Thomas H. Tung

Effects of motor versus sensory nerve grafts on peripheral nerve regeneration.

Autologous nerve grafting is the current standard of care for nerve injuries resulting in a nerve gap. This treatment requires the use of sensory grafts to reconstruct motor defects, but the consequences of mismatches between graft and native nerve are unknown. Motor pathways have been shown to preferentially support motoneuron regeneration. Functional outcome of motor nerve reconstruction depends on the magnitude, rate, and precision of end organ reinnervation. This study examined the role of pathway type on regeneration across a mixed nerve defect. Thirty-six Lewis rats underwent tibial nerve transection and received isogeneic motor, sensory or mixed nerve grafts. Histomorphometry of the regenerating nerves at 3 weeks demonstrated robust nerve regeneration through both motor and mixed nerve grafts. In contrast, poor nerve regeneration was seen through sensory nerve grafts, with significantly decreased nerve fiber count, percent nerve, and nerve density when compared with mixed and motor groups (P < 0.05). These data suggest that use of motor or mixed nerve grafts, rather than sensory nerve grafts, will optimize regeneration across mixed nerve defects.

Nerve Transfers: Indications, Techniques, and Outcomes

This article provides an update of the current strategies of motor and sensory nerve transfers for peripheral nerve lesions of the upper extremity. Indications, techniques, and outcomes are summarized for both well-established transfers used in the management of proximal and brachial plexus injuries as well as those more recently developed for more distal and isolated nerve injuries in the forearm and hand.

Binary imaging analysis for comprehensive quantitative histomorphometry of peripheral nerve.

Quantitative histomorphometry is the current gold standard for objective measurement of nerve architecture and its components. Many methods still in use rely heavily upon manual techniques that are prohibitively time consuming, predisposing to operator fatigue, sampling error, and overall limited reproducibility. More recently, investigators have attempted to combine the speed of automated morphometry with the accuracy of manual and semi-automated methods. Systematic refinements in binary imaging analysis techniques combined with an algorithmic approach allow for more exhaustive characterization of nerve parameters in the surgically relevant injury paradigms of regeneration following crush, transection, and nerve gap injuries. The binary imaging method introduced here uses multiple bitplanes to achieve reproducible, high throughput quantitative assessment of peripheral nerve. Number of myelinated axons, myelinated fiber diameter, myelin thickness, fiber distributions, myelinated fiber density, and neural debris can be quantitatively evaluated with stratification of raw data by nerve component. Results of this semi-automated method are validated by comparing values against those obtained with manual techniques. The use of this approach results in more rapid, accurate, and complete assessment of myelinated axons than manual techniques.

The spectrum of complications of immunosuppression: Is the time right for hand transplantation?

• Life-threatening complications of long-term immunosuppression include malignancy, infection, and metabolic disorders such as renal failure and diabetes. • Up to three-fourths or more of patients on chronic immunosuppressive medications experience an infectious complication. • The hand transplants to date have had multiple episodes of acute rejection. • The frequency and timing of episodes of acute rejection, even if the episodes are easily treated, are predictive of chronic allograft dysfunction and failure. • Chronic allograft rejection is not effectively treated with current immunosuppressive medications, and it has become a primary cause of long-term allograft failure. The introduction of cyclosporine A in the early 1980s revolutionized solid organ transplantation. There were marked improvements not only in preserving graft function, but also in prolonging patient survival following solid organ transplantation 1. As the viability of transplanted organs improved, the indications for clinical transplantation expanded to include not only acutely life-threatening conditions, but also more chronic conditions that adversely affected longevity and quality of life. Composite tissue allotransplantation involves the transplantation of nonvital tissues for reconstruction of deficits following trauma or tumor resection. If successful, composite tissue allotransplantation would facilitate the recovery of lost function through grafting of complex, disparate tissue types. However, composite tissue allotransplantation also poses unique challenges. Solid organs, such as the kidneys, may be more tolerant of rejection episodes than are composite tissues, for which the risk of rejection of one or more components is high. Parenchymal organs may have a tremendous functional reserve so that a substantial amount of tissue can be lost before organ function is compromised, but composite tissue allografts tend to have complex architecture with limited built-in redundancy. Thus, while the majority of kidney function may be lost before blood urea nitrogen or creatinine levels are elevated, comparable loss of the function of composite …

Airway Epithelium is the Primary Target of Allograft Rejection in Murine Obliterative Airway Disease

Murine heterotopic tracheal allografts develop obliterative airway disease (OAD), a suitable model of chronic lung allograft rejection. This model, however, fails to account for the behavior of the allograft when adjacent to recipient airway tissues, particularly the epithelium. This study was performed to determine the immunologic role of the epithelium in development of OAD. BALB/c (H2d) tracheal allografts were transplanted orthotopically into C57BL/6 (H2b) mice and harvested 14–150 days post‐transplantation. The phenotype of the allograft epithelium after orthotopic transplantation was determined with immunofluorescent staining. Orthotopic BALB/c tracheal allografts harvested at 28 days were re‐transplanted heterotopically into BALB/c or C57BL/6 mice, harvested after 28 days, and assessed for OAD. Orthotopic allografts displayed mild cellular infiltration, no fibrosis and preserved epithelium at 28 days post‐transplant. The presence of recipient‐derived epithelium within the allograft was demonstrated with immunofluorescent staining at day 14. Significantly, BALB/c orthotopic allografts re‐transplanted heterotopically into BALB/c mice developed OAD by day 28, whereas BALB/c orthotopic allografts re‐transplanted heterotopically into C57BL/6 mice did not. Repopulation of orthotopic tracheal allografts with recipient‐derived epithelium confers a protective effect against OAD after heterotopic re‐transplantation. This indicates that the airway epithelium plays a crucial role in OAD development.

Brachial plexus injuries.

Severe trauma to the brachial plexus most often occurs in young adult men and is a crippling injury that requires management in a timely fashion for optimal functional recovery and pain control. The surgical management of such injuries is well established, and the techniques continue to evolve. Current management options consist of primary repair in the acute setting, neurolysis, neuroma resection and nerve grafting, motor and sensory nerve transfers, and muscle and tendon transfers. Shoulder andwrist fusion can also play a role in the overall management of these patients. The best operative plan varies depending on the patients level and extent of injury and the surgeons preference and experience. The pre- and postoperative care of these patients is ideally managed by a team that has experience with such problems, including personnel knowledgeable in their postoperative rehabilitation. The total reconstructive process generally consists of more than one operation, and the postoperative rehabilitation is long and intensive. Nevertheless, with a highly motivated patient and a dedicated and specialized surgical team, the prognosis for functional recovery is good, and these patients can still lead productive and satisfying lives.

Effect of FK506 on peripheral nerve regeneration through long grafts in inbred swine

Numerous small-animal studies have demonstrated that FK506 enhances nerve regeneration and accelerates functional recovery after nerve injury. However, no experimental study has corroborated these neuroregenerative effects in larger animals. This study investigated the effects of FK506 on nerve regeneration in inbred miniature swine. Eight animals received 8-cm ulnar nerve autografts and allografts. Treated animals received 0.1 to 0.4 mg/kg FK506 injections twice weekly to maintain immunosuppressive serum FK506 levels. At 24 weeks posttransplant, nerve grafts were harvested for histomorphometric analysis. Mixed lymphocyte cultures demonstrated alloreactivity in 1 treated animal and all untreated animals. In autografts, mean fiber count, nerve density, and percent neural tissue were doubled with FK506 therapy. In allografts, significant neuroregeneration was observed in animals treated with FK506, whereas untreated animals had no regeneration. Treatment with FK506 resulted in a trend toward enhanced axonal regeneration through nerve autografts and allografts in a large-animal model with defined histocompatibility barriers.

Fibrin glue mitigates the learning curve of microneurosurgical repair.

Microneurosurgical technique has a steep learning curve. An alternative to microepineurial suture repair of peripheral nerves that circumvents this learning curve would be ideal. We investigated the effect of surgeon experience on suture versus fibrin glue coaptations in a mouse sciatic nerve graft model. Sixty‐four mice received sciatic nerve grafts with either suture or fibrin glue repair by either a naïve surgeon (medical student) or a surgeon with extensive microsurgical experience. Grafts underwent quantitative histomorphometry at 3 weeks postoperatively. Suture repairs performed by the naïve surgeon demonstrated significantly poorer distal regeneration than all other repairs. Histomorphometric parameters of suture and glue repairs performed by the experienced surgeon were not significantly different from the glue coaptation by the naïve surgeon. Fibrin glue may be considered as an alternative to microepineurial suture repair, particularly in the setting of relative surgeon inexperience with microsurgical technique.

Median to radial nerve transfer for treatment of radial nerve palsy. Case report.

The purpose of this study is to report a surgical technique of nerve transfer to restore radial nerve function after a complete palsy due to a proximal injury to the radial nerve. The authors report the case of a patient who underwent direct nerve transfer of redundant or expendable motor branches of the median nerve in the proximal forearm to the extensor carpi radialis brevis and the posterior interosseous branches of the radial nerve. Assessment included degree of recovery of wrist and finger extension, and median nerve function including pinch and grip strength. Clinical evidence of reinnervation was noted at 6 months postoperatively. The follow-up period was 18 months. Recovery of finger and wrist extension was almost complete with Grade 4/5 strength. Pinch and grip strength were improved postoperatively. No motor or sensory deficits related to the median nerve were noted, and the patient is very satisfied with her degree of functional restoration. Transfer of redundant synergistic motor branches of the median nerve can successfully reinnervate the finger and wrist extensor muscles to restore radial nerve function. This median to radial nerve transfer offers an alternative to nerve repair, graft, or tendon transfer for the treatment of radial nerve palsy.

Nerve Allotransplantation as it Pertains to Composite Tissue Transplantation

Nerve allografts provide a temporary scaffold for host nerve regeneration and allow for the repair of significant segmental nerve injuries. From rodent, large animal, and nonhuman primate studies, as well as clinical experience, nerve allografts, with the use of immunosuppression, have the capacity to provide equal regeneration and function to that of an autograft. In contrast to solid organ transplantation and composite tissue transfers, nerve allograft transplantation requires only temporary immunosuppression. Furthermore, nerve allograft rejection is difficult to assess, as the nerves are surgically buried and are without an immediate functional endpoint to monitor. In this article, we review what we know about peripheral nerve allograft transplantation from three decades of experience and apply our current understanding of nerve regeneration to the emerging field of composite tissue transplantation.