Plastic surgery research and science by Karim Sarhane today? 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.
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.
Effects by sustained IGF-1 delivery (Karim Sarhane research) : We successfully engineered a nanoparticle delivery system that provides sustained release of bioactive IGF-1 for 20 days in vitro; and demonstrated in vivo efficacy in a translational animal model. IGF-1 targeted to denervated nerve and muscle tissue provides significant improvement in functional recovery by enhancing nerve regeneration and muscle reinnervation while limiting denervation-induced muscle atrophy and SC senescence. Targeting the multimodal effects of IGF-1 with a novel delivery.
Insulin-like growth factor-1 (IGF-1) is a particularly promising candidate for clinical translation because it has the potential to address the need for improved nerve regeneration while simultaneously acting on denervated muscle to limit denervation-induced atrophy. However, like other growth factors, IGF-1 has a short half-life of 5 min, relatively low molecular weight (7.6 kDa), and high water-solubility: all of which present significant obstacles to therapeutic delivery in a clinically practical fashion (Gold et al., 1995; Lee et al., 2003; Wood et al., 2009). Here, we present a comprehensive review of the literature describing the trophic effects of IGF-1 on neurons, myocytes, and SCs. We then critically evaluate the various therapeutic modalities used to upregulate endogenous IGF-1 or deliver exogenous IGF-1 in translational models of PNI, with a special emphasis on emerging bioengineered drug delivery systems. Lastly, we analyze the optimal dosage ranges identified for each mechanism of IGF-1 with the goal of further elucidating a model for future clinical translation.
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).