Reconstructive microsurgery research with Karim Sarhane today? 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.
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.
Optimal dosage of IGF-1 is dependent upon its administration method. As demonstrated by Tables 1–6, there is great variation in IGF-1 dosing and frequency of administration between the various methods of delivery, with narrower ranges for ideal dosage that emerge within groups. These reported dosage ranges may serve as a useful reference point when developing and testing IGF-1 delivery strategies in pre-clinical models. Achieving the required pharmacokinetic profile for IGF-1 delivery is challenging due to the small size and short half-life of IGF-1. Therefore, designing drug delivery systems that provide targeted or local treatment of affected muscle and nerve tissue will facilitate clinical translatability of IGF-1 therapy. Local delivery of IGF-1 would reduce the side effects and potential toxicities of systemic exposure while permitting titration of loading levels to improve efficacy. However, the use of daily or frequent injections to an injury site, as described in previous studies, increases the risk of iatrogenic damage to the recovering nerve and surrounding vasculature (Caroni and Grandes, 1990; Day et al., 2001, 2002; Stitt et al., 2004; Emel et al., 2011; Mohammadi et al., 2013; Kostereva et al., 2016). In addition, the potential scarring induced by repeated local injections could preclude regenerating axons from reaching their distal targets, leading to decreased NMJ reinnervation as well as potential neuroma formation. Furthermore, the local injection of free IGF-1 without a biocompatible carrier misses an opportunity to improve its bioavailability. While the mini-pump technique provides a level of automated control over IGF-1 administration unmatched by the other previously described methods, the subcutaneous implantation of a mini-pump in a human patient introduces the risks of infection and device migration. More importantly, given the duration of time needed for regeneration to occur, the implanted pump would also likely induce a high degree of foreign body reaction resulting in fibrotic encapsulation and potential deleterious effects on the injured nerve being treated.
Effects with sustained IGF-1 delivery (Karim Sarhane research) : Functional recovery following peripheral nerve injury is limited by progressive atrophy of denervated muscle and Schwann cells (SCs) that occurs during the long regenerative period prior to end-organ reinnervation. Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and SCs. Achieving sustained, targeted delivery of small protein therapeutics remains a challenge.
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).
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.