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Using NGF heparin-poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury.

ABSTRACT: OBJECTIVE:Nerve growth factor (NGF) has potential in spinal cord injury (SCI) therapy, but limited by the poor physicochemical stability and low ability to cross the blood spinal cord barrier. Novel heparin-poloxamer (HP) thermo-sensitive hydrogel was constructed to enhance the NGF regeneration on SCI. METHOD:NGF-HP thermo-sensitive hydrogel was prepared and related characteristics including gelation temperature, rheological behavior and micromorphology were measured. Local NGF delivery to the injured spinal cord was achieved by in situ injection in the injured space. The cellular uptake of NGF-HP hydrogel was evaluated with PC12 cells in vitro. Pathologic characteristics and neuron regeneration effects on the SCI rats were studied to evaluate the enhanced therapy of NGF-HP hydrogel. Endoplasmic reticulum (ER) stress-induced apoptosis was analyzed to explore the related mechanism in SCI regeneration. RESULTS:NGF-HP hydrogel showed good morphology and stable bioactivity of NGF in vitro. NGF-HP hydrogel combined treatment significantly enhanced the efficiency of NGF cellular uptake (P<0.05) without obvious cytotoxicity. Significant improvements in both neuron functions and tissue morphology on the SCI rats were observed in NGF-HP hydrogel group. Compared with free HP hydrogel and NGF treatment groups, NGF-HP hydrogel group showed significant inhibition on the formation of glial scars in the extreme crushed rat SCI model. The neuroprotective effects of NGF-HP were related to the inhibition of chronic ER stress-induced apoptosis. CONCLUSIONS:HP hydrogel combined with orthotopic injection technique might be an effective method to deliver NGF into the injured site, which will provide an effective strategy for SCI regeneration. STATEMENT OF SIGNIFICANCE:Spinal cord injury (SCI) is a devastating condition that can lead to sudden loss of sensory and autonomic function. Current treatment includes decompression surgery, injury stabilization, secondary complications prevention and rehabilitation. However, neurological recovery is limited. Nerve growth factor (NGF) has potential in SCI therapy, but limited by the poor physicochemical stability and low ability to cross the blood spinal cord barrier. Hydrogels have good affinity and compatibility to biological tissue. In this study, we developed a novel heparin-poloxamer (HP) thermo-sensitive hydrogel to enhance the spinal cord regeneration of NGF. From SCI rat experiment, HP hydrogel combined with orthotopic injection technique showed best neuroprotective effects among experimental groups. This novel combined technique will provide an effective strategy for SCI regeneration.

SUBMITTER: Zhao YZ

PROVIDER: S-EPMC7517710 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Using NGF heparin-poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury.

Zhao Ying-Zheng YZ Jiang Xi X Xiao Jian J Lin Qian Q Yu Wen-Ze WZ Tian Fu-Rong FR Mao Kai-Li KL Yang Wei W Wong Ho Lun HL Lu Cui-Tao CT

Acta biomaterialia 20151022

<h4>Objective</h4>Nerve growth factor (NGF) has potential in spinal cord injury (SCI) therapy, but limited by the poor physicochemical stability and low ability to cross the blood spinal cord barrier. Novel heparin-poloxamer (HP) thermo-sensitive hydrogel was constructed to enhance the NGF regeneration on SCI.<h4>Method</h4>NGF-HP thermo-sensitive hydrogel was prepared and related characteristics including gelation temperature, rheological behavior and micromorphology were measured. Local NGF de ...[more]

PMID: 26472614

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Project description:OBJECTIVE:Spinal cord injury (SCI) affects a quarter million individuals in the United States, and there is currently no clinical treatment. Both fresh and acellular peripheral nerve grafts can induce spinal axon regeneration and support functional recovery in experimental injury models. Nonetheless, a scaffold that can be injected into a spinal contusion would be far less invasive to apply. We aimed to develop the first injectable acellular nerve graft for promoting repair after contusion SCI. APPROACH:We report a method to enzymatically solubilize optimized acellular (OA) nerve-a decellularized peripheral nerve graft developed in our laboratory and currently used clinically-to obtain an injectable solution that undergoes thermal gelation under physiological conditions. We quantified multiple physical and compositional properties of this novel material as well as tested its efficacy at acute and chronic time points following cervical contusion SCI. MAIN RESULTS:This injectable optimized acellular (iOA) nerve graft retains native chemical cues such as collagens and glycosaminoglycans. By varying hydrogel concentration, the rheological properties and compressive modulus of iOA were similar to that previous reported for rat central nervous tissue. iOA solution was compatible with rat Schwann cells in culture, and hydrogel injection into a rat cervical contusion model significantly reduced the ratio of M1:M2 macrophages after one week, favoring regenerative phenotypes (p < 0.05). Furthermore, while iOA treatment did not affect locomotor or respiratory recovery over an eight week period, the percentage of axonal coverage increased at the distal tissue interface (p < 0.05), suggesting enhanced axonal extension within this region. SIGNIFICANCE:Our data indicate that this novel injectable form of acellular nerve grafts is amenable for use after contusion SCI and may bolster a simultaneous therapy by acutely modulating the inflammatory milieu and supporting axonal growth.

Project description:The regenerative capacity of the peripheral nervous system is closely related to the role that Schwann cells (SCs) play in construction of the basement membrane containing multiple extracellular matrix proteins and secretion of neurotrophic factors, including laminin (LN) and brain-derived neurotrophic factor (BDNF). Here, we developed a self-assembling peptide (SAP) nanofiber hydrogel based on self-assembling backbone Ac-(RADA)4-NH2 (RAD) dual-functionalized with laminin-derived motif IKVAV (IKV) and a BDNF-mimetic peptide epitope RGIDKRHWNSQ (RGI) for peripheral nerve regeneration, with the hydrogel providing a three-dimensional (3D) microenvironment for SCs and neurites. Methods: Circular dichroism (CD), atomic force microscopy (AFM), and scanning electron microscopy (SEM) were used to characterize the secondary structures, microscopic structures, and morphologies of self-assembling nanofiber hydrogels. Then the SC adhesion, myelination and neurotrophin secretion were evaluated on the hydrogels. Finally, the SAP hydrogels were injected into hollow chitosan tubes to bridge a 10-mm-long sciatic nerve defect in rats, and in vivo gene expression at 1 week, axonal regeneration, target muscular re-innervation, and functional recovery at 12 weeks were assessed. Results: The bioactive peptide motifs were covalently linked to the C-terminal of the self-assembling peptide and the functionalized peptides could form well-defined nanofibrous hydrogels capable of providing a 3D microenvironment similar to native extracellular matrix. SCs displayed improved cell adhesion on hydrogels with both IKV and RGI, accompanied by increased cell spreading and elongation relative to other groups. RSCs cultured on hydrogels with IKV and RGI showed enhanced gene expression of NGF, BDNF, CNTF, PMP22 and NRP2, and decreased gene expression of NCAM compared with those cultured on other three groups after a 7-day incubation. Additionally, the secretion of NGF, BDNF, and CNTF of RSCs was significantly improved on dual-functionalized peptide hydrogels after 3 days. At 1 week after implantation, the expressions of neurotrophin and myelin-related genes in the nerve grafts in SAP and Autograft groups were higher than that in Hollow group, and the expression of S100 in groups containing both IKV and RGI was significantly higher than that in groups containing either IKV or RGI hydrogels, suggesting enhanced SC proliferation. The morphometric parameters of the regenerated nerves, their electrophysiological performance, the innervated muscle weight and remodeling of muscle fibers, and motor function showed that RAD/IKV/RGI and RAD/IKV-GG-RGI hydrogels could markedly improve axonal regeneration with enhanced re-myelination and motor functional recovery through the synergetic effect of IKV and RGI functional motifs. Conclusions: We found that the dual-functionalized SAP hydrogels promoted RSC adhesion, myelination, and neurotrophin secretion in vitro and successfully bridged a 10-mm gap representing a sciatic nerve defect in rats in vivo. The results demonstrated the synergistic effect of IKVAV and RGI on axonal regrowth and function recovery after peripheral nerve injury.

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Using NGF heparin-poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury.

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Using NGF heparin-poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury.

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