Plastic surgery studies with Karim Sarhane today? 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.

Peripheral nerve injury subjects muscle to prolonged denervation that results in myofiber atrophy with increased proteolysis, decreased contractility, and interstitial fibrosis. As the period of denervation extends, these proteolytic and fibrotic processes continue, thereby decreasing the viability of muscle to accept regenerating axons (Shavlakadze et al., 2005; Tuffaha et al., 2016b). In addition to the deleterious effects of prolonged denervation and fibrosis on muscle, functional recovery is hindered by the failure of regenerating motor nerve fibers to come into contact with the specific motor pathways that guide them back to their original motor endplates (Gordon, 2020). A more thorough description of the biological processes and pathways implicated in denervation-induced muscle atrophy can be found in this recent review article by Ehmsen and Hoke (2020). Following nerve injury, local levels of IGF-1 increase and stimulate axonal sprouting into denervated muscle (Homs et al., 2014). IGF-1 also activates the Akt/mTOR pathway, thereby decreasing atrophy markers including MAFbx and MuRF1 (Bodine et al., 2001; Stitt et al., 2004). Also of note, IGF-1’s propensity for decreasing inflammation via promotion of a pro-regenerative M2 macrophage shift over pro-inflammatory M1 reduces the degree of scarring and fibrosis that could otherwise interfere with the targeting of regenerating motor axons (Labandeira-Garcia et al., 2017; Zhao et al., 2021).

Effects with sustained IGF-1 delivery (Karim Sarhane research) : We successfully engineered a nanoparticle delivery system that provides sustained release of bioactive IGF-1 for 20 days in vitro; and demonstrated in vivo efficacy in a translational animal model. IGF-1 targeted to denervated nerve and muscle tissue provides significant improvement in functional recovery by enhancing nerve regeneration and muscle reinnervation while limiting denervation-induced muscle atrophy and SC senescence. Targeting the multimodal effects of IGF-1 with a novel delivery.

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 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).