Recovering the regenerative potential in chronically injured nerves by using conditioning electrical stimulation

OBJECTIVE Chronically injured nerves pose a significant clinical challenge despite surgical management. There is no clinically feasible perioperative technique to upregulate a proregenerative environment in a chronic nerve injury. Conditioning electrical stimulation (CES) significantly improves sensorimotor recovery following acute nerve injury to the tibial and common fibular nerves. The authors’ objective was to determine if CES could foster a proregenerative environment following chronically injured nerve reconstruction. METHODS The tibial nerve of 60 Sprague Dawley rats was cut, and the proximal ends were inserted into the hamstring muscles to prevent spontaneous reinnervation. Eleven weeks postinjury, these chronically injured animals were randomized, and half were treated with CES proximal to the tibial nerve cut site. Three days later, 24 animals were killed to evaluate the effects of CES on the expression of regeneration-associated genes at the cell body (n = 18) and Schwann cell proliferation (n = 6). In the remaining animals, the tibial nerve defect was reconstructed using a 10-mm isograft. Length of nerve regeneration was assessed 3 weeks postgrafting (n = 16), and functional recovery was evaluated weekly between 7 and 19 weeks of regeneration (n = 20). RESULTS Three weeks after nerve isograft surgery, tibial nerves treated with CES prior to grafting had a significantly longer length of nerve regeneration (p < 0.01). Von Frey analysis identified improved sensory recovery among animals treated with CES (p < 0.01). Motor reinnervation, assessed by kinetics, kinematics, and skilled motor tasks, showed significant recovery (p < 0.05 to p < 0.001). These findings were supported by immunohistochemical quantification of motor endplate reinnervation (p < 0.05). Mechanisms to support the role of CES in reinvigorating the regenerative response were assessed, and it was demonstrated that CES increased the proliferation of Schwann cells in chronically injured nerves (p < 0.05). Furthermore, CES upregulated regeneration-associated gene expression to increase growth-associated protein–43 (GAP-43), phosphorylated cAMP response element binding protein (pCREB) at the neuronal cell bodies, and upregulated glial fibrillary acidic protein expression in the surrounding satellite glial cells (p < 0.05 to p < 0.001). CONCLUSIONS Regeneration following chronic axotomy is impaired due to downregulation of the proregenerative environment generated following nerve injury. CES delivered to a chronically injured nerve influences the cell body and the nerve to re-upregulate an environment that accelerates axon regeneration, resulting in significant improvements in sensory and motor functional recovery. Percutaneous CES may be a preoperative strategy to significantly improve outcomes for patients undergoing delayed nerve reconstruction.

A Rare Case of Bilateral Spaghetti Injuries in Children due to Assault by Mother and Analysis of Functional Outcome at Three Years

Management of child abuse with flexor tendons, neurovascular injuries, and life-threatening conditions is challenging. It needs a multisectoral coordinated and synchronized team effort for successful outcomes. We present a case series of children abused by a parent with a sharp object. The children sustained multiple flexor tendon injuries, neurovascular injuries in upper limbs, and tracheal injury compromising respiration. We performed a tracheostomy to save a child and subsequently repaired numerous flexor tendons, nerves, and arteries. During follow-up, these children required secondary reconstruction (tenolysis, tendon lengthening, nerve reconstruction) for flexor contractures, stiffness, and sensory loss in distal forearms. We measured the range of movements and assessed the children’s functional outcome using the Strickland score at 3-year follow-up. The range of movement and functional outcome was excellent in both children in our series. A timely performance of surgery, aided with efficient intensive care, therapy, and consistent posttraumatic psychosocial rehabilitation, produced excellent results in our series.

Matrix Metalloproteinase-9 is Involved in the Fibrotic Process in Denervated Muscles after Sciatic Nerve Trauma and Recovery

Fibrosis of the injured muscles is a problem of recovery from trauma and denervation. The aim of the work was to investigate the interconnection of matrix metalloproteinase-9 (ММР-9) activity in denervated muscles with fibrosis and to estimate its role in nerve restoration by the epineurial suture, fibrin-based glue, and polyethylene glycol hydrogel. The activity of matrix metalloproteinases was estimated by gelatin zymography. Collagen density in muscles was determined histochemically. An increased level of the active MMP-9 is associated with the fibrous changes in the denervated skeletal muscles and after an epineurial suture. The use of fibrin glue and polyethylene glycol hydrogel resulted in a lower level of collagen and ММР-9 activity, which may be a therapeutic target in the treatment of neuromuscular lesions, and has value in fibrosis analysis following microsurgical intervention for peripheral nerve reconstruction.

Inverted Human Umbilical Artery as a 3D Scaffold for Sciatic Nerve Regeneration in Rats.

Background: Treatment of peripheral nerve injuries (PNIs) remains a challenge. Interposing a graft delivers better regenerative outcomes. Autografts present major drawbacks which have given rise to the development of alternatives such as artificial scaffolds, some of which are very promising. This study was designed to investigate the potential use of an inverted human umbilical cord artery (iHUA) as a 3D scaffold nerve chamber, for nerve regeneration after transection of the sciatic nerve (SN) in rats.Methods: Rats underwent surgical SN transection in their right hindlimb, followed by suture of the device at the resected stumps. Local tolerance, insert biodegradability and nerve reconstruction over time were thoroughly studied by histopathological and morphometric analysis, completed by functional test assessment of sensitivity and motricity recovery.Results: We have demonstrated that nerve reconstruction in the presence of an iHUA insert is effective. The device is well tolerated and highly biodegraded. Although the regenerated nerve is still immature at the end of our study, signs of sensitivity and partial functional recovery were witnessed, confirming our histological findings. Conclusions: Our results support the potential clinical use of iHUA as a 3D scaffold to bridge nerve discontinuity and guide axonal regrowth in selected cases of PNIs.

Nerve grafts and transfers

Following Cruickshank’s (1795) ingenious (and at first disbelieved) demonstration of the regenerative capacity of mammalian nerves, the eighteenth and nineteenth centuries saw a pan-European enthusiasm to redress the nihilism surrounding nerve injury. The first recorded experimental nerve grafts were performed by Philipeaux and Vulpian who attempted both nerve autografting as well as allografting in dogs. At that time, and for many years, allografts were thought to behave similarly to autografts, a belief that persisted well into the twentieth century in some clinics and laboratories. These early attempts at nerve grafting yielded poor results and most surgeons aimed for primary nerve repair despite nerve gaps. Other techniques to allow direct repair involved alteration of position, transposition of the nerve, and even sometimes bone shortening. Although primary repair was frequently possible, after these measures the repair was under tension and mechanical failure was common. Spurling (1945), Whitcomb (1946), and Woodall (1956) showed failure rates of 4%, 7.5%, and 22.4% respectively. Some recovery of function following nerve grafting was documented by Sanders (1942), Seddon (1954), and Brooks (1955). Millesi subsequently published his results for nerve grafting for injuries to the upper limb in 1984. These papers demonstrated more significant recovery of function and highlighted the detriment of delay in treatment to final outcome. Microsurgical advances were central to Millesi’s results, and he emphasized atraumatic dissection and the deleterious effect of tension at the repair site resulting in fibrosis preventing axonal regrowth. Nerve autograft is now the standard for orthotopic nerve reconstruction when primary repair cannot be achieved.

Neurobiology of injury (compression, traction, laceration) and repair, and grading of injuries

The functioning nervous system is an integrated system including conscious and subconscious pathways in the brain and spinal cord, the peripheral nerves, and specialized target organs. Efferent and afferent feedback pathways integrate at multiple levels, and there is interplay with mood, life function, growth, and development. The peripheral nervous system provides homeostatic and pain functions, and links the virtual world of our consciousness to the physical body that senses and manipulates the world around us. Injury disconnects the central nervous system from physical reality and induces profound, time-dependent changes at all levels of the system that mostly impede functional restitution after nerve reconstruction. For surgery to optimize outcomes it must be timely, and applied with precision, neurobiological awareness, and aided by adjuvant therapies or technologies that modulate responses within the central nervous system, primary motor and sensory neurons, repair site, distal nerve stump, and target organs.