nerve regeneration
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Consistent application of neurotropic factors is necessary in peripheral nerve regeneration, yet challenging to achieve. Here we used a novel neurotropic factor controlled release system consisted of fibrin, fibronectin and hydrogel to slowly release two neurotrophic factors. At the same time, physiological saline and reverse nerve suturing were used as negative and positive control. A year after surgery, animals which were treated by neurotrophic factor slow release system achieved far better neural regeneration and myelination, as well as superior recovery of hindfoot than the negative control group. In the meanwhile, the results in the experimental group are still inferior to the nerve allograft group. In can be concluded from those results that, consistent releasing of neurotrophic factors can significantly promote long peripheral nerve regeneration, but still short of achieving the results same as the gold standard of autologous nerve grafting.

Keratoconus is the most common primary corneal ectasia characterized by progressive focal thinning. Patients experience increased irregular astigmatism, decreased visual acuity and corneal sensitivity. Corneal collagen crosslinking (CXL), a minimally invasive procedure, is effective in halting disease progression. Historically, keratoconus research was confined to ex vivo settings. In vivo confocal microscopy (IVCM) has been used to examine the corneal microstructure clinically. In this review, we discuss keratoconus cellular changes evaluated by IVCM before and after CXL. Cellular changes before CXL include decreased keratocyte and nerve densities, disorganized subbasal nerves with thickening, increased nerve tortuosity and shortened nerve fibre length. Repopulation of keratocytes occurs up to 1 year post procedure. IVCM also correlates corneal nerve status to functional corneal sensitivity. Immediately after CXL, there is reduced nerve density and keratocyte absence due to mechanical removal of the epithelium and CXL effect. Nerve regeneration begins after 1 month, with nerve fibre densities recovering to pre-operative levels between 6 months to 1 year and remains stable up to 5 years. Nerves remain tortuous and nerve densities are reduced. Corneal sensitivity is reduced immediately postoperatively but recovers with nerve regeneration. Our article provides comprehensive review on the use of IVCM imaging in keratoconus patients.

Abstract Background Peripheral nerve injury (PNI) is one of the essential causes of physical disability with a high incidence rate. The traditional tissue engineering strategy, Top-Down strategy, has some limitations. A new tissue-engineered strategy, Bottom-Up strategy (tissue-engineered microtissue strategy), has emerged and made significant research progress in recent years. However, to the best of our knowledge, microtissues are rarely used in neural tissue engineering; thus, we intended to use microtissues to repair PNI. Methods We used a low-adhesion cell culture plate to construct adipose-derived mesenchymal stem cells (ASCs) into microtissues in vitro, explored the physicochemical properties and microtissues components, compared the expression of cytokines related to nerve regeneration between microtissues and the same amount of two-dimension (2D)-cultured cells, co-cultured directly microtissues with dorsal root ganglion (DRG) or Schwann cells (SCs) to observe the interaction between them using immunocytochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA). We used grafts constructed by microtissues and polycaprolactone (PCL) nerve conduit to repair sciatic nerve defects in rats. Results The present study results indicated that compared with the same number of 2D-cultured cells, microtissue could secrete more nerve regeneration related cytokines to promote SCs proliferation and axons growth. Moreover, in the direct co-culture system of microtissue and DRG or SCs, axons of DRG grown in the direction of microtissue, and there seems to be a cytoplasmic exchange between SCs and ASCs around microtissue. Furthermore, microtissues could repair sciatic nerve defects in rat models more effectively than traditional 2D-cultured ASCs. Conclusion Tissue-engineered microtissue is an effective strategy for stem cell culture and therapy in nerve tissue engineering.

Abstract Introduction Collagen and human amniotic membrane (hAM) are Food and Drug Administration (FDA)-approved biomaterials that can be used as nerve wraps or conduits for repair of peripheral nerve injuries. Both biomaterials have been shown to reduce scarring and fibrosis of injured peripheral nerves. However, comparative advantages and disadvantages have not been definitively shown in the literature. The purpose of this systematic review is to comprehensively evaluate the literature regarding the roles of hAM and collagen nerve wraps and conduits on peripheral nerve regeneration in preclinical models. Methods The MEDLINE database was queried using the PubMed search engine on July 7, 2019, with the following search strategy: (“amniotic membrane” OR “amnion”) OR (“collagen conduit” OR “nerve wrap”)] AND “nerve.” All resulting articles were screened by two independent reviewers. Nerve type, lesion type/injury model, repair type, treatment, and outcomes were assessed. Results Two hundred and fifty-eight articles were identified, and 44 studies remained after application of inclusion and exclusion criteria. Seventeen studies utilized hAM, whereas 27 studies utilized collagen wraps or conduits. Twenty-three (85%) of the collagen studies utilized conduits, and four (15%) utilized wraps. Six (35%) of the hAM studies utilized conduits and 11 (65%) utilized wraps. Two (9%) collagen studies involving a conduit and one (25%) involving a wrap demonstrated at least one significant improvement in outcomes compared with a control. While none of the hAM conduit studies showed significant improvements, eight (73%) of the studies investigating hAM wraps showed at least one significant improvement in outcomes. Conclusion The majority of studies reported positive outcomes, indicating that collagen and hAM nerve wraps and conduits both have the potential to enhance peripheral nerve regeneration. However, relatively few studies reported significant findings, except for studies evaluating hAM wraps. Preclinical models may help guide clinical practice regarding applications of these biomaterials in peripheral nerve repair.

Cell-based therapy is a promising treatment to favor tissue healing through less invasive strategies. Mesenchymal stem cells (MSCs) highlighted as potential candidates due to their angiogenic, anti-apoptotic and immunomodulatory properties, in addition to their ability to differentiate into several specialized cell lines. Cells can be carried through a biological delivery system, such as fibrin glue, which acts as a temporary matrix that favors cell-matrix interactions and allows local and paracrine functions of MSCs. Thus, the aim of this systematic review was to evaluate the potential of fibrin glue combined with MSCs in nerve regeneration. The bibliographic search was performed in the PubMed/MEDLINE, Web of Science and Embase databases, using the descriptors (“fibrin sealant” OR “fibrin glue”) AND “stem cells” AND “nerve regeneration”, considering articles published until 2021. To compose this review, 13 in vivo studies were selected, according to the eligibility criteria. MSCs favored axonal regeneration, remyelination of nerve fibers, as well as promoted an increase in the number of myelinated fibers, myelin sheath thickness, number of axons and expression of growth factors, with significant improvement in motor function recovery. This systematic review showed clear evidence that fibrin glue combined with MSCs has the potential to regenerate nervous system lesions.

Peripheral nerve adhesion after neurolysis leads to nerve dysfunction, limiting nerve regeneration and functional recovery. We previously developed an electrospun polycaprolactone (PCL)-amnion nanofibrous membrane for preventing adhesion formation. In this study, we investigated the effect of protective nerve wrapping and promoting nerve regeneration in a rat sciatic nerve compression model. A total of 96 SD rats after sciatic nerve chronic compression were randomly divided into three groups: the PCL-amniotic group, in which nerves were wrapped with a PCL-amniotic membrane for treatment; the chitosan group, in which nerves were wrapped with a clinically used chitosan hydrogel; the control group, which involved neurolysis alone without treatment. Twelve weeks postoperatively, the nerve regeneration was evaluated by general and ultrastructure observation, as well as the expressions of neuronal regeneration and inflammatory reaction biomarkers. The nerve functions were assessed with gastrocnemius muscle measurement, hot-plate test, and walking track analysis. Compared with the chitosan hydrogel, the PCL-amnion nanofibrous membrane significantly reduced peripheral nerve adhesion and promoted nerve regeneration. The morphological properties of axons in the nerve wrap group were preserved. Intraneural macrophage invasion, as assessed by the number of CD68-positive cells, was less severe in the PCL-amnion group than in the other groups. Additionally, the gastrocnemius muscle weight and muscle bundle area were significantly higher in the PCL-amnion group than those in the chitosan group. The abilities of sense and movement of the rats in the PCL-amnion group were significantly improved compared to the other groups. In summary, electrospun PCL-amnion nanofibrous membranes effectively prevented post-neurolysis peripheral nerves from developing adhesion, whereas promoted nerve repair and regeneration, which make PCL-amnion nanofibrous membranes a promising biomaterial for clinical application.

Functionally distinct subtypes/clusters of dorsal root ganglion (DRG) neurons, which differ in soma size and neurochemical properties, may play different roles in nerve regeneration and pain. However, details about transcriptomic changes in different neuronal subtypes under maladaptive neuropathic pain conditions remain unclear. Chronic constriction injury (CCI) of the sciatic nerve represents a well-established model of neuropathic pain that mimics the etiology of clinical conditions. Therefore, we conducted single-cell RNA-sequencing (scRNA-seq) to characterize subtype-specific perturbations of transcriptomes in lumbar DRG neurons 7 days after sciatic CCI. By using Pirt-EGFPf mice that selectively express enhanced green fluorescent protein in DRG neurons, we established a highly efficient purification process to enrich neurons for scRNA-seq. We observed a loss of marker genes in injured neurons of 12 standard neuronal clusters, and the emergence of four prominent CCI-induced clusters at this peak-maintenance phase of neuropathic pain. Importantly, a portion of injured neurons from a subset of the 12 standard clusters (NP1, PEP5, NF1, and NF2) were spared from injury-induced identity loss, suggesting subtype-specific transcriptomic changes in injured neurons. Moreover, uninjured neurons, which are necessary for mediating the evoked pain, also demonstrated subtype-specific transcriptomic perturbations in these clusters, but not others. Notably, male and female mice showed differential transcriptomic changes in multiple neuronal clusters after CCI, suggesting transcriptomic sexual dimorphism in primary sensory neurons after nerve injury. Collectively, these findings may contribute to the identification of new target genes and development of DRG neuron subtype-specific therapies for optimizing neuropathic pain treatment and nerve regeneration.

Peripheral nerve injury (PNI) occurs frequently, and the prognosis is unsatisfactory. As the gold standard of treatment, autologous nerve grafting has several disadvantages, such as lack of donors and complications. The use of functional biomaterials to simulate the natural microenvironment of the nervous system and the combination of different biomaterials are considered to be encouraging alternative methods for effective tissue regeneration and functional restoration of injured nerves. Considering the inherent presence of an electric field in the nervous system, electrically conductive biomaterials have been used to promote nerve regeneration. Due to their singular physical properties, hydrogels can provide a three-dimensional hydrated network that can be integrated into diverse sizes and shapes and stimulate the natural functions of nerve tissue. Therefore, conductive hydrogels have become the most effective biological material to simulate human nervous tissue’s biological and electrical characteristics. The principal merits of conductive hydrogels include their physical properties and their electrical peculiarities sufficient to effectively transmit electrical signals to cells. This review summarizes the recent applications of conductive hydrogels to enhance peripheral nerve regeneration.

Peripheral nerve injuries are common conditions that can arise from trauma (e.g., compression, severance) and can lead to neuropathic pain as well as motor and sensory deficits. Although much knowledge exists on the mechanisms of injury and nerve regeneration, treatments that ensure functional recovery following peripheral nerve injury are limited. Schwann cells, the supporting glial cells in peripheral nerves, orchestrate the response to nerve injury, by converting to a “repair” phenotype. However, nerve regeneration is often suboptimal in humans as the repair Schwann cells do not sustain their repair phenotype long enough to support the prolonged regeneration times required for successful nerve regrowth. Thus, numerous strategies are currently focused on promoting and extending the Schwann cells repair phenotype. Low-intensity ultrasound (LIU) is a non-destructive therapeutic approach which has been shown to facilitate peripheral nerve regeneration following nerve injury in rodents. Still, clinical trials in humans are scarce and limited to small population sizes. The benefit of LIU on nerve regeneration could possibly be mediated through the repair Schwann cells. In this review, we discuss the known and possible molecular mechanisms activated in response to LIU in repair Schwann cells to draw support and attention to LIU as a compelling regenerative treatment for peripheral nerve injury.