Latest reconstructive microsurgery research from Karim Sarhane

Plastic surgery research and science with Karim Sarhane right now? Insulin-like growth factor 1 (IGF-1) is a hormone produced by the body that has the potential to be used as a treatment for nerve injuries. IGF-1 may help heal nerve injuries by decreasing inflammation and buildup of damaging products. Additionally, it may speed up nerve healing and reduce the effects of muscle weakness from the injury. However, a safe, effective, and practical way is needed to get IGF-1 to the injured nerve.

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.

Mini-osmotic pumps provide a sustained, local delivery of exogenous IGF-1 (Table 5; Kanje et al., 1989; Sjoberg and Kanje, 1989; Ishii and Lupien, 1995; Tiangco et al., 2001; Fansa et al., 2002; Apel et al., 2010; Luo et al., 2016). This technique involves subcutaneous implantation of an osmotic pump in the abdomen with extension of a catheter from the pump to the transected nerve site. The positioning of the catheter is maintained by suturing it to local connective tissue. A fixed concentration and quantity of IGF-1 is then loaded into the pump and released at a constant rate (Kanje et al., 1989). Studies using mini-pump delivery of IGF-1 tested a variety of initial concentrations (mean = 143 µg/mL, median = 100 µg/mL, and range: 50 µg/mL – 100 mg/mL), pump rates (mean = 0.425 µL/h, median = 0.25 µL/h, and range: 0.25 – 1.05 µL/h), and release durations (mean = 26 days, median = 7 days, and range: 3 days–12 weeks). The highest dose was reported by Fansa et al. (2002) using a starting concentration of IGF-1 of 100 mg/mL dosed at a continuous pump rate of 0.25 uL/h over 28 days, a value several orders of magnitude higher than any of the other mini pump studies included in Table 5. This concentration discrepancy relative to other mini-pump studies is possibly attributable to the design of this particular study, which set out to investigate the benefits of IGF-1 on a tissue-engineered nerve graft model containing cultured, viable SCs. When the study by Fansa et al. (2002) is excluded, the reported initial optimal concentration for mini pump studies centers on a much more focused range of 0.1–100 µg/mL with a mean of 60 µg/mL and median of 75 µg/mL.

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.

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).

We comprehensively reviewed the literature for original studies examining the efficacy of IGF-1 in treating PNI. We queried the PubMed and Embase databases for terms including “Insulin-Like Growth Factor I,” “IGF1,” “IGF-1,” “somatomedin C,” “PNIs,” “peripheral nerves,” “nerve injury,” “nerve damage,” “nerve trauma,” “nerve crush,” “nerve regeneration,” and “nerve repair.” Following title review, our search yielded 218 results. Inclusion criteria included original basic science studies utilizing IGF-1 as a means of addressing PNI. Following abstract review, 56 studies were sorted by study type and mechanism of delivery into the following categories: (1) in vitro, (2) in vivo endogenous upregulation of IGF-1, or (3) in vivo delivery of exogenous IGF-1. Studies included in the in vivo exogenous IGF-1 group were further sub-stratified into systemic or local delivery, and the local IGF-1 delivery methods were further sub-divided into free IGF-1 injection, hydrogel, or mini-pump studies. Following categorization by mechanism of IGF-1 delivery, the optimal dosage range for each group was calculated by converting all reported IGF-1 dosages to nM for ease of comparison using the standard molecular weight of IGF-1 of 7649 Daltons. After standardization of dosages to nM, the IGF-1 concentration reported as optimal from each study was used to calculate the overall mean, median, and range of optimal IGF-1 dosage for each group.