Day: June 15, 2022

Peripheral nerve regeneration research from Karim Sarhane 2022? We performed a study with rodents and primates that showed this new delivery method provided steady release of IGF-1 at the target nerve for up to 6 weeks,” Dr. Karim Sarhane reported. Compared to animals without this hormone treatment, IGF-1 treated animals (rodents and primates) that were injected every 6 weeks showed a 30% increase in nerve recovery. This has the potential to be a very meaningful therapy for patients with nerve injuries. Not only do these results show increased nerve recovery but receiving a treatment every 6 weeks is much easier on a patient’s lifestyle than current available regiments that require daily treatment.

Dr. Sarhane is published in top-ranked bioengineering, neuroscience, and surgery journals. He holds a patent for a novel Nanofiber Nerve Wrap that he developed with his colleagues at the Johns Hopkins Institute for NanoBioTechnology and the Johns Hopkins Department of Neuroscience (US Patent # 10500305, December 2019). He is the recipient of many research grants and research awards, including the Best Basic Science Paper at the Johns Hopkins Residents Research Symposium, the Basic Science Research Grant Prize from the American Foundation for Surgery of the Hand, the Research Pilot Grant Prize from the Plastic Surgery Foundation, and a Scholarship Award from the American College of Surgeons. He has authored to date 46 peer-reviewed articles, 11 book chapters, 45 peer-reviewed abstracts, and has 28 national presentations. He is an elected member of the Plastic Surgery Research Council, the American Society for Reconstructive Microsurgery, the American Society for Reconstructive Transplantation, and the American Society for Peripheral Nerves.

Gene delivery targeted to skeletal myocytes has also demonstrated promise as a method of upregulating IGF-1 production in PNI models (Flint et al., 2004; Rabinovsky and Draghia-Akli, 2004; Nagata et al., 2014; Tsai et al., 2016). This approach has been applied both systemically as well as directly to the local site of PNI. Amongst the gene delivery protocols included in Table 2, the work of Nagata et al. (2014) is notable given its use of a biocompatible polyplex nanomicelle as a means of delivering IGF-1 plasmid DNA (pDNA) to the local site of PNI (Nagata et al., 2014). The diverse strategies employed by these systemic GH axis modifiers demonstrate the flexibility with which IGF-1 can potentially be incorporated into future translational approaches. However, these systemic therapeutic approaches are all limited by the resulting systemic upregulation of IGF-1 with the associated risks and side effects as well as the lack of fine control of IGF-1 levels within the target tissues, specifically the injured nerve and denervated muscle.

Effects by sustained IGF-1 delivery (Karim Sarhane research) : Under optimized conditions, uniform PEG-b-PCL NPs were generated with an encapsulation efficiency of 88.4%, loading level of 14.2%, and a near-zero-order release of bioactive IGF-1 for more than 20 days in vitro. The effects of locally delivered IGF-1 NPs on denervated muscle and SCs were assessed in a rat median nerve transection-without- repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy, reinnervation, and recovery of motor function were assessed in a model in which chronic denervation is induced prior to nerve repair. IGF-1 NP treatment resulted in significantly greater recovery of forepaw grip strength, decreased denervation-induced muscle atrophy, decreased SC senescence, and improved neuromuscular reinnervation.

Following surgical repair, axons often must regenerate over long distances at a relatively slow rate of 1–3 mm/day to reach and reinnervate distal motor endplates. Throughout this process, denervated muscle undergoes irreversible loss of myofibrils and loss of neuromuscular junctions (NMJs), thereby resulting in progressive and permanent muscle atrophy. It is well known that the degree of muscle atrophy increases with the duration of denervation (Ishii et al., 1994). Chronically denervated SCs within the distal nerve are also subject to time-dependent senescence. Following injury, proliferating SCs initially maintain the basal lamina tubes through which regenerating axons travel. SCs also secrete numerous neurotrophic factors that stimulate and guide axonal regeneration. However, as time elapses without axonal interaction, SCs gradually lose the capacity to perform these important functions, and the distal regenerative pathway becomes inhospitable to recovering axons (Ishii et al., 1993; Glazner and Ishii, 1995; Grinsell and Keating, 2014).

We comprehensively reviewed the literature for original studies examining the efficacy of IGF-1 in treating PNI. We queried the PubMed and Embase databases for terms including “Insulin-Like Growth Factor I,” “IGF1,” “IGF-1,” “somatomedin C,” “PNIs,” “peripheral nerves,” “nerve injury,” “nerve damage,” “nerve trauma,” “nerve crush,” “nerve regeneration,” and “nerve repair.” Following title review, our search yielded 218 results. Inclusion criteria included original basic science studies utilizing IGF-1 as a means of addressing PNI. Following abstract review, 56 studies were sorted by study type and mechanism of delivery into the following categories: (1) in vitro, (2) in vivo endogenous upregulation of IGF-1, or (3) in vivo delivery of exogenous IGF-1. Studies included in the in vivo exogenous IGF-1 group were further sub-stratified into systemic or local delivery, and the local IGF-1 delivery methods were further sub-divided into free IGF-1 injection, hydrogel, or mini-pump studies. Following categorization by mechanism of IGF-1 delivery, the optimal dosage range for each group was calculated by converting all reported IGF-1 dosages to nM for ease of comparison using the standard molecular weight of IGF-1 of 7649 Daltons. After standardization of dosages to nM, the IGF-1 concentration reported as optimal from each study was used to calculate the overall mean, median, and range of optimal IGF-1 dosage for each group.