The effects of intrathecal injection of a hyaluronan-based hydrogel on inflammation, scarring and neurobehavioural outcomes in a rat model of severe spinal cord injury associated with arachnoiditis

Austin, James W.; Kang, Catherine E.; Baumann, M. Douglas; DiDiodato, Lisa; Satkunendrarajah, Kajana; Wilson, Jefferson R.; Stanisz, Greg J.; Shoichet, Molly S.; Fehlings, Michael G.

doi:10.1016/j.biomaterials.2012.03.022

Cited by 93 publications

(95 citation statements)

References 47 publications

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“…instead, it is combined with other supportive materials to enhance growth promotion [35,39,52,53] and cell differentiation [54] . Recently, it was shown that the [86] iHC [31,32,38] Bladder function [31,32] BBB [87] inclined plane [87] Walking movements [40] Reflexive behaviors [40] Climbing ability [40] Electrophysiology [40] BBB [49,88] Combined behavior score [88] iHC [49,88] Robotic recording [88] Von Frey filaments [89] iHC [62,[89][90][91] Horizontal ladder [91] Beamwalk [91] BBB [70,71,92] inclined plane [70] Von Frey [70] iHC [70,92,93] Electrophysiology [70,72] Structural MRi [70] BBB [85,94,95] iHC [85,94,95] Electrophysiology …”

Section: Polymersmentioning

confidence: 99%

“…HA binds to a variety of membrane-associated proteins including versican, aggrecan and glial HAbinding protein [65] . Modified HA supports cell attachment and migration, and when combined with brain-derived neurotrophic factor, may improve regeneration and motor function as an implanted scaffold after SCi [70,71] . Due to its natural role as a structural component in the CNS, it has been used both alone as well as in functionalized and combination formats to provide structure and guidance for regenerating axons after injury [71,72] .…”

Section: Polymersmentioning

confidence: 99%

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Biomaterials for spinal cord repair

Haggerty

Oudega

2013

Neurosci. Bull.

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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.Keywords: spinal cord injury; axon regeneration; biodegradable materials; extracellular matrix proteins; functional recovery; growth factor; guidance; injury and repair; spinal motor neuron IntroductionSpinal cord injury (SCi) causes loss of neurons and axons resulting in motor and sensory function impairments. There are thousands of new cases of SCi in the world annually [1,2] occurring often in young adults. The lack of endogenous repair and the significant costs to the individual, family and society [1] are important motivations behind the continuing efforts to develop effective therapies. Promoting axonal regeneration is considered a potential repair strategy because it could lead to recovery of axonal circuits involved in motor and/or sensory function [3] .The central nervous system (CNS) neurons are intrinsically capable of some regeneration of damaged axons [4] but their attempts after SCi are frustrated by structural and chemical obstructions in the damaged nervous tissue [5] . Spinal cord repair approaches typically lead to small functional gains. one feature that most of these approaches have in common is a poor axonal regeneration response, suggesting that promoting axonal regeneration, including synapse formation, is essential to achieve substantial functional repair after SCi. if so, it is rational to anticipate that effective spinal cord therapies will need to include interventions addressing the axon growth-inhibition that leads to the poor axonal growth responses. As introduced above, axonal regeneration is considered an important repair mechanism for the injured spinal cord. Therefore, this review focuses on materials that have shown most promise to elicit an axonal regeneration response to foster functional restoration after ...

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Section: Polymersmentioning

confidence: 99%

Section: Polymersmentioning

confidence: 99%

Biomaterials for spinal cord repair

Haggerty

Oudega

2013

Neurosci. Bull.

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“…The materials themselves offer some neuroprotection by providing structural support, attenuating gliosis and inflammation, and reducing cavitation. Bioactive materials, like HA, reduce inflammation through the CD44 receptor by inhibiting leukocyte migration and inflammation (Forrester and Wilkinson, 1981;Cooper et al, 2008), resulting in reduced microglial activation (Wang et al, 2012b) and stroke infarct volume (Hou et al, 2005;Austin et al, 2012;Wang et al, 2013;Tuladhar et al, 2015).…”

Section: Protecting Neural Cellsmentioning

confidence: 99%

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

2018

Self Cite

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“…21 It has been used in many medical applications and is frequently investigated as a potential biomaterial for tissue engineering. 1,3,11,13,18,19,28,37,54 Hyaluronic acid is highly biocompatible, immunologically and chemically inert, and nontoxic; thus, using it prevents the problem of neural tissue rejection. Furthermore, high-molecular-weight HA promotes neuroprotective cell-signaling cascades.…”

Section: 27mentioning

confidence: 99%

“…They also found that the HA hydrogel decreased the presence of microglia and macrophages up to 10 days after injury; however, Khaing et al 28 did not study the effect of this decreased inflammation on neuron survival. Austin et al 3 studied an HA/ methylcellulose composite hydrogel in vivo by using a compression-injury model. They found that at 6 weeks, the composite hydrogel reduced fibrotic and glial inflammation and scarring.…”

Section: 27mentioning

confidence: 99%

Hyaluronic acid scaffold has a neuroprotective effect in hemisection spinal cord injury

Kushchayev

Giers

Eng

et al. 2016

SPI

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OBJECTIVE Spinal cord injury occurs in 2 phases. The initial trauma is followed by inflammation that leads to fibrous scar tissue, glial scarring, and cavity formation. Scarring causes further axon death around and above the injury. A reduction in secondary injury could lead to functional improvement. In this study, hyaluronic acid (HA) hydrogels were implanted into the gap formed in the hemisected spinal cord of Sprague-Dawley rats in an attempt to attenuate damage and regenerate tissue. METHODS A T-10 hemisection spinal cord injury was created in adult male Sprague-Dawley rats; the rats were assigned to a sham, control (phosphate-buffered saline), or HA hydrogel–treated group. One cohort of 23 animals was followed for 12 weeks and underwent weekly behavioral assessments. At 12 weeks, retrograde tracing was performed by injecting Fluoro-Gold in the left L-2 gray matter. At 14 weeks, the animals were killed. The volume of the lesion and the number of cells labeled from retrograde tracing were calculated. Animals in a separate cohort were killed at 8 or 16 weeks and perfused for immunohistochemical analysis and transmission electron microscopy. Samples were stained using H & E, neurofilament stain (neurons and axons), silver stain (disrupted axons), glial fibrillary acidic protein stain (astrocytes), and Iba1 stain (mononuclear cells). RESULTS The lesions were significantly smaller in size and there were more retrograde-labeled cells in the red nuclei of the HA hydrogel–treated rats than in those of the controls; however, the behavioral assessments revealed no differences between the groups. The immunohistochemical analyses revealed decreased fibrous scarring and increased retention of organized intact axonal tissue in the HA hydrogel–treated group. There was a decreased presence of inflammatory cells in the HA hydrogel–treated group. No axonal or neuronal regeneration was observed. CONCLUSIONS The results of these experiments show that HA hydrogel had a neuroprotective effect on the spinal cord by decreasing the magnitude of secondary injury after a lacerating spinal cord injury. Although regeneration and behavioral improvement were not observed, the reduction in disorganized scar tissue and the retention of neurons near and above the lesion are important for future regenerative efforts. In addition, this gel would be useful as the base substrate in the development of a more complex scaffold.

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The effects of intrathecal injection of a hyaluronan-based hydrogel on inflammation, scarring and neurobehavioural outcomes in a rat model of severe spinal cord injury associated with arachnoiditis

Cited by 93 publications

References 47 publications

Biomaterials for spinal cord repair

Biomaterials for spinal cord repair

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

Hyaluronic acid scaffold has a neuroprotective effect in hemisection spinal cord injury

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