Liqiang Gu

Safety and efficacy evaluation of a human acellular nerve graft as a digital nerve scaffold: a prospective, multicentre controlled clinical trial

This study developed a human acellular nerve graft (hANG) as an alternative to autogenous nerve and reports on its safety and efficacy. There were two groups comprised of 72 patients that received digital nerve repair with hANG (test) and 81 that received conventional direct tension‐free suture repair of the nerve defect (control). The efficacy of the treatment was evaluated by static 2‐point discrimination (s2PD) and Semmes‐Weinstein monofilament testing. Safety was evaluated by local wound response and laboratory testing. Mean age of patients in the test group was 33.0 ± 11.1 years (range 18‐61 years) and in the control group 36.9 ± 13.4 years (range 15‐77 years) (p = 0.0470). Mean time from injury to repair in the test group was 23.7 ± 52 days (range 0‐200 days) and in the control group 1.5 ± 10.4 days (range 0‐91 days) (p = 0.0005). Mean length of nerve graft was 1.80 ± 0.82 cm (range 1‐5 cm). All surgeries were performed successfully and without complications. The excellent and good rate of s2PD in the test group was 65.28% and 95% CI was 51.98‐78.93%. s2PD in the test group improved over time and average distance was 12.81 ± 5.99 mm at 6 months postoperatively. No serious adverse or product‐related events were reported. These results indicate that hANG is a safe and effective for the repair of nerve defects of 1‐5 cm in size.

Etifoxine provides benefits in nerve repair with acellular nerve grafts

Introduction: Acellular nerve grafts are good candidates for nerve repair, but the clinical outcome of grafting is not always satisfactory. We investigated whether etifoxine could enhance nerve regeneration. Methods: Seventy‐two Sprague‐Dawley rats were divided into 3 groups: (1) autograft; (2) acellular nerve graft; and (3) acellular nerve graft plus etifoxine. Histological and electrophysiological examinations were performed to evaluate the efficacy of nerve regeneration. Walking‐track analysis was used to examine functional recovery. Quantitative polymerase chain reaction was used to evaluate changes in mRNA level. Results: Etifoxine: (i) increased expression of neurofilaments in regenerated axons; (ii) improved sciatic nerve regeneration measured by histological examination; (iii) increased nerve conduction velocity; (iv) improved walking behavior as measured by footprint analysis; and (v) boosted expression of neurotrophins. Conclusions: These results show that etifoxine can enhance peripheral nerve regeneration across large nerve gaps repaired by acellular nerve grafts by increasing expression of neurotrophins. Muscle Nerve 50:235–243, 2014

Three-dimensional Reconstruction of the Microstructure of Human Acellular Nerve Allograft

The exact inner 3D microstructure of the human peripheral nerve has been a mystery for decades. Therefore, it has been difficult to solve several problems regarding peripheral nerve injury and repair. We used high-resolution X-ray computed microtomography (microCT) to scan a freeze-dried human acellular nerve allograft (hANA). The microCT images were then used to reconstruct a 3D digital model, which was used to print a 3D resin model of the nerve graft. The 3D digital model of the hANA allowed visualization of all planes. The magnified 3D resin model clearly showed the nerve bundles and basement membrane tubes of the hANA. Scanning electron microscopy (SEM) was used to analyse the microstructure of the hANA. Compared to the SEM images, the microCT image clearly demonstrated the microstructure of the hANA cross section at a resolution of up to 1.2 μm. The 3D digital model of the hANA facilitates a clear and easy understanding of peripheral nerve microstructure. Furthermore, the enlarged 3D resin model duplicates the unique inner structure of each individual hANA. This is a crucial step towards achieving 3D printing of a hANA or nerve that can be used as a nerve graft.

Etifoxine promotes glial‑derived neurotrophic factor‑induced neurite outgrowth in PC12 cells

Nerve regeneration and functional recovery are major issues following nerve tissue damage. Etifoxine is currently under investigation as a therapeutic strategy for promoting neuroprotection, accelerating axonal regeneration and modulating inflammation. In the present study, a well‑defined PC12 cell model was used to explore the underlying mechanism of etifoxine‑stimulated neurite outgrowth. Etifoxine was found to promote glial‑derived growth factor (GDNF)‑induced neurite outgrowth in PC12 cells. Average axon length increased from 50.29±9.73 to 22.46±5.62 µm with the use of etifoxine. However, blockage of GDNF downstream signaling was found to lead to the loss of this phenomenon. The average axon length of the etifoxine group reduces to a normal level after the blockage of the GDNF family receptor α1 (GFRα1) and receptor tyrosine kinase (RETS) receptors (27.46±3.59 vs. 22.46±5.62 µm and 25.31±3.68 µm vs. 22.46±5.62 µm, respectively, p>0.05). In addition, etifoxine markedly increased GDNF mRNA and protein expression (1.55‑ and 1.36-fold, respectively). However, blockage was not found to downregulate GDNF expression. The results of the current study demonstrated that etifoxine stimulated neurite outgrowth via GDNF, indicating that GDNF represents a key molecule in etifoxine‑stimulated neurite outgrowth in PC12 cells.

Analysis of human acellular nerve allograft reconstruction of 64 injured nerves in the hand and upper extremity: a 3 year follow-up study.

Human acellular nerve allografts have been increasingly applied in clinical practice. This study was undertaken to investigate the functional outcomes of nerve allograft reconstruction for nerve defects in the upper extremity. A total of 64 patients from 13 hospitals were available for this follow‐up study after nerve repair using human acellular nerve allografts. Sensory and motor recovery was examined according to the international standards for motor and sensory nerve recovery. Subgroup analysis and logistic regression analysis were conducted to identify the relationship between the known factors and the outcomes of nerve repair. Mean follow‐up time was 355 ± 158 (35–819) days; mean age was 35 ± 11 (14–68) years; average nerve gap length was 27 ± 13 (10–60) mm; no signs of infection, tissue rejection or extrusion were observed among the patients; 48/64 (75%) repaired nerves experienced meaningful recovery. Univariate analysis showed that site and gap length significantly influenced prognosis after nerve repair using nerve grafts. Delay had a marginally significant relationship with the outcome. A multivariate logistic regression model revealed that gap length was an independent predictor of nerve repair using human acellular nerve allografts. The results indicated that the human acellular nerve allograft facilitated safe and effective nerve reconstruction for nerve gaps 10–60 mm in length in the hand and upper extremity. Factors such as site and gap length had a statistically significant influence on the outcomes of nerve allograft reconstruction. Gap length was an independent predictor of nerve repair using human acellular nerve allografts. Copyright

Functioning free gracilis transfer to reconstruct elbow flexion and quality of life in global brachial plexus injured patients

In the study, the functional recovery and relative comprehensive quality of life of cases of global brachial plexus treated with free functioning muscle transfers were investigated. Patients who received functioning gracilis muscle transfer between August 1999 and October 2014 to reconstruct elbow flexion, wrist and fingers extension were recruited. The mean age of the patients was 26.36 (range, 16–42) years. The mean period of time from gracilis transfer to the last follow-up was 54.5 months (range, 12–185 months). Muscle power, active range of motion of the elbow flexion, wrist extension, and total active fingers extension were recorded. SDS, SAS and DASH questionnaires were given to estimate patients’ quality of life. 35.71% reported good elbow flexion and 50.00% reported excellent elbow flexion. The average ROM of the elbow flexion was 106.5° (range, 0–142°) and was 17.00° (range, 0–72°) for wrist extension. The average DASH score was 51.14 (range, 17.5–90.8). The prevalence of anxiety and depression were 42.86% and 45.24%. Thrombosis and bowstringing were the most common short and long-term complications. Based on these findings, free gracilis transfer using accessory nerve as donor nerve is a satisfactory treatment to reconstruct the elbow flexion and wrist extension in global-brachial-plexus-injured patients.

Development of a novel experimental rat model for brachial plexus avulsion injury.

Brachial plexus injuries (BPI) are devastating events that frequently result in severe functional impairment of the upper extremity, and yet, present surgical reconstruction provides limited results. An animal model is an important tool to study peripheral nerve repair and regeneration. Here, a passive traction apparatus that allowed a multidirectional force exerted on a fixed forelimb was designed to produce a BPI rat model in a noninvasive manner. Behavioral and histological analyses were carried out to assess the suitability of the model. Using the apparatus, a reproducible upper BPI model was established with the forelimb abducted 30° and a test weight of 2 kg. Avulsion of the nerve roots resulted in almost a total loss of forelimb function and the average Terzis score was decreased significantly compared with the sham group. No obvious recovery of shoulder and elbow movements was noted during the test period. In addition, nerve roots avulsion injury led to severe retrograde degeneration of motoneurons in the C5-C7 spinal cord segments. Nissl staining results showed that motoneurons decreased significantly in number and appeared to have irregular morphologies. These results indicated that a novel noninvasive rat model for BPI that simulates the mechanism of a human lesion could be produced using our passive traction apparatus, and it is expected to produce reliable preclinical evidence in the assessment of new therapeutic strategies for this lesion.

A simple model of radial nerve injury in the rhesus monkey to evaluate peripheral nerve repair.

Current research on bone marrow stem cell transplantation and autologous or xenogenic nerve transplantation for peripheral nerve regeneration has mainly focused on the repair of peripheral nerve defects in rodents. In this study, we established a standardized experimental model of radial nerve defects in primates and evaluated the effect of repair on peripheral nerve injury. We repaired 2.5-cm lesions in the radial nerve of rhesus monkeys by transplantation of autografts, acellular allografts, or acellular allografts seeded with autologous bone marrow stem cells. Five months after surgery, regenerated nerve tissue was assessed for function, electrophysiology, and histomorphometry. Postoperative functional recovery was evaluated by the wrist-extension test. Compared with the simple autografts, the acellular allografts and allografts seeded with bone marrow stem cells facilitated remarkable recovery of the wrist-extension functions in the rhesus monkeys. This functional improvement was coupled with radial nerve distal axon growth, a higher percentage of neuron survival, increased nerve fiber density and diameter, increased myelin sheath thickness, and increased nerve conduction velocities and peak amplitudes of compound motor action potentials. Furthermore, the quality of nerve regeneration in the bone marrow stem cells-laden allografts group was comparable to that achieved with autografts. The wrist-extension test is a simple behavioral method for objective quantification of peripheral nerve regeneration.

Diagnostic Value and Surgical Implications of the 3D DW-SSFP MRI On the Management of Patients with Brachial Plexus Injuries

Three-dimensional diffusion-weighted steady-state free precession (3D DW-SSFP) of high-resolution magnetic resonance has emerged as a promising method to visualize the peripheral nerves. In this study, the application value of 3D DW-SSFP brachial plexus imaging in the diagnosis of brachial plexus injury (BPI) was investigated. 33 patients with BPI were prospectively examined using 3D DW-SSFP MR neurography (MRN) of brachial plexus. Results of 3D DW-SSFP MRN were compared with intraoperative findings and measurements of electromyogram (EMG) or somatosensory evoked potentials (SEP) for each injured nerve root. 3D DW-SSFP MRN of brachial plexus has enabled good visualization of the small components of the brachial plexus. The postganglionic section of the brachial plexus was clearly visible in 26 patients, while the preganglionic section of the brachial plexus was clearly visible in 22 patients. Pseudomeningoceles were commonly observed in 23 patients. Others finding of MRN of brachial plexus included spinal cord offset (in 16 patients) and spinal cord deformation (in 6 patients). As for the 3D DW-SSFP MRN diagnosis of preganglionic BPI, the sensitivity, the specificity and the accuracy were respectively 96.8%, 90.29%, and 94.18%. 3D DW-SSFP MRN of brachial plexus improve visualization of brachial plexus and benefit to determine the extent of injury.

Vascularized proximal fibular epiphyseal transfer for Bayne and Klug type III radial longitudinal deficiency in children.

Background: Treatment of Bayne and Klug type III radial longitudinal deficiency with fibular epiphyseal transplantation in children has had limited success to date. The purpose of this investigation was to review the authors’ results of microvascular epiphyseal transplantation for radial longitudinal deficiency. Methods: Between 2007 and 2009, four children with a mean age of 4.3 years (range, 3.3 to 5.8 years) who had a type III radial longitudinal deficiency underwent microsurgical reconstruction of the distal radius with vascularized proximal fibular transplantation, including the physis, partial superior tibiofibular joint, and a variable length of the diaphysis. All of the grafts were supplied by the inferior lateral genicular artery. In all patients, the range of motion of the digits, wrist, forearm, and elbow; the length of the forearm; and the deviation of the wrist were evaluated. Results: The mean duration of follow-up was 42 months (range, 24 to 65 months). All four transfers survived and united with the host bone within 3 months postoperatively. An average correction of 28 degrees in the hand-forearm angle was obtained. Forearm length was 67.9 percent that of the normal side on average at the final follow-up. The overall range of wrist motion was approximately 55 percent that of the contralateral extremity. No major complications were observed. Conclusions: Vascularized proximal fibular epiphyseal transfer, based on the inferior lateral genicular artery, is a technically feasible method for treatment of type III radial longitudinal deficiency, which maintains hand-forearm alignment, provides excellent function, and minimizes the length discrepancy between the distal radius and ulna. Clinical question/level of evidence: Therapeutic, IV.