Fluctuations in cortical synchronization in pediatric traumatic brain injury.

Traumatic brain injury (TBI) is the leading cause of death and acquired disability in the pediatric population worldwide. We hypothesized that electroencephalography (EEG) synchrony and its temporal variability, analyzed during the acute phase following TBI, would be altered from that of normal children and as such would offer insights into TBI pathophysiology. Seventeen pediatric patients with mild to severe head injury admitted to a pediatric critical care unit were recruited along with 10 age- and gender-matched controls. Patients had two electroencephalographs performed 3 days apart. Outcome was measured at 1 year post-TBI utilizing the Pediatric Cerebral Performance Category score (PCPC). Maximal synchrony between EEG channels correlated to areas of primary injury as seen on computed tomography (CT) scan. The temporal variability of phase synchronization among EEG electrodes increased as patients recovered and emerged from coma (p < 0.001). This temporal variability correlated with outcome (Pearson coefficient of 0.74) better than the worst Glasgow Coma Scale score, length of coma, or extent of injury on CT scan. This represents a novel approach in the evaluation of TBI in children.

Prolonged target deprivation reduces the capacity of injured motoneurons to regenerate.

OBJECTIVE: To investigate whether or not it is the frustrated growth state (no axon growth) that reduces regenerative capacity or the inability of axotomized motoneurons to remake muscle connections (axon growth-no muscle contact) that accounts for poor regenerative capacity of chronically axotomized motoneurons. METHODS: We chronically axotomized rat femoral motoneurons for 2 months by cutting the nerve and either capping the proximal nerve to prevent axon regeneration (Group 1, no axon growth for 2 mo) or encouraging axon regeneration but not target reinnervation by suture to the distal stump of cut saphenous nerve (Group 2, axon growth with no muscle contact). In the control fresh axotomy group (axon growth with muscle contact), femoral nerve stumps were resutured immediately. Two months later, the femoral nerve was recut and sutured immediately to encourage regeneration in a freshly cut saphenous nerve stump for 6 weeks. Regenerating axons in the saphenous nerve were back-labeled with fluorogold for enumeration of the femoral motoneurons that regenerated their axons into the distal nerve stump. RESULTS: We found that significantly fewer chronically axotomized motoneurons regenerated their axons than freshly axotomized motoneurons that regenerated their axons to reform nerve-muscle connections in the same length of time. The number of motoneurons that regenerated their axons was reduced in both the conditions of no axon growth and axon growth with no muscle contact; thus chronic axotomy for a 2-month period reduced regenerative success irrespective of whether the motoneurons were prevented from regenerating or encouraged to regenerate their axons in that same period of time. CONCLUSION: Axonal regeneration does not protect motoneurons from the negative effects of prolonged axotomy on regenerative capacity. It is the period of chronic axotomy, in which motoneurons remain without target nerve-muscle connection, and not simply a state of frustrated growth that accounts for the reduced regenerative capacity of those neurons.

Coil-reinforced hydrogel tubes promote nerve regeneration equivalent to that of nerve autografts.

Despite spontaneous sprouting of peripheral axons after transection injury, peripheral regeneration is incomplete and limited to short gaps, even with the use of autograft tissue, which is considered to be the "gold" standard. In an attempt to obviate some of the problems associated with autografts, including limited donor tissue and donor site morbidity, we aimed to synthesize a synthetic nerve guidance channel that would perform as well as the nerve autograft. Given that the patency of the nerve guidance channel is critical for repair, we investigated a series of nerve guidance channel designs where patency and the resulting regenerative capacity were compared in a transected rat sciatic nerve injury model. Three tube designs were compared to autograft tissue: plain, corrugated and coil-reinforced tubes of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate). Of the three designs, the coil-reinforced tubes demonstrated superior performance in terms of patency. By electrophysiology and histomorphometry, the coil-reinforced tubes demonstrated outcomes that were comparable to autografts after both 8 and 16 weeks of implantation. The nerve action potential (NAP) velocity and muscle action potential (MAP) velocity for the coil-reinforced PHEMA-MMA tube was 54.6+/-10.1 and 10.9+/-1.3 m/s, respectively at 16 weeks, which was statistically equivalent to those of the autograft at 37.5+/-7.9 and 11.3+/-2.0 m/s. The axon density in the coil-reinforced tube was 2.16+/-0.61x10(4) axons/mm2, which was statistically similar to that of the autograft of 2.41+/-0.62x10(4) axons/mm2 at 16 weeks. These coil-reinforced tubes demonstrated equivalence to autografts for nerve regeneration, demonstrating the importance of channel design to regenerative capacity and more specifically the impact of patency to regeneration.

Peripheral nerve regeneration through a synthetic hydrogel nerve tube.

PURPOSE: As alternatives to nerve grafts for peripheral nerve repair, we have synthesized 12 mm long poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (PHEMA-MMA) porous tubes and studied their regenerative capacity for the repair of surgically-created 10 mm rat sciatic nerve gaps. We compared the in vivo regenerative efficacy of these artificial tubes with the gold standard, the nerve autograft. METHODS: Tubes were assessed in vivo for their ability to support nerve regeneration at 4, 8, and 16 weeks post-implantation by histology, electrophysiology, histomorphometry, and reinnervated lateral gastrocnemius (LG) dry muscle mass. RESULTS: Axonal regeneration within the tubes was observed by 8 weeks, with outcome parameters comparable to autografts. This finding was further supported by the electrophysiological and histomorphometric results. The 16 week tube group had a bimodal response, with 60% of the tubes having a similar response to autografts and the other 40% having significantly lower (p < 0.05) outcome measures in several parameters. CONCLUSIONS: Axonal regeneration in artificial tubes was similar to that in autografts at 8 and 16 weeks, however, a bimodal distribution of regeneration was observed in 16 week tubes.

Long-term in vivo biomechanical properties and biocompatibility of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) nerve conduits.

Artificial grafts are promising alternatives to nerve grafts for peripheral nerve repair because they obviate the complications and disadvantages associated with autografting such as donor site morbidity and limited tissue availability. We have synthesized poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (PHEMA-MMA) porous tubes and studied their efficacy in vivo. Specifically, we studied the short- and long-term stability and biocompatibility of 12 mm long tubes for the repair of surgically created 10 mm nerve gaps in rat sciatic nerves. Prior to implantation, tubes were analyzed in vitro using a micro-mechanical tester to measure displacement achieved with load applied. These results served as a calibration curve, y = 6.8105 x -0.0073 (R2 = 0.9750, n = 28), for in vivo morphometric tube compression measurements. In vivo, most of the PHEMA-MMA conduits maintained their structural integrity up to 8 weeks, but 29% (4/14) of them collapsed by 16 weeks. Interestingly, the tube wall area of collapsed 16-week tubes was significantly lower than those of patent tubes. Tubes were largely biocompatible; however, a small subset of 16-week tubes displayed signs of chronic inflammation characterized by "finger-like" tissue extensions invading the inner tube aspect, inflammatory cells (some of which were ED1+macrophages) and giant cells. Tubes also demonstrated signs of calcification, which increased from 8 to 16 weeks. To overcome these issues, future nerve conduits will be re-designed to be more robust and biocompatible.

Peripheral nerve regeneration through guidance tubes.

Biological nerve grafts have been extensively utilized in the past to repair peripheral nerve injuries. More recently, the use of synthetic guidance tubes in repairing these injuries has gained in popularity. This review focuses on artificial conduits, nerve regeneration through them, and an account of various synthetic materials that comprise these tubes in experimental animal and clinical trials. It also lists and describes several biomaterial considerations one should regard when designing, developing, and manufacturing potential guidance channel candidates. In the future, it it likely that the most successful synthetic nerve conduit will be one that has been fabricated with some of these strategies in mind.