Spinal cord injury (SCI) causes immediate damage to the nervous tissue accompanied by loss of motor and sensory function. The limited self-repair competence of injured nervous tissue underscores the ...need for reparative interventions to recover function after SCI. The vasculature of the spinal cord plays a crucial role in SCI and repair. Ruptured and sheared blood vessels in the injury epicenter and blood vessels with a breached blood-spinal cord barrier (BSCB) in the surrounding tissue cause bleeding and inflammation, which contribute to the overall tissue damage. The insufficient formation of new functional vasculature in and near the injury impedes endogenous tissue repair and limits the prospect of repair approaches. Limiting the loss of blood vessels, stabilizing the BSCB, and promoting the formation of new blood vessels are therapeutic targets for spinal cord repair. Inflammation is an integral part of injury-mediated vascular damage, which has deleterious and reparative consequences. Inflammation and the formation of new blood vessels are intricately interwoven. Biomaterials can be effectively used for promoting and guiding blood vessel formation or modulating the inflammatory response after SCI, thereby governing the extent of damage and the success of reparative interventions. This review deals with the vasculature after SCI, the reciprocal interactions between inflammation and blood vessel formation, and the potential of biomaterials to support revascularization and immunomodulation in damaged spinal cord nervous tissue.
There is no treatment for people with spinal cord injury that leads to significant functional improvements. The extracellular matrix is an intricate, 3-dimensional, structural framework that defines ...the environment for cells in the central nervous system. The components of extracellular matrix have signaling and regulatory roles in the fate and function of neuronal and non-neuronal cells in the central nervous system. This review discusses the therapeutic potential of extracellular matrix components for spinal cord repair.
An injury to the spinal cord causes long-lasting loss of nervous tissue because endogenous nervous tissue repair and regeneration at the site of injury is limited. We engineered an injectable ...nanofiber-hydrogel composite (NHC) with interfacial bonding to provide mechanical strength and porosity and examined its effect on repair and neural tissue regeneration in an adult rat model of spinal cord contusion. At 28 days after treatment with NHC, the width of the contused spinal cord segment was 2-fold larger than in controls. With NHC treatment, tissue in the injury had a 2-fold higher M2/M1 macrophage ratio, 5-fold higher blood vessel density, 2.6-fold higher immature neuron presence, 2.4-fold higher axon density, and a similar glial scar presence compared with controls. Spared nervous tissue volume in the contused segment and hind limb function was similar between groups. Our findings indicated that NHC provided mechanical support to the contused spinal cord and supported pro-regenerative macrophage polarization, angiogenesis, axon growth, and neurogenesis in the injured tissue without any exogenous factors or cells. These results motivate further optimization of the NHC and delivery protocol to fully translate the potential of the unique properties of the NHC for treating spinal cord injury.
The current clinical standard of harvesting a nerve autograft for repair of long-segment peripheral nerve injuries (PNIs) is associated with many potential complications. Guidance channels offer an ...alternative therapy. The authors investigate whether autologous Schwann cells (SCs) implanted within a novel collagen-glycosaminoglycan conduit will improve axonal regeneration in a long-segment PNI model.
Novel NeuraGen 3D collagen matrix conduits were implanted with autologous SCs to investigate axonal regeneration across a critical size defect (13 mm) in male Fischer rat sciatic nerve. Reversed sciatic nerve autografts served as positive controls, and conduits filled with serum only as negative controls. Electrophysiological assessments were made in vivo. Animals were killed at 4 or 16 weeks postinjury, muscle weights were measured, and grafts underwent immunohistochemical and morphometric analysis.
SC survival was confirmed by the presence of green fluorescent protein-labeled SCs within regenerated fibers. Regeneration and elongation of myelinated axons in all segments of the graft were significantly enhanced at 16 weeks in the SC-filled conduits compared to the conduit alone and were statistically similar to those of the autograft. Nerves repaired with SC-filled conduits exhibited onset latencies and nerve conduction amplitudes similar to those of the contralateral controls and autograft (p < 0.05). Adding SCs to the conduit also significantly reduced muscle atrophy compared to conduit alone (p < 0.0001).
Repair of long-segment PNI of rat sciatic nerve is significantly enhanced by SC-filled NeuraGen 3D conduits. Improvements in the total number of myelinated axons, axon diameter, and myelin thickness throughout SC-filled conduits allow for significant recovery in nerve conduction and a decrease in muscle atrophy.
Biomaterials for spinal cord repair Haggerty, Agnes E.; Oudega, Martin
Neuroscience Bulletin/Neuroscience bulletin,
08/2013, Letnik:
29, Številka:
4
Journal Article
Recenzirano
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Spinal cord injury （SCI） results in permanent loss of function leading to often devastating personal, economic and social problems. A contributing factor to the permanence of SCI is that damaged ...axons do not regenerate, which prevents the re-establishment of axonal circuits involved in function. Many groups are working to develop treatments that address the lack of axon regeneration after SCI. The emergence of biomaterials for regeneration and increased collaboration between engineers, basic and translational scientists, and clinicians hold promise for the development of effective therapies for SCI. A plethora of biomaterials is available and has been tested in various models of SCI. Considering the clinical relevance of contusion injuries, we primarily focus on polymers that meet the specific criteria for addressing this type of injury. Biomaterials may provide structural support and/or serve as a delivery vehicle for factors to arrest growth inhibition and promote axonal growth. Designing materials to address the specific needs of the damaged central nervous system is crucial and possible with current technology. Here, we review the most prominent materials, their optimal characteristics, and their potential roles in repairing and regenerating damaged axons following SCI.
It was previously reported that a tube holding chitosan carriers loaded with neurotrophin-3 (NT-3), after insertion into a 5 mm long transection gap in the adult rat spinal cord, triggered de novo ...neural tissue generation and functional recovery. Here, we report an effort to validate these findings using stringent blinding methodologies, which are crucial for robustness in reproducing biomedical studies. Radio frequency identification (RFID) chips were utilized to label rats that were randomly assigned into three experimental groups: transection with chitosan-NT-3 implant (C-NT3), transection only (T-controls), and laminectomy only (S-controls), blinding the experimenters to the treatments. Three months after surgery, animals only known by their RFID were functionally, electrophysiologically, and anatomically assessed. The data were then collected into the proper groups and statistically analyzed. Neural tissue with nestin-, Tuj1-, and NeuN-positive cells was found bridging the transection gap in C-NT3 rats, but not in T-controls. Motor- and somatosensory-evoked potentials were detected in C-NT3 rats and S-controls, but not in T-controls. Hind limb movement was significantly better in C-NT3 rats compared with T-controls. Our validation study indicates that C-NT3 implants facilitate neural tissue generation, at least in part, by eliciting endogenous neurogenesis. Our data support the use of C-NT3 implants for tissue remodeling in the injured spinal cord.
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Promoting axon growth after peripheral nerve injury may support recovery. Soluble laminin polymers formed at pH 4 (aLam) accelerate axon growth from adult dorsal root ganglion neurons ...in vitro. We used an adult rat model of a peripheral (peroneal) nerve crush to investigate whether an injection of aLam enhances axon growth and functional recovery in vivo. Rats that received an injection of aLam into the crush at 2 days post-injury show significant improvements in hind limb motor function at 2 and 5 weeks after injury compared with control rats that received phosphate-buffered saline. Functional improvement was not associated with changes in sensitivity to thermal or mechanical stimuli. Treatment with aLam decreased the occurrence of autophagia and abolished non-compliance with treadmill walking. Rats treated with aLam showed increased axon presence in the crush site at 2 weeks post-injury and larger axon diameter at 10 weeks post-injury compared with controls. Treatment with aLam did not affect Schwann cell presence or axon myelination. Our results demonstrated that aLam accelerates axon growth and maturity in a crushed peroneal nerve associated with expedited hind limb motor function recovery. Our data support the therapeutic potential of injectable aLam polymers for treatment of peripheral nerve crush injuries.
Incidence of peripheral nerve injury has been estimated to be as high as 5% of all cases entering a Level 1 trauma center and the majority of cases are young males. Peripheral nerves have some endogenous repair capabilities, but overall recovery of function remains limited, which typically has devastating effects on the individual, family, and society, as wages are lost and rehabilitation is extended until the nerves can repair. We report here that laminin polymers injected into a crush accelerated repair and recovery, had no adverse effects on sensory function, obliterated non-compliance for walking tests, and decreased the occurrence of autophagia. These data support the use of laminin polymers for safe and effective recovery after peripheral nerve injury.
•Examined whether SSRIs normalize amygdala activity or dampen responsiveness.•Responders and non-responders did not differ in amygdala activity prior to treatment.•SSRI responders had increased ...amygdala activation to positive stimuli after treatment.•SSRI responders also had decreased amygdala activation to negative stimuli after treatment.
There are conflicting reports on the impact of antidepressants on neural reactions for positive information. We thus hypothesized that there would be clinically important individual differences in neural reactivity to positive information during SSRI therapy. We further predicted that only those who responded to SSRIs would show increased amygdala reactivity to positive information following treatment to a level similar to that seen in healthy participants. Depressed individuals (n = 17) underwent fMRI during performance of a task involving rating the self-relevance of emotionally positive and negative cue words before and after receiving 12 weeks of SSRI therapy. At post-treatment, SSRI responders (n = 11) had increased amygdala activity in response to positive stimuli, and decreased activity in response to negative stimuli, compared to non-responders (n = 6). Results suggest that normalizing amygdala responses to salient information is a correlate of SSRI efficacy. Second line interventions that modulate amygdala activity, such as fMRI neurofeedback, may be beneficial in those who do not respond to SSRI medications.
Mesenchymal stromal cells (MSC) are used for cell therapy for spinal cord injury (SCI) because of their ability to support tissue repair by paracrine signaling. Preclinical and clinical research ...testing MSC transplants for SCI have revealed limited success, which warrants the exploration of strategies to improve their therapeutic efficacy. MSC are sensitive to the microenvironment and their secretome can be altered in vitro by exposure to different culture media. Priming MSC with inflammatory stimuli increases the expression and secretion of reparative molecules. We studied the effect of macrophage-derived inflammation priming on MSC transplants and of primed MSC (pMSC) acute transplants (3 days) on spinal cord repair using an adult rat model of moderate–severe contusive SCI. We found a decrease in long-term survival of pMSC transplants compared with unprimed MSC transplants. With a pMSC transplant, we found significantly more anti-inflammatory macrophages in the contusion at 4 weeks post transplantation (wpt). Blood vessel presence and maturation in the contusion at 1 wpt was similar in rats that received pMSC or untreated MSC. Nervous tissue sparing and functional recovery were similar across groups. Our results indicate that macrophage-derived inflammation priming does not increase the overall therapeutic potential of an MSC transplant in the adult rat contused spinal cord.
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