Bioengineered Composite for the Treatment of Peripheral Arterial Disease

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PROJECT SUMMARY Peripheral artery disease (PAD) affects 8-10 million people in the US. Clinical trials evaluating stem cell, growth factor, or gene therapy systems for the treatment of PAD have shown some promising results. Use of biomaterial matrices either to enhance therapies or as a standalone treatment are just beginning to be explored in small animal models of PAD, with promising findings indicating that a biomaterial strategy can enhance the efficacy of intramuscular cell therapies in treating the effects of leg ischemia. There are important requirements for optimal delivery, retention, and performance of a bioengineered composite in the mechanically, histologically, and biochemically dynamic intramuscular environment of the PAD leg. The material should: (a) undergo minimal swelling once inside the target tissue; (b) have proper mechanical properties with high resilience to tolerate repeated compressive strain during muscle contraction for its long-term intramuscular retention; (c) be porous enough to facilitate the exchange of trophic factors with the surrounding environment and to permit recruitment of host progenitor and endothelial cells; and (d) have antioxidative and angiogenic properties that can be beneficial to the management of the myopathy of PAD. The objective of the current proposal is to characterize and optimize a biomaterial-based treatment for PAD. We have recently developed an injectable, angiogenic, nanofiber-hydrogel composite with unique interfacial bonding between the hydrogel matrices and the fibers, and successfully applied the composite for the regeneration of soft tissue defects in a rabbit model. We have further modified the hydrogel to have antioxidant properties with minimal swelling and optimized mechanical characteristics to mimic skeletal muscle. Testing in a rat model of PAD, the hydrogel reduced lipid oxidation, enhanced local blood flow in the muscle, and improved running capacity of the treated rats. In addition, we have developed and validated a porcine model of hindlimb ischemia (iliofemoral artery ligation/excision), which recapitulates key aspects of the pathophysiology of human PAD/claudication and can be a platform for the development of therapies for PAD. We are now primed to develop and test our novel therapies for PAD in our porcine model. We have all of the tools in place to address the central hypothesis that a nanofiber-hydrogel composite with optimized mechanical, angiogenic, and antioxidative characteristics will improve hemodynamic, histologic, and physiological endpoints of the ischemic hindlimb in rat and porcine models of PAD. Successful completion of this project will deliver the first off-the-shelf synthetic composite matrix for the treatment of PAD patients. As providing local therapy for the ischemic leg is critical to prevent myopathy and to improve the performance of the affected lower limbs in PAD patients, this study will provide an important advancement over other currently available treatments for PAD. The composite developed in this project can also be readily applied to treat other disease entities, including skeletal and possibly heart muscle pathologies related to ischemia/reperfusion, trauma, infection, and inflammation.