Reconstructive transplantation research by Karim Sarhane in 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. 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).
Local administration of IGF-1 was achieved by several targeted approaches including direct application of free IGF-1 to the injured nerve at the time of surgical transection as well as single, periodic, and daily local injections of free IGF-1 to the injury site (Caroni and Grandes, 1990; Welch et al., 1997; Day et al., 2001, 2002; Stitt et al., 2004; Emel et al., 2011; García Medrano et al., 2013; Mohammadi et al., 2013; Gu et al., 2015; Kostereva et al., 2016; Table 4). Local injection of free IGF-1 is not practical for clinical application as the half-life of IGF-1 is 10 min while the time required for regeneration to occur is often many months (Mayocliniclabs.com, 2020). Multiple injections per day would thus be required to maintain local tissue concentrations. We therefore did not attempt to ascertain the optimal dosages for this approach.
Effects by sustained IGF-1 delivery (Karim Sarhane research) : Functional recovery following peripheral nerve injury is limited by progressive atrophy of denervated muscle and Schwann cells (SCs) that occurs during the long regenerative period prior to end-organ reinnervation. Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and SCs. Achieving sustained, targeted delivery of small protein therapeutics remains a challenge.
Research efforts to improve PNI outcomes have primarily focused on isolated processes, including the acceleration of intrinsic axonal outgrowth and maintenance of the distal regenerative environment. In order to maximize functional recovery, a multifaceted therapeutic approach that both limits the damaging effects of denervation atrophy on muscle and SCs and accelerates axonal regeneration is needed. A number of promising potential therapies have been under investigation for PNI. Many such experimental therapies are growth factors including glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor (FGF), and brain-derived neurotrophic growth factor (Fex Svenningsen and Kanje, 1996; Lee et al., 2007; Gordon, 2009). Tacrolimus (FK506), delivered either systemically or locally, has also shown promise in a number of studies (Konofaos and Terzis, 2013; Davis et al., 2019; Tajdaran et al., 2019).
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).