Tyrosine-Derived Polycarbonate Nerve Guidance Tubes Elicit Pro-Regenerative Extracellular Matrix Deposition When Used to Bridge Segmental Nerve Defects in Swine

Promising biomaterials for facilitating regeneration should be tested in appropriate large animal models that better recapitulate human inflammatory and regenerative responses than rodent models. Previous studies have shown tyrosine-derived polycarbonates (TyrPC) are versatile biomaterials with a wide range of tissue engineering applications across multiple disciplines. The library of TyrPC has been well studied and consists of thousands of polymer compositions with tunable mechanical characteristics and degradation and resorption rates that are useful for the design of nerve guidance tubes (NGTs). NGTs made of different TyrPCs have been used in segmental nerve defect models in small animals. The current study is an extension of this work and evaluates the effects of NGTs made using two different TyrPC compositions in a porcine model of peripheral nerve injury and repair. We first evaluated a nondegradable TyrPC formulation in a 1 cm segmental nerve defect model in pigs, demonstrating proof-of-concept of chronic regenerative efficacy up to 6 months, at which time nerve/muscle electrophysiology and nerve morphometry were similar to those attained by an autograft repair control. Next, we characterized the acute regenerative response to a degradable TyrPC formulation using the same 1 cm segmental defect model. After 2 weeks in vivo, this TyrPC NGT was found to promote the deposition by host cells of pro-regenerative extracellular matrix (ECM) constituents (in particular collagen I, collagen III, collagen IV, laminin and fibronectin) at levels exceeding those deposited inside commercially available collagen-based NGTs. This corresponded with dense and rapid infiltration of host Schwann cells and axons into the lumen of the NGT and axonal crossing of the lesion into the distal nerve segment. These findings confirmed results reported previously in a mouse model and reveal that TyrPC NGTs were well tolerated in swine and facilitated host axon regeneration and Schwann cell infiltration in the acute phase across segmental defects - likely by eliciting a favorable neurotrophic ECM milieu. This regenerative response ultimately can contribute to functional recovery.