IGF-1 Nanoparticles in a Nanofiber Hyrdogel-based Drug Delivery System to Enhance Functional Recovery After Peripheral Nerve Injury
Thomas G.W. Harris, MBChB1, Karim A. Sarhane, MD2, Chenhu Qiu, BS3, Philip J Hanwright, MD2, Nicholas von Guionneau, MD1, Connor Glass, BS1, Alison Wong, MD1, Harsha Malapati, BS1, Nicholas Hricz, BS1, Erica B Lee, MS2, Matthew Generoso, BS1, Ahmet Hoke, MD PhD2, Hai-Quan Mao, PhD3 and Sami Tuffaha, MD4, (1)Johns Hopkins School of Medicine, Baltimore, MD, (2)Johns Hopkins University School of Medicine, Baltimore, MD, (3)Johns Hopkins University, Baltimore, MD, (4)Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Introduction
Insulin-like growth factor 1 (IGF-1) is a potent mitogen that augments axonal regeneration and minimizes the deleterious effects of prolonged denervation on muscle and Schwann cells (SC). Local delivery of IGF-1 is limited though by its short half-life. Previously we demonstrated sustained, steady release of IGF-1 encapsulated within nanoparticles (NP) and subsequently developed a nanofiber fiber hydrogel composite (NHC) carrier to optimize in vivo retention at target tissue sites. Here we aim to further characterize the efficacy and dose-response relationship with this IGF-1 NP-NHC delivery system in a rodent forelimb chronic denervation model.
Materials and Methods
Release kinetics, biocompatibility and immune response of the IGF-1 NP-NHC delivery system were characterized and optimized in vitro and in vivo. The IGF-1 NP-NHC delivery system was evaluated in a rodent forelimb model in which chronic denervation was induced before nerve repair using a range of dosages (300, 950 and 1600 μg/mL). The effect of our delivery system on axonal regeneration, muscle atrophy, SC proliferation and recovery of stimulated grip strength were assessed.
Results
Release kinetics of the NHC delivery system were superior to fibrin gel in vitro and in vivo. Sustained release of bioactive IGF-1 was achieved for more than 6 weeks in vivo using the optimized NP-NHC delivery system. The NHC closely resembled extracellular matrix fat and resulted in minimal inflammatory response 25 days following injection (Figure 1). IGF-1 treated animals exhibited significantly increased functional recovery compared to negative controls with no dose dependence observed at the concentrations tested (Figure 2).
Conclusion
The NP-NHC delivery system provides sustained release of bioactive IGF-1. IGF-1 NP treatment in vivo improves functional recovery of forelimb grip strength by ameliorating axonal regeneration and reducing SC and muscle atrophy. Clinical application of this therapeutic approach has potential as IGF-1 and elements of the delivery system are utilized in FDA approved formulations. A non-human primate study using this IGF-1 NP-NHC delivery system is under way.
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