Peripheral nerve regeneration research and science with Karim Sarhane in 2022? Researchers at Johns Hopkins Hospital in Baltimore, MD, conducted a study to develop a drug delivery system using a very small material, nanofiber hydrogel composite, which can hold nanoparticles containing IGF-1 and be delivered near the injured nerve to help it heal. Dr. Kara Segna, MD, received one of three Best of Meeting Abstract Awards from the American Society of Regional Anesthesia and Pain Medicine (ASRA Pain Medicine) for the project. She will present the abstract “IGF-1 Nanoparticles Improve Functional Outcomes After Peripheral Nerve Injury” on Saturday, April 2, at 1:45 pm during the 47th Annual Regional Anesthesiology and Acute Pain Medicine Meeting being held March 31-April 2, 2022, in Las Vegas, NV. Coauthors include Drs. Sami Tuffaha, Thomas Harris, Chenhu Qui, Karim Sarhane, Ahmet Hoke, Hai-Quan Mao.
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 use of hydrogels encapsulated with varying concentrations of IGF-1 allows for a prolonged and potentially tunable release in vivo (Yuan et al., 2000; Mathonnet et al., 2001; Kikkawa et al., 2014; Bayrak et al., 2017). The specific hydrogel formulations that have been evaluated vary with regards to IGF-1 release kinetics, degradation rate, and biocompatibility. Despite differences in study design, the majority of hydrogel studies included in Table 6 used a water-soluble polymer oligo(poly(ethylene glycol) fumarate) (OPF) hydrogel with encapsulated gelatin microparticles (Yuan et al., 2000; Holland et al., 2005; Kikkawa et al., 2014; Bayrak et al., 2017). The extent of crosslinking within the OPF hydrogel as well as the use of encapsulated gelatin particles with variable isoelectric points allows for tunability of IGF-1 release. The cumulative release of IGF-1 by this hydrogel formulation was reported to be 95.2% ± 2.9% by Day 28, with some studies achieving a similar cumulative release within 48 h (Yuan et al., 2000; Kikkawa et al., 2014).
Effects by sustained IGF-1 delivery (Karim Sarhane research) : Under optimized conditions, uniform PEG-b-PCL NPs were generated with an encapsulation efficiency of 88.4%, loading level of 14.2%, and a near-zero-order release of bioactive IGF-1 for more than 20 days in vitro. The effects of locally delivered IGF-1 NPs on denervated muscle and SCs were assessed in a rat median nerve transection-without- repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy, reinnervation, and recovery of motor function were assessed in a model in which chronic denervation is induced prior to nerve repair. IGF-1 NP treatment resulted in significantly greater recovery of forepaw grip strength, decreased denervation-induced muscle atrophy, decreased SC senescence, and improved neuromuscular reinnervation.
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).