Long-Term Survival and Integration of Transplanted Engineered Nervous Tissue Constructs Promotes Peripheral Nerve Regeneration

Although peripheral nerve injury is a common consequence of trauma or surgery, there are insufficient means for repair. In particular, there is a critical need for improved methods to facilitate regeneration of axons across major nerve lesions. Here, we engineered transplantable living nervous tissue constructs to provide a labeled pathway to guide host axonal regeneration. These constructs consisted of stretch-grown, longitudinally aligned living axonal tracts inserted into poly(glycolic acid) tubes. The constructs (allogenic) were transplanted to bridge an excised segment of sciatic nerve in the rat, and histological analyses were performed at 6 and 16 weeks posttransplantation to determine graft survival, integration, and host regeneration. At both time points, the transplanted constructs were found to have maintained their pretransplant geometry, with surviving clusters of graft neuronal somata at the extremities of the constructs spanned by tracts of axons. Throughout the transplanted region, there was an intertwining plexus of host and graft axons, suggesting that the transplanted axons mediated host axonal regeneration across the lesion. By 16 weeks posttransplant, extensive myelination of axons was observed throughout the transplant region. Further, graft neurons had extended axons beyond the margins of the transplanted region, penetrating into the host nerve. Notably, this survival and integration of the allogenic constructs occurred in the absence of immunosuppression therapy. These findings demonstrate the promise of living tissue-engineered axonal constructs to bridge major nerve lesions and promote host regeneration, potentially by providing axon-mediated axonal outgrowth and guidance

Hand function after nerve repair.

Treatment of injuries to major nerve trunks in the hand and upper extremity remains a major and challenging reconstructive problem. Such injuries may cause long-lasting disabilities in terms of lost fine sensory and motor functions. Nowadays there is no surgical repair technique that can ensure recovery of tactile discrimination in the hand of an adult patient following nerve repair while very young individuals usually regain a complete recovery of functional sensibility. Post-traumatic nerve regeneration is a complex biological process where the outcome depends on multiple biological and environmental factors such as survival of nerve cells, axonal regeneration rate, extent of axonal misdirection, type of injury, type of nerve, level of the lesion, age of the patient and compliance to training. A major problem is the cortical functional reorganization of hand representation which occurs as a result of axonal misdirection. Although protective sensibility usually occurs following nerve repair, tactile discriminative functions seldom recover - a direct result of cortical remapping. Sensory re-education programmes are routinely applied to facilitate understanding of the new sensory patterns provided by the hand. New trends in hand rehabilitation focus on modulation of central nervous processes rather than peripheral factors. Principles are being evolved to maintain the cortical hand representation by using the brain capacity for visuo-tactile and audio-tactile interaction for the initial phase following nerve injury and repair (phase 1). After the start of the re-innervation of the hand (phase 2), selective de-afferentation, such as cutaneous anaesthesia of the forearm of the injured hand, allows expansion of the nerve-injured cortical hand representation, thereby enhancing the effects of sensory relearning. Recent data support the view that training protocols specifically addressing the relearning process substantially increase the possibilities for improved functional outcome after nerve repair