Peripheral nerve regeneration research by Karim Sarhane in 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.

The hydrogels were soaked in IGF-1 solutions, with concentrations ranging from 0.05 to 1 mg/ml. The duration of soaking time and biomaterials used for fabrication differed between studies, thereby complicating further direct comparisons beyond individual consideration. Regardless of concentration of IGF-1 soaking solution, duration of soaking time, or hydrogel composition, the fundamental property in predicting utility for nerve regeneration is the sustained concentration of released IGF-1 that is reaching the site of PNI. Unfortunately, only two of the studies included in Table 6 quantified IGF-1 release in vivo using either fluid sampling with ELISA or radiolabeled IGF-1 (Yuan et al., 2000; Kikkawa et al., 2014). Using ELISA, one study reported significantly greater in vivo IGF-1 concentration, peaking at 1.25 µg/mL at Post-operative Day 1 (POD 1) and returning to the physiologic levels of the control group by POD 7 (Kikkawa et al., 2014). Using radiolabeling, the other in vivo quantification study reported a biphasic IGF-1 release profile with an initial burst of approximately 80% of the starting concentration of IGF-1 at 1 h followed by sustained release of the remaining 15% ± 2.9% over the subsequent 48-h period (Yuan et al., 2000). Conversely, a different study reported failure of IGF-1 to prevent motoneuron death, a finding which was noted to be contrary to previous results and required additional investigation. This study described the use of a soaked gel foam plug but did not specify the IGF-1 release profile of this material (Bayrak et al., 2017). As such, further analysis and testing is needed to determine the optimal fabrication parameters, loading strategy, and concentration of released IGF-1 required for successful local delivery via hydrogel.

Effects 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.

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).

The positive trophic and anti-apoptotic effects of IGF-1 are primarily mediated via the PI3K-Akt and MAP-kinase pathways (Ho and 2007 GH Deficiency Consensus Workshop Participants, 2007; Chang et al., 2017). Autophosphorylation of the intracellular domain of IGF-1 receptors results in the activation of insulin receptor substrates 1–4, followed by activation of Ras GTPase, and then the successive triggering of Raf, MEK, and lastly ERK. Through activation of Bcl-2, ERK has been shown to prevent apoptosis and foster neurite growth. Ras activation also triggers aPKC and Akt (Homs et al., 2014), with the active form of the latter inhibiting GSK-3ß and thus inhibiting a number of pro-apoptotic pathways (Kanje et al., 1988; Schumacher et al., 1993; Chang et al., 2017). Additionally, the JAK-STAT pathway is an important contributor toward the stimulation of neuronal outgrowth and survival by facilitating Growth Hormone (GH) receptor binding on target tissue to induce IGF-1 release (Meghani et al., 1993; Cheng et al., 1996; Seki et al., 2010; Chang et al., 2017). These biochemical mechanisms enable GH and IGF-1 to exert anabolic and anti-apoptotic effects on neurons, SCs, and myocytes (Tuffaha et al., 2016b).