Reconstructive transplantation research with Karim Sarhane 2022

Posted by John Concrane on June 22, 2022 in Science

Peripheral nerve regeneration research by 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.

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.

Schwann cells are instrumental to recovery following PNI given their ability to support and guide axonal regeneration via the secretion of neurotrophic factors and maintenance of basal lamina tubes (Scheib and Hoke, 2013, 2016a,b; Tuffaha et al., 2016b). Initially after injury, myelinating SCs distal to the site of injury undergo conversion to a more immature, proliferating repair phenotype (Nocera and Jacob, 2020). Throughout this process, SCs express a variety of genes that dynamically control the regenerative process by promoting survival of neurons, breakdown of damaged axons, clearance of myelin, axonal regrowth, and guidance to the axons’ former targets, finally leading to remyelination of the regenerated axon (Chen et al., 2015; Gordon, 2020; Nocera and Jacob, 2020). Unfortunately, upregulation of pro-regenerative gene expression is temporary and the SCs gradually lose the continued ability to support axonal regrowth as time elapses without axonal interaction (Gordon, 2020). A more detailed description of the biological processes underpinning the role of SCs in peripheral nerve regeneration can be found in a recent review article by Nocera and Jacob (2020). IGF-1 supports SCs by promoting their proliferation, maturation, and differentiation to myelinating phenotypes, while concurrently inhibiting SC apoptosis via the PI3K pathway (Scheib and Hoke, 2013; Tuffaha et al., 2016b). IGF-1’s ability to initiate myelination centers around regulating the balance between ERK, a pathway suppressing SC differentiation, and PI3K-Akt, a pathway promoting SC differentiation via increased expression of myelin basic protein and myelin-associated glycoprotein (Schumacher et al., 1993; Stewart et al., 1996; Conlon et al., 2001; Scheib and Hoke, 2016a).

Recovery 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 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).