Peripheral nerve regeneration research with Karim Sarhane 2022? One-fifth to one-third of patients with traumatic injuries to their arms and legs experience nerve injury, which can be devastating. It can result in muscle weakness or numbness, prevent walking or using the arms, and reduce the ability to perform daily activities. Even with surgery, some nerve injuries never recover, and currently there are not many medical options to address this problem. In 2022, the researchers plan to perform this research on more primates to triple the size of the original group. The study can then move into phase I clinical trials for humans.
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).
Systemic delivery of IGF-1 is achieved via either daily subcutaneous or intraperitoneal injections of free IGF-1. Reported optimal dosages for regeneration of nerve, SC, and muscle range from 0.001 to 1.00 mg/kg/day with a mean of 0.59 mg/kg/day and a median of 0.75 mg/kg/day of IGF-1 (Contreras et al., 1993, 1995; Vaught et al., 1996; Vergani et al., 1998; Lutz et al., 1999; Mohammadi and Saadati, 2014; Table 3). The calculated mean and median IGF-1 concentrations for systemic delivery were the highest of any of the delivery mechanisms included in our analysis. This finding emphasizes that the use of a systemic approach necessitates greater dosages of IGF-1 to account for off-target distribution and degradation/clearance prior to reaching the injury site. Notably, almost none of the systemic studies included in this analysis quantified the concentration of IGF-1 at the target injury site, which raises significant concerns about the validity of the findings. With regards to clinical applicability, systemic IGF-1 delivery is severely limited by the risk of side effects, including hypoglycemia, lymphoid hyperplasia, body fat accumulation, electrolyte imbalances, and mental status changes (Elijah et al., 2011; Tuffaha et al., 2016b; Vilar et al., 2017). In contrast to upregulation of systemic IGF-1 via GH Releasing Hormone (GHRH), treatment with systemic IGF-1 does not have the benefit of upstream negative feedback control and therefore poses a greater risk of resulting in spiking IGF-1 levels.
Recovery by sustained IGF-1 delivery (Karim Sarhane research) : To realize the therapeutic potential of IGF-1 treatment for PNIs, we designed, optimized, and characterized a novel local delivery system for small proteins using a new FNP-based encapsulation method that offers favorable encapsulation efficiency with retained bioactivity and a sustained release profile for over 3 weeks. The IGF-1 NPs demonstrated favorable in vivo release kinetics with high local loading levels of IGF-1 within target muscle and nerve tissue.
Patients who sustain peripheral nerve injuries (PNIs) are often left with debilitating sensory and motor loss. Presently, there is a lack of clinically available therapeutics that can be given as an adjunct to surgical repair to enhance the regenerative process. Insulin-like growth factor-1 (IGF-1) represents a promising therapeutic target to meet this need, given its well-described trophic and anti-apoptotic effects on neurons, Schwann cells (SCs), and myocytes. Here, we review the literature regarding the therapeutic potential of IGF-1 in PNI. We appraised the literature for the various approaches of IGF-1 administration with the aim of identifying which are the most promising in offering a pathway toward clinical application. We also sought to determine the optimal reported dosage ranges for the various delivery approaches that have been investigated.
The amount of time that elapses between initial nerve injury and end-organ reinnervation has consistently been shown to be the most important predictor of functional recovery following PNI (Scheib and Hoke, 2013), with proximal injuries and delayed repairs resulting in worse outcomes (Carlson et al., 1996; Tuffaha et al., 2016b). This is primarily due to denervation-induced atrophy of muscle and Schwann cells (SCs) (Fu and Gordon, 1995). 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).