Reconstructive microsurgery research and science with Karim Sarhane today? 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.

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 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.

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).

Insulin-like growth factor-1 (IGF-1) is a particularly promising candidate for clinical translation because it has the potential to address the need for improved nerve regeneration while simultaneously acting on denervated muscle to limit denervation-induced atrophy. However, like other growth factors, IGF-1 has a short half-life of 5 min, relatively low molecular weight (7.6 kDa), and high water-solubility: all of which present significant obstacles to therapeutic delivery in a clinically practical fashion (Gold et al., 1995; Lee et al., 2003; Wood et al., 2009). Here, we present a comprehensive review of the literature describing the trophic effects of IGF-1 on neurons, myocytes, and SCs. We then critically evaluate the various therapeutic modalities used to upregulate endogenous IGF-1 or deliver exogenous IGF-1 in translational models of PNI, with a special emphasis on emerging bioengineered drug delivery systems. Lastly, we analyze the optimal dosage ranges identified for each mechanism of IGF-1 with the goal of further elucidating a model for future clinical translation.