Macroporous nanofiber wraps promote axonal regeneration and functional recovery in nerve repair by limiting fibrosis

Sarhane, Karim A.; Ibrahim, Zuhaib; Martin, Russell; Krick, Kellin; Cashman, Christopher R.; Tuffaha, Sami H.; Broyles, Justin M.; Prasad, Nagarajan Rajendra; Yao, Zhi Cheng; Cooney, Damon S.; Mi, Ruifa; Lee, WP Andrew; Höke, Ahmet; Mao, Hai Quan; Brandacher, Gerald

doi:10.1016/j.actbio.2019.02.034

Cited by 40 publications

(29 citation statements)

References 63 publications

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“…Consistent with this, we previously observed that overexpression of BDNF at the lesion site of spinal cord injury increased the proportion of the M2 macrophages, which contributed to a notable improvement of functional recovery (35). In addition, Sarhane et al reported that macroporous nanofiber wrap shifted the macrophage polarization toward a pro-regenerative M2 phenotype at the repair site and concomitantly improved axonal regeneration in a rat sciatic nerve cut model (36). Furthermore, several recent reports documented that drugs and transplantation of stem cells improved neurological functional recovery and prevented inflammation-induced demyelination by promoting microglial M2 polarization and inhibiting proinflammatory cytokine expression (37-40).…”

Section: Discussionsupporting

confidence: 77%

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

Shi

Zhang

et al. 2020

Front. Neurol.

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Intracerebral hemorrhage (ICH) is a fatal subtype of stroke, and effective interventions to improve the functional outcomes are still lacking. Suppressor of cytokine signaling 3 (SOCS3) plays critical roles in the inflammatory response by negatively regulating cytokine-Jak–Stat signaling. However, the role of SOCS3 in the regulation of macrophage polarization is highly controversial and the fine regulation exerted by SOCS3 needs further understanding. In this study, rat ICH models were established by infusion of collagenase into the caudate nucleus. To decrease SOCS3 expression into microglia/macrophages in the hemorrhagic lesion area, we injected lentiviral short hairpin RNA (shSOCS3) (Lenti-shSOCS3) into the hematoma cavity at 24 h following ICH. We found that the number of iNOS-positive cells (M1 phenotype) was significantly reduced, whereas arginase-1-positive cells (M2 phenotype) were markedly elevated in animals that received Lenti-shSOCS3 injections compared with those in the Lenti-EGFP and saline groups. The increase in arginase-1-positive cells was associated with a significantly lower pro-inflammatory microenvironment, which included the downregulation of pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, and TNF-α] and concurrent upregulation of anti-inflammatory (IL-10) mediators. In addition, this marked shift toward the M2 phenotype was associated with suppressed NF-κB activation. Furthermore, these changes notably enhanced the neuroprotective effects and functional recovery in Lenti-shSOCS3-injected animals. Our findings indicated that reduction in SOCS3 expression caused a marked bias toward the M2 phenotype and ameliorated the inflammatory microenvironment, which enhanced neuroprotective effects and resulted in notable improvement in functional recovery after ICH.

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Section: Discussionsupporting

confidence: 77%

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

Shi

Zhang

et al. 2020

Front. Neurol.

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“…In fact, the LFPm are made of fibrin meshes, platelets and mesenchymal stem cell populations which are highly immuno-tolerated 29,30 without causing rejection, necrosis or suppuration in the implantation site or in the surrounding tissues following implantation 31–35 . Controlling the inflammatory response at the suture-site influences injury-repair; it allows the nerve fibers for both faster crossing of neurorrhaphy site and regeneration of the early axons 36 . Supporting this assumption, for all experimental groups, the repaired tissues were positive to the specific markers for axons and Schwann cells (β-tubulin and S100, respectively) proving the preservation of nervous tissue 24,37 .…”

Section: Discussionmentioning

confidence: 99%

New bioresorbable wraps based on oxidized polyvinyl alcohol and leukocyte-fibrin-platelet membrane to support peripheral nerve neurorrhaphy: preclinical comparison versus NeuraWrap

Stocco

Barbon

Macchi

et al. 2019

Sci Rep

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Nerve wrapping improves neurorrhaphy outcomes in case of peripheral nerve injuries (PNIs). The aim of this preclinical study was to assess the efficacy of two novel biodegradable wraps made of a synthetic 1% oxidized polyvinyl alcohol (OxPVA) and a natural leukocyte-fibrin-platelet membrane (LFPm) versus the commercial product NeuraWrap. After rats sciatic nerve transection and neurorrhaphy, the wraps were implanted and compared for functional outcome, by sciatic function index assessment; structural characteristics, by histological/immunohistochemical analysis; ultrastructural features, by transmission electron microscopy. Moreover, a morphometric study was also performed and collagen distribution was observed by Second Harmonic Generation microscopy. After 12 weeks from implantation, all wraps assured nerve function recovery; no scar tissue/neuromas were visible at dissection. LFPm wraps were completely resorbed, while residues of OxPVA and NeuraWrap were observed. In all groups, biocompatibility was confirmed by the absence of significant inflammatory infiltrate. According to histological/immunohistochemical analysis and morphometric findings, OxPVA and LFPm wraps were both effective in preserving nerve integrity. These results assess that bioengineered OxPVA and LFPm wraps successfully guarantee favorable lesion recovery after PNI/neurorrhaphy and, in future, may be considered an interesting alternative to the commercial NeuraWrap.

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“…In addition, refinements can be introduced in the fabrication of the conduit itself (fiber pore and size, etc.) to modulate the inflammatory response at the repair site towards a regenerative phenotype, as we have previously shown in an acute injury model [44]. Such bioactive synthetic scaffolds loaded with growth factors might hold promising avenues in chronic denervation models.…”

Section: Discussionmentioning

confidence: 72%

Glial Cell Line–Derived Neurotrophic Factor and Chondroitinase Promote Axonal Regeneration in a Chronic Denervation Animal Model

et al. 2019

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Functional recovery following nerve injury declines when target re-innervation is delayed. Currently, no intervention exists to improve outcomes after prolonged denervation. We explored the neuroregenerative effects of glial cell line-derived neurotrophic factor (GDNF) and chondroitinase (CDN) in a chronic denervation animal model. A fibrin-based sustained delivery method for growth factors was optimized in vitro and in vivo, and then tested in our animal model. GDNF, CDN, and GDNF+CDN were injected into the denervated stump at the time of nerve repair. Histomorphometry and retrograde labeling were used to assess axonal regeneration. The mechanisms promoting such regeneration were explored with immunofluorescence. Five weeks after repair, the GDNF+CDN group had the highest number and maturity of axons. GDNF was noted to preferentially promote axonal maturity, whereas CDN predominantly increased the number of axons. GDNF favored motor neuron regeneration, and upregulated Ki67 in Schwann cells. CDN did not favor motor versus sensory regeneration and was noted to cleave inhibitory endoneurial proteoglycans. Early measures of nerve regeneration after delayed repair are improved by activating Schwann cells and breaking down the inhibitory proteoglycans in the distal nerve segment, suggesting a role for GDNF+CDN to be translated for human nerve repairs.

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Macroporous nanofiber wraps promote axonal regeneration and functional recovery in nerve repair by limiting fibrosis

Cited by 40 publications

References 63 publications

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

New bioresorbable wraps based on oxidized polyvinyl alcohol and leukocyte-fibrin-platelet membrane to support peripheral nerve neurorrhaphy: preclinical comparison versus NeuraWrap

Glial Cell Line–Derived Neurotrophic Factor and Chondroitinase Promote Axonal Regeneration in a Chronic Denervation Animal Model

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