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A Novel Hydrogel-based Nanofiber Drug Delivery System For Sustained Release Of Igf-1 Nanoparticles To Improve Functional Outcomes After Nerve Repair
Karim A. Sarhane, MD, MSc, Chenhu Qiu, PhD candidate, Benjamin R. Slavin, MD candidate, Nicholas Hricz, BS, Marcos Iglesias, PhD, DVM, Nicholas von Guionneau, MBBS, Philip J. Hanwright, MD, Ruifa Mi, MD, PhD, Ahmet Höke, MD, PhD, Hai-Quan Mao, PhD, Sami H. Tuffaha, MD.
Johns Hopkins University, Baltimore, MD, USA.

PURPOSE:Despite extensive research efforts, no therapeutic agents are currently clinically indicated for the treatment of peripheral nerve injuries. Insulin-like growth factor 1 (IGF-1) is an ideal therapeutic candidate as it can accelerate axonal regeneration and also minimize the deleterious effects of prolonged denervation on muscle and Schwann cells. However, given its short half-life, a practical delivery system is needed to stabilize the protein and provide sustained release to target tissues. Using a novel encapsulation method, we demonstrated sustained release of bioactive IGF-1 from nanoparticles, in vitro, and improved nerve regeneration and functional recovery, in vivo. An optimized carrier system to maintain the nanoparticles at target tissue sites for the duration of drug release and avoid frequent re-dosing is now needed. We therefore developed a biocompatible nanofiber hydrogel composite that could be loaded with IGF-1 nanoparticles; fine-tuned its drug release kinetics in vitro and in vivo; and applied it in a chronic denervation median nerve model to assess its impact on functional recovery.
METHODS:An injectable nanofiber-hydrogel composite system (made of PCL nanofibers covalently bonded to hyaluronic acid) was developed by electrospinning. Its 3-D structure was formulated to mimic that of fat extracellular matrix (ECM), Figures 1A and 1B. The release kinetics of this delivery system were then optimized in vitro and in vivo (using ELISA and immunofluorescent staining) to achieve controlled release of IGF-1 at therapeutic levels (~10 times EC50) for a prolonged period, Figure 1C. Finally, using a chronic median nerve denervation model, we tested the effects of this modality on axonal regeneration, Schwann cell senescence, muscle atrophy and muscle force.
RESULTS: The level of synthetic mimicry between our drug-delivery system and ECM fat was noted to confer high levels of biocompatibility as evidenced by a minimal inflammatory response 25 days post injection (Figures 1D, 1E, 1F). The composite system polarized the invading macrophages into an anti-inflammatory and pro-regenerative M2 phenotype (Figure 1G, 1H, 1I). The release kinetics of IGF-1 from the nanofiber system were superior to other carriers (fibrin glue and saline), both in vitro and in vivo (Figure 1J). When injected into the target muscle and deposited at the nerve coaptation site in a chronic median nerve denervation model, functional outcomes were improved (although not reaching a customary level of statistical significance, Figure 1K.
CONCLUSION: We introduce a novel drug delivery system in which IGF-1 nanoparticles are combined with a nanofiber hydrogel carrier to provide sustained local concentrations of bioactive IGF-1within target nerve and muscle. This therapeutic approach has the potential to improve functional outcomes via enhanced axonal regeneration and maintenance of denervated muscle and Schwann cells. IGF-1 and the polymer components of the engineered delivery system are currently used in FDA-approved formulations and devices, which will facilitate clearance of regulatory hurdles.


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