Comparison of Collagen and Human Amniotic Membrane Nerve Wraps and Conduits for Peripheral Nerve Repair in Preclinical Models: A Systematic Review of the Literature

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.

Electrospun Polycaprolactone (PCL)-Amnion Nanofibrous Membrane Promotes Nerve Repair after Neurolysis

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.

Spidroin-Based Biomaterials in Tissue Engineering: General Approaches and Potential Stem Cell Therapies

Spider silks are increasingly gaining interest for potential use as biomaterials in tissue engineering and biomedical applications. Owing to their facile and versatile processability in native and regenerated forms, they can be easily tuned via chemical synthesis or recombinant technologies to address specific issues required for applications. In the past few decades, native spider silk and recombinant silk materials have been explored for a wide range of applications due to their superior strength, toughness, and elasticity as well as biocompatibility, biodegradation, and nonimmunogenicity. Herein, we present an overview of the recent advances in spider silk protein that fabricate biomaterials for tissue engineering and regenerative medicine. Beginning with a brief description of biological and mechanical properties of spidroin-based materials and the cellular regulatory mechanism, this review summarizes various types of spidroin-based biomaterials from genetically engineered spider silks and their prospects for specific biomedical applications (e.g., lung tissue engineering, vascularization, bone and cartilage regeneration, and peripheral nerve repair), and finally, we prospected the development direction and manufacturing technology of building more refined and customized spidroin-based protein scaffolds.

Neuroprotective Effects of Hesperetin in Regulating Microglia Polarization after Ischemic Stroke by Inhibiting TLR4/NF-κB Pathway

This study aimed to explore the influence of hesperidin on the polarization of microglia to clarify the key mechanism of regulating the polarization of M2 microglia. C57BL/6 mice were randomly divided into middle cerebral artery occlusion model group (MCAO group), MCAO + hesperidin treatment group (MCAO + hesperidin group), and sham group (sham operation group). The mice were assessed with neurological scores for their functional status. 2,3,5-Triphenyltetrazole chloride (TTC) was used to determine the volume of cerebral infarction. Hematoxylin and eosin (H&E) staining was performed to detect brain loss. The system with 1% O2, 5% CO2, and 92% N2 was applied to establish BV2 in vitro model induced by MCAO. TNF-α, IL-1β, TGF-β, and IL-10 levels of cytokines in the supernatant were detected by ELISA. RT-qPCR was used to detect mRNA levels of M1 iNOS, CD11b, CD32, and CD86, and mRNA levels of M2 CD206, Arg-1, and TGF-β. The Iba-1, iNOS, and Arg-1 of microglia and protein levels of TLR4 and p-NF-κB related to the pathway were detected by Western blot. After treatment with hesperidin, BV2 cells induced by MCAO in vitro can reduce the proinflammatory cytokines of TNF-α and IL-1β significantly, further upregulating anti-inflammatory cytokines of TGF-β, IL-10 while inhibiting TLR4 and p-NF-κB expression. The MCAO-induced BV2 cells treated by TLR-4 inhibitor TAK-242 and NF-κB inhibitor BAY 11-7082 had similar polarization effects to those treated with hesperidin. This study found that hesperetin gavage treatment can improve the neurological deficit and regulate the polarization of microglia in MCAO mice. In vitro experiments further verified that hesperidin plays a neuroprotective role by inhibiting the TLR4-NF-κB pathway, thus providing new targets and strategies for neuroprotection and nerve repair after ischemic stroke.

Peripheral Nerve Defects: Repair Using Autogenous Vein Grafts Filled with PRP and Active Nerve Microtissues and Evaluation by Novel Multimodal Ultrasound Techniques

Background: Developing biocompatible nerve conduits that accelerate peripheral nerve regeneration, lengthening and functional recovery remains a challenge. The combined application of nerve microtissues and platelet-rich plasma (PRP) provides abundant Schwann cells (SCs) and various natural growth factors and can compensate for the deficiency of SCs in the nerve bridge, as well as the limitations of applying a single type of growth factor. Multimodal ultrasound evaluation can provide additional information on the stiffness and microvascular flow perfusion of the tissue. This study was designed to investigate the effectiveness of a novel tissue-engineered nerve graft composed of an autogenous vein, nerve microtissues and PRP in reconstructing a 12-mm tibial nerve defect and to explore the value of multimodal ultrasound techniques in evaluating the prognosis of nerve repair. Methods: In vitro, nerve microtissue activity was first investigated, and the effects on SC proliferation, migration, factor secretion, and axonal regeneration of dorsal root ganglia (DRG) were evaluated by coculture with nerve microtissues and PRP. In vivo, seventy-five rabbits were equally and randomly divided into Hollow, PRP, Micro-T (Microtissues), Micro-T+PRP and Autograft groups. By analysing the neurological function, electrophysiological recovery, and the comparative results of multimodal ultrasound and histological evaluation, we investigated the effect of these new nerve grafts in repairing tibial nerve defects. Results: Our results showed that the combined application of nerve microtissues and PRP could significantly promote the proliferation, secretion and migration of SCs and the regeneration of axons in the early stage. The Micro-T+PRP group and Autograft groups exhibited the best nerve repair 12 weeks postoperatively. In addition, the changes in target tissue stiffness and microvascular perfusion on multimodal ultrasound (shear wave elastography; contrast-enhanced ultrasonography; Angio PlaneWave UltrasenSitive, AngioPLUS) were significantly correlated with the histological results, such as collagen area percentage and VEGF expression, respectively. Conclusion: Our novel tissue-engineered nerve graft shows excellent efficacy in repairing 12-mm defects of the tibial nerve in rabbits. Moreover, multimodal ultrasound may provide a clinical reference for prognosis by quantitatively evaluating the stiffness and microvescular flow of nerve grafts and targeted muscles.

Surgical Treatment of Radial Nerve Injuries Associated With Humeral Shaft Fracture—A Single Center Experience

Radial nerve injuries are often associated with humeral shaft fractures. The results of treatment of these injuries, by contemporary surgical approaches, remain diverse. In this paper we presented the outcomes and analyzed the patient, clinical, and surgical procedure related characteristics and factors that may influence the outcome overall, in 77 patients treated at Clinic for Neurosurgery, Clinical Center of Serbia during a 20 years period. The nerve injuries were verified by US and EMNG. The majority of patients were treated by neurolysis or sural nerve grafting, while only few were treated by direct suture. The final recovery was evaluated by muscle strength assessment and classified using MRC. We analyzed extension of the wrist, extension of the fingers including the thumb, and abduction of the thumb. There was a significant statistical difference in MRC grade following the treatment. The total rate of useful functional recovery was achieved in 69 (89.61%) out of all studied patients, out of whom 20 (28.99%) achieved excellent recovery, 26 (37.68%) achieved good recovery and 23 (33.33%) achieved fair recovery. Only 8 (10.39%) out of all studied patients achieved poor recovery. The injured nerves, that were preserved in continuity, acquired by a low-energy trauma, and treated earlier than the 6 months were associated with better functional outcome following the surgery. In addition, there was a trend of better functional improvement with aging, keeping in mind that the old were subjected to lower energy trauma. The expectant management followed by surgery of radial nerve injury associated with humeral shaft fracture should be around 3 months, and the surgical nerve repair should not be performed later than the 6 months after injury. The energy of trauma may be a factor predicting patient's final recovery following the treatment.

Biomaterial and Therapeutic Approaches for the Manipulation of Macrophage Phenotype in Peripheral and Central Nerve Repair

Injury to the peripheral or central nervous systems often results in extensive loss of motor and sensory function that can greatly diminish quality of life. In both cases, macrophage infiltration into the injury site plays an integral role in the host tissue inflammatory response. In particular, the temporally related transition of macrophage phenotype between the M1/M2 inflammatory/repair states is critical for successful tissue repair. In recent years, biomaterial implants have emerged as a novel approach to bridge lesion sites and provide a growth-inductive environment for regenerating axons. This has more recently seen these two areas of research increasingly intersecting in the creation of ‘immune-modulatory’ biomaterials. These synthetic or naturally derived materials are fabricated to drive macrophages towards a pro-repair phenotype. This review considers the macrophage-mediated inflammatory events that occur following nervous tissue injury and outlines the latest developments in biomaterial-based strategies to influence macrophage phenotype and enhance repair.