سلسلة سرطان الغدة الدرقية – كل ما تريد معرفته عن عقيدات الغدة الدرقية (فيديو 1/11) – من هو الدكتور كريم؟
الدكتور كريم سرحان استشاري الجراحة ورئيس القسم الجراحة العامة والمناظير دبلوم البورد الأمريكي للجراحة زميل مشارك، كلية الجراحين الأمريكية العين، أبو ظبي، الإمارات العربية المتحدة
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Karim Ahmad Sarhane, MD MSc Consultant Surgeon and Head of Department General and Laparoscopic Surgery Diplomate of the American Board of Surgery Associate Fellow, American College of Surgeons Al Ain, Abu Dhabi, UAE
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Global incidence rates for peripheral nerve injury (PNI) are not well aggregated. However, US data collected shows that 20 million Americans suffer from peripheral nerve injury caused by trauma and medical disorders. When a tension-free early repair is possible, microsurgical direct nerve repair with epineural sutures remains the gold standard of care. The current standard for large nerve defects is autologous nerve grafts. However, disadvantages for this treatment approach include risk of neuroma formation and loss of donor nerve function. Acellular nerve conduits limit the disadvantages associated with autologous grafts. However, conduits are still insufficient for large deficits and require a combination of pharmacological and molecular therapies to yield prime results. Research indicates that these therapy additions should focus on both axonal regeneration and Schwann cell renewal. Insulin-like growth factor (IGF-1) has shown promising results because it optimizes axonal regeneration and Schwann cell renewal simultaneously. Previously reported encapsulation methods for growth factors either release the payload too rapidly or achieve prolonged presence through covalent conjugation. Therefore, there is a strong need to develop a delivery system that can provide sustained release of small proteins for an extended duration while maintaining encapsulation efficiency and bioactivity.
Karim Sarhane MD at Johns Hopkins created a nanoparticle-based delivery system that provides sustained release of bioactive insulin like growth-factor 1 (IGF-1) for 20 days in vitro to denervated nerve and muscle tissue within the peripheral nervous system. The delivery system fulfills the need to create a nanoparticle-based drug delivery system that provides sustained and controllable release of IGF-1 without sacrificing on encapsulation efficiency or retention of bioactivity. Preliminary results support potential to improve functional outcomes for PNI patients suffering from severe injury, presenting a significant value proposition with potential to improve significant sensory and motor impairments associated with 4th and 5th degree injury.
Substantial advances have been made in enhancing nerve regeneration across gaps through the use of conduits and acellular nerve grafts. However, very few therapeutic approaches have been successfully studied in primary end-to-end repairs. Post-repair histologic studies commonly demonstrate scar tissue between coapted nerve stumps. In this study, we propose a novel semi-permeable nanofiber nerve wrap prepared from FDA approved biocompatible materials (polycaprolactone) to reduce inflammation at nerve coaptation site through inhibition of inflammatory cell infiltration while allowing diffusion of essential nutrients and growth factors.
Methods
Nerve wraps were synthesized by electrospinning of randomly oriented 650-nm nanofibers, and constructs with pores smaller than 10 μm were obtained. Using Thy-1 GFP Sprague-Dawley rats, we performed sciatic nerve transection and epinureal repair (control group) and with wrapping the coaptation site using the neuro-protective nanofiber construct (experimental group). Five weeks later, histologic analysis (Masson’s Trichrome staining, ED1+TUJ1 immunofluorescence co-staining) was performed on nerve sections at the repair site to assess fibrosis (collagen deposition) and inflammation (macrophage invasion) (n=5/group). Additionally, retrograde labeling was performed, and at the same time, the distal stump was harvested for histo-morphometric evaluation (n=8/group).
Results: Masson’s Trichrome and double immunofluorescence staining (ED1+TUJ1) of nerve longitudinal sections 5 weeks following repair showed a significantly decreased level of intraneural scarring and inflammation in the nanofiber nerve wrap group, as determined by collagen quantification (7.4% ± 1.3 vs. 3.2% ± 1.3, p<0.05) and macrophage counting (32.2 ± 2.4 cells/mm2 vs. 14.6 ± 1.8 cells/mm2, p<0.05) in the repair site. Collagen was trapped outside the nerve wrap in the experimental group. Nerve cross sections taken 5 mm distal to the coaptation site demonstrated a significantly increased number of myelinated axons in the experimental group. Retro- grade labeling showed a trend towards higher number of sensory dorsal root ganglion neurons that regenerated their axons in the nanofiber wrap group when compared to control.
Conclusion
These results provide new insights into a novel targeted anti-inflammatory approach in peripheral nerve repair. Electrospun nanofiber nerve wrap constructs protect the coaptation site from inflammation, promoting scar-free nerve repair, and enhancing axonal regeneration. This new therapeutic strategy utilizing FDA approved products holds great translational potential.
Institution Johns Hopkins University-School of Medicine
Funding Mechanism Pilot Research Grant
Focus Area Peripheral Nerve, Tissue Engineering
Abstract Peripheral nerve injury (PNI) remains a challenging problem. Despite best efforts at surgical reconstruction and postoperative rehabilitation, patients with PNI are often left with persistent, debilitating motor and sensory deficits. Therapies to enhance the regenerative process are lacking. Poor outcomes result from prolonged periods of latency prior to reinnervation. Over time, the absence of muscle innervation causes irreversible atrophy that limits functional motor recovery. Further hindering outcomes, chronically denervated Schwann cells within the distal nerve stump senesce over time and lose their capacity to support regenerating axons. Therapies are needed to accelerate axonal regeneration and maintain denervated muscle and Schwann cells. Augmentation of the growth hormone (GH) axis has emerged as a promising therapeutic approach, the effects of which are primarily mediated by insulin-like growth factor 1 (IGF-1). IGF-1 acts on neurons to speed axonal regeneration and acts independently on denervated muscle and Schwann cells to limit denervation atrophy and senescence. Despite promising experimental results, GH therapies have undesirable side effects resulting from the need for systemic administration; they also require costly and inconvenient daily dosing injections. To overcome these obstacles, we developed biodegradable nanoparticles to encapsulate and release IGF-1 over 70 days with near zero order kinetics. We now need a biocompatible carrier that can fixate the nanoparticles to nerve and muscle for the duration of IGF-1 release without interfering with the favorable release kinetics achieved from the nanoparticles. Our collaborator, Prof. Hai-Quan Mao has developed a nanofiber hydrogel composite with characteristics that make it ideal for this purpose (favorable biocompatibility, biointegration, injectability, mechanical properties, and tunable degradation time). In the proposed studies, we will prepare two sets of nanofiber-hyaluronic acid hydrogel composites with low and high viscosity characteristics (Aim 1) for delivery to muscle and nerve, respectively. We will optimize the release kinetics of the IGF-1 NPs in the hydrogel composites by varying the crosslinking density. We will then (Aim 2) test the effects of the IGF-1 NPs delivered within the optimized hydrogel composite on axonal regeneration, SC proliferation, and muscle reinnervation using a rat chronic denervation model.
Biography I believe I am very well suited to successfully carry out the proposed project. I have extensive research experience in the field of peripheral nerve. I started peripheral nerve research back in 2012 in that same laboratory. I have not only developed advanced microsurgical skills to reliably perform the surgeries, but also learnt the necessary bench techniques that are required to study nerve regeneration (nerve and muscle histomorphometry, nerve conduction studies, stimulated grip strength testing, in addition to NMJ staining and other key immunohistochemical stains). I also developed strong research bonds with multiple collaborators in Johns Hopkins in the Departments of Neuroscience and Material Science. These efforts culminated in several publications, with a few still in the review process.
