Obstetric brachial plexus palsy is a devastating birth injury. While many children recover spontaneously, 20-25% are left with a permanent impairment of the affected limb. So far, concepts of pathology and recovery have focused on the injury of the peripheral nerve. Proximal nerve injury at birth, however, leads to massive injury-induced motoneuron loss in corresponding motoneuron pools and therefore limits the extent of functional recovery. In the present study, the role of spinal cord plasticity after injury and recovery from obstetric brachial plexus lesions was investigated. A selective injury to spinal roots C5 and C6 was induced in newborn Sprague-Dawley rats, leading to motoneuron loss in corresponding motoneuron pools. Recovery of extremity function was evaluated with different behavioural paradigms. Permanent changes of adjacent motoneuron pools were quantitatively evaluated by retrograde tracing and functional muscle testing. We report that the adjacent C7 motoneuron contribution to biceps muscle innervation increased four-fold after upper trunk lesions in newborns, thus compensating for the injury-induced motoneuron loss. These results indicate that, in obstetric brachial plexus palsy, changes in spinal cord architecture are an integral part not only of primary pathology but also of the subsequent recovery process. While present treatment is directed towards the restoration of neural continuity, future treatment strategies must recognize and take advantage of CNS participation in the injury and recovery process.

Over the last decade, several models have investigated the usefulness of different biologic and/or synthetic matrices as alternatives to conventional nerve grafts. Still, axonal regeneration did not occur over longer (> 3 cm) distances. One problem may be that a growth-promoting environment not only includes physical cues but also a rich spectrum of different growth factors only provided by reactive Schwann cells. In the current study, we investigated whether a hybrid graft consisting of first-generation autologous Schwann cells seeded onto an acellular auto- or homograft can aid regeneration across a critical nerve defect in a rat model. In this paradigm, Schwann cells were not expanded in vitro but harvested from the proximal stump neuroma at the time of reconstruction and seeded into either an acellular homo- or autograft. Regeneration was then quantitated with functional muscle testing, regular histology, histomorphometry, and retrograde tracing techniques 12 weeks after reconstruction. Results showed successful regeneration over the entire distance regardless of whether Schwann cells were transplanted onto auto- or homologous acellular matrix. Schwann cells did populate both grafts; however, only sensory axons persisted through the entire distance. The functional outcome was dismal with no motor and poor sensory recovery. Control group C with homologous matrix only without Schwann cells showed no signs of directed axonal regeneration. Control group D with autologous reverse graft showed excellent recovery, as was expected. The present experiment sought to create a hybrid graft where the proximal stump neuroma is used as a biological resource for autologous Schwann cells that are seeded unto an acellular matrix, thus providing both physical and chemical support to regenerating axons. The results are encouraging in that successful regeneration was observed over the entire distance; however, only sensory axons had enough regenerative potential to also make end-organ contact. For motor axons, further refinements in conduit preparation have to be done.

No abstract

Motoneurons of the neonate rat respond to proximal axonal injury with morphologic and functional changes and ultimately with neuronal death. Recent studies showed that both glial cell-line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) reduce induced degeneration of motoneurons after axotomy and avulsion. Whether rescued motoneurons are functionally intact has been argued. In the present investigation, the authors have used a proximal crush lesion of the brachial plexus in neonatal rats as the experimental model of neuronal injury. This allowed the authors to study the effects of trophic factor administration on injured motoneurons and the relationship between motoneuron survival and extremity function. Trophic factors were locally released by small polymer implants in a low-dose slow-release mode. Six groups of 10 animals were prepared: BDNF, GDNF, GDNF/BDNF, control, sham, and normals. The number of surviving motoneurons was determined by retrograde tracer techniques using Fluorogold and Fastblue. Extremity function was quantitatively evaluated with functional muscle testing at day 56. The results of this study demonstrate that trophic factors applied separately had no effect, whereas combined trophic factor application (GDNF/BDNF group) had a dramatic rescue effect on motoneuron survival as compared with the control groups, which also effected significantly greater strength. The authors conclude that a combination of trophic factors leads to enhanced motoneuron survival, with improved voluntary function as the animal enters adulthood so that exogenous trophic support of motoneurons might have a role in the treatment of all types of severe neonatal plexopathies, maintaining the viability of motoneurons until reconstructive surgery provides them with a pathway for regeneration and endogenous trophic support.

Ideal reconstructions of complex defects in the midface require the restitution not only of bone and soft tissue, but also of a thin and durable lining of the oral cavity. So far, split-thickness skin grafts, intestinal grafts, and in vitro cultured mucosal grafts have been used for the reconstruction of the oral lining. The use of skin as a substitute for oral mucosa is controversial because contraction, hair growth, maceration, and dysplastic changes can occur. This clinical and histologic study was performed to evaluate the suitability of dermis as a substitute for oral lining. Twelve complex defects of the midface were reconstructed with dermis-prelaminated scapula flaps. A bony flap from the lateral border of the scapula was prepared, and osseointegrated implants were placed. The bone flap was then prelaminated with dermis and covered with a Gore-Tex membrane to prevent adhesions. The composite flap was transferred to the midface 2 to 3 months later. The oral lining of the flap was evaluated clinically and histologically at 2, 4, and 6 weeks and at 3 to 41 months after the reconstruction. In all patients, the reconstructed bone was covered with a thin and lubricated surface without hair growth. None of the patients showed any signs of maceration. Histologically, these findings corresponded to a keratinized stratified squamous epithelium with highly developed connective-tissue papillae. These features closely resemble those of the normal mucosa of the hard palate and the gingiva. Thus, dermis prelamination is an effective method for reconstructing the mucosa of the alveolar ridge and the hard palate.

Injuries of the peripheral nerve in the early post-natal period are known to cause massive loss in the motoneuron pools of the spinal cord. However, the exact time frame and extent of motoneuron death in the cervical spinal cord after a brachial plexus lesion and the altered course after neuroprotection with different trophic factors is not known. In the present study, the time course of induced motoneuron death after a neonatal peripheral nerve injury and the effect of GDNF was investigated over a 4 week time period to determine the window of opportunity for possible therapeutic interventions in obstetrical plexus palsy. The brachial plexus of a total of 70 animals was explored within 12 hours after birth and divided at trunc level. The plexus was then labeled with a fluorescent tracer to identify the corresponding motoneuron pool. Two groups were prepared: Group I remained untreated to assess the natural course of induced neuronal death. Group II received GDNF immediately after the lesion. Post-operatively the animals were evaluated sequentially over 29 days. Surviving motoneurons were evaluated quantitatively counting the nucleoli. The entire brachial plexus of the rat is supplied by a total of about 4000 motoneurons. After injury the number of motoneurons steadily diminished within the first 10 days to reach a plateau of about 20% of the original number. At this time the GDNF treated group still had 85% (3330 +/- 247) of motoneurons viable. This further decreased so that at the termination of the experiment at day 29 there were still 2527 +/- 285 motoneurons alive. This study clearly shows that pathology after a brachial plexus injury in the newborn is not restricted to the peripheral nerve alone. In this model 64% of motoneurons underwent apoptosis within the first week after injury, reaching a plateau after 10 days at 20%. GDNF successfully rescued motoneurons so that after 4 weeks still 65% were present. We conclude that GDNF leads to enhanced motoneuron survival so that exogenous trophic support of motoneurons might have a role in the treatment of all types of severe neonatal plexopathies, maintaining the viability of motoneurons until reconstructive surgery provides them with a pathway for regeneration and endogenous trophic support.

Motoneurons of the neonate rat respond to proximal axonal injury with morphologic and functional changes and ultimately with neuronal death. Recent studies showed that both glial cell-line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) reduce induced degeneration of motoneurons after axotomy and avulsion. Whether rescued motoneurons are functionally intact has been argued. In the present investigation, the authors have used a proximal crush lesion of the brachial plexus in neonatal rats as the experimental model of neuronal injury. This allowed the authors to study the effects of trophic factor administration on injured motoneurons and the relationship between motoneuron survival and extremity function. Trophic factors were locally released by small polymer implants in a low-dose slow-release mode. Six groups of 10 animals were prepared: BDNF, GDNF, GDNF/BDNF, control, sham, and normals. The number of surviving motoneurons was determined by retrograde tracer techniques using Fluorogold and Fastblue. Extremity function was quantitatively evaluated with functional muscle testing at day 56. The results of this study demonstrate that trophic factors applied separately had no effect, whereas combined trophic factor application (GDNF/BDNF group) had a dramatic rescue effect on motoneuron survival as compared with the control groups, which also effected significantly greater strength. The authors conclude that a combination of trophic factors leads to enhanced motoneuron survival, with improved voluntary function as the animal enters adulthood so that exogenous trophic support of motoneurons might have a role in the treatment of all types of severe neonatal plexopathies, maintaining the viability of motoneurons until reconstructive surgery provides them with a pathway for regeneration and endogenous trophic support.

The reconstruction of maxillary defects is a challenge in plastic surgery. The so-called prefabricated scapula flap consists of syngeneic bone covered with syngeneic dermis and is used to reconstruct maxillary defects. After placing these flaps into the oral cavity, they are reepithelialized within a short time period, raising the question of the cellular origin of the "neomucosa." We therefore obtained sequential biopsy samples of the prefabricated flap and of the flap after being placed into the oral cavity and analyzed the keratin expression profile of epithelial cells. We expected that after placing the prefabricated flap into the oral cavity, keratinocytes from adnexal structures of the dermal component of the graft would migrate onto the surface and reepithelialize the flap. Unexpectedly, reepithelialization occurred earlier. The flap had acquired a mucosa-like epithelium at the interface between the Gore-Tex coating and the dermis while still being positioned within the scapular region. The keratin expression profile of this epithelium was very similar to that of mucosal epithelium. Thus, the prefabricated scapula flap not only consisted of bone covered with connective tissue, but was also covered with epithelial cells derived from adnexal structures of the dermal graft. This seems to be the reason for the rapid restoration of an intact mucosa and the excellent outcome achieved with this surgical technique.