Abstract 107: IGF-1 Nanoparticles Improve Functional Recovery After Nerve Repair

Abstract

PURPOSE: Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and Schwann cells (SCs). Local delivery of IGF-1 is limited by its short half-life. The aims of this study are to (1) encapsulate IGF-1 into biodegradable nanoparticles (NPs) that stabilize IGF-1 in its bioactive state and enable sustained release at target tissue sites that persist throughout the regenerative period; and (2) assess the efficacy of locally delivered IGF-1 NPs in augmenting axonal regeneration while also reducing denervation-induced muscle atrophy and SC senescence to thereby improve functional recovery following nerve injury. METHODS: (1) NP Fabrication: IGF-1 was first complexed with dextran sulfate to create hydrophobic ionic paired (HIP) complexes, which were then encapsulated in biodegradable NPs. Varying ratios of HIP:polymer were evaluated to maximize loading efficiency and release kinetics. In vitro NP release kinetics were evaluated and mitogenic activity of released IGF-1 was compared to native IGF-1. (2) The effects of locally-delivered IGF-1 NPs on denervated muscle and Schwann cells were assessed in a rat median nerve transection-without-repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy and reinnervation, and recovery of forepaw function were assessed in a model in which chronic denervation is induced prior to nerve repair; functional recovery was assessed weekly with stimulated grip strength testing prior to sacrifice at 15 weeks for histologic analyses. RESULTS: (1) Fabrication of uniform NPs with an encapsulation efficiency of 83.2% was achieved. NPs composed of 1:5 PEG5k-PCL40k yielded optimal release of IGF-1. Near-zero-order release of IGF-1 can be achieved for at least 70 days and released IGF-1 exhibits comparable bioactivity to native IGF-1. (2) IGF-1 treated animals recovered significantly more forceful grip strength compared to negative controls. IGF-1 NP treatment limits muscle atrophy during periods of denervation compared to negative controls (620 vs. 340μm2, respectively; p <0.05). CONCLUSION: Encapsulation of bioactive IGF-1 with sustained release for over 70 days was achieved. IGF-1 NP treatment in vivo limits muscle atrophy during denervation and improves functional recovery of forelimb grip strength.