Click-crosslinked injectable hyaluronic acid hydrogel is safe and biocompatible in the intrathecal space for ultimate use in regenerative strategies of the injured spinal cord

Führmann, Tobias; Obermeyer, Jaclyn M.; Tator, Charles H.; Shoichet, Molly S.

doi:10.1016/j.ymeth.2015.03.023

Cited by 68 publications

(57 citation statements)

References 46 publications

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“…For instance, results could be improved by adding growthpromoting signaling factors (i.e., neural growth factor), growth-inhibitory signaling suppressors (i.e., neurite outgrowth inhibitor 66 receptor antibody), cell-attachment moieties, and various types of progenitor cells. Much of this work has already been performed or is underway by other research groups; 22,47,48,50,51 however, the work de- scribed here highlights the importance of base material choices in the development of complex scaffolding systems.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…One of these is gelation properties that must be compatible with the injection conditions necessary to avoid additional injury to the cord tissue: a syringe capable of delivering small volumes at a controlled rate equipped with a small needle. Specific sizes depend upon the injury model used, with needles as small as 33 G used for rodent studies [Gupta et al, 2006;Sontag et al, 2014;Führmann et al, 2015], and needles up to as large as 23 G used in human clinical trials [Oraee-Yazdani et al, 2016;Shin et al, 2015]. These requirements dictate that the precursor must be liquid or highly deformable.…”

Section: Design Considerations For Hydrogels Promoting Sci Repairmentioning

confidence: 99%

“…There are, however, common accepted standards for volumes of 1-2 μl of cell solutions or hydrogels injected per site into the mouse cord [Shin et al, 2015;Oraee-Yazdani et al, 2016] or 5-10 μl in the rat spinal cord [Yang et al, 2009a;Lu et al, 2012;Song et al, 2012;Führmann et al, 2015]. Complicating the situation, the acceptable range for injection volumes is likely to be specific to the unique swelling properties of each hydrogel formulation.…”

Section: Design Considerations For Hydrogels Promoting Sci Repairmentioning

confidence: 99%

“…Commonly used conditions to trigger in situ crosslinking include: (1) exposure to a specific wavelength of light [Piantino et al, 2006;Khaing et al, 2011], temperature [Gupta et al, 2006;Bearat et al, 2012], or pH [Prang et al, 2006;Pawar et al, 2015b], and (2) combining two separate components that spontaneously react upon mixing [Johnson et al, 2010a;Nimmo et al, 2011;Liang et al, 2013;Führmann et al, 2015;Kim et al, 2016]. In situ crosslinking of hydrogels in response to various triggers has been achieved by covalent chemistries (e.g.…”

Section: Fabrication Strategies For Injectable Hydrogelsmentioning

confidence: 99%

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Injectable Hydrogels for Spinal Cord Repair: A Focus on Swelling and Intraspinal Pressure

Khaing

Ehsanipour

Hofstetter

et al. 2016

Cells Tissues Organs

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Spinal cord injury (SCI) is a devastating condition that leaves patients with limited motor and sensory function at and below the injury site, with little to no hope of a meaningful recovery. Because of their ability to mimic multiple features of central nervous system (CNS) tissues, injectable hydrogels are being developed that can participate as therapeutic agents in reducing secondary injury and in the regeneration of spinal cord tissue. Injectable biomaterials can provide a supportive substrate for tissue regeneration, deliver therapeutic factors, and regulate local tissue physiology. Recent reports of increasing intraspinal pressure after SCI suggest that this physiological change can contribute to injury expansion, also known as secondary injury. Hydrogels contain high water content similar to native tissue, and many hydrogels absorb water and swell after formation. In the case of injectable hydrogels for the spinal cord, this process often occurs in or around the spinal cord tissue, and thus may affect intraspinal pressure. In the future, predictable swelling properties of hydrogels may be leveraged to control intraspinal pressure after injury. Here, we review the physiology of SCI, with special attention to the current clinical and experimental literature, underscoring the importance of controlling intraspinal pressure after SCI. We then discuss how hydrogel fabrication, injection, and swelling can impact intraspinal pressure in the context of developing injectable biomaterials for SCI treatment.

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“…It interacts with cells mainly through CD44 and RHAMM receptors [28,29], but cannot crosslink to form hydrogel per se. Therefore, HA has been always used as side chains chemically modified product to facilitate gel formation [30][31][32] or as mixture with matrix forming polymers [33]. Blended HA with Methyl Cellulose (MC) was used to make an injectable rapidly inverse-gelling polymer which could gel at physiological temperature, and the gel was further formulated with PDGF-A via streptavidin-biotin system to apply for SCI repair.…”

Section: Hyaluronic Acid (Or Hyaluronan Ha)mentioning

confidence: 99%

The Application of Stem Cell Based Tissue Engineering in Spinal Cord Injury Repair.

Niu¹,

Zeng²

2015

J Tissue Sci Eng

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Spinal Cord Injury (SCI) results in the permanent functional impairment, leading to monoplegia, paraplegia or tetraplegia with tremendous social and economic burden. The intrinsic repair mechanism has been proven to be insufficient. The complex pathophysiology after injury imposes enormous challenging to functional recovery, given the most advanced medical intervention nowadays. Therefore, the development of effective therapeutic strategy for spinal cord injury management is in great need. Here we review a stem cell based tissue engineering approach under preclinical or clinical development for spinal cord injury, with a focus on promoting functional recovery after SCI, aiming to provide some beneficial suggestion on stem cell based tissue engineering design.

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Click-crosslinked injectable hyaluronic acid hydrogel is safe and biocompatible in the intrathecal space for ultimate use in regenerative strategies of the injured spinal cord

Cited by 68 publications

References 46 publications

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

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

Injectable Hydrogels for Spinal Cord Repair: A Focus on Swelling and Intraspinal Pressure

The Application of Stem Cell Based Tissue Engineering in Spinal Cord Injury Repair.

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