Klaus-Peter Schmitz

University of Rostock, Rostock, Mecklenburg-Vorpommern, Germany

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Publications (95)227.13 Total impact

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    Preview · Article · Oct 2015
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    ABSTRACT: Polyelectrolyte multilayer (PEM) films, established by layer-by-layer deposition, are attractive for drug delivery systems as drug delivery can be systematically controlled. However, one limitation of this coating method is the time-consuming character. The adsorption time of one layer typically takes minutes and commonly, investigated multilayers loaded with drugs contain more than 80 layers. Within our study we systematically evaluate parameters allowing the generation of a PEM-based drug delivery system on poly(L-lactide) (PLLA) with a reduced time consuming construction process and a controlled delivery of physiological amounts of active drugs. Therefore, several PEM based on PLLA with only five tetralayers consisting of polycation/polyanion/drug/polyanion are established and investigated regarding the release profiles of avidin fluorescein isothiocyanate as model substance and vascular endothelial growth factor (VEGF). We demonstrate that the polyelectrolyte nature and molecular weight of polyanions (hyaluronic acid, polyacrylic acid) and polycations (poly-L-lysine, chitosan) strongly influence the drug release profiles. Furthermore, in vitro cell culture studies show that the released VEGF amount and the cover layer from the favorite coating systems can beneficially enhance human umbilical vein endothelial cell (HUVEC) proliferation.
    No preview · Article · Aug 2015
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    ABSTRACT: Lately, drug-coated balloons have been introduced in interventional cardiology as an approach to treat occluded blood vessel. They were developed for the rapid transfer of antiproliferative drugs during the angioplasty procedure in stenosed vessels with the intent to reduce the risk of restenosis. In this study five different paclitaxel (PTX) balloon coatings were tested in vitro in order to examine how solvents and additives influence coating stability and drug transfer rates. PTX-coated balloons were advanced through a guiding catheter and a simulated coronary artery pathway under perfusion and were then inflated in a hydrogel acceptor compartment. The fractions transferred to the gel, remaining on the balloon and the PTX lost in the simulated coronary pathway were then analysed. The results obtained suggest that the solvent used for the coating process strongly influences the surface structure and the stability of the coating. Ethanol/water and acetone based PTX coatings showed the lowest drug transfer rates to the simulated vessel wall (both <1%) due to their high drug losses during the prior passage through the coronary artery model (more than 95%). Balloons coated with PTX from ethyl acetate-solutions showed smaller drug loss (83% +/- 9%), but most of the remaining PTX was not transferred (mean balloon residue approximately 15%). Beside the solvent, the use of additives seemed to have a great impact on transfer properties. The balloon pre-treatment with a crosslinked polyvinylpyrrolidone (PVP) film was able to increase the PTX transfer rate from less than 1% (without PVP) to approximately 6%. The best results in this study were obtained for balloon coatings with commercially available SeQuent
    No preview · Article · Aug 2015 · European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
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    ABSTRACT: In this study we present the development of an injectable polymeric drug delivery system for subconjunctival treatment of primary open angle glaucoma. The system consists of hyaluronic acid sodium salt (HA), which is commonly used in ophthalmology in anterior segment surgery, and an isocyanate - functionalized 1,2-ethylene glycol bis(dilactic acid) (ELA-NCO). The polymer mixtures with different ratios of HA to ELA-NCO (1/1, 1/4, and 1/10 (v/v)) were investigated for biocompatibility, degradation behavior and applicability as a sustained release system. For the latter, the lipophilic latanoprost ester pro-drug (LA) was incorporated into the HA/ELA-NCO system. In vitro, a sustained LA release over a period of about 60days was achieved. In cell culture experiments, the HA/ELA-NCO (1/1, (v/v)) system was proven to be biocompatible for human and rabbit Tenon's fibroblasts. Examination of in vitro degradation behavior revealed a total mass loss of more than 60% during the observation period of 26weeks. In vivo, LA was continuously released for 152days into rabbit aqueous humor and serum. Histological investigations revealed a marked leuko-lymphocytic infiltration soon after subconjunctival injection. Thereafter, the initial tissue reaction declined concomitantly with a continuous degradation of the polymer, which was completed after 10months. Our study demonstrates the suitability of the polymer resulting from the reaction of HA with ELA-NCO as an injectable local drug delivery system for glaucoma therapy, combining biocompatibility and biodegradability with prolonged drug release. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jul 2015 · Journal of Controlled Release
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    ABSTRACT: A novel glaucoma drainage device (GDD) with local drug delivery (LDD) system was created and characterized for safety and effectiveness after implantation into the suprachoroidal space (SCS) of rabbit eyes. Thin films of two different polymers, Poly(3-hydroxybutyrate) (P(3HB)) and Poly(4-hydroxybutyrate) (P(4HB)), containing the drugs mitomycin C (MitC) or paclitaxel (PTX) were attached to silicone-tubes to create LDD devices. The release kinetics of these drugs were explored in vitro using high performance liquid chromatography (HPLC). Twenty-four New Zealand white rabbits, randomly divided into eight groups, were implanted with different kinds of microstents into SCS. The intraocular pressure (IOP) was monitored noninvasively. After 6 weeks, rabbits were sacrificed and enucleated eyes were used for anterior segment optical coherence tomography (OCT), micro magnetic resonance imaging (MRI), and histology. In vitro, faster drug release from both polymers was observed for MitC compared to PTX. Comparing polymers, the release from P(3HB) matrix was slower for both drugs. MRI and OCT showed all implants maintained a proper location. An effective IOP reduction was observed for up to 6 weeks in eyes with microstents combined with a drug-releasing LDD system. Overall, the surrounding tissue revealed mild-to-moderate inflammation. No pronounced fibrosis was observed in any of the groups. However, both drugs caused damage to the neighboring retina. The suprachoroidal microstent reduced IOP with mild inflammation in rabbit eyes. To avoid negative effects on the retina, it is necessary to identify novel drugs with less cytotoxicity. Future studies are needed to explore the fibrotic process over the long-term. The presented data serve as a proof of principle study for the concept of a suprachoroidal drug eluting microstent. Future device improvements will be focused on the design of LDD systems and the use of specific anti-inflammatory or antifibrotic agents with less cytotoxicity compared to MitC or PTX. Long-term animal studies using a reliable glaucoma model will be a further step towards clinical application and improvement of surgical glaucoma therapy.
    Full-text · Article · Jun 2015
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    ABSTRACT: Minimally invasive treatment of vertebral fractures is basically characterized by cement augmentation. Using the combination of a permanent implant plus cement, it is now conceivable that the amount of cement can be reduced and so this augmentation could be an attractive opportunity for use in traumatic fractures in young and middle-aged patients. The objective of this study was to determine the smallest volume of cement necessary to stabilize fractured vertebrae comparing the SpineJack system to the gold standard, balloon kyphoplasty. 36 fresh frozen human cadaveric vertebral bodies (T11-L3) were utilized. After creating typical compression wedge fractures (AO A1.2.1), the vertebral bodies were reduced by SpineJack (n=18) or kyphoplasty (n=18) under preload (100N). Subsequently, different amounts of bone cement (10%, 16% or 30% of the vertebral body volume) were inserted. Finally, static and dynamic biomechanical tests were performed. Following augmentation and fatigue tests, vertebrae treated with SpineJack did not show any significant loss of intraoperative height gain, in contrast to kyphoplasty. In the 10% and 16%-group the height restoration expressed as a percentage of the initial height was significantly increased with the SpineJack (>300%). Intraoperative SpineJack could preserve the maximum height gain (mean 1% height loss) better than kyphoplasty (mean 16% height loss). In traumatic wedge fractures it is possible to reduce the amount of cement to 10% of the vertebral body volume when SpineJack is used without compromising the reposition height after reduction, in contrast to kyphoplasty that needs a 30% cement volume. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · May 2015 · Clinical biomechanics (Bristol, Avon)
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    ABSTRACT: Drug eluting stents (DES) consist of platform, coating and drug. The platform often is a balloon-expandable bare metal stent made of the CoCr alloy L-605 or stainless steel 316L. The function of the coating, typically a permanent polymer, is to hold and release the drug, which should improve therapeutic outcome. Before implantation, DES are compressed (crimped) to allow implantation in the human body. During implantation, DES are expanded by balloon inflation. Crimping, as well as expansion, causes high stresses and high strains locally in the DES struts, as well as in the polymer coating. These stresses and strains are important design criteria of DES. Usually, they are calculated numerically by finite element analysis (FEA), but experimental results for validation are hardly available. In this work, the X-ray diffraction (XRD) sin(2)ψ-technique is applied to in-situ determination of stress conditions of bare metal L-605 stents, and Poly-(L-lactide) (PLLA) coated stents. This provides a realistic characterization of the near-surface stress state and a validation option of the numerical FEA. XRD-results from terminal stent struts of the bare metal stent show an increasing compressive load stress in tangential direction with increasing stent expansion. These findings correlate with numerical FEA results. The PLLA-coating also bears increasing compressive load stress during expansion. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Apr 2015 · Journal of the Mechanical Behavior of Biomedical Materials
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    ABSTRACT: Drug-coated balloons (DCB), which have emerged as a therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficacy and safety within a number of clinical studies. In vitro studies elucidating the correlation between coating additive and DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this regard, we examined three different DCB-systems, which were developed in former studies based on the ionic liquid cetylpyridinium salicylate, the body-own hydrogel hyaluronic acid and the pharmaceutically well-established hydrogel polyvinylpyrrolidone, considering coating morphology, coating thickness, drug-loss, drug-transfer to the vessel wall, residual drug-concentration on the balloon surface and entire drug-load during simulated use in an in vitro vessel model. Moreover, we investigated particle release of the different DCB during simulated use and determined the influence of the three coatings on the mechanical behavior of the balloon catheter. We could show that coating characteristics can be indeed correlated with the performance of DCB. For instance, paclitaxel incorporation in the matrix can reduce the drug wash-off and benefit a high drug transfer. Additionally, a thin coating with a smooth surface and high but delayed solubility can reduce drug wash-off and decrease particle burden. As a result, we suggest that it is very important to characterize DCB in terms of mentioned properties in vitro in addition to their clinical efficacy in order to better understand their function and provide more data for the clinicians to improve the tool of DCB in coronary angioplasty.
    Full-text · Article · Mar 2015 · PLoS ONE
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    ABSTRACT: Functionality of implant surfaces is considerably determined by the conformations of immobilized biomolecules adjustable by the applied surface modification approach. Moreover, surface modification of drug eluting systems often needs to be thoroughly optimized with regard to possible drug losses associated with a loss of functionality. Here, we thoroughly investigate biomolecule surface loading, functionality, morphology and stability in dependence of modification conditions at the example of a site-selective immobilization of anti-CD34 antibodies (CD34-Ab) to drug-eluting stents with the aim of providing general information on the biofunctionalization of drug eluting systems. In this context, we demonstrate that the reaction time of biomolecule immobilization defines achievable surface loads but also drug loss. We could moreover show that the used site-selective immobilization procedure elevated the surface functionality considerably in comparison to surfaces modified by random physisorption. Furthermore investigated bionfunctional stability gives important indications for storage conditions of biofunctionalized implants.
    Full-text · Article · Jan 2015
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    ABSTRACT: Drug-coated balloon catheters are a novel clinical treatment alternative for coronary and peripheral artery diseases. Calcium alginate, poly(vinylethylimidazolium bromide) and polyacrylamide hydrogels were used as vessel models in this in vitro study. In comparison to a simple silicone tube their properties can be easily modified simulating different types of tissue. Local drug delivery after balloon dilation in the first crucial minute was determined in a vessel-simulating flow-through cell by a simulated blood stream. Balloon catheters were coated with paclitaxel using the ionic liquid cetylpyridinium salicylate as a novel carrier. Drug transfer from coated balloon catheters to different simulated vessel walls was evaluated and compared to a silicone tube. The highest paclitaxel delivery upon dilation was achieved with calcium alginate as the vessel model (60%) compared to polyacrylamide with 20% drug transfer. The silicone tube showed the least amount of wash-off (<1%) by a simulated blood stream after one minute from the vessel wall. The vessel-simulating flow-through cell was combined with a model coronary artery pathway to estimate drug loss during simulated use in an in vitro model. Calcium alginate and polyacrylamide hydrogels were used as tissue models for the simulated anatomic implantation process. In both cases, similar transfer rates for paclitaxel upon dilation were detected.
    Full-text · Article · Jan 2015 · RSC Advances
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    Full-text · Poster · Sep 2014
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    ABSTRACT: As it has been demonstrated that bioactive substances can be delivered locally using coated surgical suture materials we developed a vascular endothelial growth factor (VEGF)-releasing suture material that should promote vascularization and potentially wound healing. In this context, we focused on the characterization of the developed suture material and the verification of its biological activity, as well as established a coating process which allows reproducible and stable coating of a commercially available polydioxanone (PDS) suture material with poly(L-lactide) (PLLA) and 0.1μg and 1.0μg VEGF. The in vitro VEGF release kinetics was studied using a Sandwich ELISA. The biological activity of the released VEGF was investigated in vitro using human umbilical vein endothelial cells (HUVECs). The potential of the VEGF-releasing suture material was also studied in vivo as five days after implantation in the hind limb of Wistar rats histological findings were analyzed. As essential result, enhanced cell viability in vitro as well as significantly increased vascularization in vivo were achieved using the PLLA/1.0μg VEGF-coated suture material. Furthermore, ELISA measurements revealed a high reproducibility of the VEGF release behavior. Based on the achieved results regarding the dose-effect relationship of VEGF, the stability during its processing and the release behavior it can be predicted that a bioactive suture material would be successful in later in vivo studies. Therefore, this knowledge could be the basis for future studies where bioactive substances with different modes of action will be combined for a targeted, overall enhancement of wound healing.
    No preview · Article · Sep 2014 · Acta Biomaterialia
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    ABSTRACT: The high degree of clinical routine in percutaneous transluminal coronary angioplasty (PTCA) with and without stenting has not changed the fact that a large number of coronary heart disease patients are still affected by post-operative complications such as restenosis and thrombosis. Because re-endothelialization is the crucial aspect of wound healing after cardiovascular implant surgery, there is a need for modern biomaterials to aid endothelial cells in their adhesion and functional recovery post-stenting. This study systematically examines the potential of numerous chemical polymer modifications with regard to endothelialization. Poly(ε-caprolactone) (PCL) and its chemically activated forms are investigated in detail, as well as the impact of polymer surface morphology and precoating with matrix protein. Human umbilical vein endothelial cells (HUVECs) are used to characterize endothelial cell responses in terms of in vitro viability and adhesion. As a potential component in drug eluting implants, VEGF is applied as stimulus to boost endothelial cell proliferation on the polymer. In conclusion, plasma chemical activation of PCL combined with VEGF stimulation best enhances in vitro endothelialization. Examining the impact of morphological, chemical and biological modifications of PCL, this study makes an important new contribution towards the existing body of work on polymer endothelialization.
    No preview · Article · May 2014 · Journal of Materials Science Materials in Medicine
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    ABSTRACT: Enhanced proliferation of human coronary artery smooth muscle cells (HCASMCs) and thereby formation of neointima is one of the factors contributing to failure of coronary stents. Even if the use of drug eluting stents and thereby the local delivery of cytotoxic compounds has significantly improved clinical outcome, unselective cytotoxicity is assumed to hamper clinical success. Novel pharmacological approaches are required to enhance cellular selectivity of locally delivered drugs. Cell specific overexpression of a drug transporter could be used to enhance cellular accumulation and therefore cell specificity. In the herein reported study we tested the possibility of cell specific transporter expression to enhance drug effects in HCASMCs. We generated adenoviral constructs to overexpress the organic cation transporter 1 (OCT1) under control of the promoter of SM22α, which had been previously reported as muscle cell-specific gene. First the activity of the SM22α-promoter was assessed in various cell types supporting the notion of muscle cell-specificity. Subsequently, the activity of the transporter was compared in infected human coronary artery endothelial cells (HCAECs) and HCASMCs revealing enhanced accumulation of substrate drugs in HCASMCs in presence of the SM22α-promoter. Testing the hypothesis that this kind of targeting might serve as a mechanism for cell-specific drug effects we investigated the impact on paclitaxel treatment in HCASMC and HCAECs, showing significantly increased anti-proliferative activity of this substrate drug on muscle cells. Taken together, our findings suggest that cell-specific expression of transport proteins serves as mechanism governing the uptake of cytotoxic compounds for a selective impact on targeted cells.
    No preview · Article · Feb 2014 · Molecular Pharmaceutics
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    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. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013.
    Full-text · Article · Feb 2014 · Journal of Biomedical Materials Research Part B Applied Biomaterials
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    ABSTRACT: Impaired re-endothelialization and stent thrombosis are a safety concern associated with drug-eluting stents (DES). PI3K/p110α controls cellular wound healing pathways, thereby representing an emerging drug target to modulate vascular homoeostasis after injury. PI3K/p110α was inhibited by treatment with the small molecule inhibitor PIK75 or a specific siRNA. Arterial thrombosis, neointima formation, and re-endothelialization were studied in a murine carotid artery injury model. Proliferation and migration of human vascular smooth muscle cell (VSMC) and endothelial cell (EC) were assessed by cell number and Boyden chamber, respectively. Endothelial senescence was evaluated by the β-galactosidase assay, endothelial dysfunction by organ chambers for isometric tension. Arterial thrombus formation was delayed in mice treated with PIK75 when compared with controls. PIK75 impaired arterial expression and activity of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); in contrast, plasma clotting and platelet aggregation did not differ. In VSMC and EC, PIK75 inhibited expression and activity of TF and PAI-1. These effects occurred at the transcriptional level via the RhoA signalling cascade and the transcription factor NFkB. Furthermore, inhibition of PI3K/p110α with PIK75 or a specific siRNA selectively impaired proliferation and migration of VSMC while sparing EC completely. Treatment with PIK75 did not induce endothelial senescence nor inhibit endothelium-dependent relaxations. In line with this observation, treatment with PIK75 selectively inhibited neointima formation without affecting re-endothelialization following vascular injury. Following vascular injury, PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization. Hence, PI3K/p110α represents an attractive new target in DES design.
    Full-text · Article · Dec 2013 · European Heart Journal
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    ABSTRACT: Polyvinylpyrrolidone (PVP) is a conventionally applied hydrophilic lubricious coating on catheter-based cardiovascular devices, used in order to ease movement through the vasculature. Its use as drug reservoir and transfer agent on drug-coated balloons (DCB) is therefore extremely promising with regard to the simplification of its approval as a medical device. Here, we developed a PVP-based coating for DCB, containing paclitaxel (PTX) as a model drug, and studied the impact of crosslinking via UV radiation on drug stability, wash off, and transfer during simulated use in an in vitro vessel model. We showed that crosslinking was essential for coating stability and needed to be performed prior to PTX incorporation due to decreased drug bioavailability as a result of photodecomposition and/or involvement in vinylic polymerization with PVP under UV radiation. Moreover, the crosslinking time needed to be carefully controlled. While short radiation times did not provide enough coating stability, associated with high wash off rates during DCB insertion, long radiation times lowered drug transfer efficiency upon balloon expansion. A ten minutes radiation of PVP, however, combined a minimized drug wash off rate of 34% with an efficient drug transfer of 49%, underlining the high potential of photochemically crosslinked PVP as a coating matrix for DCB.
    Full-text · Article · Dec 2013 · Coatings Magazine
  • Axel Haverich · Klaus-Peter Schmitz

    No preview · Article · Oct 2013 · Biomedizinische Technik/Biomedical Engineering
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    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.
    Full-text · Article · Oct 2013
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    Full-text · Article · Sep 2013 · Biomedizinische Technik/Biomedical Engineering