Frank Luderer

Biodegradable Sirolimus-loaded Poly(lactide) Nanoparticles as Drug Delivery System for the Prevention of In-Stent Restenosis in Coronary Stent Application

The administration of drugs using biodegradable polymer nanoparticles as carriers has generated immense interest due to their excellent biocompatibility and the prolonged drug release. The scope of this work was to determine the applicability of sirolimus-loaded biodegradable poly(D,L-lactide) (PDLLA) nanoparticles as drug carriers to prevent restenotic processes after stent implantation. The average 250 nm sized 20%(w/w) sirolimus-loaded nanoparticles were extensively characterized with regard to in vitro degradation, biocompatibility and in vitro drug release. The particles show biphasic release kinetics consisting of a short burst release of 50%(w/w) sirolimus payload, followed by a longer, slower release phase, which are desirable for the application as a drug delivery carrier. All presented results exhibit the potential of sirolimus-loaded PDLLA nanoparticles as promising local and sustained drug delivery systems administered intraluminally to reduce in-stent restenosis after stent implantation.

VEGF-releasing suture material for enhancement of vascularization: Development, in vitro and in vivo study

As it has been demonstrated that bioactive substances can be delivered locally using coated surgical suture materials, the authors developed a vascular endothelial growth factor (VEGF)-releasing suture material that should promote vascularization and potentially wound healing. In this context, the study focused on the characterization of the developed suture material and the verification of its biological activity, as well as establishing a coating process that allows reproducible and stable coating of a commercially available polydioxanone 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. The potential of the VEGF-releasing suture material was also studied in vivo 5days after implantation in the hind limb of Wistar rats, when the histological findings were analyzed. The essential results, enhanced cell viability in vitro as well as significantly increased vascularization in vivo, were achieved using PLLA/1.0μg VEGF-coated suture material. Furthermore, ELISA measurements revealed a high reproducibility of the VEGF release behavior. Based on the results achieved 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 are combined for targeted, overall enhancement of wound healing.

Enhanced visualization of biodegradable polymeric vascular scaffolds by incorporation of gold, silver and magnetite nanoparticles:

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.

Chemical activation and changes in surface morphology of poly(ε-caprolactone) modulate VEGF responsiveness of human endothelial cells

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.

Suitability of Nanoparticles for Stent Application

The scope of our studies was to evaluate to which extent nanoparticles incorporated in stent matrices are suitable for stent application regarding local drug delivery to prevent in-stent restenosis and visual enhancement of polymer stents trough incorporated nanoparticles as X-ray or magnetic resonance contrast agents. Nanoparticles used were polyamidoamine (PAMAM) dendrimers generation 4.0 (size approx. 4.5 nm) with different functional surface groups as well as silica nanoparticles (size approx. 70 nm) loaded with pharmaceuticals (disulfiram, sirolimus and ibuprofen) for drug delivery. Gold nanoparticles (size approx. 6 nm) were employed for visual enhancement studies. Nanoparticles were characterized by transmission and scanning electron microscopy. Biocompatibility studies were performed in vitro in cell culture tests (viability and proliferation). Nanoparticle ingestion into cells was tracked via dye loaded nanoparticles by confocal laser scanning microscopy.

Implant-associated local drug delivery systems for different medical applications

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 in- teraction 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. En- gineering 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 re- search into such medical technology.

The effect of metronidazole releasing polymer coatings on in vitro biofilm formation

Abstract Background The aim of the study was to evaluate the antibacterial effect of a drug releasing poly (3-hydroxybutyrate) (P(3HB)) implant coating in comparison to pure titanium on Aggregatibacter actinomycetemcomitans as a model periodontopathogen to prevent biofilm formation on implant surfaces. Methods Titanium discs were coated with P(3HB) containing 5% (w) and 10% (w) of metronidazole, either with and without a P(3HB) topcoat. The biofilm formation was evaluated after 1, 4 and 9 days in a dynamic flow chamber system. Microbial adherence was quantified by determination of bacterial surface coverage. Results The evaluated formulations of P(3HB)/metronidazole showed an antibacterial effect especially in the first 24 h. Prolonged incubation for 9 days showed reduced bacterial adhesion only on polymer coatings loaded with 10% (w) of metronidazole both with and without topcoat. Conclusions The evaluated coating formulations can provide protection from an Aggregatibacter actinomycetemcomitans in vitro biofilm formation for the time period which was evaluated.

Direct sprayed endothelialization, basement membrane and cell junction development on biological and artificial products are highly substrate-dependent and require optimized biofunctionalization

Abstract Background: Optimizing endothelialization of medical implants requires deep mechanistic insight into cellular adhesion, cell junction and physiological basement membrane development at the endothelial cell-to-scaffold substrate interface. Methods and results: We employed and standardized endothelial cells and fibrin hydrogel for simultaneous cell-plus-fibrin (EC-Fib) spray application using the Maslanka® spray pen. Quality assessment illustrated excellent structural integrity of EC-Fib. Acellular SynerGraft® showed improved intimal endothelial recellularization after short-term physical and chemical preconditionings including dry-freezing, sodium desoxycholate, Triton-X, acetic acid and collagenase treatments. Artificial substrates poly-L-lactic acid (PLLA), and polyamide-6 (PA-6) were tested regarding their mechanical appropriateness, revealed complete endothelialization following EC-Fib application and showed partially physiological basement membrane development. Additional laminin 1 biofunctionalization on PA-6 moderately enhanced basement membrane gene and protein expression. However, scanning electron microscopy, immunohistology and PCR analyses underlined immature endothelialization, basement membrane and cell junction development on all substrates with clear substrate-dependent differences. Conclusions: Direct sprayed endothelialization outlined the necessity for preconditioning acellular SynerGraft® prostheses for adequate recellularization. Laminin 1 biofunctionalization could slightly improve endothelialization of PA-6 substrates whereas physiological organization of the microenvironment remained immature and seemed highly substrate dependent.