IGF-1 Nanoparticles Improve Functional Recovery After Nerve Repair
Philip Hanwright, MD, Chenhu Qiu, BS, Jennifer Rath, BS, Nicholas von Guionneau, MBBS, Karim Sarhane, MD, Thomas Harris, Harsha Malapati, BS, W. P. Andrew Lee, Ahmet Hoke, MD, PhD, Hai-Quan Mao, PhD, Sami Tuffaha, MD.
Johns Hopkins, Baltimore, MD, USA.
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 (Figure 1). (2) IGF-1 treated animals recovered significantly more forceful grip strength compared to negative controls (Figure 2). 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.
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