Nerve growth factor (NGF) was discovered 50 years ago as a molecule that promoted the survival and differentiation of sensory and sympathetic neurons. Its roles in neural development have been characterized extensively, but recent findings point to an unexpected diversity of NGF actions and indicate that developmental effects are only one aspect of the biology of NGF. This article considers expanded roles for NGF that are associated with the dynamically regulated production of NGF and its receptors that begins in development, extends throughout adult life and aging, and involves a surprising variety of neurons, glia, and nonneural cells. Particular attention is given to a growing body of evidence that suggests that among other roles, endogenous NGF signaling subserves neuroprotective and repair functions. The analysis points to many interesting unanswered questions and to the potential for continuing research on NGF to substantially enhance our understanding of the mechanisms and treatment of neurological disorders.

Nerve growth factor signaling, neuroprotection, and neural repair

Nerve regeneration is a complex biological phenomenon. In the peripheral nervous system, nerves can regenerate on their own if injuries are small. Larger injuries must be surgically treated, typically with nerve grafts harvested from elsewhere in the body. Spinal cord injury is more complicated, as there are factors in the body that inhibit repair. Unfortunately, a solution to completely repair spinal cord injury has not been found. Thus, bioengineering strategies for the peripheral nervous system are focused on alternatives to the nerve graft, whereas efforts for spinal cord injury are focused on creating a permissive environment for regeneration. Fortunately, recent advances in neuroscience, cell culture, genetic techniques, and biomaterials provide optimism for new treatments for nerve injuries. This article reviews the nervous system physiology, the factors that are critical for nerve repair, and the current approaches that are being explored to aid peripheral nerve regeneration and spinal cord repair.

Neural tissue engineering: strategies for repair and regeneration.

Immune and inflammatory mechanisms in neuropathic pain.

In spite of an enormous amount of new experimental laboratory data based on evolving neuroscientific concepts during the last 25 years peripheral nerve injuries still belong to the most challenging and difficult surgical reconstructive problems. Our understanding of biological mechanisms regulating posttraumatic nerve regeneration has increased substantially with respect to the role of neurotrophic and neurite-outgrowth promoting substances, but new molecular biological knowledge has so far gained very limited clinical applications. Techniques for clinical approximation of severed nerve ends have reached an optimal technical refinement and new concepts are needed to further increase the results from nerve repair. For bridging gaps in nerve continuity little has changed during the last 25 years. However, evolving principles for immunosuppression may open new perspectives regarding the use of nerve allografts, and various types of tissue engineering combined by bioartificial conduits may also be important. Posttraumatic functional reorganizations occurring in brain cortex are key phenomena explaining much of the inferior functional outcome following nerve repair, and increased knowledge regarding factors involved in brain plasticity may help to further improve the results. Implantation of microchips in the nervous system may provide a new interface between biology and technology and developing gene technology may introduce new possibilities in the manipulation of nerve degeneration and regeneration.

A 25-year perspective of peripheral nerve surgery: evolving neuroscientific concepts and clinical significance.

https://personalpages.manchester.ac.uk/staff/j.gough/lectures/te/nerve/adiposestem_schwann.pdf

Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro

The peripheral nervous system retains a considerable capacity for regeneration. However, functional recovery rarely returns to the preinjury level no matter how accurate the nerve repair is, and the more proximal the injury the worse the recovery. Among a variety of approaches being used to enhance peripheral nerve regeneration are the manipulation of Schwann cells and the use of neurotrophic factors. Such factors include, first, nerve growth factor (NGF) and the other recently identified members of the neurotrophin family, namely, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5); second, the neurokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF); and third, the transforming growth factors (TGFs)-β and their distant relative, glial cell line–derived neurotrophic factor (GDNF). In this review article we focus on the roles in peripheral nerve regeneration of Schwann cells and of the neurotrophin family, CNTF and GDNF, and the relationship between these. Finally, we discuss what remains to be understood about the possible clinical use of neurotrophic factors. © 1998 Wiley-Liss, Inc. MICROSURGERY 18:397–405, 1998

Schwann cells, neurotrophic factors, and peripheral nerve regeneration

Successful peripheral nerve regeneration requires optimal conditions both in the macro-environment and micro-environment. Many methods have been used to improve the macro-environment for the regenerating nerve. However, much less is known about the micro-environment, and in particular the complex neurochemical interactions involved. Several neurotrophic factors have been shown to play an essential trophic role in the development, maintenance and regulation of neuronal function. These include nerve growth factor (NGF) and several recently identified members of the NGF family, namely brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5) and neurotrophin-6 (NT-6). In this review we summarize recent studies of the effects of these neurotrophins on neurones, especially their effects on motor neurones and their axonal outgrowth. We discuss prospects for the future and point out what remains to be understood about the role of neurotrophins to enhance peripheral nerve regeneration.

Neurotrophins, neurones and peripheral nerve regeneration

Neurotrophin-4 (NT-4) is a recently identified neurotrophic factor with potential trophic effects on subpopulations of neurons. Little is known about its role in peripheral nerve regeneration following nerve injury. To investigate this, 48 Sprague-Dawley rats underwent left sciatic nerve transection and immediate repair. Fibrin glue mixed with either NT-4 or vehicle (control) was injected around the nerve repair site. Nerve regeneration was assessed both functionally and histomorphometrically. The results showed that the NT-4-treated group had a significant increase compared with the control in the regeneration distance at 5 days. The sciatic function index was significantly greater in the NT-4 group from 40 to 60 days after nerve repair. Morphometric analysis revealed that nerves treated with NT-4 had significant improvement in the number of regenerated axons, axonal diameter, and myelin thickness. These results suggest that NT-4 is a potent factor improving rat sciatic nerve regeneration.

Neurotrophin‐4 delivered by fibrin glue promotes peripheral nerve regeneration

Purpose: The purpose of this study was to review the results of distal biceps tendon repair via suture anchors through a single anterior incision. Methods: This is a retrospective review of 17 patients (18 repairs) treated for complete distal biceps tendon rupture between 1998 and 2005 by use of G4 Superanchors (DePuy Mitek, Raynham, MA) in our unit. The length of follow-up was 14 to 70 months (mean, 45 months). Results: There was a mean loss of 5.3° (range, 0° to 50°; SD, 14.12) of extension when compared with the uninjured side. Of the 17 patients, 6 achieved full extension when compared with the uninvolved elbow. The mean loss of flexion was 6.2° (range, 0° to 15°; SD, 6.11). There was a mean loss of 11.0° of pronation (range, 0° to 30°; SD, 11.34) and 6.4° of supination (range, 0° to 45°; SD, 17.45). Flexion in supination strength measured by a handheld dynamometer was 82.1% of that of the injured side (range, 59% to 102%; SD, 11.26). There were two complications in our series: transient superficial radial nerve palsy in one case and heterotopic ossification in the other. The mean Disabilities of the Arm, Shoulder and Hand score was 14.45 (range, 0 to 55.17; SD, 4.76). Six months after surgery, all patients but one returned to their preinjury levels of activity and employment. Conclusions: Our study shows that repair of distal biceps tendon ruptures via suture anchors is safe and yields clinically objective and functional results comparable to measurements in the other, uninjured extremity. Level of Evidence: Level IV, therapeutic case series.

Qi Yin

Papers

Schwann cells, neurotrophic factors, and peripheral nerve regeneration

Neurotrophins, neurones and peripheral nerve regeneration

Neurotrophin‐4 delivered by fibrin glue promotes peripheral nerve regeneration

Repair of distal biceps tendon ruptures using suture anchors through a single anterior incision.

Suture anchors for treatment of sternoclavicular joint instability.