Aligned chitosan nanofiber hydrogel grafted with peptides mimicking bioactive brain-derived neurotrophic factor and vascular endothelial growth factor repair long-distance sciatic nerve defects in rats

Rao, Feng; Wang, Yanhua; Zhang, Dianying; Lu, Chang; Cao, Zheng; Sui, Jiajie; Wu, Mengjiao; Zhang, Yawen; Pi, Wei; Wang, Bo; Kou, Yuhui; Wang, Xiumei; Zhang, Peixun; Jiang, Baoguo

doi:10.7150/thno.36272

Cited by 147 publications

(119 citation statements)

References 64 publications

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“…Hydrogel could simulate ECM-like structures to provide a suitable microenvironment for cell to grow and proliferate as well as to encapsulate bioactive growth factors to achieve ae sustained-release profile. Various type of hydrogels have been wildly tested in nerve tissue engineering [ 2 , 19 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Application of bioactive hydrogels combined with dental pulp stem cells for the repair of large gap peripheral nerve injuries

Luo

Jin

et al. 2021

Bioactive Materials

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Due to the limitations in autogenous nerve grafting or Schwann cell transplantation, large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit. Cell based therapies provide a novel treatment for peripheral nerve injuries. In this study, we first experimented an optimal scaffold material synthesis protocol, from where we selected the 10% GFD formula (10% GelMA hydrogel, recombinant human basic fibroblast growth factor and dental pulp stem cells (DPSCs)) to fill a cellulose/soy protein isolate composite membrane (CSM) tube to construct a third generation of nerve regeneration conduit, CSM-GFD. Then this CSM-GFD conduit was applied to repair a 15-mm long defect of sciatic nerve in a rat model. After 12 week post implant surgery, at histologic level, we found CSM-GFD conduit could regenerate nerve tissue like neuron and Schwann like nerve cells and myelinated nerve fibers. At physical level, CSM-GFD achieved functional recovery assessed by a sciatic functional index study. In both levels, CSM-GFD performed like what gold standard, the nerve autograft, could do. Further, we unveiled that almost all newly formed nerve tissue at defect site was originated from the direct differentiation of exogeneous DPSCs in CSM-GFD. In conclusion, we claimed that this third-generation nerve regeneration conduit, CSM-GFD, could be a promising tissue engineering approach to replace the conventional nerve autograft to treat the large gap defect in peripheral nerve injuries.

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Section: Discussionmentioning

confidence: 99%

Application of bioactive hydrogels combined with dental pulp stem cells for the repair of large gap peripheral nerve injuries

Luo

Jin

et al. 2021

Bioactive Materials

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“…From nerve regeneration especially PNS regeneration strategies, the design of biological materials requires full consideration of regenerative microenvironment, such as simulation of extracellular matrix by modifying scaffolds with IKVAV and RGD, addition of growth factors or peptide motifs derived from growth factors for the insufficient neurotrophic factor in this study, modification with antibodies to the nogo66 receptor to shield suppressor for the suppression of microenvironment, and presenting aligned topography and soft stiffness in our previous study 11 , 88 . In a word, the nerve regeneration is very complex, and the function of single factor is not enough.…”

Section: Discussionmentioning

confidence: 94%

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

et al. 2020

Self Cite

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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 -NH 2 (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, my...

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“…Peripheral nerve injury is one of the most frequently encountered clinical settings resulting in morbidity and lifelong disability and poses a considerable burden for both the individual and the society 1 , 2 . Despite the progress in surgical intervention, the outcome of peripheral nerve injury remains unsatisfactory 3 , 4 . Schwann cells (SCs), the glial cells in the PNS, form the myelin sheath around neuronal axons, are essential for the rapid saltatory propagation of action potential, and maintain the integrity of axons 5 , 6 .…”

Section: Introductionmentioning

confidence: 99%

Mechanical stimulation of Schwann cells promote peripheral nerve regeneration via extracellular vesicle-mediated transfer of microRNA 23b-3p

Xia¹,

Gao²,

Li³

et al. 2020

Theranostics

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Rationale: Peripheral nerves are unique in their remarkable elasticity. Schwann cells (SCs), important components of the peripheral nervous system (PNS), are constantly subjected to physiological and mechanical stresses from dynamic stretching and compression forces during movement. So far, it is not clear if SCs sense and respond to mechanical signals. It is also unknown whether mechanical stimuli can interfere with the intercellular communications between neurons and SCs, and what role extracellular vesicles (EVs) play in this process. The present study aimed to examine the effect of mechanical stimuli on the EV-mediated intercellular communication between neurons and SCs, explore their effect on axonal regeneration, and investigate the underlying mechanism. Methods: Purified SCs were stimulated using a magnetic force-based mechanical stimulation (MS) system and EVs were purified from mechanically stimulated SCs (MS-SCs-EVs) and non-stimulated SCs (SCs-EVs). The effect of MS-SCs-EVs on axonal elongation was examined in vitro and in vivo . High throughput miRNA sequencing was performed to compare the differential miRNA profiles between MS-SCs-EVs and SCs-EVs. The functional role of differentially expressed miRNAs on neurite extension in MS-SCs-EVs was examined. Also, the putative target genes of differentially expressed miRNAs in MS-SCs-EVs were predicted by bioinformatics tools, and the regulatory effect of those miRNAs on putative target genes was validated both in vitro and in vivo . Results: The MS-SCs-EVs showed an average size of 137.52±1.77 nm, and could be internalized by dorsal root ganglion (DRG) neurons. Compared to SCs-EVs, MS-SCs-EVs showed a stronger ability to enhance neurite outgrowth in vitro and nerve regeneration in vivo . High throughput miRNA sequencing identified a number of differentially expressed miRNAs in MS-SCs-EVs. Further analysis of those EV-miRNAs demonstrated that miR-23b-3p played a predominant role in MS-SCs-EVs since its deprivation abolished their enhanced axonal elongation. Furthermore, we identified neuropilin 1 (Nrp1) in neurons as the target gene of miR-23b-3p in MS-SCs-EVs. This observation was supported by the evidence that miR-23b-3p could decrease Nrp1-3'-UTR-WT luciferase activity in vitro and down-regulate Nrp1 expression in neurons. Conclusion: Our findings suggested that mechanical stimuli are capable of modulating the intercellular communication between neurons and SCs by altering miRNA composition in MS-SCs-EVs. Transfer of miR-23b-3p by MS-SCs-EVs from mechanically stimulated SCs to neurons decreased neuronal Nrp1 expression, which was responsible, at least in part, for the beneficial effect of MS-SCs-EVs on axonal regeneration. Our results highlighted the potential therapeutic value of MS-SCs-EVs and miR-23b-3p-en...

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Aligned chitosan nanofiber hydrogel grafted with peptides mimicking bioactive brain-derived neurotrophic factor and vascular endothelial growth factor repair long-distance sciatic nerve defects in rats

Cited by 147 publications

References 64 publications

Application of bioactive hydrogels combined with dental pulp stem cells for the repair of large gap peripheral nerve injuries

Application of bioactive hydrogels combined with dental pulp stem cells for the repair of large gap peripheral nerve injuries

Self-assembling peptide hydrogels functionalized with LN- and BDNF- mimicking epitopes synergistically enhance peripheral nerve regeneration

Mechanical stimulation of Schwann cells promote peripheral nerve regeneration via extracellular vesicle-mediated transfer of microRNA 23b-3p

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