Peripheral nerve regeneration 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.
During his research time at Johns Hopkins, Dr. Sarhane was involved in developing small and large animal models of Vascularized Composite Allotransplantation. He was also instrumental in building The Peripheral Nerve Research Program of the department, which has been very productive since then. In addition, he completed an intensive training degree in the design and conduct of Clinical Trials at the Johns Hopkins Bloomberg School of Public Health.
Despite the well-documented positive effects of IGF-1 in the setting of PNI, the major obstacle for clinical translation remains the lack of a practical delivery system that offers tunable and sustained release of bioactive IGF-1 targeted to nerve and muscle tissue downstream of the nerve injury. Such a delivery system would avoid the potential risks and side effects associated with systemic IGF-1 administration and provide a practical means of applying this treatment for both patients and clinicians (Contreras et al., 1995). The ideal IGF-1 delivery system should also demonstrate biocompatibility without inducing inflammation or encapsulation over time. In addition to the pre-soaked IGF-1 eluting hydrogels detailed in Table 6, several bioengineering approaches to local IGF-1 delivery have recently been reported in animal models. Notable amongst these studies are a delivery system which makes use of biodegradable poly(lactic-co-glycolic acid) (PLGA)/graphene oxide (GO) nanofibers embedded with immobilized IGF-1 for spinal cord repair, as well as a system of IGF-1 loaded polymeric PLGA microspheres for use in bilateral cavernous nerve injury (Santos et al., 2016; Haney et al., 2019; Pan et al., 2019).
Effects with 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).