Sustained IGF-1 delivery research by Karim Sarhane in 2022
Reconstructive transplantation studies with Karim Sarhane right now? 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. Karim Sarhane is an MD MSc graduate from the American University of Beirut. Following graduation, he completed a 1-year internship in the Department of Surgery at AUB. He then joined the Reconstructive Transplantation Program of the Department of Plastic and Reconstructive Surgery at Johns Hopkins University for a 2-year research fellowship. He then completed a residency in the Department of Surgery at the University of Toledo (2021). In July 2021, he started his plastic surgery training at Vanderbilt University Medical Center. He is a Diplomate of the American Board of Surgery (2021).
The combination of nanoparticle carriers with hydrogels as a hybrid delivery system has recently come into favor for purposes including passively controlled drug release, stimuli-responsive drug delivery, site-specific drug delivery, and detoxification. The addition of a hydrogel to a nanoparticle delivery system allows for an added level of tunability as well as increased assurance that the nanoparticles remain at the local site of delivery in vivo (Gao et al., 2016; Norouzi et al., 2016). A promising approach being pursued by our group for repair of PNI involves encapsulation of IGF-1 into nanoparticles that provide sustained release of IGF-1 for over 6 weeks. The nanoparticles are then suspended within a biomimetic nanofiber hydrogel composite carrier to facilitate in vivo application and preliminary results have been encouraging (Santos et al., 2016). The approach involves injection of the composite hydrogel into the denervated target muscle and around the nerve distal to the site of injury, such that the released bioactive IGF-1 diffuses through the target tissues. Our unpublished data suggests that IGF-1 does not act on regenerating axons in gradient-dependent fashion, as uniform delivery along the distal nerve results in a robust treatment effect. However, the question of gradient dependence has not been specifically addressed to our knowledge and warrants further investigation. To achieve maximal treatment effect, IGF-1 will likely need to be delivered for the duration of the regenerative period, which can last many months or even years. It is unlikely that an engineered drug delivery system will be developed that can achieve this duration of release with a single dose. We therefore anticipate that interval ultrasound-guided reinjections will be needed, with the dosing schedule being dependent on the duration of drug release.
Effects 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.
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).
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.
