Reconstructive microsurgery research from 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.
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.
Mini-osmotic pumps provide a sustained, local delivery of exogenous IGF-1 (Table 5; Kanje et al., 1989; Sjoberg and Kanje, 1989; Ishii and Lupien, 1995; Tiangco et al., 2001; Fansa et al., 2002; Apel et al., 2010; Luo et al., 2016). This technique involves subcutaneous implantation of an osmotic pump in the abdomen with extension of a catheter from the pump to the transected nerve site. The positioning of the catheter is maintained by suturing it to local connective tissue. A fixed concentration and quantity of IGF-1 is then loaded into the pump and released at a constant rate (Kanje et al., 1989). Studies using mini-pump delivery of IGF-1 tested a variety of initial concentrations (mean = 143 µg/mL, median = 100 µg/mL, and range: 50 µg/mL – 100 mg/mL), pump rates (mean = 0.425 µL/h, median = 0.25 µL/h, and range: 0.25 – 1.05 µL/h), and release durations (mean = 26 days, median = 7 days, and range: 3 days–12 weeks). The highest dose was reported by Fansa et al. (2002) using a starting concentration of IGF-1 of 100 mg/mL dosed at a continuous pump rate of 0.25 uL/h over 28 days, a value several orders of magnitude higher than any of the other mini pump studies included in Table 5. This concentration discrepancy relative to other mini-pump studies is possibly attributable to the design of this particular study, which set out to investigate the benefits of IGF-1 on a tissue-engineered nerve graft model containing cultured, viable SCs. When the study by Fansa et al. (2002) is excluded, the reported initial optimal concentration for mini pump studies centers on a much more focused range of 0.1–100 µg/mL with a mean of 60 µg/mL and median of 75 µg/mL.
Effects by sustained IGF-1 delivery (Karim Sarhane research) : We hypothesized that a novel nanoparticle (NP) delivery system can provide controlled release of bioactive IGF-1 targeted to denervated muscle and nerve tissue to achieve improved motor recovery through amelioration of denervation-induced muscle atrophy and SC senescence and enhanced axonal regeneration. Biodegradable NPs with encapsulated IGF-1/dextran sulfate polyelectrolyte complexes were formulated using a flash nanoprecipitation method to preserve IGF-1 bioactivity and maximize encapsulation efficiencies.
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).