Tyrosine‐derived polycarbonate nerve guidance tubes elicit proregenerative extracellular matrix deposition when used to bridge segmental nerve defects in swine

Abstract

Promising biomaterials should be tested in appropriate large animal models that recapitulate human inflammatory and regenerative responses. Previous studies have shown tyrosine‐derived polycarbonates (TyrPC) are versatile biomaterials with a wide range of 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 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 NGTs made using two different TyrPC compositions in a 1 cm porcine peripheral nerve repair model. We first evaluated a nondegradable TyrPC formulation, demonstrating proof‐of‐concept chronic regenerative efficacy up to 6 months with similar nerve/muscle electrophysiology and morphometry to the autograft repair control. Next, we characterized the acute regenerative response using a degradable TyrPC formulation. After 2 weeks in vivo, TyrPC NGT promoted greater deposition of pro‐regenerative extracellular matrix (ECM) constituents (in particular collagen I, collagen III, collagen IV, laminin, and fibronectin) compared to commercially available collagen‐based NGTs. This corresponded with dense Schwann cell infiltration and axon extension across the lumen. 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.

Orally administered boldine reduces muscle atrophy and promotes neuromuscular recovery in a rodent model of delayed nerve repair

“…For example, a scaled safe and effective dose range can be calculated based on the species body weight and body surface area ( Nair and Jacob, 2016 ). While boldine may be a promising intervention, additional preclinical testing in large animal models is necessary to determine the mechanism(s)-of-action and evaluate functional recovery ( Burrell et al, 2020 , 2021 ; Petrov et al, 2022 ). Additionally, pharmacological treatment of muscle denervation may be a useful adjunct for advanced tissue engineering strategies that replace damaged nervous structures ( Zhang et al, 2018a , b , 2021 , 2022 ; Katiyar et al, 2020 , 2021 ; Shultz et al, 2021 ; Burrell et al, 2022 ; Smith et al, 2022 ).…”

Tyrosine-Derived Polymers as Potential Biomaterials: Synthesis Strategies, Properties, and Applications

“…However, there was a noticeable difference in the ECM deposition, wherein an elevated collagen III and laminin concentration was observed inside the walls of E1001­(1K) NGTs compared to collagen NGTs. In addition, no inflammatory responses or toxicity was associated with the implant under functional electrophysiological recordings in the 6 month study duration …”

“…In addition, no inflammatory responses or toxicity was associated with the implant under functional electrophysiological recordings in the 6 month study duration. 172 4.2.3. Muscle Tissue Engineering.…”

A sciatic nerve gap-injury model in the rabbit

“…1C–E ). Then followed the proximal and distal anchoring of a braided Tyrosine-derived polymeric artificial nerve-guide [ 52 ] of 3 mm inner diameter (Fig. 1F ).…”