Influence of cross-linked hyaluronic acid hydrogels on neurite outgrowth and recovery from spinal cord injury

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>Therapies that use bioactive materials as replacement extracellular matrices may hold the potential to mitigate the inhibition of regeneration observed after central nervous system trauma. Hyaluronic acid (HA), a nonsulfated glycosaminoglycan ubiquitous in all tissues, was investigated as a potential neural tissue engineering matrix.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Chick dorsal root ganglia were cultured in 3D hydrogel matrices composed of cross-linked thiol-modified HA or fibrin. Samples were cultured and images were acquired at 48-, 60-, and 192-hour time points. Images of all samples were analyzed at 48 hours of incubation to quantify the extent of neurite growth. Cultures in cross-linked thiolated HA exhibited more than a 50% increase in neurite length compared with fibrin samples. Furthermore, cross-linked thiolated HA supported neurites for the entire duration of the culture period, whereas fibrin cultures exhibited collapsed and degenerating extensions beyond 60 hours.</jats:p> <jats:p>Two concentrations of the thiolated HA (0.5 and 1%) were then placed at the site of a complete thoracic spinal cord transection in rats. The ability of the polymer to promote regeneration was tested using motor evoked potentials, retrograde axonal labeling, and behavioral assessments. There were no differences in any of the parameters between rats treated with the polymer and controls.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The use of a cross-linked HA scaffold promoted robust neurite outgrowth. Although there was no benefit from the polymer in a rodent spinal cord injury model, the findings in this study represent an early step in the development of semisynthetic extracellular matrice scaffolds for the treatment of neuronal injury.</jats:p></jats:sec>

Preparation of the acellular scaffold of the spinal cord and the study of biocompatibility

“…[16][17][18][19] As their pores and channels are artificial, it is difficult to completely simulate the conduction channels of normal spinal cords. Moreover, these scaffold materials have their respective disadvantages, such as degradation products that are unfit for neuronal survival and axonal regeneration; low adhesiveness of cells; and much poorer biological and physical characteristics.…”

Cell encapsulation using biopolymer gels for regenerative medicine

“…One of the major challenges facing researchers in this area is stimulation of guided axonal extension (Norman et al 2009). To this end, Horn et al (2007) encapsulated chick dorsal ganglia in HA and fibrin gels which were evaluated both in vitro. Both gels were shown to support neutrites within the first 60 h, but after 192 h a 50% increase in neutrite length was seen in HA gels when compared with the fibrin gels.…”

Biomaterials for spinal cord repair

“…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 …”

“…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] . [19] .…”

“…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] .Combination ECM-derived Polymers Recently, some groups have focused on creating a more complete ECM environment containing multiple molecules from native ECM [19] . Previously, it was shown that various basement membranes containing a full arsenal of ECM molecules enhance neurite outgrowth in vitro [73,74] and axonal extension in the lesioned adult brain [74] .…”