Peripheral Nerves Reconstruction
Most injuries caused by home, sport and car accidents or acts of violence and war activities involve the nervous system. While the bones and connective tissues regenerate and can be rehabilitated to a satisfactory level, the recovery of muscles and especially the nerves is very slow and often insufficient. Moreover, the denervated muscles deteriorate very fast. Major operations followed by intense and prolonged physiotherapy help to regain the function of the injured peripheral nerves in some patients, but fail to do so successfully in many others. In cases of complete peripheral nerve injuries with a massive nerve loss, autologous nerve grafting is the treatment of choice However, this treatment has a major disadvantage, in the need to retrieve donor material from the patient, with added morbidity and concomitant loss of sensory function, together with potential infection, cosmetic deficit and secondary neuroma formation. Moreover, only 40–50% of patients undergoing nerve autografts show functional beneﬁts. Many laboratories and medical researchers all over the world are involved in experimental projects in an effort to improve the present rate of success in regenerating the injured nerves. A number of tubes and gels are used, leading to some positive results. For now it is relative just for reconnection of short nerve defects, but still there is no solution in treatment of massive nerve defect.
Guiding Regenerative Gel for Peripheral Nerve Injury (PNI)
On a pilot pre-clinical study, we evaluated the efficacy of GRG in promoting axonal growth in peripheral nerves with massive loss defect after autologous nerve graft (gold standard) and a 17 mm long implantation of tube, with and without GRG (Rochkind and Nevo, Biomed Res Int. 2014). Histological observation of the nerves, after 3 months since surgery, showed no axonal growth through the tube in the empty tube group (regeneration within the empty tube in rats is possible only when the gap is smaller than 7mm).
Whereas, in the group treated with a tube filled with GRG, growth of myelinated axons and continuation of axonal sprouting through the tube to the distal part of the nerve was observed. Moreover, the histological pictures of the GRG group versus autologous nerve transplanted group showed no significant differences between both groups. This data emphasizes, that the GRG enabled optimal axonal regeneration as compared to gold standard, without dependence on the addition of any external growth factors.
On a recent functional study, we evaluated the efficacy of GRG in restoring function to left paralyzed limb following massive nerve loss defect of 15 mm. Three groups were studied; autologous nerve graft and a 17 mm long implantation of tube, with and without GRG. After 6 months of follow up we found the group with tubes filled with GRG to be the only one to exhibit regain of function. These results shed light on the GRG is superior to the current gold standard treatment by its ability to regain function.
Nerve Guidance Channels for Peripheral Nerve Injury (PNI)
The use of bioartificial nerve guidance channels (NGCs) provide a physical scaffold for axonal growth, minimize the infiltration of fibrous scar tissue, and maximize the accumulation of soluble regeneration promoting molecules produced by the connected nerve ends (Pfister et al., J Peripher Nerv Syst, 2007). In the EU-funded collaborative project BIOHYBRID (EU-FP7-278612), we, as part of a consortium, demonstrated that chitosan-based hollow NGCs allow effective regeneration in rat models when bridging 10mm sciatic nerve gaps (Haastert-Talini et al., Biomaterials, 2013; Shapira et al., Microsurgery, 2015). These specific NGCs also qualified for functional repair of 15mm critical length sciatic nerve gaps in a considerably high percentage of rats(Gonzalez-Perez et al., Microsurgery, 2015). Supported by the excellent pre-clinical results, the chitosan nerve guides have received authorization for clinical use as Reaxon® Nerve Guides in Europe (CE mark), FDA authorization for their clinical use in the USA and affiliated countries is in progress. The Reaxon® Nerve Guides are produced by Medovent AG, who has also been partner in the above mentioned EU-collaborative project.
The effect of laser phototherapy (low power laser irradiation) was explored on neuronal cells and peripheral nerve. In nerve cell cultures, laser irradiation significantly accelerated axonal sprouting (Rochkind et al., Lasers Surg Med, 2009). Animal studies in a model of incomplete peripheral nerve injury showed that laser phototherapy has an immediate protective effect, maintains functional activity of the injured nerve, decreases scar tissue formation at the injury site, decreases degeneration in corresponding motor neurons of the spinal cord and significantly increases axonal growth and myelinization. In a model of complete peripheral nerve injury with segmental loss, the laser-treated group showed more intensive axonal growth and morphological reconnection compared with the control group (Rochkind. Neurosurgical Focus, 2009). Recently, we found that in early stages of muscle atrophy, laser phototherapy may preserve the denervated muscle by maintaining creatine kinase activity and the amount of acetylcholine receptors. (Rochkind and Shainberg, Photomed Laser Surg, 2013). The current projects are intended to test and validate the beneficial effect of laser phototherapy on severely injured PN with a view to move forward to clinical study in order to acquire FDA and CE approval.
Spinal Cord Reconstruction
SCI is a debilitating condition to civilians suffering motor vehicle accidents, or home, work and sporting injuries or acts of violence, as well as injuries occurring during military service. Annually, nearly 500,000 people worldwide suffer a SCI, which results in permanent loss of neurological sensory and motor function below the level of injury, since CNS axons have a limited, if any, capacity for regrowth and due to environmental factors that further inhibit any regenerative potential. SCI is characterized by an immediate and severe loss of sensory and motor function below the level of injury. Due to the trauma the axons and myelin are afflicted, which in turn leads to local ischemia and responsiveness of the immune and glial cell systems.
Guiding Regenerative Gel for Spinal Cord Injury (SCI)
Based upon our encouraging results with the GRG, which shed light on the utilization of this innovative composite implant to bridge a gap, we postulate to improve this approach and attempt reconstruction of complete SCI. Since scarring is one of the main obstacles for axonal growth and therefore spinal cord recovery, we are planning to use a biocompatible and biodegradable hydrogel based on the GRG, that would constitute a unique tool in the nerve regeneration field that will provide an optimal environment for neuronal regeneration by enhancing axonal growth and sprouting, on one hand, and by reducing the scar barrier and preventing its further formation, on the other hand.