Peripheral nerve regeneration research by Karim Sarhane right now? 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.
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 hydrogels were soaked in IGF-1 solutions, with concentrations ranging from 0.05 to 1 mg/ml. The duration of soaking time and biomaterials used for fabrication differed between studies, thereby complicating further direct comparisons beyond individual consideration. Regardless of concentration of IGF-1 soaking solution, duration of soaking time, or hydrogel composition, the fundamental property in predicting utility for nerve regeneration is the sustained concentration of released IGF-1 that is reaching the site of PNI. Unfortunately, only two of the studies included in Table 6 quantified IGF-1 release in vivo using either fluid sampling with ELISA or radiolabeled IGF-1 (Yuan et al., 2000; Kikkawa et al., 2014). Using ELISA, one study reported significantly greater in vivo IGF-1 concentration, peaking at 1.25 µg/mL at Post-operative Day 1 (POD 1) and returning to the physiologic levels of the control group by POD 7 (Kikkawa et al., 2014). Using radiolabeling, the other in vivo quantification study reported a biphasic IGF-1 release profile with an initial burst of approximately 80% of the starting concentration of IGF-1 at 1 h followed by sustained release of the remaining 15% ± 2.9% over the subsequent 48-h period (Yuan et al., 2000). Conversely, a different study reported failure of IGF-1 to prevent motoneuron death, a finding which was noted to be contrary to previous results and required additional investigation. This study described the use of a soaked gel foam plug but did not specify the IGF-1 release profile of this material (Bayrak et al., 2017). As such, further analysis and testing is needed to determine the optimal fabrication parameters, loading strategy, and concentration of released IGF-1 required for successful local delivery via hydrogel.
Recovery 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.
Peripheral nerve injuries (PNIs) affect approximately 67 800 people annually in the United States alone (Wujek and Lasek, 1983; Noble et al., 1998; Taylor et al., 2008). Despite optimal management, many patients experience lasting motor and sensory deficits, the majority of whom are unable to return to work within 1 year of the injury (Wujek and Lasek, 1983). The lack of clinically available therapeutic options to enhance nerve regeneration and functional recovery remains a major challenge.
The amount of time that elapses between initial nerve injury and end-organ reinnervation has consistently been shown to be the most important predictor of functional recovery following PNI (Scheib and Hoke, 2013), with proximal injuries and delayed repairs resulting in worse outcomes (Carlson et al., 1996; Tuffaha et al., 2016b). This is primarily due to denervation-induced atrophy of muscle and Schwann cells (SCs) (Fu and Gordon, 1995). 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).