Although the peripheral nerve is capable of regeneration, only a small minority of patients regain normal function after surgical reconstruction of a major peripheral nerve lesion, resulting in a ...severe and lasting negative impact on the quality of life. Glial cell-line derived neurotrophic factor (GDNF) has potent survival- and outgrowth-promoting effects on motoneurons, but locally elevated levels of GDNF cause trapping of regenerating axons and the formation of nerve coils. This phenomenon has been called the "candy store" effect. In this study we created gradients of GDNF in the sciatic nerve after a ventral root avulsion. This approach also allowed us to study the effect of increasing concentrations of GDNF on Schwann cell proliferation and morphology in the injured peripheral nerve. We demonstrate that lentiviral vectors can be used to create a 4 cm long GDNF gradient in the intact and lesioned rat sciatic nerve. Nerve coils were formed throughout the gradient and the number and size of the nerve coils increased with increasing GDNF levels in the nerve. In the nerve coils, Schwann cell density is increased, their morphology is disrupted and myelination of axons is severely impaired. The total number of regenerated and surviving motoneurons is not enhanced after the distal application of a GDNF gradient, but increased sprouting does result in higher number of motor axon in the distal segment of the sciatic nerve. These results show that lentiviral vector mediated overexpression of GDNF exerts multiple effects on both Schwann cells and axons and that nerve coil formation already occurs at relatively low concentrations of exogenous GDNF. Controlled expression of GDNF, by using a viral vector with regulatable GDNF expression, may be required to avoid motor axon trapping and to prevent the effects on Schwann cell proliferation and myelination.
A human neuroma-in continuity (NIC), formed following a peripheral nerve lesion, impedes functional recovery. The molecular mechanisms that underlie the formation of a NIC are poorly understood. Here ...we show that the expression of multiple genes of the Wnt family, including Wnt5a, is changed in NIC tissue from patients that underwent reconstructive surgery. The role of Wnt ligands in NIC pathology and nerve regeneration is of interest because Wnt ligands are implicated in tissue regeneration, fibrosis, axon repulsion and guidance. The observations in NIC prompted us to investigate the expression of Wnt ligands in the injured rat sciatic nerve and in the dorsal root ganglia (DRG). In the injured nerve, four gene clusters were identified with temporal expression profiles corresponding to particular phases of the regeneration process. In the DRG up- and down regulation of certain Wnt receptors suggests that nerve injury has an impact on the responsiveness of injured sensory neurons to Wnt ligands in the nerve. Immunohistochemistry showed that Schwann cells in the NIC and in the injured nerve are the source of Wnt5a, whereas the Wnt5a receptor Ryk is expressed by axons traversing the NIC. Taken together, these observations suggest a central role for Wnt signalling in peripheral nerve regeneration.
The clinical outcome of microsurgical repair of an injured peripheral nerve with an autograft is suboptimal. A key question addressed here is: can axon regeneration through an autograft be further ...improved? In this article the impact of six neurotrophic factors (BDNF, CNTF, GDNF, NGF, NT3 or VEGF) on axon regeneration was compared after delivery to a 1cm long nerve autograft by gene therapy. To distinguish between early and late effects, regeneration was assessed at 2 and 20weeks post-surgery by histological, electrophysiological and functional analysis. BDNF, GDNF and NGF exhibited a spectrum of effects, including early stimulatory effects on axons entering the autograft and excessive axon growth and Schwann cell proliferation at 20weeks post-surgery. Persistent expression of these factors in autografts interfered with target cell reinnervation and functional recovery in a modality specific way. Autografts overexpressing VEGF displayed hypervascularization, while grafts transduced with CNTF and NT3 were indistinguishable from control grafts. These three factors did not have detectable pro-regenerative effects. In conclusion, autograft-based repair combined with gene therapy for three of the six growth factors investigated (BDNF, GDNF, NGF) showed considerable promise since these factors enhanced modality specific axon outgrowth in autografts. The remarkable and selective effects of BDNF, GDNF and NGF on motor or sensory regeneration will be exploited in future experiments that aim to carefully regulate their temporal and spatial expression since this has the potential to overcome the adverse effects on long-distance regeneration observed after uncontrolled delivery.
•Key question: can axon regeneration after autograft-based nerve repair be further improved?•Autograft-based peripheral nerve repair was combined with gene therapy for 6 neurotrophic factors.•We performed a side by side comparative morphological, electrophysiological and functional analysis.•NGF, BDNF and GDNF have modality specific effects on axon regeneration.•Persistent expression caused excessive axon growth preventing axons to leave the graft.
In patients with focal nerve injury and neuropathic pain cutting the nerve to obtain permanent pain reduction can be considered. Surgery is indicated only if a diagnostic nerve block provides ...temporary pain relief. We evaluated the predictive value of a block on the outcome of surgery.
In total, three blocks were performed at two week intervals. Patients were blinded to injections containing lidocaine 1% and a placebo was included. Surgery was offered regardless of the effect of the blocks. Twenty-four patients received 72 blocks. Sixteen patients opted for surgery, 5 patients refrained from surgery, and in 3 the blocks provided permanent pain relief. The predictive ability of the block on the outcome of surgery was assessed by calculating the area under a Receiver Operating Characteristic curve (AUC).
The AUC of the first lidocaine block was 0.35 with a 95% confidence interval from 0.077 to 0.62. At 95% confidence (two-sided), the AUC is less than 0.62, and hence the predictive ability of the block was poor. The outcome of the second lidocaine block and saline block did not change the conclusion of the first block.
We conclude that the use of blocks to select patients for surgery should be critically appraised.
A pain relieving response to one open block is currently considered mandatory before patients with focal nerve injury and neuropathic pain are offered surgery. Blinded blocks including a placebo show that responses for selection should be carefully interpreted because they may not be as predictive as generally presumed.
To assess gripforce in children with a C5 and C6 neonatal brachial plexus palsy, as it may affect hand use. Applying classic innervation patterns, gripforce should not be affected, as hand function ...is not innervated by C5 or C6. This study compares gripforce in children with a neonatal brachial plexus palsy with that in a healthy control group, and assesses correlations with hand sensibility, bimanual use and external rotation.
A total of 50 children with neonatal brachial plexus palsy (mean age 9.8 years) and 25 controls (mean age 9.6 years) were investigated. Nerve surgery had been performed in 30 children, and 20 children had been treated conservatively. Gripforce of both hands was assessed using a Jamar dynamometer. Sensibility of the hands was assessed with 2-point discrimination and Semmes-Weinstein monofilaments. External rotation was assessed using the Mallet score. Bimanual use was measured by using 1 of 3 dexterity items of the Movement Assessment Battery for Children-2. The affected side of the neonatal brachial plexus palsy group was compared with the non-dominant hand of the control group using 1-way analysis of variance (ANOVA), χ2 and Mann-Whitney tests.
The mean gripforce of the affected non-dominant hand of children with neonatal brachial plexus palsy was reduced compared with healthy controls (95 N and 123 N, respectively, with p = 0.001). The mean gripforce of the non-dominant hand in the control group was 92% of that of the dominant hand, while it was only 76% in the neonatal brachial plexus palsy group (p = 0.04). There was no relationship between gripforce reduction and sensibility, bimanual use or shoulder external rotation.
The gripforce in neonatal brachial plexus palsy infants with a C5 and C6 lesion is lower than that of healthy controls, although classic interpretation of upper limb innervation excludes this finding. The reduction in gripforce in upper neonatal brachial plexus palsy lesions is not widely appreciated as a factor inherently compromising hand use. The reduction in gripforce should be taken into consideration in planning the type of rehabilitation and future activities.
Clinical phase I/II studies have demonstrated the safety of gene therapy for a variety of central nervous system disorders, including Canavan's, Parkinson's (PD) and Alzheimer's disease (AD), retinal ...diseases and pain. The majority of gene therapy studies in the CNS have used adeno-associated viral vectors (AAV) and the first AAV-based therapeutic, a vector encoding lipoprotein lipase, is now marketed in Europe under the name Glybera. These remarkable advances may become relevant to translational research on gene therapy to promote peripheral nervous system (PNS) repair. This short review first summarizes the results of gene therapy in animal models for peripheral nerve repair. Secondly, we identify key areas of future research in the domain of PNS-gene therapy. Finally, a perspective is provided on the path to clinical translation of PNS-gene therapy for traumatic nerve injuries. In the latter section we discuss the route and mode of delivery of the vector to human patients, the efficacy and safety of the vector, and the choice of the patient population for a first possible proof-of-concept clinical study.
The detailed outcome of surgical repair of high isolated clean sharp (HICS) ulnar nerve lesions has become relevant in view of the recent development of distal nerve transfer. Our goal was to ...determine the outcome of HICS ulnar nerve repair in order to create a basis for the optimal management of these lesions.
High ulnar nerve lesions are defined as localized in the area ranging from the proximal forearm to the axilla just distal to the branching of the medial cord of the brachial plexus. A meta-analysis of the literature concerning high ulnar nerve injuries was performed. Additionally, a retrospective study of the outcome of nerve repair of HICS ulnar nerve injuries at our institution was performed. The Rotterdam Intrinsic Hand Myometer and the Rosén-Lundborg protocol were used.
The literature review identified 46 papers. Many articles presented outcomes of mixed lesion groups consisting of combined ulnar and median nerves, or the outcome of high and low level injuries was pooled. In addition, outcome was expressed using different scoring systems. 40 patients with HICS ulnar nerve lesions were found with sufficient data for further analysis. In our institution, 15 patients had nerve repair with a median interval between trauma and reconstruction of 17 days (range 0-516). The mean score of the motor and sensory domain of the Rosen's Scale instrument was 58% and 38% of the unaffected arm, respectively. Two-point discrimination never reached less then 12 mm.
From the literature, it was not possible to draw a definitive conclusion on outcome of surgical repair of HICS ulnar nerve lesions. Detailed neurological function assessment of our own patients showed that some ulnar nerve function returned. Intrinsic muscle strength recovery was generally poor. Based on this study, one might cautiously argue that repair strategies of HICS ulnar nerve lesions need to be improved.
Eggers et al. show that time-restricted GDNF gene therapy with an immune-evasive gene switch in a longitudinal rat spinal lesion model promotes motoneuron survival, long-distance axon regeneration ...and electromyographical recovery and attenuates axon entrapment. Neurotrophic factor gene therapy is a promising adjunct treatment for nerve repair.
Abstract
Neurosurgical repair in patients with proximal nerve lesions results in unsatisfactory recovery of function. Gene therapy for neurotrophic factors is a powerful strategy to promote axon regeneration. Glial cell line-derived neurotrophic factor (GDNF) gene therapy promotes motor neuron survival and axon outgrowth; however, uncontrolled delivery of GDNF results in axon entrapment. We report that time-restricted GDNF expression (1 month) using an immune-evasive doxycycline-inducible gene switch attenuated local axon entrapment in avulsed reimplanted ventral spinal roots, was sufficient to promote long-term motor neuron survival (24 weeks) and facilitated the recovery of compound muscle action potentials by 8 weeks. These improvements were associated with an increase in long-distance regeneration of motor axons. In contrast, persistent GDNF expression impaired axon regeneration by inducing axon entrapment. These findings demonstrate that timed expression can resolve the deleterious effect of uncontrolled growth factor delivery and shows that inducible growth factor gene therapy can be employed to enhance the efficacy of axon regeneration after neurosurgical repair of a proximal nerve lesion in rats. This preclinical study is an important step in the ongoing development of a neurotrophic factor gene therapy for patients with severe proximal nerve lesions.
Cancer has become one of the deadliest diseases in our society. Surgery accompanied by subsequent chemotherapy is the treatment most used to prolong or save the patient's life. Still, it carries ...secondary risks such as infections and thrombosis and causes cytotoxic effects in healthy tissues. Using nanocarriers such as smart polymer micelles is a promising alternative to avoid or minimize these problems. These nanostructured systems will be able to encapsulate hydrophilic and hydrophobic drugs through modified copolymers with various functional groups such as carboxyls, amines, hydroxyls, etc. The release of the drug occurs due to the structural degradation of these copolymers when they are subjected to endogenous (pH, redox reactions, and enzymatic activity) and exogenous (temperature, ultrasound, light, magnetic and electric field) stimuli. We did a systematic review of the efficacy of smart polymeric micelles as nanocarriers for anticancer drugs (doxorubicin, paclitaxel, docetaxel, lapatinib, cisplatin, adriamycin, and curcumin). For this reason, we evaluate the influence of the synthesis methods and the physicochemical properties of these systems that subsequently allow an effective encapsulation and release of the drug. On the other hand, we demonstrate how computational chemistry will enable us to guide and optimize the design of these micelles to carry out better experimental work.
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