Reconstructive transplantation 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.

Dr. Sarhane is published in top-ranked bioengineering, neuroscience, and surgery journals. He holds a patent for a novel Nanofiber Nerve Wrap that he developed with his colleagues at the Johns Hopkins Institute for NanoBioTechnology and the Johns Hopkins Department of Neuroscience (US Patent # 10500305, December 2019). He is the recipient of many research grants and research awards, including the Best Basic Science Paper at the Johns Hopkins Residents Research Symposium, the Basic Science Research Grant Prize from the American Foundation for Surgery of the Hand, the Research Pilot Grant Prize from the Plastic Surgery Foundation, and a Scholarship Award from the American College of Surgeons. He has authored to date 46 peer-reviewed articles, 11 book chapters, 45 peer-reviewed abstracts, and has 28 national presentations. He is an elected member of the Plastic Surgery Research Council, the American Society for Reconstructive Microsurgery, the American Society for Reconstructive Transplantation, and the American Society for Peripheral Nerves.

The combination of nanoparticle carriers with hydrogels as a hybrid delivery system has recently come into favor for purposes including passively controlled drug release, stimuli-responsive drug delivery, site-specific drug delivery, and detoxification. The addition of a hydrogel to a nanoparticle delivery system allows for an added level of tunability as well as increased assurance that the nanoparticles remain at the local site of delivery in vivo (Gao et al., 2016; Norouzi et al., 2016). A promising approach being pursued by our group for repair of PNI involves encapsulation of IGF-1 into nanoparticles that provide sustained release of IGF-1 for over 6 weeks. The nanoparticles are then suspended within a biomimetic nanofiber hydrogel composite carrier to facilitate in vivo application and preliminary results have been encouraging (Santos et al., 2016). The approach involves injection of the composite hydrogel into the denervated target muscle and around the nerve distal to the site of injury, such that the released bioactive IGF-1 diffuses through the target tissues. Our unpublished data suggests that IGF-1 does not act on regenerating axons in gradient-dependent fashion, as uniform delivery along the distal nerve results in a robust treatment effect. However, the question of gradient dependence has not been specifically addressed to our knowledge and warrants further investigation. To achieve maximal treatment effect, IGF-1 will likely need to be delivered for the duration of the regenerative period, which can last many months or even years. It is unlikely that an engineered drug delivery system will be developed that can achieve this duration of release with a single dose. We therefore anticipate that interval ultrasound-guided reinjections will be needed, with the dosing schedule being dependent on the duration of drug release.

Recovery 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.

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.

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).