Nektarios Sinis

Synthetic nerve guide implants in humans: a comprehensive survey.

OBJECTIVE:Lesions of the peripheral nervous system result in the loss of sensory and motor function and may in addition be accompanied by severe neuropathic syndromes originating from aberrant axonal regrowth. The transplantation of autologous nerve grafts represents the current “gold standard” during reconstructive surgery, despite obvious side effects. Depending on the demands of the lesion site, various donor nerves may be used for grafting (e.g., the sural, saphenous), sacrificing native functions in their target areas. Recently, several synthetic nerve guide implants have been introduced and approved for clinical use to replace autologous transplants. This alternative therapy is based on pioneering studies with experimental nerve guides. METHODS:We present a comprehensive review of all published human studies involving synthetic nerve guides. RESULTS:Data from some 300 patients suggest that for short nerve defects of a few centimeters, resorbable implants provide promising results, whereas a number of late compression syndromes have been documented for nonresorbable implants. CONCLUSIONS:To treat longer defects, further implant development is needed, a goal that could be achieved, for example, by more closely imitating the intact nerve architecture and regulatory cell-cell interactions.

Mechanical stimulation of paralyzed vibrissal muscles following facial nerve injury in adult rat promotes full recovery of whisking

Many patients suffer lifelong disabilities after peripheral nerve injury. Insufficient recovery has been attributed to excessive axonal branching, axonal regrowth to improper targets and polyneuronal reinnervation of motor endplates. We used the rat facial nerve transection/suture model to quantify the effects of mechanical stimulation on the paralyzed whisker musculature. Manual stimulation involved briskly stroking the whiskers by hand in a manner that specifically mimicked normal whisker movement. Environmental stimulation involved enhanced whisker use as rats encountered objects in an enriched environment. Manual and environmental stimulation were also combined. Video-based motion analysis of vibrissal motor performance showed that daily manual, but not environmental, stimulation for 2 months resulted in full recovery of whisking. Polyneuronal reinnervation of motor endplates was reduced but not misdirected axonal regrowth. Our findings indicate the potential of use-specific training to enhance appropriate functional outcome after peripheral nerve injury and may be useful in a clinical rehabilitation setting.

Memantine treatment of complex regional pain syndrome : A preliminary report of six cases

ObjectivesRecent studies have confirmed the contribution of the central nervous system (CNS) to the pathogenesis of Complex Regional Pain Syndrome (CRPS), because animal models of neuropathic pain syndromes demonstrate an overexpression of N-methyl-D-aspartate-receptors in the CNS. The aim of this work was to study the influence of a central acting drug—the N-methyl-D-aspartate receptor antagonist Memantine—in patients with CRPS of one upper extremity. Here we present the results of 6 patients treated with Memantine for 8 weeks. MethodsAll patients developed CRPS after traumatic injury to one upper extremity. To document changes during the study, levels of pain were measured after clenching the hand using a numeric pain intensity scale ranging from 0 (no pain) to 10 (maximum pain). Motor symptoms were documented for the fingers (fingertips to palm and fingernails to table) and the wrist (flexion/extension). Furthermore, the force was analyzed using a JAMAR-Dynamometer and a Pinchmeter. For assessment of central changes, functional magnetic resonance imaging and magnetoencephalography were used to further document the results of other experiments in 1 patient. Autonomic changes were photographed and pictures were compared before and after treatment with Memantine. ResultsSix months after treatment with Memantine, all patients showed a significant decrease in their levels of pain which coincided with an improvement in motor symptoms and autonomic changes. The functional magnetic resonance imaging and magnetoencephalography results provided evidence of cortical reorganization [changes in somatotopic maps in the primary somatosensory cortex (S1)]. These changes returned to a cortical pattern comparable to the unaffected side after treatment with Memantine. DiscussionBased on these first results, the use of Memantine for treatment of CRPS seems promising and supports the hypothesis of a CNS contribution to the pathogenesis and maintenance of neuropathic pain syndromes.

Electrical stimulation of paralyzed vibrissal muscles reduces endplate reinnervation and does not promote motor recovery after facial nerve repair in rats.

The outcome of peripheral nerve injuries requiring surgical repair is poor. Recent work has suggested that electrical stimulation (ES) of denervated muscles could be beneficial. Here we tested whether ES has a positive influence on functional recovery after injury and surgical repair of the facial nerve. Outcomes at 2 months were compared to animals receiving sham stimulation (SS). Starting on the first day after end-to-end suture (facial-facial anastomosis), electrical stimulation (square 0.1 ms pulses at 5 Hz at an ex tempore established threshold amplitude of between 3.0 and 5.0V) was delivered to the vibrissal muscles for 5 min a day, 3 times a week. Restoration of vibrissal motor performance following ES or SS was evaluated using the video-based motion analysis and correlated with the degree of collateral axonal branching at the lesion site, the number of motor endplates in the target musculature and the quality of their reinnervation, i.e. the degree of mono- versus poly-innervation. Neither protocol reduced collateral branching. ES did not improve functional outcome, but rather reduced the number of innervated motor endplates to approximately one-fifth of normal values and failed to reduce the proportion of poly-innervated motor endplates. We conclude that ES is not beneficial for recovery of whisker function after facial nerve repair in rats.

Manually-stimulated recovery of motor function after facial nerve injury requires intact sensory input

We have recently shown in rat that daily manual stimulation (MS) of vibrissal muscles promotes recovery of whisking and reduces polyinnervation of muscle fibers following repair of the facial nerve (facial-facial anastomosis, FFA). Here, we examined whether these positive effects were: (1) correlated with alterations of the afferent connections of regenerated facial motoneurons, and (2) whether they were achieved by enhanced sensory input through the intact trigeminal nerve. First, we quantified the extent of total synaptic input to motoneurons in the facial nucleus using synaptophysin immunocytochemistry following FFA with and without subsequent MS. We found that, without MS, this input was reduced compared to intact animals. The number of synaptophysin-positive terminals returned to normal values following MS. Thus, MS appears to counteract the deafferentation of regenerated facial motoneurons. Second, we performed FFA and, in addition, eliminated the trigeminal sensory input to facial motoneurons by extirpation of the ipsilateral infraorbital nerve (IONex). In this paradigm, without MS, vibrissal motor performance and pattern of end-plate reinnervation were as aberrant as after FFA without MS. MS did not influence the reinnervation pattern after IONex and functional recovery was even worse than after IONex without MS. Thus, when the sensory system is intact, MS restores normal vibrissal function and reduces the degree of polyinnervation. When afferent inputs are abolished, these effects are eliminated or even reversed. We conclude that rehabilitation strategies must be carefully designed to take into account the extent of motor and/or sensory damage.

Chapter 19 The Role of Collagen in Peripheral Nerve Repair

Collagens are extracellular proteins characterized by a triple helical structure and predominantly involved in the formation of fibrillar and microfibrillar networks of the extracellular matrix and basement membranes. There are 29 collagen types which differ in size, structure, and function. In the peripheral nervous system, two classes of collagen molecules are expressed: fibril forming collagens (type-I, III, and V) and basement membrane collagens (type-IV). Collagens are required for normal extracellular matrix assembly and play an important role in the regulation of Schwann cell function. After injury collagen production in the severed nerve often exceeds the ideal response which is suggested to hinder the growth of sprouting axons into the appropriate distal fascicles and therefore delays and limits nerve regeneration. Both surgical techniques and pharmacological agents are developed to reduce injury induced scarring but despite this nerve regeneration is frequently incomplete. The aim of the present review is to provide the reader a clear overview of the current knowledge with respect to collagens in the peripheral nervous system and to emphasize its role after nerve injury.

Manual stimulation of facial muscles improves functional recovery after hypoglossal-facial anastomosis and interpositional nerve grafting of the facial nerve in adult rats.

The facial nerve in humans is often prone to injuries requiring surgical intervention. In the best case, nerve reconstruction is achieved by a facial-facial anastomosis (FFA), i.e. suture of the proximal and distal stumps of the severed facial nerve. Although a method of choice, FFA rarely leads to a satisfactory functional recovery. We have recently devised and validated, in an established experimental paradigm in rats, a novel strategy to improve the outcome of FFA by daily manual stimulation (MS) of facial muscles. This treatment results in full recovery of facial movements (whisking) and is achieved by reducing the proportion of functionally detrimental poly-innervated motor end-plates. Here we asked whether MS could also be beneficial after two other commonly used surgical methods of clinical facial nerve reconstruction namely hypoglossal-facial anastomosis (HFA) and interpositional nerve grafting (IPNG) which, however, seem to have a poorer outcome compared to FFA. Compared to FFA, daily MS for 2 months after HFA and IPGN did not completely restore function but, nevertheless, significantly improved the amplitude of whisker movements by 50% compared with untreated animals. Functional improvement was associated with a reduction in the proportion of polyinnervated end-plates. MS did not reduce the extent of axonal branching at the lesion site nor the subsequent misdirected axonal regrowth to inappropriate targets. Our data show that a simple approach leading to improved quality of muscle fiber reinnervation is functionally beneficial after different types of clinically relevant surgical interventions.

Manual stimulation of forearm muscles does not improve recovery of motor function after injury to a mixed peripheral nerve.

Transection and re-anastomosis of the purely motor facial nerve leads to poor functional recovery. However, we have recently shown in rat that manual stimulation (MS) of denervated vibrissal muscles reduces the number of polyinnervated motor endplates and promotes full recovery of whisking. Here, we examined whether MS of denervated rat forearm muscles would also improve recovery following transection and suture of the mixed (sensory and motor) median nerve (median–median anastomosis, MMA). Following MMA of the right median nerve, animals received no postoperative treatment, daily MS of the forearm muscles or handling only. An almost identical level of functional recovery, measured by the force of grip in grams, was reached in all animals by the sixth postoperative week and maintained till 3xa0months following surgery regardless of the postoperative treatment. Also, we found no differences among the groups in the degree of axonal sprouting, the extent of motor endplate polyinnervation and in the soma size of regenerated motoneurons. Taken together, we show that while MS is beneficial following motor nerve injury, combined strategies will be required for functional recovery following mixed nerve injury.

Manual stimulation, but not acute electrical stimulation prior to reconstructive surgery, improves functional recovery after facial nerve injury in rats.

UNLABELLEDnThe outcome of peripheral nerve injuries requiring surgical repair is poor. Recent work suggested that electrical stimulation (ES) of the proximal nerve stump to produce repeated discharges of the parent motoneurons for one hour could be a beneficial therapy if delivered immediately prior to reconstructive surgery of mixed peripheral nerves.nnnPURPOSEnWe tested whether ES has a positive influence on functional recovery after repair of a purely motor nerve, the facial nerve.nnnMETHODSnElectrical stimulation (20 Hz) was delivered to the proximal nerve stump of the transected facial nerve for 1 hour prior to nerve reconstruction by end-to-end suture (facial-facial anastomosis, FFA). For manual stimulation (MS), animals received daily rhythmic stroking of the whisker pads. Restoration of vibrissal motor performance following ES or MS was evaluated using video-based motion analysis. We also assessed the degree of collateral axonal branching at the lesion site, by counting motoneuronal perikarya after triple retrograde labeling, and estimated the quality of motor end-plate reinnervation in the target musculature. Outcomes at 4 months were compared to animals receiving sham stimulation (SS) or MS.nnnRESULTSnNeither protocol reduced the degree of collateral sprouting. ES did not improve functional outcome and failed to reduce the proportion of polyinnervated motor end-plates. By contrast, MS restored normal whisking function and reduced polyinnervation.nnnCONCLUSIONnWhereas acute ES is not beneficial for facial nerve repair, MS provides long-term benefits.

TRPV channel expression in human skin and possible role in thermally induced cell death.

Cell death via necrosis and apoptosis is a hallmark of deep dermal to full-thickness cutaneous burn injuries. Keratinocytes might act as thermosensory cells that transmit information regarding ambient temperature via heat-gated transient receptor potential vanilloid (TRPV) ion channels. The aim of this study was to investigate the distribution of TRPV1, 2, 3, and 4 in uninjured and thermally burned skin. The authors investigated warmth-evoked currents in keratinocytes and cell kinetics of thermally injured keratinocytes in culture with agonists and antagonists of TRPV channels. Specimens of uninjured normal skin and discarded tissue of thermally injured skin were stained for TRPV1, 2, 3, and 4. Cultured primary human keratinocytes were heated for 5 minutes at the following temperatures: 37°C (control), 42°C, and 60°C and thereafter cultured for 24 or 48 hours at 37°C. Thermally stressed cells were treated with TRPV antagonists capsazepine or ruthenium red, and cell viability capacity was determined. TRPV1, TRPV2, TRPV3, and TRPV4 immunoreactivity was differentially identified on basal and suprabasal keratinocytes of healthy human skin. Patch clamp analysis showed a functional response of human keratinocytes at temperatures >40°C. Cell death of keratinocytes after heating at 42°C was reduced by 15 and 5% with ruthenium red and by 20 and 30% by capsazepine at 24 and 48 hours, respectively. Cell death after treatment at 60°C was significantly reduced at 24 hours with capsazepine (22%) or ruthenium red (18%) but only minimally affected after 48 hours postinjury. Interaction with TRPV channels on keratinocytes may offer a new strategy to counteract cell death after thermal injury.