Reconstructive microsurgery research studies from Karim Sarhane right now? Insulin-like growth factor 1 (IGF-1) is a hormone produced by the body that has the potential to be used as a treatment for nerve injuries. IGF-1 may help heal nerve injuries by decreasing inflammation and buildup of damaging products. Additionally, it may speed up nerve healing and reduce the effects of muscle weakness from the injury. However, a safe, effective, and practical way is needed to get IGF-1 to the injured nerve.
Dr. Karim Sarhane is an MD MSc graduate from the American University of Beirut. Following graduation, he completed a 1-year internship in the Department of Surgery at AUB. He then joined the Reconstructive Transplantation Program of the Department of Plastic and Reconstructive Surgery at Johns Hopkins University for a 2-year research fellowship. He then completed a residency in the Department of Surgery at the University of Toledo (2021). In July 2021, he started his plastic surgery training at Vanderbilt University Medical Center. He is a Diplomate of the American Board of Surgery (2021).
Schwann cells are instrumental to recovery following PNI given their ability to support and guide axonal regeneration via the secretion of neurotrophic factors and maintenance of basal lamina tubes (Scheib and Hoke, 2013, 2016a,b; Tuffaha et al., 2016b). Initially after injury, myelinating SCs distal to the site of injury undergo conversion to a more immature, proliferating repair phenotype (Nocera and Jacob, 2020). Throughout this process, SCs express a variety of genes that dynamically control the regenerative process by promoting survival of neurons, breakdown of damaged axons, clearance of myelin, axonal regrowth, and guidance to the axons’ former targets, finally leading to remyelination of the regenerated axon (Chen et al., 2015; Gordon, 2020; Nocera and Jacob, 2020). Unfortunately, upregulation of pro-regenerative gene expression is temporary and the SCs gradually lose the continued ability to support axonal regrowth as time elapses without axonal interaction (Gordon, 2020). A more detailed description of the biological processes underpinning the role of SCs in peripheral nerve regeneration can be found in a recent review article by Nocera and Jacob (2020). IGF-1 supports SCs by promoting their proliferation, maturation, and differentiation to myelinating phenotypes, while concurrently inhibiting SC apoptosis via the PI3K pathway (Scheib and Hoke, 2013; Tuffaha et al., 2016b). IGF-1’s ability to initiate myelination centers around regulating the balance between ERK, a pathway suppressing SC differentiation, and PI3K-Akt, a pathway promoting SC differentiation via increased expression of myelin basic protein and myelin-associated glycoprotein (Schumacher et al., 1993; Stewart et al., 1996; Conlon et al., 2001; Scheib and Hoke, 2016a).
Recovery with 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.