m do not favour cell adhesion.

Biomed. Tech. 2012; 57 (S1): 419-421

Kastner, C., Löbler, M., Reske, T., Sternberg, K., Guthoff, R., Schmitz, K.-P. Determination of human anterior lens capsule permeability for fluorescent model substances and after-cataract preventive drugs. Biomed. Tech.

doi: 10.1515/bmt-2012-4340

PMID: 22944942

Abstract: Cataract can nowadays be treated effectively by replacing the clouded lens by an artificial intraocular lens. However, the capability of accommodation is lost and secondary cataract may occur. Developing an injectable lens into the capsular bag to maintain accommodation, and to prevent secondary cataract by drug delivery from the lens material, it is important to know if potential constituents of the artificial lens or antiproliferative drugs can cross the capsular bag membrane and affect adjacent tissue. In this work human anterior lens capsules were used to determine the molecular weight cut off using fluorescent dextrans of different size and the permeability of antiproliferative drugs. The lens capsules were mounted into diffusion chambers and the amount of the permeated substances was determined after 24 h of incubation. The molecular weight cutoff was found to be at 163 kDa. The apparent permeability coefficients for actinomycin D and methotrexate were in the range of 5-7x10(-5) cm/s, indicating a passage through the lens capsule. An injectable lens should be designed in a way preventing lens constituent and incorporated drug escape from the capsular bag.

Biomed. Tech. 2012 Aug 27;57(S1).

Stachs, O., Reiß, S., Guthoff, R., Stolz, H. Spatially resolved Brillouin spectroscopy for in vivo determination of the biomechanical properties of the crystalline lenses.

doi: 10.1117/12.907108

Abstract: Confocal Brillouin spectroscopy is an innovative measurement method for the noninvasive determination of rheological tissue properties. Its application in ophthalmology can offer the possibility to determine in vivo the deformation properties of eye lens with spatial resolution. This seems to be a promising approach concerning current presbyopia research. Due to the spatially resolved detection of the viscoelastic lens properties, a better understanding of the natural aging process of the lens and the influences of different lens opacities on the stiffness is expected. Based on spectral data the refractive index profile, the protein concentration and the density profile within the lens tissue can be derived. A measurement set-up for confocal Brillouin microscopy based on spectral analysis of spontaneous Brillouin scattering signals by using a high-resolution dispersive device is presented. First in vivo measurements results on rabbit eyes are presented and evaluated concerning refractive index distribution, protein concentration, density and rheological significance. These data are compared with known research results of ex vivo lenses.

In: Manns, F., Söderberg, P.G., Ho, A., editors. Ophthalmic Technologies XXII. SPIE Proceedings Vol. 8209; 2012 Jan 21-26; San Francisco, CA, USA. Bellingham, WA, USA: SPIE ; 2012. P. 82090T.

Reiß, S., Sperlich, K., Hovakimyan, M., Martius, P., Guthoff, R., Stolz, H., Sachs, O. Ex vivo measurement of postmortem tissue changes in the crystalline lens by Brillouin spectroscopy and confocal reflectance microscopy. IEEE Trans. Biomed. Eng. 2012

doi: 10.1109/TBME.2012.2204054

PMID: 22711764

Abstract: Use of Brillouin spectroscopy in ophthalmology enables noninvasive, spatially resolved determination of the rheological properties of crystalline lens tissue. Furthermore, the Brillouin shift correlates with the protein concentration inside the lens. In vitro measurements on extracted porcine lenses demonstrate that results obtained with Brillouin spectroscopy depend strongly on time after death. The intensity of the Brillouin signal decreases significantly as early as 5 h postmortem. Moreover, the fluctuation of the Brillouin frequency shift inside the lens increases with postmortem time. Images of lens tissue taken with a confocal reflectance microscope between measurements reveal a degenerative aging process. These tissue changes correlate with our results from Brillouin spectroscopy. It is concluded that only in vivo measurements appropriately reflect the rheological properties of the eye lens and its protein concentration.

IEEE Trans. Biomed. Eng. 2012 Aug;59(8):2348-2354

Prakasam RK, Schwiede M, Hütz WW, Guthoff RF, Stachs O. Corneal Responses to Eye Rubbing with Spectral Domain Optical Coherence Tomography. Curr Eye Res.

doi: 10.3109/02713683.2011.622850

PMID: 22029687

Abstract: 

Purpose: Surprisingly, a significant reduction (18.4%) in epithelial thickness was found after 15 seconds of eye rubbing measured using Holden-Payor optical pachometer reported in the literature. Hence, we aimed at studying the effects of compressive and shearing pressure associated with eye rubbing on total corneal, epithelial and Bowman's membrane thickness using spectral domain OCT (SD-OCT).

Methods: SD-OCT (Spectralis; Heidelberg Engineering) was used to acquire cross-sectional images of the cornea. Central total-corneal thickness (TCT), epithelial thickness (ET) and Bowman's membrane thickness (BMT) was measured on 20 eyes of 10 subjects with normal corneas without any ocular pathology using in-house developed MATLAB (Mathworks, Inc.) program. Two different measurement methods (distance between inflection points and peak to peak distance) were performed on luminance graph to obtain thickness profile of the corneas. Baseline measurements were compared with the measurements obtained immediately after 30 seconds of circular eye rubbing over the closed eye lid with contra lateral eye at a primary gaze position.

Results: We have found that the mean difference in TCT, ET and BMT to be 0.44 +/- 6.00 mu m, 0.28 +/- 1.72 mu m, and 0.01 +/- 0.77 mu m with first method of measurement, respectively, and the mean difference in TCT and ET were -0.26 +/- 5.75 mu m, and 0.37 +/- 1.38 mu m with second method of measurement respectively before and after eye rubbing. These differences were statistically insignificant (all p > 0.05) using both measuring methods.

Conclusion: Thirty seconds of circular pattern rubbing over closed eye lids using index finger produce no significant changes on total corneal, epithelial and Bowman's membrane thickness.

 

Curr Eye Res. 2012 Jan;37(1):25-32

K. Navaneetha Pandiyaraj, J. Heeg, T. Barfels, M. Wienecke, Young Ha Rhee, Hyoung, Woo Kim, In vitro cyto and blood compatibility of titanium containing diamond-like carbon prepared by hybrid sputtering method

doi: 10.1088/1009-0630/14/9/11

Abstract: In recent years, diamond-like carbon films (DLC) have been given more attention in research in the biomedical industry due to their potential application as surface coating on biomedical materials such as metals and polymer substrates. There are many ways to prepare metal containing DLC films deposited on polymeric film substrates, such as coatings from carbonaceous precursors and some means that incorporate other elements. In this study, we investigated both the surface and biocompatible properties of titanium containing DLC (Ti-DLC) films. The Ti-DLC films were prepared on the surface of poly (ethylene terephthalate) (PET) film as a function of the deposition power level using reactive sputtering technique. The films' hydrophilicity was studied by contact angle and surface energy tests. Their surface morphology was studied by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Their elemental chemical composition was analyzed using energy dispersive X-spectra (EDX) and X-ray photoelectron spectroscopy (XPS). Their blood and cell compatibility was studied by in vitro tests, including tests on platelet adhesion, thrombus formation, whole blood clotting time and osteoblast cell compatibility. Significant changes in the morphological and chemical composition of the Ti-DLC films were observed and found to be a function of the deposition level. These morphological and chemical changes reduced the interfacial tension between Ti-DLC and blood proteins as well as resisted the adhesion and activation of platelets on the surface of the Ti-DLC films. The cell compatibility results exhibited significant growth of osteoblast cells on the surface of Ti incorporated DLC film compared with that of DLC film surface.

J. of Plasma Science and Technology Vol. 14, Iss. 8, 2012

Luderer F, Begerow I, Schmidt W, Martin H, Grabow N, Bünger CM, Schareck W, Schmitz K-P, Sternberg K. Enhanced Visualization of Biodegradable Polymeric Vascular Scaffolds by Incorporation of Gold, Silver and Magnetite Nanoparticles, J Biomater Appl.

PMID: 22492201

Abstract: Due to improved tissue regeneration and the enabling of post-operative minimally invasive interventions in the same vessel segment, biodegradable polymeric scaffolds represent a competitive approach to permanent metallic stents in vascular applications. Despite these advantages some challenges, such as the improvement of the scaffold mechanics and enhancement of scaffold visibility during the implantation procedure, are persisting. Therefore, the scope of our studies was to investigate the potential of gold, silver and magnetite nanoparticles incorporated in a polymeric blend of poly(L-lactide)/poly(4-hydroxybutyrate) for image enhancement in X-ray, magnetic resonance or near-infrared imaging. Their impact on mechanical properties of such modified scaffold materials was also evaluated.

Journal of Biomaterials Applications 2012 Apr 5. [Epub ahead of print]

Stahnke T, Löbler M, Kastner C, Stachs O, Wree A, Sternberg K, Schmitz K-P, Guthoff R. Different fibroblast subpopulations of the eye: A therapeutic target to prevent postoperative fibrosis in glaucoma therapy. Exp. Eye Res

doi: 10.1016/j.exer.2012.04.015

PMID: 22579993

Abstract: The aim of this study is the characterization of fibroblasts mainly responsible for fibrosis processes associated with trabeculectomy or microstent implantation for glaucoma therapy. Therefore we isolated human primary fibroblasts from choroidea, sclera, Tenon capsule, and orbital fat tissues. These fibroblast subpopulations were analysed in vitro for expression of the extracellular matrix components which are responsible for postoperative scarring in glaucoma therapy. For scarring the proteins of the collagen family are predominant and so we focused on the expression of collagen I, collagen III and collagen VI in every fibroblast subpopulation. Also, the extracellular matrix protein fibronectin which crosslinks collagen fibres or other extracellular matrix components and cell surfaces, was analyzed. Collagen I, III and VI were prominent in every fibroblast subpopulation. The highest amounts of collagen III were found in hCF and hOF, whereas the signal in hSF and hTF was negligible. Additionally, there is a link between scarring processes and proliferating potential of fibroblasts, in case of microstent implantation triggered through the infiltration of inflammatory cells. Thus we analyzed fibroblast subpopulations for the presence of TGF-beta 1 which is one of the most important cytokines involved in proliferation processes. TGF-beta 1 was prominent in all fibroblast subpopulations with lowest expression in hCF cultures. To prevent postoperative fibroblast proliferation we analyzed in vitro the proliferation-inhibitors paclitaxel and mitomycin C which are potential candidates in drug eluting drainage systems on ocular fibroblast subpopulations. These inhibitors arrest fibroblast proliferation and viability, being, however, not very specific and have a cytotoxic potential also on healthy tissues surrounding the microstent outflow area. Significant differences in protein synthesis of fibroblasts subpopulations which could be specific targets for inhibition may help to find out fibroblast specific inhibitors to prevent postoperative scarring and could prevent patients from secondary surgery after microstent implantation.

Exp. Eye Res. 2012 Jul 100:88-97

Ausgewählte Originalarbeiten 2011

Akin I, Schneider H, Ince H, Kische S, Rehders TC, Chatterjee T, Nienaber CA. Second- and third-generation drug-eluting coronary stents: progress and safety. Herz.

doi: 10.1007/s00059-011-3458-z

PMID:21505934

Abstract: Drug-eluting stents (DES) have revolutionized the treatment of coronary artery disease by reducing the rate of in-stent restenosis from 20-40% with bare-metal stent (BMS) to 6-8% with DES. However, with widespread use of DES, safety concerns have risen due to the observation of late stent thrombosis. With this in mind and better understanding of mechanism and pathophysiology of stent thrombosis, the technological platform, especially innovative anti-restenotic agents, polymeric coatings, and stent platforms, improved with newer DES. Two second-generation DES, the Endeavor zotarolimus-eluting stent (ZES) and the Xience-V everolimus-eluting stent (EES), have provided promising results in both randomized controlled trials (SPIRIT and ENDEAVOR) and registries (E-Five, COMPARE) compared with bare-metal stents (BMS) and first-generation DES. Newer third-generation stent technology, especially biodegradable polymers, polymer-free stents, and biodegradable stents on the basis of poly-L-lactide (PLLA) or magnesium, has been evaluated in preclinical and initial clinical trials. However, despite encouraging initial results, long-term data of large-scale randomized trials as well as registries comparing them to currently approved first- and second-generation DES are still lacking.

Herz. 2011 May;36(3):190-6.

Sternberg K, Gratz M, Koeck K, Mostertz J, Begunk R, Loebler M, Semmling B, Seidlitz A, Hildebrandt P, Homuth G, Grabow N, Tuemmler C, Weitschies W, Schmitz KP, Kroemer HK. Magnesium used in bioabsorbable stents controls ... J Biomed Mater Res B Appl Biom

doi: 10.1002/jbm.b.31918

PMID: 22114061

Abstract: Magnesium-based bioabsorbable cardiovascular stents have been developed to overcome limitations of permanent metallic stents, such as late stent thrombosis. During stent degradation, endothelial and smooth muscle cells will be exposed to locally high magnesium concentrations with yet unknown physiological consequences. Here, we investigated the effects of elevated magnesium concentrations on human coronary artery endothelial and smooth muscle cell (HCAEC, HCASMC) growth and gene expression. In the course of 24 h after incubation with magnesium chloride solutions (1 or 10 mM) intracellular magnesium level in HCASMC raised from 0.55 +/- 0.25 mM (1 mM) to 1.38 +/- 0.95 mM (10 mM), while no increase was detected in HCAEC. Accordingly, a DNA microarray-based study identified 69 magnesium regulated transcripts in HCAEC, but 2172 magnesium regulated transcripts in HCASMC. Notably, a significant regulation of various growth factors and extracellular matrix components was observed. In contrast, viability and proliferation of HCAEC were increased at concentrations of up to 25 mM magnesium chloride, while in HCASMC viability and proliferation appeared to be unaffected. Taken together, our data indicate that magnesium halts smooth muscle cell proliferation and stimulates endothelial cell proliferation, which might translate into a beneficial effect in the setting of stent associated vascular injury.

J Biomed Mater Res B Appl Biomater. 2012 Jan;100(1):41-50. Epub 2011 Nov 24.

Allemann R, Langner S, Witt M, Schmidt W, Schmitz KP, Hosten N, Guthoff R, Stachs O. Ultra high-field magnetic resonance imaging of a glaucoma microstent. Curr Eye Res.

doi: 10.3109/02713683.2011.587936

PMID: 21780921

Abstract: Purpose: The aim of the present study was to use 7.1T magnetic resonance imaging (MRI) to determine the correct anatomical position of a non-metallic glaucoma microstent following implantation in rabbit eyes.
Materials and Methods: In an in vitro experiment three microstents (made from silicone, polyurethane, and nickel titanium) were embedded in a standard vial filled with agar. In a second series of experiments a prefabricated polyurethane microstent connecting the anterior chamber with the suprachoroidal space (SCS) was implanted in rabbit eyes (n = 12). High-resolution images were acquired ex vivo (n = 6) and in vivo (n = 6) on an ultra high-field MRI unit using a 2-channel coil with four coil elements and T2-weighted turbo spin-echo sequences. Finally, the eyes were dissected and processed for histology.
Results: Artifact-free MR imaging of silicone and polyurethane microstents was achieved in vitro, with slightly higher contrast for silicone stents. Image quality for the nickel titanium stent was greatly reduced due to artifacts. MRI examination of rabbit eyes ex vivo and in vivo following polyurethane microstent implantation presented no problems in terms of the size and placement of the coil. The sequences showed good image quality; the full length of the microstent was visualized in cross-section and longitudinal section, and correct anatomical placement was demonstrated from the anterior chamber into the SCS. These findings were verified by histology.
Conclusions: The excellent image quality obtained with both of the non-metallic materials generates detailed information about microstent placement, including the surrounding tissues. High-resolution MRI can be used to monitor the anatomical position of a microstent after glaucoma surgery in animal experiments and is therefore a valuable tool for documenting experimental research findings ex vivo and in vivo.

Curr Eye Res. 2011 Aug;36(8):719-26.

Hovakimyan M , Guthoff RF, Knappe S, Zhivov A, Wree A, Krüger A, Heisterkamp A, Stachs O. Short-Term Corneal Response to Cross-Linking in Rabbit Eyes Assessed by In-Vivo Confocal Laser-Scanning Microscopy and Histology, Cornea.

doi: 10.1097/ICO.0b013e3181e16d93

PMID: 20861724

Abstract: Purpose: Corneal cross-linking for the treatment of keratoconus has been tested in animal trials and proven clinically. A combination of in vivo confocal laser scanning microscopy (CLSM) and histology was used in rabbit corneas to assess early modifications at the cellular level after corneal cross-linking.
Methods: Twelve New Zealand male rabbits were tested; in each case, the right eye was the study eye and left eye was the control eye. In vivo CLSM was performed on both eyes before and at 3 days and 1 week after cross-linking. Keratocyte and endothelial cell densities were determined by CLSM before and after cross-linking. After CLSM, the corneas were excised and processed for histology and immunohistochemistry.
Results: Massive edema was observed 3 days after cross-linking. The corneal epithelium had already closed again by day 3. No cellular structures were detected in the stroma and endothelium. One week after cross-linking, normal corneal transparency and thickness were restored. The anterior stroma still lacked nuclei. The number of nuclei in the posterior stroma was significantly lower than that in the intact corneas. Highly reflective spindle-shaped structures were detected in the posterior stroma. The endothelial monolayer had closed again but still showed significantly decreased cell density. At 1 week after cross-linking, immunohistochemical staining revealed the presence of proliferating cells in the corneal epithelium, posterior stroma, and endothelium.
Conclusions: The early response of the rabbit cornea to cross-linking was successfully characterized at the cellular level by in vivo CLSM and histology, and the results obtained with both techniques correlated positively.

Cornea, 2011 Feb;30(2):196-203.

Langner S, Krueger PC, Stachs O, Hosten N. [MR Microscopy of the Human Eye]. Klin Monbl Augenheilkd.

doi: 10.1055/s-0031-1281711

PMID: 22095150

Abstract: Ultra-high-field MR microscopy is a novel, non-invasive imaging technique to explore the strcutures of the human eye without optical distorsions. This review aims to provide an insight into the technique of the method. The normal MR microscopic anatomy of the human eye with correlations to histology is demonstrated. The use of MR microscopy in ther experimental ophthalmological setting is discussed.

Klin Monbl Augenheilkd. 2011 Dec;228(12):1073-8.

Löbler M, Sternberg K, Stachs O, Allemann R, Grabow N, Roock A, Kreiner CF, Streufert D, Neffe AT, Hanh BD, Lendlein A, Schmitz KP, Guthoff RF. Polymers and drugs suitable for the development of a drug ... J Biomed Mater Res B Appl Biomater

doi: 10.1002/jbm.b.31826

PMID: 21432996

Abstract: Implantation of a glaucoma drainage system is an appropriate therapeutic intervention in some glaucoma patients. However, one drawback with this approach is the fibrotic tissue response to the implant material, leading to reduced flow of aqueous liquid or complete blockage of the drainage system. As a basis for developing an aqueous shunt we report here investigations with poly(3-hydroxybutyrate) (P(3HB)) and poly(4-hydroxybutyrate) (P(4HB)) as polymer matrices and with paclitaxel (PTX) and triamcinolone acetonide (TA) as drugs that might, in combination, delay or prevent the process of fibrosis by reducing fibroblast activity. P(3HB) and P(4HB) were fabricated into test prototypes with 500 mu m outer and 200 mu m inner diameter and similar to 1 cm length. The antiproliferative agent PTX and the anti-inflammatory agent TA were incorporated into the polymer matrices and were released by diffusion. In vitro cell assays demonstrated that the polymers have the potential to reduce fibroblast viability, while TA showed differential inhibition of Tenon fibroblasts, but not cornea keratocytes. Implantation of polymer disks and prototype devices into rabbit eyes confirmed the good biocompatibility of the materials. The combined use of a poly(hydroxybutyrate) polymer with PTX or TA has the potential to reduce the fibrosis associated with conventional glaucoma drainage systems.

Journal of Biomedical Materials Research: Part B - Applied Biomaterials. 2011 May;97(2):388-95

Reiß S, Burau G, Stachs O, Guthoff RF, Stolz H. Spatially resolved Brillouin spectroscopy to determine the rheological properties of the eye lens. Biomed Opt Express.

doi: 10.1364/BOE.2.002144

PMID: 21833354

Abstract: Presbyopia is closely associated with the loss of accommodation, and hence with a decline in the viscoelastic properties of the human eye lens. In this article we describe a method for obtaining spatially resolved in vivo measurements of the rheological properties of the eye lens, based on the spectroscopic analysis of spontaneous Brillouin scattering using a virtually imaged phased array (VIPA). The multi-pass configuration enhances resolution to the extent that measurements are possible in elastic biological tissue characterized by intense scattering. We also present spatially resolved measurements obtained in extracted animal eyes and lenses. The results yield entirely new insights into the aging process of the eye lens.

Biomed Opt Express. 2011 Aug 1;2(8):2144-2159. Epub 2011 Jul 5.

Reiß S, Stachs O, Guthoff R, Stolz H. Non-Invasive, Spatially Resolved Determination of Tissue Properties of the Crystalline Lens with regard to Rheology, Refractive Index, Density and Protein Concentration ... Klin Monbl Augenheilkd.

doi: 10.1055/s-0031-1281952

PMID: 22167358

Abstract: The confocal Brillouin spectroscopy is an innovative measurement method that allows the non-invasive determination of the rheological properties of materials. Its application in ophthalmology can offer the possibility to determine in-vivo the deformation properties of sections of transparent biological tissue such as the cornea or eye lens with spatial resolution. This seems to be a promising approach concerning current presbyopia research. Due to the spatially resolved detection of the viscoelastic lens properties, a better understanding of the natural aging process of the lens and the influences of different lens opacities on the stiffness is expected. From the obtained spectral data the relative protein levels, the relative refractive index profile and the relative density profile within the lens tissue can be derived in addition. A measurement set-up for confocal Brillouin microscopy based on spectral analysis of spontaneous Brillouin scattering signals by using a high-resolution dispersive device is presented. First in-vitro test results on animal and human lenses are presented and evaluated concerning their rheological significance. These data are compared with known research results.

Klin Monbl Augenheilkd. 2011 Dec;228(12):1079-1085.

Witte V, Berger E, Guthoff R, Stachs O. Three-dimensional visualization of sclerotomies with ultrasound biomicroscopy: Comparison of 20 and 23 gauge incisions on the porcine eyeball. Ophthalmologe.

doi: 10.1007/s00347-010-2306-5

PMID: 21170651

Abstract: When pars plana vitrectomy is performed, the sizes of the sclerotomy cannula vary between 20 and 23 gauge. We examined the morphology of the scleral tunnels by ultrasound biomicroscopy additionally taking into account the incision angle. In each of 16 enucleated porcine eyes three 20 or 23 gauge sclerotomies with varying angles between 30 and 90A degrees to the horizontal level were performed. The vertical 20 gauge sclerotomies were additionally sealed by 7.0 vicryl cross-stitching. The resulting scleral channels were analysed by 3-D ultrasound biomicroscopy. The sclerotomies were echographically detectable in all cases. Analysis revealed that the sutured straight 20 gauge tunnels were hyporeflective in only some parts while the other incisions showed continuous hyporeflectivity along the complete channel in many cases. The smaller the instruments used and the flatter the scleral angles chosen, the smaller were the measured widths of the incision tunnels. Imaging sclerotomies ex vivo by ultrasound biomicroscopy is reliably reproducible. In the echographic pictures straight 20 gauge incisions appeared to be safely sealed by the sutures while the nonsealed tunnels often showed continuous patency. By choosing small instruments and flat incision angles the width of the resulting scleral channels can be reduced.

Ophthalmologe. 2011 Jul;108(7):658, 660-6457.

Turan RG, Bozdag-T I, Ortak J, Kische S, Akin I, Schneider H, Turan CH, Rehders TC, Rauchhaus M, Kleinfeldt T, Belu C, Brehm M, Yokus S, Steiner S, Sahin K, Nienaber CA, Ince H. Improved functional activity of bone marrow ... Stem Cell Rev.

doi: 10.1007/s12015-010-9220-8

PMID: 21188654

Abstract: There is growing evidence that intracoronary autologous bone marrow cells transplantation (BMCs-Tx) in patients with chronic myocardial infarction beneficially affects postinfarction remodelling. In this randomized controlled study we analyzed the influence of intracoronary autologous freshly isolated bone marrow cells transplantation by use of point of care system on cardiac function and on the functional activity of bone marrow derived circulating progenitor cells (BM-CPCs) in patients with ischemic heart disease (IHD).
56 patients with IHD were randomized to either received freshly isolated BMC-Tx or a control group that did not receive cell therapy. The functional activity of BM-CPCs in peripheral blood (PB) was measured by migration assay and colony forming unit assay pre- and 3, 6 as well as 12 months after procedure. Global ejection fraction (EF) and infarct size area were determined by left ventriculography.
Intracoronary transplantation of autologous freshly isolated BMCs led to a significant reduction of infarct size and an increase of global EF as well as infarct wall movement velocity after 3 and 12 months follow-up compared to control group. The colony-forming capacity of BM-CPCs significantly increased 3, 6 and 12 months after cell therapy compared to pre BMCs-Tx and control group (CFU-E: p < 0.001, CFU-GM: p < 0.001). Likewise, we found significant increase of migratory response to stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) after cell therapy compared to pre BMCs-Tx (SDF-1: p < 0.001, VEGF: p < 0.001) and to control (SDF-1: p < 0.001, VEGF: p < 0.001). There was no significant difference of migratory- and colony forming capacity between pre- and 3, 6, 12 months after coronary angiography in control group without cell therapy.
Intracoronary transplantation of autologous freshly isolated BMCs by use of point of care system may lead to improvement of BM-CPCs functional activity in peripheral blood, which might increase the regenerative potency in patients with IHD.

Stem Cell Rev 2011; 7:646-656

Turan RG, Bozdag-Turan I, Ortak J, Akin I, Kische S, Schneider H, Turan CH, Rehders TC, Rauchhaus M, Kleinfeldt T, Adolph E, Brehm M, Yokus S, Steiner S, Sahin K, Nienaber CA, Ince H. Improved mobilization of the CD34(+) and CD133(+) ... Stem Cells Dev.

doi: 10.1089/scd.2010.0373

PMID: 21190450

Abstract: Cell therapy is a promising novel option for treatment of cardiovascular disease. Because the role of bone marrow-derived circulating progenitor cells (BM-CPCs) after cell therapy is less clear, we analyzed in this randomized, controlled study the influence of intracoronary autologous freshly isolated bone marrow cell transplantation (BMC-Tx) by using a point-of-care system on cardiac function and on the mobilization of BM-CPCs in patients with ischemic heart disease (IHD). Fifty-six patients with IHD were randomized to either receive freshly isolated BMC-Tx or a control group that did not receive cell therapy. Peripheral blood concentrations of CD34/45(+) and CD133/45(+) CPCs were measured by flow cytometry pre-, immediately post-, and at 3, 6, and 12 months postprocedure in both groups. Global ejection fraction and the size of infarct area were determined by left ventriculography. We observed in patients with IHD after intracoronary transplantation of autologous freshly isolated BMCs-Tx at 3 and 12 months follow-up a significant reduction of the size of infarct area and increase of global ejection fraction as well as infarct wall movement velocity. The mobilization of CD34/45(+) and CD133/45(+) BM-CPCs significantly increased at 3, 6, and 12 months after cell therapy when compared with baseline in patients with IHD, although no significant changes were observed between pre- and immediately postintracoronary cell therapy administration. In the control group without cell therapy, there was no significant difference of CD34/45(+) and CD133/45(+) BM-CPCs mobilization between pre- and at 3, 6, and 12 months postcoronary angiography. Intracoronary transplantation of autologous freshly isolated BMCs by using a point-of-care system in patients with IHD may enhance and prolong the mobilization of CD34/45(+) and CD133/45(+) BM-CPCs in peripheral blood and this might increase the regenerative potency in IHD.

Stem Cells Dev 2011; 20:1491-1501.

Turan RG, Bozdag-Turan I, Ortak J, Akin I, Kische S, Schneider H, Rehders TC, Turan CH, Rauchhaus M, Kleinfeldt T, Chatterjee T, Sahin K, Nienaber CA, Ince H. Improvement of cardiac function by intracoronary freshly isolated bone ... Circ J.

doi: 10.1253/circj.CJ-10-0817

PMID: 21266786

Abstract: Background: We analyzed in the present study the influence of intracoronary autologous freshly isolated bone marrow cells transplantation (BMCs-Tx) on cardiac function in patients with acute myocardial infarction (AMI).
Methods and Results: The 32 patients with AMI were enrolled in this prospective nonrandomized study to either freshly isolated BMC-Tx or to a control group without cell therapy. Global left ventricular ejection fraction (LVEF) and the size of infarct area were determined by left ventriculography. We observed in patients with autologous freshly isolated BMCs-Tx at 6 months follow up a significant reduction of infarct size as compared to control group. Moreover, we found a significant increase of LVEF as well as infarct wall movement velocity at 6 months follow up in cell therapy group as compared to control group. In the control group there was no significant difference of LVEF, infarct size and infarct wall movement velocity between baseline and 6 months after AMI.
Conclusions: These results demonstrate for the first time that intracoronary transplantation of autologous freshly isolated BMCs by use of a point of care system is safe, and may lead to improvement of cardiac function in patients with AMI.

Circ J 2011; 75:683-691

Turan RG, Bozdag-T I, Ortak J, Akin I, Kische S, Schneider H, Rehders TC, Turan CH, Rauchhaus M, Rehders TC, Kleinfeldt T, Belu C, Amen S, Hermann T, Yokus S, Brehm M, Steiner S, Chatterjee T, Sahin K, Nienaber CA, Ince H. Enhanced mobilisation of the ...

PMID: 21707914

Abstract: Autologous bone marrow cell transplantation (BMCs-Tx) is a promising novel option for treatment of cardiovascular disease. We analysed in a randomized controlled study the influence of the intracoronary autologous freshly isolated BMCs-Tx on the mobilization of bone marrow-derived circulating progenitor cells (BM-CPCs) in patients with acute myocardial infarction (AMI). Sixty-two patients with AMI were randomized to either freshly isolated BMCs-Tx or to a control group without cell therapy. Peripheral blood (PB) concentrations of CD34/45(+) - and CD133/45(+) -circulating progenitor cells were measured by flow cytometry in 42 AMI patients with cell therapy as well as in 20 AMI patients without cell therapy as a control group on days 1, 3, 5, 7, 8 and 3, 6 as well as 12 months after AMI. Global ejection fraction (EF) and the size of infarct area were determined by left ventriculography. We observed in patients with freshly isolated BMCs-Tx at 3 and 12 months follow up a significant reduction of infarct size and increase of global EF as well as infarct wall movement velocity. The mobilization of CD34/45(+) and CD133/45(+) BM-CPCs significantly increased with a peak on day 7 as compared to baseline after AMI in both groups (CD34/45(+) : P < 0.001, CD133/45(+) : P < 0.001). Moreover, this significant mobilization of BM-CPCs existed 3, 6 and 12 months after cell therapy compared to day 1 after AMI. In control group, there were no significant differences of CD34/45(+) and CD133/45(+) BM-CPCs mobilization between day 1 and 3, 6 and 12 months after AMI. Intracoronary transplantation of autologous freshly isolated BMCs by use of point of care system in patients with AMI may enhance and prolong the mobilization of CD34/45(+) and CD133/45(+) BM-CPCs in PB and this might increase the regenerative potency after AMI.

J Cell Mol Med 2011

Turan RG, Turan CH, Bozdag-Turan I, Ortak J, Akin I, Kische S, Schneider H, Kleinfeldt T, Rehders TC, Rauchhaus M, Adolph E, Amen S, Hermann T, Yokus S, Brehm M, Steiner S, Sahin K, Nienaber CA, Ince H. Impaired Mobilization of CD133 Bone ... Circ J.

doi: 10.1253/circj.CJ-10-1284

PMID: 21828932

Abstract: Background: The influence of the number of diseased coronary arteries on the mobilization of CD133/45(+) bone marrow-derived circulating progenitor cells (BM-CPCs) in peripheral blood (PB) in patients with ischemic heart disease (IHD) was analyzed.
Methods and Results: Mobilization of CD133/45(+) BM-CPCs by flow cytometry was measured in 120 patients with coronary 1 vessel (IHD1, n=40), coronary 2 vessel (IHD2, n=40), and coronary 3 vessel disease (IHD3, n=40), and in a control group (n=40). The mobilization of CD133/45(+), BM-CPCs was significantly reduced in patients with IHD compared to the control group (P<0.001). The mobilization of CD133/45(+), BM-CPCs was impaired in patients with IHD3 compared to IHD1 (P<0.001) and to IHD2 (P<0.001). But there was no significant difference in mobilization of CD133/45(+) BM-CPCs between the patients with IHD2 and IHD1 (P=0.35). Moreover, we found significantly reduced CD133/45(+) cell mobilization in patients with a high SYNTAX-Score (SS) compared to a low SS (P<0.001) and an intermediate SS (P<0.001). In subgroup analyzes, we observed a significantly negative correlation between levels of hemoglobin A(1c) and the mobilization of CD133/45(+) BM-CPCs (P=0.001, r=-0.6).
Conclusions: The mobilization of CD133/45(+) BM-CPCs in PB is impaired in patients with IHD. This impairment might augment with increased number of diseased coronary arteries. Moreover, mobilization of CD133/45(+) BM-CPCs in ischemic tissue is further impaired by diabetes in patients with IHD.

Circ J 2011; 75: 2635-2641

Bozdag-T I, Turan RG, Turan CH, Ludovicy S, Akin I, Kische S, Arsoy NS, Schneider H, Ortak J, Rehders T, Hermann T, Paranskaya L, Kohlschein P, Bastian M, Ulus AT, Sahin K, Ince H, Nienaber CN. Relation between the ... Cardiovascular Diabetology.

doi: 10.1186/1475-2840-10-107

PMID: 22118372

Abstract: Background: Bone marrow-derived circulating progenitor cells (BM-CPCs) in patients with coronary heart disease are impaired with respect to number and mobilization. However, it is unknown whether the mobilization of BM-CPCs depends on the number of diseased coronary arteries. Therefore, in our study, we analysed the correlation between the diseased coronary arteries and the frequency of CD34/45+ BM-CPCs in peripheral blood (PB) in patients with ischemic heart disease (IHD).
Methods: The frequency of CD34/45(+) BM-CPCs was measured by flow cytometry in 120 patients with coronary 1 vessel (IHD1, n = 40), coronary 2 vessel (IHD2, n = 40), coronary 3 vessel disease (IHD3, n = 40) and in a control group of healthy subjects (n = 40). There was no significant difference of the total number of cardiovascular risk factors between IHD groups, beside diabetes mellitus (DM), which was significantly higher in IHD3 group compared to IHD2 and IHD1 groups.
Results: The frequency of CD34/45(+) BM-CPCs was significantly reduced in patients with IHD compared to the control group (CD34/45(+); p < 0.001). The frequency of BM-CPCs was impaired in patients with IHD3 compared to IHD1 (CD34/45(+); p < 0.001) and to IHD2 (CD34/45(+); p = 0.001). But there was no significant difference in frequency of BM-CPCs between the patients with IHD2 and IHD1 (CD34/45(+); p = 0.28). In a subgroup we observed a significant negative correlation between levels of hemoglobin AIc (HbAIc) and the frequency of BM-CPCs (CD34/45(+); p < 0.001, r = -0.8).
Conclusions: The frequency of CD34/45(+) BM-CPCs in PB is impaired in patients with IHD. This impairment may augment with an increased number of diseased coronary arteries. Moreover, the frequency of CD34/45(+) BM-CPCs in ischemic tissue is further impaired by diabetes in patients with IHD.

Cardiovascular Diabetology 2011; 10: 107.

Just T, Zehlicke T, Specht O, Sass W, Punke C, Schmidt W, Lankenau E, Behrend D, Pau HW: Detection of tympanic membrane movement using film patch with integrated strain gauge, assessed by optical coherence tomography: experimental study. J Laryngol Otol.

doi: 10.1017/S0022215110002859

PMID: 21269559

Abstract: Objective: We report an ex vivo and in vivo experimental study of a device designed to measure tympanic membrane movement under normal and pathological conditions, assessed using optical coherence tomography.
Materials and methods: We designed two types of flexible, round film patch with integrated strain gauge, to be attached to the tympanic membrane in order to measure tympanic membrane movement. Tympanic membrane attachment was assessed using optical coherence tomography. The devices were tested experimentally using an ex vivo model with varying middle-ear pressure.
Results: Optical coherence tomography reliably assessed attachment of the film patch to the tympanic membrane, before and after middle-ear pressure changes. Strain gauge voltage changes were directly proportional to middle-ear pressure recordings, for low pressure changes. Tympanic membrane perforations smaller than 2 mm could be sealed off with the film patch.
Conclusion: Attachment of the film patch with integrated strain gauge to the tympanic membrane was not ideal. Nevertheless, the strain gauge was able to precisely detect small pressure changes within the middle ear, in this experimental model.

J Laryngol Otol (2011), 125(5): 467-473.

Pau HW, Warkentin M, Specht O ,Krentz H, Herrmann A, Ehrt K. Experiments on the mechanism of underwater hearing. Acta Oto-Laryngologica.

doi: 10.3109/00016489.2011.607845

PMID: 21888565

Abstract: Conclusion: The findings suggest that underwater sound perception is realized by the middle ear rather than by bone conduction, at least in shallow water conditions.
Objective: To prove whether underwater sound perception is effected by bone conduction or by conduction via the middle ear.
Methods: Five divers, breathing through snorkels, were tested in a swimming pool, to determine whether a sound was louder when the acoustic source placed was in front of the head in comparison with a lateral application facing the ear region. The second experiment investigated whether sound perception is influenced by ear protection plugs in underwater conditions. Also, the effect of a 5 mm thick neoprene hood was determined, with and without an additional perforation in the ear region.
Results: Sounds were louder when applied from a position laterally facing the ear, louder without than with a protection plug, louder without than with a neoprene hood on, and louder when the neoprene hood had a perforation in the region of the ear than with an intact hood.

Acta Oto-Laryngologica vol. 131, p. 1279-1285.

Seidlitz A, Nagel S, Semmling B, Grabow N, Sternberg K und Weitschies W, Biorelevant Dissolution Testing of Drug-Eluting Stents: Experiences with a Modified Flow-Through Cell Setup. Dissolution Technol.

Abstract: In vitro dissolution testing of drug-eluting stents (DES) poses a special challenge in terms of apparatus design due to the very specialized local treatment of the vessel wall in the immediate vicinity of the blood flowing through the vessel and the stent lumen. A vessel-simulating flow-through cell was designed to emulate the placement of a DES in vivo and the flow through the lumen in a simplified in vitro setup, which also allows for the examination of distribution processes. The method is based on the compendial flow-through cell apparatus (USP 4), which was modified by the addition of a hydrogel compartment that represents the vessel wall and the adaptation of the flow rate to the blood flow rate in the coronary vessels. A comparison of the dissolution and release results obtained with the vessel-simulating flow-through cell with standard paddle (USP 2) and flow-through cell (USP 4) apparatus methods shows that release from the coating was decelerated by embedding in the hydrogel in the adapted apparatus. Further experiments with both hydrophilic and hydrophobic fluorescent model compounds coated onto the stents were performed to investigate the effects of different method parameters and variations in the coating composition. While release and distribution of hydrophilic fluorescein sodium were dependent on the flow rate and implantation technique, release kinetics of hydrophobic triamterene were influenced by the coating thickness and the model substance content of the coating. These results illustrate the importance of choosing the correct apparatus design and test parameters adapted to biorelevant conditions for specialized dosage forms such as DES.

Dissolution Technol 2011; 18 (4): 26-34.

Abid OR, Nawaz M, Ibad MF, Rasheed Khera RA, Iaroshenko V, Langer P. Synthesis of functionalized arylpyridines and -pyrimidines by domino [4+2]/retro [4+2] cycloadditions of electron-rich dienes with alkynylpyridines and –pyrimidines, Org. Biomol. Chem.

doi: 10.1039/c0ob00755b

PMID: 21298164

Abstract: Aryl-substituted pyridines and pyrimidines were prepared by [4+2] cycloadditions of alkynyl-substituted pyridines and -pyrimidines with electron-rich dienes. The reactions proceed by formation of a bridged cycloadduct and subsequent thermal extrusion of ethylene. The pyridine moiety plays a crucial role for the success of the reaction.

Org. Biomol. Chem., 2011, 9, 2185–2191.

Iaroshenko VO, Ostrovskyi D, Petrosyan A, Mkrtchyan S, Villinger A, Langer P. Synthesis of Fluorinated Purine and 1-Deazapurine Glycosides as Potential Inhibitors of Adenosine Deaminase, J. Org. Chem.

doi: 10.1021/jo102579g

PMID: 21395333

Abstract: The synthesis of 2- and 6-trifluoromethylated purines and 1-deazapurines was performed by formal [3 + 3]-cyclization reactions of 5-aminoimidazoles with a set of trifluoromethyl-substituted 1,3-CCC- and 1,3-CNC-dielectrophiles. The corresponding fluorinated nucleosides were synthesized by glycosylation of 9-unsubstituted purines and 1-deazapurines with peracetylated beta-ribose, beta-glucose, and rhamnose and subsequent deprotection. These scaffolds can be considered as potential inhibitors of adenosine deaminase (ADA) and inosine monophosphate dehydrogenase (IMPDH) enzymes.

J. Org. Chem., 2011, 76, 2899–2903

Ostrovskyi D, Iaroshenko VO, Ali I, Mkrtchyan S, Villinger A, Tolmachev A, Langer P. 3-Methoxalylchromone – A Versatile Reagent for the Regioselective Synthesis of 1-Desazapurine, Synthesis.

doi: 10.1055/s-0030-1258339

Abstract: The reaction of 5-amino-1H-imidazoles with 3-methoxalylchromone provided a set of imidazo[4,5-b]pyridines (1-desazapurines) bearing the CO(2)Me substituent at the alpha-position of the pyridine core. The corresponding acids were synthesized by subsequent hydrolysis of the ester function. Being typical purine isosteres, 1-desazapurines are considered to be potent pharmacophores, and are widely used in drug design and medicinal chemistry.

Synthesis, 2011, 133–141.

Knepper I, Iaroshenko VO, Vilches-Herrera M, Domke L, Mkrtchyan S, Zahid M, Villinger A, Langer P. 3-Acylindoles as versatile starting materials for pyridine ring annulation: synthesis of 1-deazapurine isosteres, Tetrahedron.

doi: 10.1016/j.tet.2011.05.037

Abstract: The reaction of electron-rich aminoheterocycles with 3-acyl- and 3-formylindoles results in indole ring opening and cyclocondensation to give heteroannulated pyridines, which can be regarded as purine isosteres. The transformations reported herein represent rare examples of domino reactions, which include the cleavage of an indole moiety.

Tetrahedron, 2011, 67, 5293–5303.

Iaroshenko VO, Specowius V, Vlach K, Vilches-Herrera M, Ostrovskyi D, Mkrtchyan S, Villinger A, Langer P. A general strategy for the synthesis of difluoromethyl-containing pyrazoles, pyridines and pyrimidines, Tetrahedron.

doi: 10.1016/j.tet.2011.05.085

Abstract: Difluoromethyl-containing heteroannulated pyridines, pyrimidines and pyrazoles are prepared by a two step method. The regioselective cyclizations of electron-excessive aminoheterocycles, hydrazines and amidines with CF(2)Cl-substituted 1,3-dicarbonyl compounds provide the corresponding CF(2)Cl-substituted heterocycles. Subsequent radical reactions with trimethylstannane or allyltrimethylstannane gave difluoromethyl-containing heteroannulated pyridines, pyrimidines and pyrazoles, respectively.

Tetrahedron, 2011, 67, 5663–5677.

Iaroshenko VO, Abbasi M, Villinger A, Langer P. Synthesis of 6H-benzo[c]chromen-6-ones by cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-formylcoumarin, Tetrahedron Lett.

doi: 10.1016/j.tetlet.2011.07.140

Abstract: 6H-benzo[c]chromen-6-ones were prepared by base mediated cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-formylcoumarin.

Tetrahedron Lett., 2011, 52, 5910–5912.

Iaroshenko VO, Maalik A, Ostrovskyi D, Villinger A, Spannenberg A, Langer P. Efficient synthesis of purines by inverse electron-demand Diels-Alder reactions of 1-substituted-1H-imidazol-5-amines with 1,3,5-triazines, Tetrahedron, 2011, 67, 8321–8330.

doi: 10.1016/j.tet.2011.08.082

Abstract: The reaction of 1,3,5-triazine and 2,4,6-tri(trifluoromethyl)-1,3,5-triazine with in situ generated 1-substituted 5-amino-1H-imidazoles led to a set of functionalized purines. The developed practical route could serve as a fundament for the preparation of related ADA inhibitors.

Tetrahedron, 2011, 67, 8321–8330.

Iaroshenko VO, Ali S, Babar TM, Dudkin S, Mkrtchyan S, Rama NH, Villinger A, Langer P. 4-Chloro-3-(trifluoroacetyl)coumarin as a novel building block for the synthesis of 7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-ones, Tetrahedron Lett.

doi: 10.1016/j.tetlet.2010.11.028

Abstract: 4-Chloro-3-(trifluoroacetyl)coumarin was synthesized for the first time via direct TMSCl-mediated acylation of 4-hydroxycoumarin with TFAA followed by the treatment with POCl(3). The reaction of 4-chloro-3-(trifluoroacetyl)coumarin with commercially available anilines is a two-step method, which affords a set of 7-(trifluoromethyl)-6H-chromeno[4,3-b]quinolin-6-ones in good to excellent yields.

Tetrahedron Lett., 2011, 52, 373–376.

Löbler M, Rehmer A, Guthoff R, Martin H, Sternberg K, Stachs O. Suitability and calibration of a rebound tonometer to measure IOP in rabbit and pig eyes. Vet Ophthalmol.

doi: 10.1111/j.1463-5224.2010.00794.x

PMID: 21199282

Abstract: OBJECTIV: To utilize the Icare tonometer TAO1 for intraocular pressure (IOP) determination in experimental animals. To calculate true IOP calibration functions for rabbit and porcine eyes.
ANIMALS: Enucleated eyes of 3-year-old healthy experimental rabbits (New Zealand white), and healthy 1 year old experimental pigs (Deutsche Landrasse) were used for the determination of IOP.
PROCEDURES: Manometric (Geuder GmbH, Heidelberg/Germany) and rebound tonometry (Icare tonometer TAO1, Icare, Helsinki/Finland) were used to record IOP in enucleated animal eyes (rabbit n = 2, pig n = 3).
RESULTS: The Icare tonometer TAO1 measurements underestimated true IOP by 37–60% in rabbit eyes and 17–63% in porcine eyes. IOP values obtained by both rebound and manometric tonometry for rabbit and porcine eyes followed a linear regression curve. Linear functions were calculated to correct the Icare tonometer TAO1 measurements to true IOP for both rabbit (p = 1.4244p ic + 4.2421) and porcine eyes (p = 1.0799p ic + 5.8557).
CONCLUSIONS: The Icare tonometer TAO1 can be utilized for IOP determination in rabbit and porcine eyes when measured values are corrected with the appropriate linear function.

Vet Ophthalmol.2011;14(1):66-8.

Rohm HW, Lurtz C, Wegmann J, Odermatt EK, Behrend D, Schmitz KP, Sternberg K. Development of a biodegradable tissue adhesive based on Functionalized 1,2-ethylene glycol bis(dilactic acid). II. J Biomed Mater Res B Appl Biomater.

doi: 10.1002/jbm.b.31787

PMID: 21290575

Abstract: In body regions where damage and bleeding must be avoided, a substitute for mechanical tissue fixation by sutures or staplers is needed. Since tissue adhesives provide easy and fast handling they are a promising alternative. The present study reports the development and analysis of a tissue adhesive that consists of two adhesive components: hexamethylene diisocyanate (HDI) functionalized 1,2-ethylene glycol bis(dilactic acid) (ELA-NCO) and chitosan chloride. This composition was chosen based on preliminary studies on several chain elongation agents. The present study evaluates this adhesive system by IR-spectroscopy, tensile tests, and gel point measurements in comparison to fibrin glue. The system's in vitro biocompatibility was tested with mouse fibroblasts (L929) according to ISO 10993-5. Furthermore, an implantation study was performed in SPF-Wistar rats. The adhesive strength of manually applied mixtures or mixtures applied by double chamber syringes with a mixing extruder was determined to be significantly higher than that of fibrin glue on bovine muscle tissue at 37°C. Tensile strength increased further when exposure time of the adhesive was increased from 10 min to 48 h. The rheological gel point determination showed that the mixture of ELA-NCO/DMSO and chitosan chloride offers a time window large enough to readjust the fused joint during surgery, as opposed to fibrin glue. Additionally, the in vitro and in vivo biocompatibility studies of the adhesive system revealed no toxic effects on the surrounding tissue.

J.Cataract Refract.Surg. 2011 Apr;97(1):66-73.

Seidlitz A, Nagel S, Semmling B, Grabow N, Martin H, Senz V, Harder C, Sternberg K, Schmitz KP, Kroemer HK und Weitschies W. Examination of drug release and distribution from drug-eluting stents with a vessel-simulating flow-through cell.

doi: 10.1016/j.ejpb.2010.12.021

PMID: 21182943

Abstract: The recently introduced vessel-simulating flow-through cell offers new possibilities to examine the release from drug-eluting stents in vitro. In comparison with standard dissolution methods, the additional compartment allows for the examination of distribution processes and creates dissolution conditions which simulate the physiological situation at the site of implantation. It was shown previously that these conditions have a distinct influence on the release rate from the stent coating. In this work, different preparation techniques were developed to examine the spatial distribution within the compartment simulating the vessel wall. These methods allowed for the examination of diffusion depth and the distribution resulting in the innermost layer of the compartment simulating the vessel wall. Furthermore, the in vitro release and distribution examined experimentally were modelled mathematically using finite element (FE) methods to gain further insight into the release and distribution behaviour. The FE modelling employing the experimentally determined diffusion coefficients yielded a good general description of the experimental data. The results of the modelling also provided important indications that inhomogeneous coating layer thicknesses around the strut may result from the coating process which influence release and distribution behaviour. Taken together, the vessel-simulating flow-through cell in combination with FE modelling represents a unique method to analyse drug release and distribution from drug-eluting stents in vitro with particular opportunities regarding the examination of spatial distributions within the vessel-simulating compartment.

Eur J Pharm Biopharm. 2011;78(1):36-48.

Stachs O, Langner S, Terwee T, Sternberg K, Martin H, Schmitz KP, Hosten N, Guthoff RF. In vivo 7.1 T magnetic resonance imaging to assess the lens geometry in rabbit eyes 3 years after lens refilling surgery. J.Cataract Refract.Surg.

doi: 10.1016/j.jcrs.2010.10.057

PMID: 21420601

Abstract: PURPOSE: To evaluate the utility of high-resolution magnetic resonance imaging (MRI) in assessing the normal and refilled lens geometry in rabbits after lens-refilling surgery.
SETTING: University of Rostock, Rostock, Germany.
DESIGN: Experimental study.
METHODS: High-resolution ocular MRIs were acquired (7.1 T ClinScan) using a 2-channel coil with 4 coil elements and T2-weighted turbo spin-echo sequences (slice thickness 700 μm, field of view 40 mm × 40 mm) in rabbits after lens refilling surgery combined with intraoperative treatment to prevent lens epithelial cell proliferation. Single slices were used to assess the refilled lenses 3 years postoperatively. RESULTS: The entire geometry (cross-sectional area, radius of curvature, axial and equatorial diameters) of the crystalline and refilled lenses was visualized by in vivo 7.1T MRI 3 years postoperatively (in-plane resolution: 125 μm × 125 μm). In refilled eyes, the capsule and the homogenous silicone polymer remained in close contact with no visible interface. The dimensions of the refilled lens were significantly smaller than those of the crystalline lens of the contralateral eye.
CONCLUSIONS: High-resolution MRI allows in vivo visualization and analysis of the spatial arrangement of the lens in rabbit eyes after lens refilling surgery and overcomes a number of major limitations in the quantitative evaluation of the lens shape. Further efforts are required to optimize the amount of polymer injected during lens refilling to achieve a predictable refractive outcome after lens refilling surgery.
FINANCIAL DISCLOSURE: Drs. Stachs, Langner, Sternberg, Martin, Schmitz, Hosten and Guthoff have no financial or proprietary interest in any material or method mentioned. Additional financial disclosure is found in the footnotes.

J.Cataract Refract.Surg. 2011-Apr;37(4):749-5

Quosdorf D, Brede M, Leder A, Lootz D, Martin H, Schmitz KP. Using Micro-Particle-Image-Velocimetry for Measuring Velocities in a Coronary Vessel Treated by a Stent. TM-TECHNISCHES MESSEN.

doi: 10.1524/teme.2011.0134

Abstract: This article describes a Micro-Particle-Image-Velocimetry measuring setup (Micro-PIV), which allows to measure the three-dimensional flow field inside a transparent 1: 1 model of an original coronary stent. The treatment of the coronary heart disease is of utmost importance due to its high prevalence. Often coronary stents are implanted which lead to adverse effects originating from the altered blood flow through the vessel treated.

 TM-TECHNISCHES MESSEN. 78(5):239-245.

Behrend D, Warkentin M, Specht O, Schmidt W, Rosentritt M, Ottl P. Materialography Examinations on Dental Materials. Prakt. Metallogr.

Abstract: There is a continuously increasing need, due to demographic development, for materials and biomaterials which are suited for the maintenance of teeth and even for dental prostheses. Attention is mainly focused here on materials which present appropriate physicochemical, mechanical, and biological characteristics and, therefore, significantly improve the quality and longevity in the fields of minimal invasive prophylaxis, filling therapy, dental prosthetic surgery, and implantology. It is only via a combination of various microscopic examination methods that it becomes possible to investigate and characterize a structure-property correlation in detail. Hence, it permits to achieve optimum functionality parameters of such materials in order to obtain dental materials with optimum properties.  

Prakt. Metallogr. 48(1):8-15.

Ausgewählte Originalarbeiten 2010

Haamann D, Keul H, Klee D, Möller M. Functionalization of Linear and Star-Shaped Polyglycidols with Vinyl Sulfonate Groups and Their Reaction with Different Amines and Alcohols. Macromolecules.

doi: 10.1021/ma100901q

Abstract: Linear and star-shaped polyglycidols were prepared using ethoxy ethyl glycidyl ether (EEGE) as monomer and 3-phenyl-1-propanol and dipentaerythritol as initiator, respectively. These polymers were treated with 2-chloroethylsulfonyl chloride to form reactive vinyl sulfonate end groups. The high reactivity of the vinyl sulfonate end groups toward amines, alcohols, and amino acids was investigated. All polymers were characterized by nuclear magnetic resonance and size exclusion chromatography.

Macromolecules. 2010;43(15):6295-6301.

Langner S, Martin H, Terwee T, Koopmans SA, Krüger PC, Hosten N, Schmitz KP, Guthoff RF, Stachs O. 7.1 T MRI to assess the anterior segment of the eye. Invest Ophthalmol Vis Sci.

doi: 10.1167/iovs.09-4865

PMID: 20688731

Abstract: PURPOSE: Visualization of the anterior segment and biometric evaluation of the entire crystalline lens pose significant challenges for imaging techniques because of tissue-induced distortion artifacts. The present study was conducted to demonstrate the advantages of high-resolution magnetic resonance imaging (micro-MRI) for visualizing the anterior segment.
METHODS: High-resolution MR ocular images were acquired on an ultra-high-field MR unit using a two-channel coil with four coil elements and T(2)-weighted turbo spin echo sequences ex vivo in pig, rabbit, monkey, and human donor eyes and in vivo in rabbits. Tissue heating, reproducibility, and signal-to-noise ratio were investigated in vivo. Monkey eye lens thickness (LT) was also measured using A-scan ultrasonography (US).
RESULTS: Anterior segment details of phakic eyes were obtained ex vivo (pig, rabbit, monkey, and human donor eyes) with pixel matrix size 512 × 512 (in-plane resolution 80 × 80 μm) and in vivo (rabbit eyes) with pixel matrix size 320 × 320 (in-plane resolution 125 × 125 μm). Complete quantification of lens dimensions as they correlate with the sulcus-sulcus and angle-angle plane can be performed. In LT determinations in monkey eyes, no significant difference was detected between micro-MRI and A-scan US (P > 0.05, Mann-Whitney U test). Biometric analysis of one pseudophakic monkey eye confirmed the absence of relevant distortion artifacts.
CONCLUSIONS: Micro-MRI allows ex vivo and in vivo visualization and quantification of the spatial arrangement of the anterior eye segment. Imaging of the retroiridian region, including the entire crystalline lens, overcomes a number of major limitations in the quantitative evaluation of the anterior segment.

Invest Ophthalmol Vis Sci. 2010;51:6575-81.

Sternberg K, Rohm HW, Lurtz C, Wegmann J, Odermatt EK, Behrend D, Michalik D, Schmitz KP. Development of a biodegradable tissue adhesive based on Functionalized 1,2-ethylene glycol bis(dilactic acid). I. J Biomed Mater Res B Appl Biomater.

doi: 10.1002/jbm.b.31654

PMID: 20552615

Abstract: Tissue adhesives are a valuable alternative for mechanical tissue fixation by sutures or staples. Adhesives are desirable in body regions where damage and bleeding must be avoided. Tissue adhesives provide easy and fast handling. This study reports the development of a tissue adhesive based on 1,2-ethylene glycol bis(dilactic acid) (ELA) functionalized with hexamethylene diisocyanate (HDI) to produce isocyanate terminated ELA-NCO which was characterized by NMR and FTIR spectroscopy. ELA-NCO together with chain elongation agents forms an adhesive system suitable for tissue fixation. Several biodegradable polymers, such as hyaluronic acid, gelatin, chitosan acetate, and chitosan chloride were tested as chain elongation agents to obtain an adhesive system and studied on bovine muscle tissue to evaluate their adhesive strength and compared to fibrin glue. Tensile strength of glued joints was determined by a Zwick universal testing machine at ambient temperature. Mixtures of ELA-NCO and chitosan acetate or chloride, showed significantly higher adhesive strength than fibrin glue. Reaction between ELA-NCO and chitosan chloride produced polyurethane was traced by FTIR spectroscopy. NMR, FTIR, and rheological measurements demonstrated that ELA-NCO and chitosan chloride can be sterilized by gamma-rays or superheated water vapor without alterations, respectively. A mixture of ELA-NCO and chitosan chloride can be useful as medical tissue adhesive.

J Biomed Mater Res B Appl Biomater. 2010 Aug;94(2): 318-26.

Sternberg K, Terwee T, Stachs O, Guthoff R, Löbler M, Schmitz KP. Drug-induced secondary cataract prevention: experimental ex vivo and in vivo results with disulfiram, methotrexate and actinomycin D. Ophthalmic Res.

doi: 10.1159/000316696

PMID: 20699626

Abstract: BACKGROUND/AIMS: A clinical approach to prevent secondary cataract after lens implantation involves the intraocular application of pharmacological agents. The goals of our study were to develop an ex vivo model to test the drug effectiveness for lens epithelial cell ablation from the basal membrane and to verify the data in rabbit intraocular lens implantation experiments.
METHODS: Human capsular rhexis specimens were incubated with drugs and the residual cells were differentiated by use of the Live-Dead assay and quantified by staining with Hoechst dye. After phakoemulsification of rabbit eyes and before intraocular lens implantation, capsular bags were filled with drug-loaded hyaluronic acid for 5 min.
RESULTS: An ex vivo model was established which allows the testing of drugs on lens epithelial cell ablation. Drug treatment reduced the number of viable cells on the specimens drastically, ranging between 0.44 ± 0.53% (6.0 ± 7.3 cells/mm²) for disulfiram, 0.27 ± 0.50% (3.7 ± 6.9 cells/mm²) for methotrexate and 0.07 ± 0.19% (0.1 ± 0.27 cells/mm²) for actinomycin D. Rabbit eyes treated with a mixture of methotrexate/actinomycin D showed no posterior capsule opacification at 4 months and a low opacification 6 months postoperatively. Without drug treatment low opacification starts 6 weeks postoperatively.
CONCLUSIONS: The drug screening in the described ex vivo model can help to reduce the number of preclinical studies for secondary cataract prevention. The successful ex vivo cell ablation by methotrexate/actinomycin D was confirmed by a delayed in vivo secondary cataract formation.

Ophthalmic Res. 2010;44(4):225-36.

Navaneetha Pandiyaraj K, Selvarajan V, Heeg J, Junge F, Lampka A, Barfels T, Wienecke M, Young Ha Rhee, Hyoung Woo Kim. Influence of bias voltage on diamond like carbon (DLC) film deposited on poly-ethylene terephthalate (PET) film surfaces using PECVD ..

doi: 10.1016/j.diamond.2010.03.016

Abstract: In this paper, diamond like carbon (DLC) films were coated on polyethylene terephthalate (PET) film substrate as a function of biasing voltage using plasma enhanced chemical vapour deposition. The surface morphology of the DLC films was analyzed by scanning electron microscopy and atomic force microscopy. The chemical state and structure of the films were analyzed by X-ray photoelectrons spectroscopy and Raman spectroscopy. The micro hardness of the DLC films was also studied. The surface energy of interfacial tension between the DLC and blood protein was investigated using contact angle measurements. In addition, the blood compatibility of the films was examined by in vitro tests. For a higher fraction of sp3 content, maximum hardness and surface smoothness of the DLC films were obtained at an optimized biasing potential of − 300 V. The in vitro results showed that the blood compatibility of the DLC coated PET film surfaces got enhanced significantly.

Diamond and Related Materials. 19 (2010):1085-1092.

 

Guthoff RF, Stachs O. Microsystem technology in medicine - intelligent implants in ophthalmology. Klin Monbl Augenheilkd.

doi: 10.1055/s-0029-1245944

PMID: 21157660

Klin Monbl Augenheilkd. 2010;227:925.

Grabow N, Martin DP, Schmitz KP, and Sternberg K. Absorbable polymer stent technologies for vascular regeneration. J Chem Technol Biotechnol.

doi: 10.1002/jctb.2282

Abstract: Stents are structural implants with widespread clinical use in vascular intervention to re-open stenotic vessels for the treatment of coronary artery disease and peripheral arterial occlusive disease. Apart from their mechanical function, current drug-eluting stents (DES) utilize local drug delivery from a drug-incorporated permanent polymer coating to prevent in-stent restenosis. This delayed closure of the stented vessel is considered one of the major limitations of conventional bare metal stents (BMS). The long-term safety of DES, however, is still under debate, with reported cases of delayed healing, late thrombosis and hypersensitivity demanding further evolution in this field. A promising approach to circumvent the limitations of first generation DES is the application of degradable polymer coatings in second generation DES, and fully absorbable polymer stents. From a materials and engineering perspective, this paper provides a mini-review of current clinically relevant DES technology and recent advancements in the development of stents from degradable polymeric materials as an alternative to permanent BMS and DES. This review, includes work on degradable stents and coatings based on blends of polylactic acid and the microbially-produced poly(4-hydroxybutyrate).  

J Chem Technol Biotechnol.2010;85(6):744-51.

Nagel JA, Beck C, Harms H, Stiller P, Guth H, Stachs O, Bretthauer G. Energy and memory efficient calculation of the accommodation demand in the artificial accommodation system. Klin Monbl Augenheilkd.

doi: 10.1055/s-0029-1245929

PMID: 21157661

Abstract: Presbyopia and cataract are gaining more and more importance in the ageing society. Both age-related complaints are accompanied with a loss of the eye's ability to accommodate. A new approach to restore accommodation is the Artificial Accommodation System, an autonomous micro system, which will be implanted into the capsular bag instead of a rigid intraocular lens. The Artificial Accommodation System will, depending on the actual demand for accommodation, autonomously adapt the refractive power of its integrated optical element. One possibility to measure the demand for accommodation non-intrusively is to analyse eye movements. We present an efficient algorithm, based on the CORDIC technique, to calculate the demand for accommodation from magnetic field sensor data. It can be shown that specialised algorithms significantly shorten calculation time without violating precision requirements. Additionally, a communication strategy for the wireless exchange of sensor data between the implants of the left and right eye is introduced. The strategy allows for a one-sided calculation of the demand for accommodation, resulting in an overall reduction of calculation time by 50%. The presented methods enable autonomous microsystems, such as the Artificial Accommodation System, to save significant amounts of energy, leading to extended autonomous run-times.

Klin Monbl Augenheilkd. 2010;227:930-4.

Bretthauer G, Gengenbach U, Stachs O, Guthoff R. A new mechatronic system to restore the accommodation ability of the human eye. Klin Monbl Augenheilkd.

doi: 10.1055/s-0029-1245888

PMID: 21157662

Abstract: In this paper a new approach for restoring human accommodation is presented. It is an artificial accommodation system based on the latest results of microtechnology, electronics and automatic control. The concept of the overall system is described and the results obtained for the different subsystems are discussed.

Klin Monbl Augenheilkd. 2010;227:935-9.

Schmidt W, Schultze C, Stachs O, Allemann R, Löbler M, Sternberg K, Hinze U, Chichkov BN, Guthoff R, Schmitz KP. Concept of a pressure-controlled microstent for glaucoma therapy. Klin Monbl Augenheilkd.

doi: 10.1055/s-0029-1245928

PMID: 21157664

Abstract: A pressure-controlled microstent could permanently normalise the intraocular pressure (IOP) for open-angle glaucoma therapy by drainage into the suprachoroidal space. The complex requirements demand new technical solutions as well as an improved understanding of specific cell biological processes at the implant's surface to develop effective local drug delivery (LDD) concepts and surface modifications. Fluid mechanical requirements were derived from physiological data and the analysis of commercial glaucoma implants. The technological basics for the production of suitable structures are refined ultra-short pulse laser technology and 2-photon polymerisation (2PP). All known glaucoma implants induce unwanted cell proliferation resulting in a loss of function. It is assumed that the activity of fibroblasts is low in the suprachoroidal space. However, it was seen that LDD concepts are required to control cell proliferation. Fibroblasts from sclera and choroidea were isolated und cultured as the most relevant cell types for in vitro investigation. Potential materials and drugs were investigated by cell viability tests for biocompatibility or suppression of cell viability. The fluid mechanical analysis leads to smallest stent lumina (ID = 50 mu m) at anatomically suitable implant lengths (7 - 10 mm). Only pressure control can manage the individual conditions with changing IOP. Finite element analysis of valves showed the need for highly flexible structures. This can be achieved by combining basic structures with micromechanically active valves added by 2PP. The potential materials show perfect in vitro and in vivo biocompatibility. Ormocers which are best suited for 2PP are also highly biocompatible. The selected drugs paclitaxel and triamcinolon acetonide open a wide therapeutic window to impair fibroblast growth. The surgical procedure was established by implantation of prototypes in rabbit eyes, connecting the anterior chamber with the suprachoroidal space. Highly flexible implants are required for correct placement within the eye. The new concept of the microstent combines biomechanical approaches, technologies for microfabrication and current LDD concepts and opens new perspectives for glaucoma therapy.

Klin Monbl Augenheilkd. 2010;227:946-52.

Mkrtchyan S, Iaroshenko VO, Dudkin S, Gevorgyan A, Vilches-Herrera M, Ghazaryan G, Volochnyuk DM, Ostrovskyi D, Ahmed Z, Villinger A, Sosnovskikh V Y, Langer P, 3-Methoxalylchromone - a novel versatile reagent for the regioselective purine isostere ...

doi: 10.1039/c0ob00379d

PMID: 20938501

Abstract: The first synthesis of 3-methoxalylchromone was described. The reaction of the latter with electron-rich aminohetero-cycles afforded a set of heteroannelated pyridines bearing a CO(2)Me substituent located at the alpha-position of the pyridine core.

Org Biomol Chem. 2010;8:5280-5286.

 

Pau HW, Herrmann A, Mühlberg S, Schmidt W, Behrend D. Entwicklung einer Kryo-Schlifftechnik für Felsenbeinpräparate: Neue Möglichkeit zur Beurteilung ex-vivo implantierter CI-Test-Elektroden, Biomed Tech.

doi: 10.1515/BMT.2010.028

PMID: 20569052

Abstract: BACKGROUND: Prior to clinical application, newly developed prototypes of cochlear implant electrode arrays must prove their suitability with the smallest possible tissue damage in ex vivo temporal bones. So far, after insertion of the electrodes the temporal bone specimens have to be processed in a rather intricate technique, including embedding, sectioning or grinding prior to histological evaluation. The question remains whether for special indications this time-consuming method, which even causes artifacts, can be replaced by a new technique based on cryo-grinding.
Materials and methods: The main principle of the method described is to grind the temporal bone with the inserted electrode in a frozen state, provided by a fixation device filled with dry ice. After creating a plane surface and staining it (still in a frozen state), the specimen can be examined and photographed with a projection microscope. This procedure is continued by subsequently grinding and examining new surfaces in defined distances.
Results: In numerous trial runs the method proved feasible, saving much time and manpower. After grinding, each plane could be examined sufficiently; the site of the electrodes and the corresponding tissue damage could be documented properly.
Discussion: The new concept of cryo-grinding provides relatively easy and fast examinations of temporal bones after inserting test electrodes. The examiner is enabled to correlate his "sensations" during the insertion (e. g., smoothness, resistances) almost directly with the morphologic findings, without having to wait a long time while the temporal bone specimens are being processed conventionally. Furthermore, this method avoids artifacts due to soft tissue shrinking during drying. In further steps of development, the grinding device will be optimized for standard use.

Biomed Tech. 2010 Aug;55(4):237-43.

Ausgewählte Tagungsbeiträge 2013

Reiß S, Hovakimyan M, Stolz H, Guthoff RF, Stachs O. Nicht-invasive Bestimmung der rheologischen Eigenschaften der Hornhaut des Auges. 111. DOG Kongress

111. DOG Kongress; 19.9.-22.9.2013; Berlin.

Reiß S, Stachs O, Guthoff RF, Stolz H. Advances in Brillouin microscopy of the Cornea. 9th International Congress of Corneal Cross-Linking; 6.12.-7.12.2013; Dublin.

6.12.-7.12.2013; Dublin.

Kragl U, Stein F, Petersen S, Kaule S, Sternberg K. On the hunt: ionic liquids for biomedical coatings. Proceedings of COIL, Marina de Vilamoura, 2013.

Proceedings of COIL, Marina de Vilamoura, 2013.

Bandomir J, Stein F, Petersen S, Sternberg K, Kragl U. Cetylpyridinium salicylate for coating of implants: synthesis, characterization and application. Proceedings of COIL

Proceedings of COIL, Marina de Vilamoura, 2013.

Strohbach A, Lang S, Busch MC, Felix SB, Busch R. Hemodynamic shear stress regulates the apelin/APJ - system in human endothelial cells. European Heart Journal.

doi: 10.1093/eurheartj/eht307.P586

European Heart Journal. 2013; 34 (1):111.

Strohbach A, Dressler R, Lang S, Felix SB, Busch R. The Apelin-13/APJ-System Influences Monocyte Adhesion on Human Umbilical Venous Endothelial Cells. Clin Res Cardiol.

Clin Res Cardiol. 2013;102 (1).

Heeg J, Schütz A, Lampka A, Freymann B, Brauns H and Wienecke M. Porous a-C:H and a-SiC:H coatings by modified PECVD for medical application. International Porous and Powder Materials Symposium and Exhibition, Cesme, 2013

International Porous and Powder Materials Symposium and Exhibition, Cesme, 2013

Barfels T, Heeg J, Lampka A, Leprich M. Studies on growing of nano-diamond particles by RF-PECVD on different surfaces for biomedical applications. International Conference on Diamond and Carbon Materials

International Conference on Diamond and Carbon Materials, Riva del Garda, 2013

Heeg J, Mewes Ch, Schütz A, Barfels T, Wienecke M, Podbielski A, Arndt K, Rebl H, Nebe B. Nano Composite DLC Coating for Antimicrobial Medical Applications. E-MRS Spring Meeting

E-MRS Spring Meeting, Strasbourg, May 2013

M. Vehse, H. Seitz: Kompakte Mikro-Stereolithographieanlage auf Basis eines Diodenlasers. Workshop 3D Druck: Verfahren und Anwendungen

Workshop 3D Druck: Verfahren und Anwendungen, Darmstadt, 13.11.2013 (invited)

M. Vehse, J. Hennig, H. Seitz: Mikro-Stereolithographie als Fertigungsverfahren für die Mikrofluidik. Workshop „Kleine Volumenströme in der Medizintechnik“

Workshop „Kleine Volumenströme in der Medizintechnik“, Lübeck, 05.06.2013

Petersen S, Schmitz K-P, Sternberg K. Design, Surface Modification and Processing of Biodegradable Polymeric Drug Delivery Systems and their implications for drug delivery. Polym. Adv. Technol.

Polym. Adv. Technol. 2013; 24: 156.

Semmling B, Nagel S, Seidlitz A, Brand T, Sternberg K, Weitschies W. Development of long-term stable gels for drug-eluting stent testing in the vFTC. Clinical Pharmacology 2013

Clinical Pharmacology, a Bridge for Basic Sciences to Clinical Applications, Greifswald, 12. – 13. September 2013.

Seidlitz A. Biorelevant in Vitro Performance Testing of Drug-Eluting Stents. Annual Meeting of the American Association of Pharmaceutical Scientists 2013

Annual Meeting of the American Association of Pharmaceutical Scientists 2013, San Antonio, 10. – 14. November 2013.

Stahnke T, Löbler M, Wree A, Stachs O, Schmitz KP, Guthoff RF. Characterization of human ocular fibroblast-subpopulations to prevent fibrosis following fistulating glaucoma surgeries. ARVO Annual Meeting. 2013

ARVO Annual Meeting. 2013 May 5-9. Vortrag. Program number: 2139

Stahnke T, Löbler M, Wree A, Stachs O, Schmitz KP, Guthoff RF. Evaluation of TGF-beta induced fibrotic response in different ocular fibroblast-subpopulations. 111. Kongress der Deutschen Ophthalmologischen Gesellschaft (DOG).

111. Kongress der Deutschen Ophthalmologischen Gesellschaft (DOG). 2013 Sep. 19-22. Posterbeitrag (PDo05-06, Der Ophthalmologe, Supplement 1, 2013).

Quosdorf D, Brede M, Stiehm M, Wolter A, Sakowski J, Leder A. Measuring Phase averaged Wall shear stress distributions in a Coronary stent, Exposed to pulsatile flow, using Micro-PIV. 8th World Conference on Experimental Heat Transfer...

8th World Conference on Experimental Heat Transfer, Fluid Mechanics, and Thermodynamics, Veranstaltung vom 16.-20.6. 2013, Lisbon, Portugal

Reiß S. Der Ursache der Alterssichtigkeit auf der Spur. Universität Rostock, Akademisches Jahrbuch 2011/2012.

Reiß S. Der Ursache der Alterssichtigkeit auf der Spur. Universität Rostock, Akademisches Jahrbuch 2011/2012. 79, 2013.

Reiß S, Stolz H, Stachs O, Guthoff R. Brillouin-Spektroskopie in der Augenheilkunde. DOG Spitzenforschung in der Ophthalmologie

DOG Spitzenforschung in der Ophthalmologie. ISSN 1841-4620, 188-192, 2013.

Reiß S. Advances in Brillouin microscopy of the Cornea. Crosslinking Congress, Dublin

Crosslinking Congress, Dublin, Dec. 2013

Langner S. Infection and Inflammation of the Orbit. 26th Annual Meeting of the European Society of Head and Neck Radiology.

26th Annual Meeting of the European Society of Head and Neck Radiology. 3.- 5. October 2013

Leppin K. Pathophysiological analysis of cellular and nerval responses of the cornea in diabetes mellitus. 17. Chirurgische Forschungstage 2013

17. Chirurgische Forschungstage 2013

Loch C, Bogdahn M, Stein S, Nagel S, Weitschies W und Seidlitz A: New In-vitro Model for the Investigation of Drug Distribution in the Vitreous Body. Clinical Pharmacology, a Bridge for Basic Sciences to Clinical Applications, Greifswald

Clinical Pharmacology, a Bridge for Basic Sciences to Clinical Applications, Greifswald, 12. – 13. September 2013.

Probst M, Scheuch E, Kühn JP, Seidlitz A, Oswald S und Weitschies W: Investigating the distribution behavior of intramuscular applied dosage forms in rats using MRI and LC-MS/MS. Clinical Pharmacology, a Bridge for Basic Sciences to Clinical Applications

Clinical Pharmacology, a Bridge for Basic Sciences to Clinical Applications, Greifswald, 12. – 13. September 2013.

Loch C, Bogdahn M, Stein S, Nagel S, Weitschies W und Seidlitz A: Eye Movement System and Vitreous Model: In-vitro Investigation of Distribution Processes in the Vitreous Body. Annual Meeting of the American Association of Pharmaceutical Scientists 2013

Annual Meeting of the American Association of Pharmaceutical Scientists 2013, San Antonio, 10. – 14. November 2013.

Probst M, Kühn JP, Hadlich S, Kindermann K, Scheuch E, Oswald S, Siegmund W, Seidlitz A, Weitschies W: Arzneimitteltransportwege nach intramuskulärer Injektion am Tiermodell. Greifswalder Kleintier-MRT Symposium

Greifswalder Kleintier-MRT Symposium 27. November 2013.

Seidlitz A. Biorelevant in vitro release testing of dosage forms for intravascular and intravitreal delivery. DPhG Jahrestagung 2013

DPhG Jahrestagung 2013, Freiburg, 09. – 11. Oktober 2013, p. 94.

Seidlitz A. Biorelevant in Vitro Performance Testing of Drug-Eluting Stents. Annual Meeting of the American Association of Pharmaceutical Scientists 2013, San Antonio

Annual Meeting of the American Association of Pharmaceutical Scientists 2013, San Antonio, 10. – 14. November 2013.

Wentzlaff M, Seidlitz A, Senz V, Grabow N, Harder C, Sternberg K, Weitschies W: Large scale coating of cardiovascular Stents. German-Russian forum on nanotechnology, Tomsk

German-Russian forum on nanotechnology, Tomsk, 22. – 23. Mai 2013.

Wentzlaff M, Seidlitz A, Senz V, Grabow N, Sternberg K und Weitschies W: Large scale coating of stents via fluidized-bed technology. Clinical Pharmacology, a Bridge for Basic Sciences to Clinical Applications, Greifswald

Clinical Pharmacology, a Bridge for Basic Sciences to Clinical Applications, Greifswald, 12. – 13. September 2013.

Ausgewählte Tagungsbeiträge 2012

B. Semmling, A. Seidlitz, S. Nagel, N. Grabow, K. Sternberg, W. Weitschies: Biorelevant dissolution testing of coronary stents: Development of modified alginate matrices for the vessel-simulating flow-through cell test setup. DPhG Doktorandentagung 2012

DPhG Doktorandentagung, Weimar, 14. – 17. November 2012

Loch C, Nagel S, Guthoff R, Seidlitz A und Weitschies W: An in vitro test system to examine release in the vitreous humor; DPhG Jahrestagung 2012

DPhG Jahrestagung 2012, Greifswald 11. – 13. Oktober

Semmling B, Seidlitz A, Trip E, Reske T, Sternberg K und Weitschies W: Examination of steroid release from screw-in pacing leads, BMT Jena 2012

doi: 10.1515/bmt-2012-4138

PMID: 23096332

Abstract: Although constant progress in pacing lead design and life time of pacemaker battery has contributed to the clinical success of this treatment option, the mechanism of drug release from steroid-eluting pacing leads is not completely understood. Besides, drug concentrations of steroids released into the heart-tissue remain unclear. Therefore, three different dissolution test methods were examined: a non-standardized (reagent tube), a compendial USP (paddle) and a hydrogel method. The experimental results indicate that dissolution from pacing leads is governed by a diffusion-controlled mechanism and occurs over a prolonged time. Furthermore, the integration of a hydrogel compartment seemed to have an impact on drug release leading to a decrease in release rate. Nevertheless, the experimental results emphasize different experimental parameters in dissolution testing may have a distinct influence on drug dissolution.

BMT Jena, 16. – 19. September 2012

Loch C., Zakelj, S., Kristl, A., Nagel, S., Guthoff, R., Weitschies, W., Seidlitz, A., Permeability studies of ophthalmic drugs for different ophthalmic tissues in interspecies comparison: 8th World Meeting on Pharmaceutics etc., Istanbul 2012

8th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Istanbul, 19. – 22.März 2012

Paasche G, Ullrich F, Salcher R, Eckardt F, Lenarz T. Die Heidschnucke als Modell für die humane Eustachische Röhre – ein Dimensionsvergleich. HNO-Abstractband

HNO-Abstractband 2012, S. 194

Stachs, O. Towards MR Histology in vivo – a case study of a Malignant Melanoma of Choriodea, SIDUO 2012

SIDUO 2012, Sao Paulo, Brasilien

Stachs O, HF ultrasound and high field MRI for anterior segment imaging, SIDUO 2012

SIDUO 2012, Sao Paulo, Brasilien, invited

Stahnke T, Löbler M, Wree A, Stachs O, Schmitz K-P, Guthoff RF. Die TGF-ß Signalkaskade okulärer Fibroblasten als Ansatzpunkt zur Unterdrückung postoperativer Fibrose in der Glaukom-Therapie. DOG Kongress in Berlin

DOG Kongress in Berlin, 20.09.- 23.09.2012, Posterbeitrag, (PD 002-010)

I. Minrath, S. Petersen, K.-P. Schmitz, K. Sternberg. Untersuchung der Wirkstoffpermeabilität von Hydrogelen für die Entwicklung eines Stimulus-induzierten Local Drug Delivery Systems. Jahrestagung der Deutschen Gesellschaft für Biomaterialien

Jahrestagung der Deutschen Gesellschaft für Biomaterialien, Hamburg 1-3. November 2012

S. Petersen, T. Reske, N. Grabow, K.-P. Schmitz, K. Sternberg. Novel designs of vascular implant-associated local drug delivery systems. 22nd Annual BioInterface Conference, Dublin 23-25.Oktober 2012

22nd Annual BioInterface Conference, Dublin 23-25.Oktober 2012

Semmling B, Nagel S, Seidlitz A, Schütt R, Brand T, Grabow N, Sternberg K, Weitschies W. Development of long-term stable hydrogel matrices for a vessel-simulating flow-through cell. Jahrestagung der Deutschen Pharmazeutischen Gesellschaft

Jahrestagung der Deutschen Pharmazeutischen Gesellschaft, Greifswald 11.-13. Oktober 2012

S. Petersen, G. Kurtbay, M. Boeck, H. K. Kroemer, K.-P. Schmitz, H. Meyer zu Schwabedissen, K.Sternberg. Tailored design of implant surfaces by modification with elastin-like proteins. BMT, Jena 2012

S. Petersen, G. Kurtbay, M. Boeck, H. K. Kroemer, K.-P. Schmitz, H. Meyer zu Schwabedissen, K.Sternberg. Tailored design of implant surfaces by modification with elastin-like proteins. BMT, Jena 16.–19. September 2012

G. Kurtbay, M. Boeck, S. Beyer, T. Schweder, E. Hammer, F. Schmidt, K. Sternberg, U. Bornscheuer, H.K. Kroemer, S. Petersen, H. Meyer zu Schwabedissen. Engineering of modified elastin-like proteins to enhance ... 78. Jahrestg. der DGPT

78. Jahrestagung der Deutschen Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie e. V. (DGPT), Dresden 19.-22. März 2012

Semmling B, Nagel S, Seidlitz A, Grabow N, Sternberg K, Weitschies W. In vitro dissolution testing for drug-eluting stents: Development of long-term stable hydrogel matrices for a vessel-simulating flow-through cell. 8th World Meeting on Pharmaceutics

8th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Istanbul 19.-22. März 2012

Seitz H, Vehse M. „Selektive Wirkstoffbeladung von Implantat-Oberflächen mittels Einzeltropfenerzeuger“ Workshop „Kleine Volumenströme in der Medizintechnik“, Lübeck

Workshop „Kleine Volumenströme in der Medizintechnik“, Lübeck, 13.06.2012

W. Kowalski, M. Dammer, F. Backzewitz, O. Keßler, In-situ XRD stress analysis during expansion of stents, 9th Int. Conf. on Residual Stresses

9th Int. Conf. on Residual Stresses, 6.-9.10.2012, Garmisch-Partenkirchen, Germany

M. Frotscher, M. Dammer, F. Bakczewitz, O. Keßler, Charakterisierung von Gefügeveränderungen beim Processing von Stents aus NiTi-Formgedächtnislegierungen, in: Fortschritte in der Metallographie

In: Fortschritte in der Metallographie (Ed. O. Keßler, M. Rettenmayr), Sonderbände der Praktischen Metallographie, Band 44, DGM Inventum, Frankfurt, 2012, 143-148

Strohbach A, Begunk R, Meyer zu Schwabedissen HE, Felix SB, Busch R. The antiproliferative effect of Atorvastatin is dependent on stent surface material. European Heart Journal

European Heart Journal 33; Suppl 1, 2012

Strohbach A, Begunk R, Meyer zu Schwabedissen HE, Walz SA, Busch M, Felix SB, Busch R. The antiproliferative effect of Atorvastatin is dependent on stent surface material. Clin Res Cardiol

Clin Res Cardiol 101, Suppl 1, April 2012

Storm T, Teske M, Löbler M, Wulf K, Schmitz KP, Sternberg K. Influence of cell source and adhesion substrate on growth factor responsiveness in primary endothelial cells. Biomed Tech

doi: 10.1515/bmt-2012-4369

PMID: 22945093

Abstract: In vitro testing is an important step in the development of new implant materials. With regard to applicability of results obtained in vitro to later preclinical and clinical tests, primary cell culture is best suited to yield meaningful results in terms of biocompatibility of newly developed biomaterials. However, unlike cell lines primary cells cannot be propagated to infinity, a fact that necessitates a fairly frequent change of cell source. We are using primary human umbilical vein endothelial cells (HUVECs) to test surface-functionalized polymers for their cell stimulatory potential. In addition to polymers, polystyrol and glass are parallel-tested as reference substrates. Cell viability and proliferation tests were done consecutively in the same microtiter plate. Here we present data on the variability of stimulation of HUVECs from six different donors with vascular endothelial growth factor (VEGF) which was in various ways coupled to a polymer surface. In 24 individual measurements of cell proliferation, the extent of stimulation through VEGF ranged from 0.71 to 3.5-fold. When comparing different reference substrates, same-origin cells could be stimulated from 1.52 to 1.65-fold or 0.71 to 3.11-fold, respectively. On the functionalized polymer itself, cell viability and proliferation could be stimulated up to 0.76 and 2.07-fold, respectively. The degree of variability in growth factor responsiveness is remarkable. This finding implies that for in vitro testing on primary cells in general, and for biomaterial testing in particular, a representative number of both cell batches and reference materials should always be included.

Biomed Tech (Berl). 2012 Aug 31

Storm T, Löbler M, Teske M, Wulf K, Sternberg K, Schmitz KP. Influence of cell source and adhesion substrate on growth factor responsiveness in primary endothelial cells. 4. International Symposium Interface Biology of Implants

P-109, 4th International Symposium Interface Biology of Implants, 9-11 May 2012, Warnemünde

Sperlich K., Reiß S., Stolz H. Comprehensive study on Virtually Imaged Phased Arrays - experiment, theory and optical simulation. Posterpräsentation: DPG Frühjahrstagung der Sektion AMOP; 2012

Posterpräsentation: DPG Frühjahrstagung der Sektion AMOP; 2012 March 12-16; Stuttgart.

Reiß S., Stachs O., Hovakimyan M., Guthoff R., Stolz H. Ex vivo measurement of postmortem tissue changes in the crystalline lens by brillouin spectroscopy and confocal reflectance microscopy. Oral presentation at: ARVO 2012

The Accommodation Club; 2012 May 06-09; Fort Lauderdale, FL, USA.

Zettl, S., Stachs, O., Terwee, T., Reiß, S., Guthoff, R. Mini-Monovision in der Kataraktchirurgie als Option zur Brillenunabhängigkeit im Alltag. 110. DOG Kongress; 2012

Posterpräsentation: 110. DOG Kongress; 20.9.-23.9.2012; Berlin.

Dittrich, B.; Koch, B.; Kooten, T. v.; Kastner, C.; Guthoff, R.; Sternberg, K.; Möller, M. Drug delivery system for sustained delivery of caffeic acid phenethyl ester within lens capsule after cataract surgery. Biomed. Tech.

doi: 10.1515/bmt-2012-4474

PMID: 22962149

Biomed. Tech. (Berl). 2012 Sep 6;57(Suppl. 1)

Ullrich F, Salcher R, Scheper V, Rau T, Lenarz T, Paasche G (2012) Morphometric Study of the Eustachian Tube in Sheep as a Model for Eustachian Tube Disorders in Human. ARO

ARO (2012)

S. Kischkel, N. Grabow, M. Kabelitz, B. Erdle, W. Schareck, B. Vollmar, D.P. Martin, S.F. Williams, K. Sternberg, K.P. Schmitz, E. Klar, and C.M. Bünger, Biocompatibility of biodegradable polymeric stents in an interventional porcine ... Biomed Tech

PMID: 22944932

Abstract: -

Biomed Tech. 2012 57(S1), 913

Gieseke M, Kirbach S, Hustedt M, Kaierle S, Wesling V, Haferkamp H, Additive Fertigung komplexer Mikroimplantate. Mikroproduktion 01/12; 2012

Mikroproduktion 01/12; S. 26-31, 2012

Ausgewählte Tagungsbeiträge 2011

Busch R, Strohbach A, Walz S, Rethfeldt S, Felix SB, Sternberg K. Interaktion von humanen Endothelzellen, glatten Muskelzellen und Thrombozyten mit neuen Stent-Polymeroberflächen. DGK-Jahrestagung 2011.

DGK-Jahrestagung 2011.

Storm T, Wulf K, Löbler M., Theiler S, Keul H, Schmitz K-P, Sternberg K: Influence of surface-bound ligands on cellular adhesion at the implant-endothelial interface. Biomed. Tech. 2011; 56 (S1).

doi: 10.1515/BMT.2011.292

Abstract: Introduction: In current clinical practice, endothelialisation of vascular implants, particularly of drug-eluting stents and bioartificial vessel prostheses, is unsatisfactory. VEGF (vascular endothelial growth factor) is an endothelial-specific growth factor. Using it as a model ligand, we are aiming to attract endothelial cells to the strut surface and thus enhance reendothelialisation of vascular implants.
Methods: The surface of a moderately degradable, star-shaped, acrylate functional poly(ε-caprolactone) was activated either through wet chemical processes or through oxygen plasma, and the resulting modified polymers were tested for their biocompatibility. Using primary cell culture, endothelial cells were grown on polymer surfaces and subjected to both viability and proliferation assays. These assays were also used to validate the stimulation of endothelial cells with VEGF. In addition, shear stress was applied to primary endothelial cells in a perfusion chamber and the cell response was monitored through live microscopy.
Results: In stationary tests, VEGF was successfully used to stimulate endothelial cells over a wide range of concentrations. Adequate medium composition is of key importance in such stimulation experiments. There is a distinct influence of stimulation time on the magnitude of the cell response. In perfusion experiments, morphological changes of endothelial cells in response to shear stress were observed.
Conclusion: Endothelial cells can be reliably stimulated by VEGF. Modified surfaces have the potential for aiding endothelial adhesion, viability and proliferation. The perfusion chamber setup can be used to simulate laminar flow on primary endothelial cells and assess the impact of physiological shear forces and therefore enables testing of new polymer surfaces in a setting that more closely resembles the situation in vivo than static cell culture.

Biomed. Tech. 2011; 56 (S1).

Junge F, Ward L, Lampka A, Dobbertin M , Mewes C and Wienecke M, Deposition and Characterization of Ultra Flexible DLC Coatings on 316L Stainless Steel for medical Implants, EMRS-Spring Meeting 2011, Nice, France

Abstract: Although DLC has proven its outstanding tribological properties in many technical applications, contradicting results are reported on DLC coated load bearing implants. Increased wear and coating delamination and corrosion are reported e.g. for joint implants. To overcome these problems in the present work, we deposit ultra flexible DLC coatings with unusual high sp2 contents which lead to decreased Youngs modulus along with high hardness and wear resistance. Medical grade 316L stainless steel is widely used in artificial hip joint systems. Thus in our work 316L was coated with hydrogenated amorphous diamond-like carbon coatings (a-C:H) by PECVD.
The effects of varied gas pressures and bias voltages on the film properties were examined. Hardness and modulus of elasticity measurements were performed using a MTS nanoindenter xp. Wear and friction tests were conducted using a 6 mm diameter ruby ball in contact with the coated steel surface using a CSEM Tribometer (pin-on-disc). All coated samples were scratch tested with a diamond tip and a constant applied load of 0.5 N. After testing, the scratch channels were analyzed using optical microscopy. The chemical state of the DLC coatings was measured using X-ray Photoelectron Spectroscopy Analyses. Low gas pressures and bias-voltages, during the deposition of DLC on 316L led to extremely flexible and wear resistant coatings. An increase of the wear resistance by a factor of ~ 550, compared with uncoated 316L, was observed. The coatings revealed hardness between 19 and 27 GPa and Youngs modulus between 153 and 233 GPa. An extreme deformability was found, neither spallings nor cracks were observed. This behaviour agreed with the high sp2 contents (~ 80 at.%) and the low modulus of elasticity.

EMRS-Spring Meeting 2011, Nice, France

Junge F, Lampka A, Mewes C, Schütz A, Wienecke M, Investigation on the corrosion behaviour of DLC coated Magnesium-alloys for biomedical application, EMRS-Spring Meeting 2011, Nice, France

Abstract: Magnesium alloys for medical applications like temporary implants are very promising because of their self-dissolving properties in corrosive body fluid. A crucial factor for the successful application in internal medicine and orthopedics is the defined adjustment of the corrosion behavior over long periods. The corrosion resistance of magnesium alloys can be influenced by the addition of alloying elements or by surface modifications. In this work corrosion properties of DLC films deposited on magnesium alloy AZ31 were investigated. Hydrogenated amorphous diamond-like carbon coatings (a-C:H) with and without SiOx interlayer, as well as SiOx doped DLC coatings (a-C:H:SiOx) were deposited on AZ31, using plasma enhanced chemical vapor deposition (PECVD). All coated samples were scratch tested with a diamond tip and a constant applied load of 0.5 N. After testing, the scratch channels were analyzed using optical microscopy and images recorded at a magnification of 500 times. Hardness and wear measurements were performed using a MTS nanoindenter xp. Corrosion performance of DLC coatings was investigated by electrochemical techniques (potentiodynamic polarization test) using current density-potential-curves. The electrolyte used in this test was a 3.5 % NaCl solution at temperature 37.5 °C. The deposition of DLC on AZ31 has been found to increase corrosions resistance. The corrosion behavior of SiOx doped DLC coatings seem to be depending on the deposition power and the silicon content. An optimum was found with an silicon content of 25 at.% for coatings deposited with 125 W and 11.6 at.% for 100 W during the deposition. The incorporation of a SiOx interlayer as well as the doping of the coating with SiOx led to a clear increase of the DLC adhesion on AZ31.

EMRS-Spring Meeting 2011, Nice, France

Fiedler S, Irsig R, Oniszczuk A W, Tiggesbäumker J, Meiwes-Broer K-H. Material processing and surface structuring with femtosecond laser pulses. Correlated Effects in Radiation Fields 2011

Correlated Effects in Radiation Fields 2011

Begunk R, Hußner J, Riefenstahl A, Sternberg K, Petersen S, Koeck K, Bien S, Schmitz KP, Kroemer HK, Meyer zu Schwabedissen HE. Influence of statins on Human Coronary Artery Smooth Muscle ... Deutsche Gesellschaft für Pharmakologie Tagung, Frankfurt 201

Abstract: Vigorous proliferation of Human Coronary Artery Smooth Muscle Cells (HCASMC) and therefore formation of neointima is one of the reasons for failure of stents implanted in coronary arteries. To prevent the formation of this neointimal hyperplasia drugs are required which selectively inhibit HCASMC proliferation without effecting Human Coronary Artery Endothelial Cell (HCAEC) viability and proliferation. Based on previous clinical findings suggesting improved outcome after DES implantation of patients treated with statins, we investigated the effects of Atorvastatin and Mevastatin on HCASMC and HCAEC proliferation and viability. Our data show that in vitro statin treatment does not exert effects on viability of both cell types, while significant differences were seen on HCASMC and HCAEC proliferation. In detail, we found significantly higher anti-proliferative statin effects on HCASMC proliferation compared to that on HCAEC. This is in accordance with our findings showing significantly higher expression levels of HMG-CoA-Reductase, the well-known statin-drug target, in HCASMCs. Supplementation of mevalonic acid abolished the effect of statins on HCASMC proliferation, this provides further evidence for the on-target effects of statins in this cell type. In conclusion, our findings suggest that statins play a more far-reaching role in the treatment of atherosclerosis despite their lipid-lowering efficacy and are able to prevent HCASMC proliferation after stent implantation.

Deutsche Gesellschaft für Pharmakologie Tagung, Frankfurt 2011

Semmling B, Seidlitz A, Nagel S, Grabow N, Sternberg K, Weitschies W. In vitro dissolution testing of drug-eluting stents: Development of modified calcium alginate matrices for a vessel simulating flow-through cell apparatus. Biomed. Tech. 2011; 56 (S1).

doi: 10.1515/BMT.2011.365

Abstract: Introduction: Coronary artery disease is one of the major causes of mortality in the industrialized nations. The implantation of intravascular stents, in particular drug-eluting stents (DES), has become the preferred treatment for stenosed arteries. In this context, in vitro dissolution test methods elucidating drug release and distribution in the arterial wall are still needed.
Methods: A vessel-simulating flow-through cell (FTC) is filled with 4 different matrices: calcium alginate hydrogel, calcium alginate/L-α-Phosphatidylcholine/LiChroprep® RP-18 hydrogel, as well as two hydrogels based on the fat emulsion Lipofundin® MCT 10% and 20%. Fluorescent diuretic triamterene was selected as a model substance. The dissolution experiments were discontinued at predetermined time intervals to determine the amount of drug released into the respective matrix and into the dissolution medium, as well as the residual DES drug content.
Results: Release profiles obtained in the vessel-simulating FTC with the modified matrices described above indicate a fast increase in detected drug amount in all dissolution media (80% after 16 h) with a simultaneous fast decrease in residual drug amount in the DES coatings (16% after 16 h). After 16 hours 4% of the total drug amount was detected in the hydrogel matrices.
Conclusion:The developed matrices for the vessel-simulating FTC enable the determination of delivered drug not only in dissolution media representing the blood, but also in hydrogel matrices simulating the vessel wall as target organ structure. Additionally, incorporation of triamterene into the matrix appears to have no important influence on the distribution process of released drug (f2≤50%).

Biomed. Tech. 2011; 56 (S1).

Petersen S, Wulf K, Schmitz K.-P., Sternberg K., Strategies for the oriented immobilization of antibodies – Novel approach to polymeric implant surfaces with improved endothelialisation. Biomed. Tech. 2011; 56 (S 1).

doi: 10.1515/BMT.2011.257

Abstract: Introduction: Biofunctionalization of implant surfaces with antibodies, capturing endothelial progenitor cells, is promising to enhance in situ endothelialization as one of the major deficiencies in for instance current stent technology. However, the required cell-specificity of the implant surface is not only defined by the chosen biological marker but also by the functionalization strategy particularly with regard to prevention of unspecific adsorption and maintenance of functionality of antibodies during the immobilization process. Hence, strategies for the oriented immobilization of antibodies to proteinrepellent spacer are evaluated in terms of biomolecule loading and functionality in comparison to random immobilization.
Methods: Recombinant anti-CD 34 antibodies and poly(L-lactide) (PLLA) were chosen as model biomolecule and model implant material, respectively. Surface activation of PLLA for the creation of terminal amino groups for further functionalization was established by a plasmachemical treatment with ammonia or by chemical modification with hexamethylenediamine. After covalent binding of the protein-repellent spacer (GGAP)4 biofunctionalization was either performed via carbodiimide/N-hydroxy succinimide crosslinking or covalent binding of site-selectively periodateoxidized anti-bodies. The antibody loading was determined via a direct ELISA and its bioactivity in terms of recognition of the recombinant CD 34 protein by a Sandwich-ELISA.
Results: For both surface activation processes the same tendency of antibody loading was observed, being the highest via covalent binding of periodateoxidized antibodies. Moreover, while random immobilization yielded antigen recognition below 25 pg/mm2, referring to less than 25% of possible recognition defined by the total amount of immobilized antibodies, the site selective immobilization of antibodies allowed to maintain the biofunctionality of almost 100 % of immobilized antibodies.
Conclusion: Maintenance of antibody functionality during the immobilization process can be notedly enhanced by their siteselective immobilization. Hence, the application of site selective antibody immobilization is a promising approach for the biofunctionalization of polymeric implant surfaces for improvement of endothelialization.

Biomed. Tech. 2011; 56 (S 1).

Osipov V, Pavelyev V, Kachalov D, and Chichkov B, Fabrication of radial DOEs with quantized relief by two-photon polymerization technique, in CLEO/Europe and EQEC 2011 Conference Digest, OSA Technical Digest (CD) (Optical Society of America, 2011).

Abstract: Application of two-photon polymerization technique for the fabrication of quantized submicron-size relief of radial diffractive optical elements (DOE's) is studied. Computer modelling and fabrication of 4-level DOE's for the formation of desired intensity distribution is realized.

CLEO/Europe and EQEC 2011 Conference Digest, OSA Technical Digest (CD) (Optical Society of America, 2011).

Pavelyev V, Osipov V, Chichkov B, Laser 2PP-based technique for fabrication of radial DOEs with 2- and 4-level microrelief, Proceedings of Asia-Pacific Conference on Fundamental Problems of Opto- and Microelectronics, July 4 - July 8, 2011.

Proceedings of Asia-Pacific Conference on Fundamental Problems of Opto- and Microelectronics, July 4 - July 8, 2011

Stahnke T, Allemann R, Stachs O, Wree A, Löbler M, Schmitz K-P, Völker U, Guthoff R. Okuläre Fibroblasten, therapeutisches Ziel zur Vermeidung postoperativer Fibrose in der Glaukom-Therapie. DOG Kongress in Berlin, 29.09.- 02.10.2011.

Abstract: Fragestellung: Das Glaukom fasst verschiedene Augenerkrankungen zusammen und ist eine der häufigsten Erblindungsursachen weltweit. Diese Erkrankungen sind durch einen erhöhten Augeninnendruck (IOP) gekennzeichnet, was zu Neurodegeneration führt. Eine mögliche Behandlungsmethode ist die Implantation von ventilgesteuerten Mikrostents, die den IOP regulieren und das Vorderkammerwasser in den Tenon'schen Raum drainieren sollen. Die Problematik dieser Methode liegt in fibrotischen Prozessen, deren gezielte Unterbindung von wesentlicher Bedeutung für die Langzeitwirksamkeit derartiger Implantate und das Ziel dieser Studie ist.
Material: Um die Fibrose näher zu charakterisieren, wurden verschiedene humane okuläre Fibroblasten-Subpopulationen (Sklera (hSF), Choroidea (hCF), Tenonkapsel (hTF)) kultiviert. Diese Zellen wurden mittels qRT-PCR einer Expressionsanalyse unterzogen und biochemisch mit diskontinuierlicher 1-D SDS-PAGE mit anschließendem Westernblot analysiert, um Unterschiede innerhalb der einzelnen Fibroblasten-Subpopulationen auch auf Proteinebene aufzuzeigen. Zur Charakterisierung von posttranslationalen Modifikationen (z. B. Phosphorylierungen und Glycosylierungen) sind durch 2-D SDS-PAGE Proteom-Analysen durchgeführt worden.
Ergebnisse: Es konnten Unterschiede der mRNA-Menge spezifischer Gene zwischen den Fibroblasten-Subpopulationen detektiert werden. Diese Unterschiede beinhalten auch mRNAs, die für Komponenten der extrazellulären Matrix (Kollagen I, III, VI und ADAM19) sowie der Zellproliferation (RGS5, MGP5, Komponenten des TGF-b-Signalweges) kodieren und konnten innerhalb der einzelnen Fibroblasten-Subpopulationen auch auf Proteinebene gezeigt werden.
Schlussfolgerung: Die Ergebnisse dieser Studie eröffnen die Möglichkeit, die durch Fibroblasten vermittelten fibrotischen Prozesse zu unterdrücken. Der Einsatz von spezifischen Inhibitoren könnte somit einen dauerhaften Abfluss des Kammerwassers gewährleisten und erneute operative Eingriffe überflüssig machen.

DOG Kongress in Berlin, 29.09.- 02.10.2011.

Allemann R, Stachs O, Vollmar B, Guthoff R. Tierexperimentelle Untersuchungen zu den Drainageeigenschaften eines Mikrostents mittels fluoreszenzmarkierter Latexbeads. DOG Kongress in Berlin, 29.09.- 02.10.2011.

Abstract: Fragestellung: Ein druckgesteuerter Mikrostent sollte dauerhaft den Intraokulardruck bei einem Offenwinkelglaukom regulieren können. Ziel ist es, bekannte Nachteile alloplastischer Implantate, insbesondere die postoperative Hypotonie und Fibrosierung im Ausstromgebiet zu beseitigen. In der vorliegenden Arbeit wird eine Methodik vorgestellt, einen Flüssigkeitsstrom von der Vorderkammer im Stentlumen nachzuweisen.
Methodik: In Kaninchen wurde ein druckgesteuerter Mikrostent(Ventilmechanismus) implantiert, wobei die Vorderkammer mit dem Suprachoroidalraum unter Anlegen eines limbusbasierten skleralen Lappens verbunden wird. Zur Einbringung der Latexbeads wurden zwei Anterior Chamber Maintainer(in,out) angebracht. Zunächst wurden fluoreszenzierende Latexbeads (Durchmesser 1 µm, Konzentration 1000 Partikel/mm3) über einen Zugang (in) iniziert. Danach wurde der zweite Zugang (out) verschlossen und der Intraokulardruck kontrolliert bis 40mmHg erhöht. Anschliessend wurde ex vivo die Stentregion mittels Kryoschnellschnitt histologisch untersucht. Es erfolgten Untersuchungen mittels Optischer Kohärenztomographie und 7,1 Tesla Magnetresonanz Tomographie.
Ergebnis: Die anatomisch korrekte Implantation des Mikrostents konnte komplikationslos durchgeführt werden. Die Messungen mittels Fluoreszenzmikroskopie zeigte eine optimale Partikelkonzentration welche zur störungsfreien Darstellung von Flussströmen benötigt wird. Es konnte ein aktiver Partikelstrom bei der Druckerhöhung nachgewiesen werden. Histologisch konnten extraluminal im suprachoroidalen Raum und intraluminal im Einstrombereich Partikel nachgewiesen werden.
Schlussfolgerung: Diese Arbeit zeigt, dass die in vivo Fluoreszenzmikroskopie geeignet ist, flussdynamisches Verhalten von Partikeln im Auge darzustellen. Am Beispiel eines druckgesteuerten Mikrostents konnte gezeigt werden, dass ein gerichteter Fluss des Kammerwassers bei Druckerhöhung in den Suprachoroidalraum stattgefunden hat. Diese Arbeit legt die Grundlage für weitere Experimente, insbesondere eignet sie sich zur Darstellung von Flussbewegungen bei mikrochirurgischen alloplastischen Implantaten im Auge.

DOG Kongress in Berlin, 29.09.- 02.10.2011.

Schultze, C., N. Grabow, W. Schmidt, H. Ince, K. Sternberg, and K.P. Schmitz, Coronary bioabsorbable polymeric stents. Biomed. Tech.

doi: 10.1515/BMT.2011.442

Abstract: Introduction: Restenosis and thrombosis represent major limitations of bare-metal and drug-eluting stents, respectively. In this context, development of a bioabsorbable stent is a promising approach to overcome these limitations. In this study, coronary bioabsorbable polymeric stents were investigated in vitro, and in vivo.
Methods: Stents (nominal dimensions: 3.0x10 mm) of a poly(L-lactide)-based (PLLA) polymer blend were manufactured with a CO2-laser [1]. All stents were expanded within 1 min to a nominal balloon diameter of 3.0 mm in a 37 °C water bath. Pressure-diameter charts were recorded to assess stent expansion behavior and elastic recoil. Subsequently, the stents were placed in thin-walled polymer tubes, and installed in a pressure chamber filled with 37 °C water. An increasing outer pressure (pressure steps of Δp = 0.01 bar) was applied to the stents. Selected stents were mounted on a balloon catheter to assess trackability and dislodgement force. A pilot in vivo study was conducted by coronary implantation in the pig.
Results: All stents show a uniform expansion behavior, and were properly expandable to the nominal diameter. The elastic recoil of the stents amounts to 3.9 ± 0.2 %. Collapse pressure was 0.49 ± 0.06 bar. A moderate trackability and dislodgement force could be assessed. Implantation of the stent system in porcine coronaries was feasible with a 6F guiding catheter. After 4 weeks, complete vascular apposition and integration of the polymer stents was confirmed in transverse sections.
Conclusion: Feasibility of a coronary bioabsorbable polymeric stent system was demonstrated in vitro and in vivo. Favorable vascular response to the bioabsorbable polymeric stent was shown after 4 weeks in porcine coronaries.

Biomed. Tech. 2011; 56 (S 1)

Schultze, C., N. Grabow, H. Rohm, K. Sternberg, and K.P. Schmitz, The influence of sterilization on the deformation behavior of coronary bioabsorbable polymeric stents. Biomed. Tech.

doi: 10.1515/BMT.2011.594

Abstract: Introduction: Development of bioabsorbable polymeric stents for the application in coronary artery disease, which is currently a lead-ing cause of death worldwide, requires the understanding of stent behavioral changes during and after sterilization. In this study the influence of the sterilization on the molecular weight and the mechanical properties were investigated.
Methods: Stents (inner/outer diameter: 1.4/1.7 mm) of the blend poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P(4HB)) in the ratio of 78/22 % (w/w) were manufactured with a CO2-laser. Two sterilization processes were considered: (i) beta irradiation at room temperature and 25 kGy, and (ii) ethylene oxide sterilization at T = 37 °C, RH = 60 % and p = 2.6 bar. The stents were expanded to a nominal balloon diameter of 3.0 mm, and were investigated with an environ-mental scanning electron microscope. Furthermore the molecular weight was determined by gel permeation chromato-graphy.
Results: The unsterile stent were properly expanded to the nominal diameter with a recoil of 7.28 ± 1.20 %, and a collapse pres-sure of 0.65 ± 0.10 bar, while the ethylene oxide sterilized stents fractured during balloon expansion. The beta-irradiated stents showed a recoil of 6.11 ± 0.39 %, and a collapse pressure of 0.51 ± 0.11 bar. The molecular weight of the unsterile stents (338,913 ± 19,403 g/mol) was reduced during sterilization: 321,560 ± 46,305 g/mol (ethylene oxide) and 206,773 ± 25,987 g/mol (beta irradiation).
Conclusion: Although ethylene oxide sterilization leads to a reduction in molecular weight of only 5 %, the stents fractured during expansion. Sterilization with beta irradiation causes a reduction in molecular weight of about 39 %. However, no influ-ences on the deformation behavior of the investigated stents were observed. Therefore, it can be stated that among the investigated sterilization protocols beta irradiation is most suitable for the sterilization of PLLA/P(4HB)-based poly-meric stents.

Biomed. Tech. 2011; 56 (S 1).

Bünger, C.M., S. Kischkel, N. Grabow, M. Kabelitz, B. Erdle, I. Bombor, K.-H. Hauenstein, W. Schareck, B. Vollmar, D.P. Martin, S.F. Williams, K. Sternberg, K.-P. Schmitz, and E. Klar, Interventional Applicability of Biodegradable ... Biomed. Tech.

doi: 10.1515/BMT.2011.443

Abstract:

Introduction: Biodegradable polymeric stents have demonstrated a potential alternative to standard metal stents, but to date, human experience with such devices is limited. The aim of this study is to assess the technical feasibility and biocompatibility of a novel biodegradable stent based on poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P4HB) for peripheral vascular applications.
Methods: Biodegradable polymeric stents (PLLA/P4HB) or non-biodegradable bare-metal stents (L605) were implanted interventionally into both common carotid arteries (CCA) of 7 female pigs via the left common iliac artery (8F-sheath). The stents were mounted on a balloon catheter (5.0x40 mm) and expanded with either 8 bar (PLLA/P4HB) or 9 bar (L605). The pigs were administered peroral aspirin (100mg) and clopidogrel (75 mg) starting 3 days before the procedure until the end of the study. After 4 weeks, before explanting the stented vessel segments, contrast enhanced angiography of the carotid vessels was performed to assess in-stent restenosis, and magnetic resonance tomography of the brain was performed to detect ischemic lesions.
Results: One pig died during the procedure due to heart arrest caused by bleeding at the iliac access. All other animals survived until the end of the study without developing neurological complications. Pushability and trackability of the stents was assessed in this study. The polymeric stents showed a moderately higher in-stent restenosis (40-50 %) compared to the bare-metal stents (20-30 %). No brain infarction was detected.
Conclusion: The overall results in an interventional endovascular porcine model demonstrate the applicability and mechanical competence of the developed polymeric vascular stent. The higher restenosis of polymeric stents in this study deserves further research, but was in accordance with our previous results of a surgical animal model. Development of a drugeluting polymeric stent will be a feasible approach to improve vascular response.

Biomed. Tech. 2011; 56 (S 1)

D. Quosdorf, M. Brede, A. Leder, D. Lootz, H. Martin, K.-P. Schmitz: Bestimmung des dreidimensionalen Geschwindigkeitsfelds am Modell eines koronaren Stents unter Nutzung von Micro-PIV/PTV Lasermethoden in der Strömungsmesstechnik, 19. Fachtagung 2011.

Lasermethoden in der Strömungsmesstechnik, 19. Fachtagung 2011, Ilmenau, Hrsg.: A. Thess, C. Resagk, B. Ruck, A. Leder, D. Dopheide, S. 41-1 bis 41-9

H. Martin, A. Leder, D. Quosdorf, D. Lootz, K.-P. Schmitz: Finite Element Investigations of the Compliance of Stent-Stenosis Systems. Biomed. Tech.

doi: 10.1515/BMT.2011.588

Abstract: Introduction: The stent therapy of cardiovascular stenoses has a significant influence on the resulting compliance of the blood vessel. It is necessary to develop new stent designs which do not substantially alter the resulting compliance. A development tool for the design of new stents is the finite element method. Therefore we want to introduce this method into the compliance calculation of stented stenoses.
Methods: Finite element models of stent-stenosis systems were modelled and analysed using the finite element system Abaqus. Cyclic symmetry of the stent-stenosis system was considered to reduce the computation time. The material properties of the several stenosed vessel components (i.e. adventitia, media, calcified and lipid plaque) were considered as elastic and the material constants were taken from the literature. The following load cases were considered: expansion of the vessel by an inner pressure, stent expansion, stent recoil and two work pressures of the vessel.
Results: The method was validated for a commercially available Cypher stent. We were able to show that the stent leads to a considerable local stiffening of the vessel which differs depending on the distance to the struts. Moreover the simulation allows assessing the shape and the stress of the vessel in the neighbourhood of the stent. Due to the consideration of cyclic symmetry, the modelling method is restricted to straight axisymmetric vessels.
Conclusion: We were able to show that with stent design care must be taken not only with respect to common quality parameters of stent, such as recoil, radial and bending stiffness, but also with respect to a better compliance match to the vessel. The finite element method is a suitable tool for optimization of stent designs for all of these parameters. For future investigations, non symmetric and curved vessels have to be considered.

Biomed. Tech. 2011; 56 (S 1).

D. Quosdorf, M. Brede, A. Leder, H. Martin, K.-P. Schmitz: In Vitro Microfluidic Measurements of the Velocity Distribution and Wall Shear Stress in Stented Artery Models, Regarding the Non-Newtonian Behaviour of Blood. Biomed. Tech.

doi: 10.1515/BMT.2011.361

Abstract: Introduction: The coronary artery disease is one of the most common causes of death in the western civilisation. A classical treatment is the implantation of a stent. Using a stent often generates adverse effects like the in-stent-restenosis or thrombosis. Both are known to be linked to the fluid flow inside the vessel. The main issue are extreme wall shear stresses which are induced by a change in the geometry caused by the stent. Measurements of the velocity distribution done by Micro-Particle-Tracking-Velocimetry (Micro-PTV) will be discussed and wall shear stresses will be derived.
Methods: The velocity fields were determined in the centre plane of a model of a stented artery that was made of silicone. The experimental setup consists of an epi-fluorescent microscope that is illuminated by a Nd: YAG-Laser and a micro flow channel that incorporates the artery model which is surrounded by a fluid for matching the refractive index. The measurements were done at a representative Reynolds Number of Re=160. The model fluid shows shear thinning properties analogue to the human blood and its refractive index also matches that of the silicone model. For obtaining the velocity fields a particle tracking algorithm is used.
Results: As a result the velocity field in the centre plane of the stent model could be determined. Upstream and downstream of the stent-struts, recirculation zones were identified and resolved. From the velocity field data the distribution of the wall shear stress component in the main flow direction could be determined. The results were obtained with regard to the non-Newtonian behaviour of the blood analogue fluid.
Conclusion: The experimental setup presented here offers the opportunity to analyse different stent design parameters. The determination of velocity distributions and wall shear stresses inside stented arteries, including the recirculation zones between the struts, has been performed successfully.

Biomed. Tech. 2011; 56 (S 1)

Quosdorf, D.; Brede, M.; Leder, A.; Lootz, D.; Martin, H.; Schmitz, K.-P. (2011): Determining the Wall Shear Stress Distribution at a Model ... In: G. Querzoli, P. Kilner und P. Pedrizzetti (Hg.): Cardiovascular Fluid Mechanics ... Euromech Colloquium

Abstract: Fighting the coronary heart disease has gained a lot of importance because of its wide spreading and mortality. In this paper a Micro-Particle-Image-Velocimetry (Micro-PIV) measuring setup is introduced, which allows to measure the velocity distribution at a strut section of a coronary stent. A blood analogue fluid is used to represent the non-Newtonian properties of blood. The measured velocity fields and the distribution of the wall shear stress are presented.

Euromech Colloquium 529. Cagliari, 27.-29.06.2011, S. 1–4.

PC Krüger, O Stachs, N Hosten, S Langner; MR-Microscopy of the human eye at 7.1T. ESMRMB 2011, Leipzig

7.1T. ESMRMB 2011, Leipzig

PC Krüger, O Stachs, K Falke, R Guthoff, N Hosten, S Langner; MR Microscopy of the human eye: Correlation with Histopathology; RSNA 2011, Leipzig; nominiert für Young Investigator Award

Abstract: PURPOSE/AIM: 1. To illustrate high-resolution ex-vivo 7.1T MR images of enucleated human eyes. 2. To correlate findings from in vivo MRI and ex-vivo specimen MRI with histopathology. 3. To describe benign and malignant MRI findings in the eye by comparing ex vivo MR images with histopathology.
CONTENT ORGANIZATION: Review of specimen imaging using a 7.1T MR scanner to compare MR images with histopathology. Description of MR findings of benign (retinal detachment, hemorrhage) and malignant lesions (melanoma, metastasis), as well as changes after lens replacement, as they correlate to histopathology. Illustration of co-registered MR and histopathology images. Discussion of the challenges involved in the confrontation between imaging and histopathology and the impact this has on clinical and research studies.
SUMMARY: To improve the quality and consistency of new technology, histopathologic validation of imaging findings is required. Correlation between Micro-MR images and histopathology can provide a better understanding of malignant eye processes and their treatment.

RSNA 2011, Leipzig; nominiert für Young Investigator Award

Herrmann A, Warkentin M, Pau HW (2011) Messung der Tubenfunktion bei chronisch mesotympanalem Trommelfelldefekt nach Applikation von Xylometazolin. 82. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie.

doi: 10.3205/11hnod356

Abstract: Eine behinderte Tubenfunktion wird als Ursache zahlreicher entzündlicher Erkrankungen des Mittelohres angesehen: z.B. die kindliche Otitis media (meist Vorliegen adenoider Vegetationen), aber auch chronische Otitiden mit Paukenergüssen, Trommelfellretraktionen oder -perforationen. Ein in Deutschland fast regelhaft durchgeführter Therapieversuch mit abschwellenden Nasentropfen wird in der Literatur oft kritisch beurteilt. Anhand von Untersuchungen an perforierten Trommelfellen soll in dieser Arbeit geprüft werden, ob sich ein Effekt topisch-abschwellender Medikation (Xylometazolin) auf den Tubenöffnungsmechanismus nachweisen lässt. Um dabei Einflüsse des Applikationsortes auszuschließen, wurden zusätzliche Untersuchungen mit intratympanaler Applikation des Medikaments durchgeführt.

82. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie. Freiburg i. Br., 01.-05.06.2011

Begunk R, Hußner J, Sternberg K, Bien S, Koeck K, Kroemer HK, Meyer zu Schwabedissen HE. Effects of platinum derivates on Human Coronary Artery Smooth Muscle Cell proliferation, Arteriosclerosis, Thrombosis, and Vascular Biology, Chicago 2011

HE. Effects of platinum derivates on Human Coronary Artery Smooth Muscle Cell proliferation, Arteriosclerosis, Thrombosis, and Vascular Biology, Chicago 2011

Hußner J, Begunk R, Iaroshenko V, Mkrtchyan S, Hein M, Supe L, Sternberg K, Langer P, Bien S, Schmitz KP, Kroemer HK, Meyer zu Schwabedissen HE Pyrazolinone-Derivatives selectively ... Deutsche Gesellschaft für Pharmakologie Tagung, Frankfurt 2011

Deutsche Gesellschaft für Pharmakologie Tagung, Frankfurt 2011, Naunyn-Schmiedeberg´s Arch. Pharmacol., 2011, 383 (Suppl 1), 19

Hußner J, Begunk R, Bien S, Koeck K, Kroemer HK, Meyer zu Schwabedissen HE. HDAC9 - A potential drug target in preventing smooth muscle cell proliferation? Arteriosclerosis, Thrombosis, and Vascular Biology, Chicago 2011

HE. HDAC9 - A potential drug target in preventing smooth muscle cell proliferation? Arteriosclerosis, Thrombosis, and Vascular Biology, Chicago 2011

Loch C, Zakelj, S., Kristl, A., Guthoff, R., Weitschies, W., Seidlitz, A., Determination of permeability coefficients of ophthalmic drugs through different layers of porcine eyes. Biomed. Tech.

doi: 10.1515/BMT.2011.859

Abstract: Introduction: Topically applied ophthalmic formulations such as eye drops are usually used to treat glaucoma or bacterial infections. In addition, novel ophthalmic implants releasing drug substances locally into different parts of the eye are available today. For the development of ophthalmic drug delivery systems in vitro dissolution test method are needed that are capable of simulating in vivo conditions. In the present work, in advance tissue permeabilities of selected drugs were determined using side-by-side-diffusion chambers.
Methods: Sclera, conjunctiva, cornea, choroidea-retina-complex and a complex of conjunctiva-sclera-choroidea-retina excised from fresh porcine eyes were mounted in side-by-side diffusion chambers. The tissue electric parameters including the trans-epithelial electrical resistance (TEER) were monitored. Donor solutions contained ciprofloxacin hydrochloride, lidocaine hydrochloride, timolol maleate and dexamethasone dissolved in Ringer buffer at 500 µM. Drug permeability coefficients (Papp) were calculated after HPLC analysis of the samples collected from acceptor compartments.
Results: The Papp value of 1.67x10-3 ± 8.15x10-4 cm/s for lidocaine hydrochloride through cornea was obtained. In comparison, Papp values for timolol maleate (Papp=2.56x10-4 ± 5.56 x10-5 cm/s), dexamethasone (Papp=2.49x10-4 ± 5.74 x10-5 cm/s) and ciprofloxacin hydrochloride (Papp=9.87x10-5 ± 3.66 x10-5cm/s) were lower. Referring to cornea, Papp values of the selected substances for conjunctiva and retina-choroidea-complex were higher but indicated same tendency. Papp values of sclera and complex of conjunctiva-sclera-choroidea-retina showed lower values.
Conclusions: The complex of conjunctiva-sclera-choroidea-retina seems to be most relevant permeation-barrier for the selected drug substances. Therefore, the preferred route of drug absorption into the eye is assumed to be through cornea and conjunctiva after topical application. Using side-by-side-diffusion chambers the Papp values of selected substances were successfully determined.

Biomed. Tech. 2011; 56 (S 1)

Loch C, Zakelj, S., Kristl, A., Guthoff, R., Weitschies, W., Seidlitz, A., Determination of permeability coefficients of ophthalmic drugs through different layers of porcine eyes, International Congress of Pharmaceutical Engineering, Graz 2011

Abstract: Introduction: Topically applied ophthalmic formulations such as eye drops are usually used to treat glaucoma or bacterial infections. In addition, novel ophthalmic implants releasing drug substances locally into different parts of the eye are available today. For the development of ophthalmic drug delivery systems in vitro dissolution test method are needed that are capable of simulating in vivo conditions. In the present work, in advance tissue permeabilities of selected drugs were determined using side-by-side-diffusion chambers.
Methods: Sclera, conjunctiva, cornea, choroidea-retina-complex and a complex of conjunctiva-sclera-choroidea-retina excised from fresh porcine eyes were mounted in side-by-side diffusion chambers. The tissue electric parameters including the trans-epithelial electrical resistance (TEER) were monitored. Donor solutions contained ciprofloxacin hydrochloride, lidocaine hydrochloride, timolol maleate and dexamethasone dissolved in Ringer buffer at 500 µM. Drug permeability coefficients (Papp)were calculated after HPLC analysis of the samples collected from acceptor compartments.
Results: The Papp value of 1.67x10-3 ± 8.15x10-4 cm/s for lidocaine hydrochloride through cornea was obtained. In comparison, Papp values for timolol maleate (Papp=2.56x10-4 ± 5.56 x10-5 cm/s), dexamethasone (Papp=2.49x10-4 ± 5.74 x10-5 cm/s) and ciprofloxacin hydrochloride (Papp=9.87x10-5 ± 3.66 x10-5cm/s) were lower. Referring to cornea, Papp values of the selected substances for conjunctiva and retina-choroidea-complex were higher but indicated same tendency. Papp values of sclera and complex of conjunctiva-sclera-choroidea-retina showed lower values.
Conclusions: The complex of conjunctiva-sclera-choroidea-retina seems to be most relevant permeation-barrier for the selected drug substances. Therefore, the preferred route of drug absorption into the eye is assumed to be through cornea and conjunctiva after topical application. Using side-by-side-diffusion chambers the Papp values of selected substances were successfully determined.

International Congress of Pharmaceutical Engineering, Graz 2011

Seidlitz A, Nagel S, Semmling B, Grabow N, Sternberg K und Weitschies W: Influence of Coating Thickness and Fractional Model Substance ... 38th Annual Meeting and Exposition of the Controlled Release Society, National Harbour, 30. Juli – 03. August 2011

38th Annual Meeting and Exposition of the Controlled Release Society, National Harbour, 30. Juli – 03. August 2011.

Semmling B, Seidlitz A, Nagel S, Trip E, Schnittker C, Grabow N, Sternberg K und Weitschies W: In Vitro Dissolution Testing for the Examination ... 38th Annual Meeting and Exposition of the Controlled Release Society, National Harbour, 30.07 – 03.08.201

38th Annual Meeting and Exposition of the Controlled Release Society, National Harbour, 30. Juli – 03. August 2011

Grabow, N., D. Bajer, S. Petersen, V. Senz, C. Schultze, W. Schmidt, K. Sternberg, and K.P. Schmitz, Process development and quality assessment for optimized longitudinal coating uniformity in spray-coated drug-eluting stents. Biomed. Tech.

doi: 10.1515/BMT.2011.595

Abstract: Introduction: Safe and efficacious clinical application of drug-eluting stents (DES) requires an adequate surface morphology and mechanical integrity of DES coatings. Beyond these primary quality parameters, uniform coating distribution is essential to warrant homogeneous drug administration from DES platforms. In this study, a spray-coating process for the fabrication of uniform and smooth polymer-based DES coatings was developed and assessed with respect to coating quality.
Methods: Cobalt chromium (L605) coronary bare metal stents (nominal dimensions: 3.0x13 mm, surface area: 60 mm²) were coated in a self-developed 2-step semi-automatic spray-coating process with a coating mass of 500 μg. The bioresorbable polymer poly(L-lactide) (PLLA) incorporated with the immunosuppressant sirolimus (SIR) in a ratio of 85/15 % w/w was used as coating compound. A parameter study was conducted to obtain optimum coating parameters. The coated DES (lot size n = 5) were evaluated for surface morphology and integrity by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Subsequently, the DES were embedded in epoxy resin and cross-sectioned in four equidistant planes for the evaluation of coating homogeneity.
Results: A qualified spray-coating parameter window (solution viscosity, air pressure, nozzle aperture, distance, time) was identified to fabricate DES with defect-free PLLA/SIR coatings. All DES were within ± 10 % of the target coating mass, indicating adequate process reproducibility. SEM evaluation confirmed complete strut coverage and smoothness of the coating surface. A mean roughness index (Ra) of less than 0.1 μm, and a roughness depth (Rz) of less than 1 μm were determined by CLSM. Analysis of coating uniformity showed a mean coating thickness of 9.9 ± 2.1 μm.
Conclusion: A reproducible spray-coating process was developed and evaluated for PLLA/SIR DES. Quality assessment demonstrated favorable surface morphology and uniform longitudinal coating distribution. The semi-automatic process is highly scalable and may be used in industrial settings.

Biomed. Tech. 2011; 56 (S 1)

Schmitt, L., K. Schümann, N. Grabow, H. Martin, and K.P. Schmitz, The Influence of Polymer/Drug Coating on the Mechanical Properties of Drug-Eluting Nitinol Stents - A Numerical Investigation. Biomed. Tech.

doi: 10.1515/BMT.2011.591

Abstract: Introduction: Over the recent years, polymer/drug coating of coronary balloon-expandable bare metal stents has evolved into a standard method for the improvement of the therapeutic outcome of stent implantation. To date, coating of self-expanding peripheral vascular stents of nitinol remains a challenge due to the characteristic material properties. In general, changes in mechanical stent properties due to polymer/drug coating have to be minimized. The focus of this study is the numerical investigation of the mechanical properties of polymer/drug-coated nitinol stents.
Methods: A CAD model (Pro/Engineer Wildfire 5.0) of a commercially available nitinol stent was created after electron microscopic assessment. Polymer/drug coatings were introduced separately by CAD methods with different coating thickness (t=20/60/120 μm). In a first FEA (Abaqus/CAE 6.7-1, Dassault Systèmes) approach, a two-dimensional model of two stent struts was created (stent: 3036 elements, coating: 3689-17473 elements, depending on coating thickness). The loading condition for stent expansion was realized as displacement, and the reaction force (RF) was analyzed. For the nitinol material, user defined material parameters were used, while the polymer/drug coating was idealized as a linearelastic material (E=70 MPa, μ=0.49).
Results: In the bare stent model the RF resulting from the applied displacement is 0.224 N. With increasing coating thickness, RF increases as follows: 0.227/0.252/0.331 N (for a coating thickness of 20/60/120 μm, respectively). These results suggest that the radial force of such polymer/drug-coated nitinol stents may decrease up to 47 %.
Conclusion: Feasibility of numerical simulation of the impact of polymer/drug coating on the mechanical properties of selfexpanding nitinol stents could be demonstrated. First results suggest a considerable decrease in radial force with increasing coating thickness. Further studies will now focus on three-dimensional models of polymer/drug-coated selfexpanding nitinol stents under three-dimensional loading during expansion and crimping. In addition, different coating thicknesses and various coating materials will be investigated.

Biomed. Tech. 2011; 56 (S 1).

Brietzke, J., M. Löbler, N. Grabow, K. Sternberg, and K.P. Schmitz, Development of a tissue culture model for investigating drug absorption and distribution within the blood vessel wall after drug-eluting stent implantation. Biomed. Tech.

doi: 10.1515/BMT.2011.363

Abstract: Introduction: Implantation of coronary drug-eluting stents (DES), as the therapy most often performed for coronary heart disease, is well researched. However, the absorption and distribution patterns of the eluted drugs within the blood vessel wall are hardly known. With the purpose to better understand these processes and to perform preliminary tests on in-house developed DES prior to in vivo studies, a tissue culture model needs to be established.
Methods: For the investigation of DES-induced tissue responses porcine coronary artery segments with a length of approx. 5 cm and an inner diameter of approx. 3 mm were fixed within a tube chamber system. Then different tissue culture media were used to perfuse the arterial segments both inside and outside. Coronary stents on the basis of a cobalt-chromium alloy were spray-coated with model fluorescent dyes such as fluorescein sodium or rhodamine B. These were then implanted and analyzed with regard to their release behaviour. Following perfusion, the concentrations of the fluorescent dye accumulated in the media and the vessel wall were determined by use of a fluorescence reader. Employing fluorescence microscopy, the tissue distribution of the dye was analyzed.
Results: Investigation of the fluorescein distribution revealed a fast dye uptake into the blood vessel wall within 30 minutes. The tissue areas around the stent fluoresced strongly, with the intensity attenuating with increasing radial distance from the stent. Furthermore, fluorescence measurements of the culture media demonstrated a continuous fluorescein release over a time frame of up to 16 hours.
Conclusion: The established tissue culture model provides a suitable in vitro system to investigate the release of fluorescent molecules, embedded in DES coatings, into the blood vessel wall. Such release studies will be incorporated in future in-house DES prototype development, providing important information for follow-up in vivo studies.

Biomed. Tech. 2011; 56 (S 1)

Seidlitz, A., M. Wentzlaff, S. Nagel, B. Semmling, C. Harder, N. Grabow, K. Sternberg, and W. Weitschies, High throughput stent coating in a fluidized bed apparatus. Biomed. Tech.

doi: 10.1515/BMT.2011.596

Abstract: Introduction: Drug-eluting stents typically consist of a metallic backbone coated with a drug/polymer mixture. Individual spray coating of single stents is associated with comparably long process times and large losses of coating liquid. To overcome these limitations, simultaneous batch coating of large quantities of stents was tested in a fluidized bed apparatus.
Methods: Stents were fluidized in a Huttlin-Mycrolab and coated with the fluorescent model substance fluorescein sodium incorporated in a copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid. The coated stents were evaluated by microscopy. The stents were incubated in phosphate buffered saline pH 7.4 and the fluorescein sodium content of the incubation buffer was determined fluorometrically.
Results: The stents (n ≈ 2500) were properly fluidized with the chosen process parameters and coated with the drug/polymer dispersion (t = 230 min). Microscopic evaluation demonstrated fairly uniform coatings with few coating defects, most likely caused by mechanical stress during the coating process. Coating bridges between the stent struts were not observed. The analysis of coating uniformity yielded a mean fluorescein sodium amount of 67.5 ± 5.1 Ag per stent. All individual contents were within ± 15% of the mean content, indicating an appropriate coating homogeneity.
Conclusion: Fluidized bed coating of stents is suitable to coat large quantities of stents in a short time. Further optimization of process parameters and coating dispersion concentrations is necessary to ensure minimum mechanical stress acting on the stents and coatings, while allowing for a sufficient coating thickness with a uniform distribution.

Biomed. Tech. 2011; 56 (S 1)

Warkentin M, Behrend D, Rosentritt M, Ottl, P: (2011) Microhardness topography of human tooth. J. Dent. Res. 90 Special Issue A

J. Dent. Res. 90 Special Issue A

Warkentin M, Busch A, Bartsch C, Ottl P, Behrend, D. (2011) Mechanical characteristics of human tooth to improve dental materials development. 45th Meeting of the CED-IADR with the Scandinavian Division (NOF), 31.08.-03.09.2011, Budapest, Ungarn

45th Meeting of the Continental European Division of the International Association of Dental Research (CED-IADR) with the Scandinavian Division (NOF), 31.08.-03.09.2011, Budapest, Ungarn

Warkentin, M., Specht, O., Schlichting, J., Behrend, D. Vergleichende mikroskopische Untersuchungen an Dentalstrukturen zur Entwicklung neuer Füllungsmaterialien. BIOmaterialien 2011, 31

doi: -

Abstract: -

BIOmaterialien 2011, 31

Warkentin, M, Brandt, C., Busch, A., Geis-Gerstorfer, J., Ottl. P., Rosentritt, M., Behrend, D (2011) Ermittlung mechanischer Kennwerte an ... Deutsche Gesellschaft für Prothetische Zahnmedizin und Biomaterialien e.V. 12.-14.05.2011, Hamburg

doi: -

Abstract: -

Deutsche Gesellschaft für Prothetische Zahnmedizin und Biomaterialien e.V. 12.-14.05.2011, Hamburg

Stein F, Löbler M, Ohno H; Kragl U. Non-toxic ionic liquids for new applications: Toxicological investigations of ionic liquid; Coil4 2011 in Washington/DC

Coil4 2011 in Washington/DC

Herrmann A, Warkentin M und Pau HW. Messung der Tubenfunktion bei chronisch mesotympanalem Trommelfelldefekt nach Applikation von Xylometazolin, 82. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie.

doi: 10.3205/11hnod356

Abstract: Eine behinderte Tubenfunktion wird als Ursache zahlreicher entzündlicher Erkrankungen des Mittelohres angesehen: z.B. die kindliche Otitis media (meist Vorliegen adenoider Vegetationen), aber auch chronische Otitiden mit Paukenergüssen, Trommelfellretraktionen oder -perforationen. Ein in Deutschland fast regelhaft durchgeführter Therapieversuch mit abschwellenden Nasentropfen wird in der Literatur oft kritisch beurteilt. Anhand von Untersuchungen an perforierten Trommelfellen soll in dieser Arbeit geprüft werden, ob sich ein Effekt topisch-abschwellender Medikation (Xylometazolin) auf den Tubenöffnungsmechanismus nachweisen lässt. Um dabei Einflüsse des Applikationsortes auszuschließen, wurden zusätzliche Untersuchungen mit intratympanaler Applikation des Medikaments durchgeführt.

Freiburg i. Br., 01.-05.06.2011. Abstractband S. 141.

 

Reiß S, Stolz H, Guthoff RF, Stachs O. Entwicklung eines Versuchsaufbaus zur ortsaufgelösten Messung des Elastizitätsmoduls menschlicher Linsen. Biomed Tech.

doi: 10.1515/BMT.2010.590

Abstract: Die Presbyopie (Alterssichtigkeit) steht in enger Verbindung mit dem Verlust der Akkommodationsfähigkeit und den viskoelastischen Eigenschaften der humanen Augenlinse. Mit den gegenwärtig zur Verfügung stehenden Techniken ist eine Bestimmung der viskoelastischen Eigenschaften nicht oder nur sehr eingeschränkt möglich. Es wird über die Entwicklung eines Verfahrens zur ortsaufgelösten Bestimmung der elastischen Eigenschaften der Augenlinse unter Verwendung der konfokalen Brillouinspektroskopie berichtet. Die ortsaufgelöste Bestimmung des Elastizitätsmoduls der menschlichen Augenlinse dient dem Verständnis - des natürlichen Alterungsprozesses der Linse des Auges - der Einflüsse von unterschiedlichen Linsentrübungen auf die elastischen Eigenschaften der Linse - zur Erfassung von Kapselsackveränderungen nach Katarakt-Chirurgie und deren Wechselwirkung mit dem Nachstar

Biomed Tech. 2010; 55 (S1).

Martius P, Stachs O, Grümmer G, Rudolf RF, Martin H. Entwicklung eines Prüfstandes zur Erfassung der Verformbarkeit von Augenlinsen. Biomed Tech.

doi: 10.1515/BMT.2010.585

Abstract: Illustrated is a test-bed that can record the elastic properties of eye lenses. For this the accommodation is simulated by applied centrifugal forces ex vivo, geometric changes can be quantified and the evaluation of the capsular bag’s influence is possible. From this followed values for the equatorial diameter, the lens thickness and the anterior plus posterior radius of curvature enable a comparison between natural and artificial lenses.

Biomed Tech. 2010; 55 (S1).

Sternberg K, Rohm HW, Lurtz C, Wegmann J, Odermatt EK, Behrend D, Michalik D, Schmitz KP. Synthesis and characterization of a biodegradable tissue adhesive based on functionalized 1,2-ethylene glycol bis(dilactic acid). Biomed Tech.

doi: 10.1515/BMT.2010.121

Abstract: This study reports the development of a tissue adhesive based on 1,2-ethylene glycol bis(dilactic acid) (ELA) functionalized with hexamethylene diisocyanate (HDI) to produce isocyanate terminated ELA-NCO which was characterized by NMR and FTIR spectroscopy. ELA-NCO together with chain elongation agents forms an adhesive system suitable for tissue fixation. Several biodegradable polymers, such as chitosan acetate, chitosan chloride, hyaluronic acid, starch and gelatin, were tested as chain elongation agents to obtain an adhesive system and studied on bovine muscle tissue to evaluate their adhesive strength and compared to fibrin glue.

Biomed Tech. 2010; 55 (S1).

Lurtz C, Rohm HW, Wegmann J, Odermatt EK, Behrend D, Schmitz KP, Sternberg K. In vitro and in vivo investigations of a biodegradable tissue adhesive based on functionalized 1,2- ethylene glycol bis(dilactic acid) and chitosan chloride. Biomed Tech.

doi: 10.1515/BMT.2010.122

Abstract: The present study reports the analysis of a tissue adhesive that consists of two adhesive components hexamethylene diisocyanate (HDI) functionalized 1,2-ethylene glycol bis(dilactic acid) (ELA-NCO) and chitosan chloride. This composition was chosen based on the results of preliminary studies on several chain elongation agents. The present study evaluates this adhesive system by tensile tests, and gel point measurements in comparison to fibrin glue. Furthermore, an implantation study was performed in SPF-Wistar-rats. The adhesive strength of mixtures applied by double chamber syringes with mixing extruder was determined to be significantly higher than that of fibrin glue on bovine muscle tissue at 37 °C. Tensile strength increased further when exposure time of the adhesive was raised from 10 min to 48 h. In contrast to fibrin, the rheological gel point determination evidenced that the mixture of ELA-NCO/DMSO and chitosan chloride offers a sufficient time frame of approx. 3 min wherein the fused joint can be readjusted during surgery. Additionally, the in vivo compatibility study of the adhesive system revealed a good biocompatibility to the surrounding tissue.

Biomed Tech. 2010; 55 (S1).

Busch R, Strohbach A, Sczodrok S, Kroemer HK, Sternberg K, Felix S. Interaktion von humanen Endothelzellen und Thrombozyten mit Polymeroberflächen Biomed Tech.

doi: 10.1515/BMT.2010.460

Abstract: Stents have been a revolutionary advance in the treatment of coronary artery disease. However, in-stent restenosis and late stent thrombosis remain major limitations in coronary intervention. The aim of this study was to investigate the interactions between human endothelial cells and platelets with new stent coatings such as novel, biocompatible polymers. We used an in vitro perfusion model to investigate the influence of shear stress and the interactions of blood cells with the polymer coatings, with emphasis on endothelialization and inflammation.

Biomed Tech. 2010; 55 (S1).

REMEDIS-Bilanzkonferenz

am 4. September 2014
in der Aula der Universität Rostock

REMEDIS Geschäftsstelle

Universität Rostock
Institut für Biomedizinische Technik
Friedrich-Barnewitz-Straße 4
18119 Rostock
Tel.: +49 381 54345 500
E-Mail schreiben
www.ibmt.med.uni-rostock.de

8. REMEDIS-Klausurtagung

21.11.2013

Symposium

Viel Fortschritt, wenig Eingriff -
Stentinnovationen für minimalinvasive Therapien

des Verbundprojektes REMEDIS

am 8. November 2012
in der IHK zu Rostock

zum Programm

Implantate: Neue Materialien erhöhen die Verträglichkeit

Film über die Forschungstätigkeit des REMEDIS-Partners DWI an der RWTH Aachen e.V. im Teilprojekt A1