(Bio)degradable Urethane-Elastomers for Electrospun Vascular Grafts

Electrospinning is a very powerful method to create cellular scaffolds for regenerative medicine – especially for artificial vascular grafts. Commercially available thermoplastic polyurethane elastomers (TPUs), like PellethaneTM are FDA approved and have already shown excellent biomechanical properties as electrospun vascular grafts. In order to induce the growth of a neo-artery and hence increase the long-term patency of the graft, the use of biodegradable TPUs is beneficial. Therefore we aim for the development of degradable TPUs. In preliminary studies the mechanical properties of segmented TPUs were examined. The tendencies of the properties of the compression-molded bulk materials were also found for the electrospun materials. It could also be shown that the substitution of the aromatic 4,4'-methylene diphenyl diisocyanate building blocks in PellethaneTM with the aliphatic hexamethylene diisocyanate – to avoid toxic aromatic amines as degradation products only causes minor loss of strength. To obtain degradable TPUs, our concept is to incorporate cleavable ester bonds into the polymer chain. For this purpose, lacticand terephthalic ester-based cleavable chain extenders were used. The expected degradation products showed no cytotoxicity in-vitro. Degradation tests of polymer samples in phosphate buffered saline at elevated temperatures confirmed the degradability of the new polymers. INTRODUCTION Diseases of the cardiovascular system are one of the main causes of morbidity and mortality in the western hemisphere. Surgical therapy of cardiovascular disorders frequently requires the replacement of the diseased tissue with prosthetic grafts. Autologous vessels are the preferred replacement grafts, but many patients have no suitable vessels for harvest due to coexisting diseases or reoperation. The search for vascular substitute materials was thus directed at bioinert materials that minimally interact with blood and tissue. Elastic polymers, like expanded polytetrafluorethylene (ePTFE) or polyethylene terephthalate (PET) are currently the standard prosthetic materials which are used in vascular surgery. However, these synthetic materials have proved to be inferior to autologous conduits, especially when used for small caliber vessels or in low-flow applications. The main reasons for the poor performance are anastomotic intimal hyperplasia and innate surface thrombogeneicity. . In-vivo studies with grafts made of biodegradable thermoplastic polyurethane elastomers (TPUs) revealed that these materials promote the growth of neo-arteries and the graft therefore exhibits long-term patency [2]. But beside the chemical properties, the microstructure of the material plays an important role for the biocompatibility of the artificial grafts. Electrospinning (ES) has proofed to be the ideal processing tool for synthetic grafts as the random orientation of the nano-fibers perfectly mimics the extracellular matrix [3-5]. The three-dimensional scaffold serves as an framework for cell adhesion, proliferation and differentiation. Therefore we were interested in the development of new biodegradable TPUs. Generally, segmented TPUs possess two different moieties – the hardand the soft-blocks. Degradability can be introduced in each or both parts of the polymer through the incorporation of (hydrolytically or enzymatically) cleavable bonds (Figure 1). hard-block soft-block diisocyanate chain extender prepolymer association soft-block degradation cleavable bond hard-block degradation Basic composition of TPUs Introduction of degradability Figure 1. Concepts for degradable thermoplastic urethane elastomers. This study aims on the systematically, stepwisely conversion of the commercial TPU PellethaneTM (Dow) into a biocompatible, biodegradable elastomer that can be spun with ES to obtain artificial (cardio)vascular grafts (Figure 2). Therefore the different components (diisocyanate, prepolymer and chain extender) were substituted in order to improve the biocompatibility and induce degradability (Table I). reference material substitution of aromatic diisocyanate • mechanical study • electrospinning concepts for hard/soft-block degradability cytotoxicity tests of the expected degradation products synthesis of cleavable chain extender (CCE) and TPUs tests of new TPUs • degradability tests • mechanical tests optimization of ES process • mechanical tests • in-vitro cell tests Figure 2. Concept for the development of degradable polyurethane-based vascular grafts. Table I. Substitution of the components for the TPU synthesis. reference modification aim diisocyante CH2 OCN 2 MDI NCO OCN HMDI avoid aromatic amines as degradation products/metabolites chain extender O H OH BDO O