Karim Sarhane MD, Msc
Johns Hopkins University-School of Medicine
Pilot Research Grant
Peripheral Nerve, Tissue Engineering
Peripheral nerve injury (PNI) remains a challenging problem. Despite best efforts at surgical reconstruction and postoperative rehabilitation, patients with PNI are often left with persistent, debilitating motor and sensory deficits. Therapies to enhance the regenerative process are lacking. Poor outcomes result from prolonged periods of latency prior to reinnervation. Over time, the absence of muscle innervation causes irreversible atrophy that limits functional motor recovery. Further hindering outcomes, chronically denervated Schwann cells within the distal nerve stump senesce over time and lose their capacity to support regenerating axons. Therapies are needed to accelerate axonal regeneration and maintain denervated muscle and Schwann cells. Augmentation of the growth hormone (GH) axis has emerged as a promising therapeutic approach, the effects of which are primarily mediated by insulin-like growth factor 1 (IGF-1). IGF-1 acts on neurons to speed axonal regeneration and acts independently on denervated muscle and Schwann cells to limit denervation atrophy and senescence. Despite promising experimental results, GH therapies have undesirable side effects resulting from the need for systemic administration; they also require costly and inconvenient daily dosing injections. To overcome these obstacles, we developed biodegradable nanoparticles to encapsulate and release IGF-1 over 70 days with near zero order kinetics. We now need a biocompatible carrier that can fixate the nanoparticles to nerve and muscle for the duration of IGF-1 release without interfering with the favorable release kinetics achieved from the nanoparticles. Our collaborator, Prof. Hai-Quan Mao has developed a nanofiber hydrogel composite with characteristics that make it ideal for this purpose (favorable biocompatibility, biointegration, injectability, mechanical properties, and tunable degradation time). In the proposed studies, we will prepare two sets of nanofiber-hyaluronic acid hydrogel composites with low and high viscosity characteristics (Aim 1) for delivery to muscle and nerve, respectively. We will optimize the release kinetics of the IGF-1 NPs in the hydrogel composites by varying the crosslinking density. We will then (Aim 2) test the effects of the IGF-1 NPs delivered within the optimized hydrogel composite on axonal regeneration, SC proliferation, and muscle reinnervation using a rat chronic denervation model.
I believe I am very well suited to successfully carry out the proposed project. I have extensive research experience in the field of peripheral nerve. I started peripheral nerve research back in 2012 in that same laboratory. I have not only developed advanced microsurgical skills to reliably perform the surgeries, but also learnt the necessary bench techniques that are required to study nerve regeneration (nerve and muscle histomorphometry, nerve conduction studies, stimulated grip strength testing, in addition to NMJ staining and other key immunohistochemical stains). I also developed strong research bonds with multiple collaborators in Johns Hopkins in the Departments of Neuroscience and Material Science. These efforts culminated in several publications, with a few still in the review process.
Karim Sarhane, MD