Reconstructive transplantation research from Karim Sarhane right now? 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.
Systemic delivery of IGF-1 is achieved via either daily subcutaneous or intraperitoneal injections of free IGF-1. Reported optimal dosages for regeneration of nerve, SC, and muscle range from 0.001 to 1.00 mg/kg/day with a mean of 0.59 mg/kg/day and a median of 0.75 mg/kg/day of IGF-1 (Contreras et al., 1993, 1995; Vaught et al., 1996; Vergani et al., 1998; Lutz et al., 1999; Mohammadi and Saadati, 2014; Table 3). The calculated mean and median IGF-1 concentrations for systemic delivery were the highest of any of the delivery mechanisms included in our analysis. This finding emphasizes that the use of a systemic approach necessitates greater dosages of IGF-1 to account for off-target distribution and degradation/clearance prior to reaching the injury site. Notably, almost none of the systemic studies included in this analysis quantified the concentration of IGF-1 at the target injury site, which raises significant concerns about the validity of the findings. With regards to clinical applicability, systemic IGF-1 delivery is severely limited by the risk of side effects, including hypoglycemia, lymphoid hyperplasia, body fat accumulation, electrolyte imbalances, and mental status changes (Elijah et al., 2011; Tuffaha et al., 2016b; Vilar et al., 2017). In contrast to upregulation of systemic IGF-1 via GH Releasing Hormone (GHRH), treatment with systemic IGF-1 does not have the benefit of upstream negative feedback control and therefore poses a greater risk of resulting in spiking IGF-1 levels.
Recovery with 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.
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).
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).