IGF-1 and Agrin Co-Delivery Nanoparticles in a Nanofiber Hydrogel-based Drug Delivery System Improve Functional Recovery After Peripheral Nerve Injury
Erica B Lee, MS1, Julia Lu, BS2, Thomas G.W. Harris, MBChB3, William M Padovano, MD MPHS1, Emma Rowley, BS1, Aidan Weitzner, BS1, Zohra V Aslami, BA1, Zachary Zamore, BA4, Ahmet Höke, MD, PhD2, Hai-Quan Mao, PhD2 and Sami H Tuffaha, MD4, 1Johns Hopkins University School of Medicine, Baltimore, MD, 2Johns Hopkins University, Baltimore, MD, 3Johns Hopkins School of Medicine, Baltimore, MD, 4Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
PURPOSE: Following peripheral nerve injury, denervated tissues undergo several progressive degenerative processes that impede regeneration and minimize the degree of functional return achievable on reinnervation. Our group has previously demonstrated the individual efficacy of IGF-1 nanoparticles (IGF-1 NPs) and agrin nanoparticles (agrin NPs) in improving functional recovery following nerve injury. We hypothesize IGF-1 and agrin will have synergistic benefits in promoting functional recovery as IGF-1 accelerates axonal regeneration and preserves Schwann cells and myocytes while agrin preserves neuromuscular junction morphology and promotes receptivity to reinnervation. This study aimed to evaluate the efficacy of co-treatment with IGF-1 NPs and agrin NPs in a rodent chronic denervation model.
METHODS: IGF-1 and agrin were encapsulated in biodegradable NPs and then embedded within a hyaluronic acid/PCL nanofiber hydrogel composite (NHC). The effects of locally delivered treatment were assessed using a chronic denervation nerve injury model in which the median nerve was denervated for 12 weeks until ulnar-to-median nerve transfer at Week 0. Following nerve transfer, all animals underwent 16 weeks of regeneration and grip strength assessment. Animals were injected with IGF-1/agrin NP co-treatment, IGF-1 NP, agrin NP, free IGF-1/agrin, or empty NP every six weeks from time of median nerve injury until Week 12. To identify the optimal timing of co-treatment, two groups alternated treatment during denervation and regeneration between either IGF-1/agrin NP co-treatment or IGF-1 NP. Upon sacrifice at Week 16, tissues were assessed for NMJ reinnervation, muscle atrophy, and axonal regeneration.
RESULTS: All nanoparticle-encapsulated drug treated animals exhibited increased functional recovery compared to free IGF-1/agrin co-treatment (p<0.01, 2-way ANOVA) and empty-NP treated animals (p<0.001 2-way ANOVA), with the greatest benefit seen in the full IGF-1/agrin NP co-treatment group. At Week 16, full IGF-1/agrin NP co-treatment animals demonstrated an increase in functional recovery of 36.5% compared to empty-NP. Full IGF-1/agrin NP co-treated animals demonstrated significantly greater NMJ reinnervation than empty NP animals (p<0.001).
CONCLUSION: IGF-1/agrin co-treatment in vivo improves functional recovery of forelimb grip strength and promotes neuromuscular junction reinnervation. Histological analyses of axonal regeneration, Schwann cell proliferation, and myofibril atrophy are currently ongoing. Our group has previously established the benefits of IGF-1 NP in ameliorating the effects of chronic denervation on these factors, and we anticipate a greater benefit will be seen with agrin NP co-treatment.
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