Tissue Engineering Scaffold Slowly Releasing Neurotrophic Factors to Bridge Long Peripheral Nerve Defect

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.

A Brief Review of In Vitro Models for Injury and Regeneration in the Peripheral Nervous System

Nerve axonal injury and associated cellular mechanisms leading to peripheral nerve damage are important topics of research necessary for reducing disability and enhancing quality of life. Model systems that mimic the biological changes that occur during human nerve injury are crucial for the identification of cellular responses, screening of novel therapeutic molecules, and design of neural regeneration strategies. In addition to in vivo and mathematical models, in vitro axonal injury models provide a simple, robust, and reductionist platform to partially understand nerve injury pathogenesis and regeneration. In recent years, there have been several advances related to in vitro techniques that focus on the utilization of custom-fabricated cell culture chambers, microfluidic chamber systems, and injury techniques such as laser ablation and axonal stretching. These developments seem to reflect a gradual and natural progression towards understanding molecular and signaling events at an individual axon and neuronal-soma level. In this review, we attempt to categorize and discuss various in vitro models of injury relevant to the peripheral nervous system and highlight their strengths, weaknesses, and opportunities. Such models will help to recreate the post-injury microenvironment and aid in the development of therapeutic strategies that can accelerate nerve repair.

Graphene-Based Materials Prove to Be a Promising Candidate for Nerve Regeneration Following Peripheral Nerve Injury

Peripheral nerve injury is a common medical condition that has a great impact on patient quality of life. Currently, surgical management is considered to be a gold standard first-line treatment; however, is often not successful and requires further surgical procedures. Commercially available FDA- and CE- approved decellularized nerve conduits offer considerable benefits to patients suffering from a completely transected nerve but they fail to support neural regeneration in gaps >30 mm. To address this unmet clinical need, current research is focused on biomaterial-based therapies to regenerate dysfunctional neural tissues, specifically damaged peripheral nerve, and spinal cord. Recently, attention has been paid to the capability of graphene-based materials (GBMs) to develop bifunctional scaffolds for promoting nerve regeneration, often via supporting enhanced neural differentiation. The unique features of GBMs have been applied to fabricate an electroactive conductive surface in order to direct stem cells and improve neural proliferation and differentiation. The use of GBMs for nerve tissue engineering (NTE) is considered an emerging technology bringing hope to peripheral nerve injury repair, with some products already in preclinical stages. This review assesses the last six years of research in the field of GBMs application in NTE, focusing on the fabrication and effects of GBMs for neurogenesis in various scaffold forms, including electrospun fibres, films, hydrogels, foams, 3D printing, and bioprinting.

Optimized, visible light-induced crosslinkable hybrid gelatin/hyaluronic acid scaffold promotes complete spinal cord injury repair

Severe microenvironmental changes after spinal cord injury (SCI) present serious challenges in neural regeneration and tissue repair. Gelatin (GL)- and hyaluronic acid (HA)-based hydrogels are attractive scaffolds because they are major components of the extracellular matrix and can provide a favorable adjustable microenvironment for neurogenesis and motor function recovery. In this study, three-dimensional hybrid GL/HA hydrogel scaffolds were prepared and optimized. The hybrid hydrogels could undergo in-situ gelation and fit the defects perfectly via visible light- induced crosslinking in the complete SCI rats. We found that the transplantation of the hybrid hydrogel scaffold significantly reduced the inflammatory responses and suppressed glial scar formation in an HA concentration-dependent manner. Moreover, the hybrid hydrogel with GL/HA ratios less than 8/2 effectively promoted endogenous neural stem cell migration and neurogenesis, as well as improved neuron maturation and axonal regeneration. The results showed locomotor function improved 60 days after transplantation, thus suggesting that GL/HA hydrogels can be considered as a promising scaffold for complete SCI repair.

Bibliometric analysis of China’s contribution to the knowledge system of cerebrovascular intervention

Background Cerebrovascular disease has become the leading cause of death in China. The purpose of this article is to analyze China’s contribution to the interventional treatment of cerebrovascular diseases. Methods Bibliometric analysis was used for evaluating the quantity, quality, research hotspots, and cooperation network of publications regarding interventional treatment of cerebrovascular diseases from China. These articles were searched from the database of Web of Science Core Collection. The authors, publication years, citation times, regions, and source journals of retrieved articles were recorded. Network analysis and visualization were performed on Citespace5.6. Results From 1991 to 2019, a total of 5052 articles regarding cerebrovascular intervention were contributed by Chinese researchers. The number of publications from China grew fastest annually in the latest 5 years among countries. These publications were cited 61,216 times, with 12.12 average citations per item. The h-index was 82. Affiliated hospitals of Capital Medical University contributed most articles. Cerebral ischemia and intracranial aneurysm were the most popular keywords over the three decades. The timeline view of keywords indicated that cerebral ischemia always was a hot spot. Stent techniques were the main treatment tools and still had a strong developing trend. Neural regeneration and neuroprotection were the hot topics of basic researches related to cerebrovascular intervention. Conclusions The number of researches grows rapidly in China over the decades, but the quality still needs further improvement. The increasing contributions of Chinese researchers to the global knowledge system of cerebrovascular intervention are promising.

Can Early Electrical Stimulation Accelerates the Neural Regeneration by Increasing the Expression of BDNF and GDNF in Distal Part of Injured Peripheral Nerve? An Animal Experimental Study

BACKGROUND: The role of neurotrophic factors (brain-derived neurotrophic factors and glial cell line-derived neurotrophic factors) and early electrical stimulation (EES) in the injured nerve has found promising in several studies. However, there is still limited knowledge about the effect of EES in the distal part of the nerve to sustain this level of expression of growth factors. AIM: We aim to evaluate the effects of EES in in neural regeneration by measuring the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in animal model. METHODS: The research was conducted starting from April to May 2021 using male Wistar rats. Using general anesthesia, the sciatic nerve was cut. The intervention group was treated with EES in the distal stump, right after nerve resection (20 Hz, 1–2 mA, 2–5 s), while the control group received no treatment after nerve resection. A reoperation on day 3 was performed in both groups to measure BDNF and GDNF expression level of the distal nerve tissue by ELISA as well as histopathological examination of sprouting axons of the injured proximal nerve. RESULTS: A total of 32 samples were included in the study. A statistically significant levels of GDNF is found higher in the EES group (n = 16) than the control group (n = 16) (35. 71 pg/100 mg, confidence interval (CI) 95% 23.93, 47.48, p < 0.05). The number of sprouting axons is found lower in the EES group (p < 0.05). The BDNF level is similar between the two groups, however not significant. After a subgroup analysis, it was found that the greater the level of GDNF, the fewer the axon sprouts in both groups (fewer axon group 58.35 [n = 22, CI 95% 45.14, 71.55] vs. more axon group 47.14 [n = 10, CI 95% 35.33, 58.95]), p < 0.05. CONCLUSION: The EES proves its benefit in accelerating the axonal regeneration by increasing the expression GDNF in the distal nerve stumps in the electrical excited degenerated sciatic nerve in the rat model.

pH-responsive delivery of H2 through ammonia borane-loaded mesoporous silica nanoparticles improves recovery after spinal cord injury by moderating oxidative stress and regulating microglial polarization

Imbalance of oxidative and inflammatory regulation is the main contributor to neurofunctional deterioration and failure of rebuilding spared neural networks after spinal cord injury (SCI). As an emerging biosafe strategy for protecting against oxidative and inflammatory damage, hydrogen (H2) therapy is a promising approach for improving the microenvironment to allow neural regeneration. However, achieving release of H2 at sufficient concentrations specifically into the injured area is critical for the therapeutic effect of H2. Thus, we assembled SiO2@mSiO2 mesoporous silica nanoparticles and loaded them with ammonia borane (AB), which has abundant capacity and allows controllable release of H2 in an acid-dependent manner. The release of H2 from AB/SiO2@mSiO2 was satisfactory at pH 6.6, which is approximately equal to the microenvironmental acidity after SCI. After AB/SiO2@mSiO2 were intrathecally administered to rat models of SCI, continuous release of H2 from these nanoparticles synergistically enhanced neurofunctional recovery, reduced fibrotic scar formation and promoted neural regeneration by suppressing oxidative stress reaction. Furthermore, in the subacute phase of SCI, microglia were markedly polarized toward the M2 phenotype by H2 via inhibition of TLR9 expression in astrocytes. In conclusion, H2 delivery through AB/SiO2@mSiO2 has the potential to efficiently treat SCI through comprehensive modulation of the oxidative and inflammatory imbalance in the microenvironment.

Agonistic analog of growth hormone–releasing hormone promotes neurofunctional recovery and neural regeneration in ischemic stroke

Ischemic stroke can induce neurogenesis. However, most stroke-generated newborn neurons cannot survive. It has been shown that MR-409, a potent synthetic agonistic analog of growth hormone–releasing hormone (GHRH), can protect against some life-threatening pathological conditions by promoting cell proliferation and survival. The present study shows that long-term treatment with MR-409 (5 or 10 μg/mouse/d) by subcutaneous (s.c.) injection significantly reduces the mortality, ischemic insult, and hippocampal atrophy, and improves neurological functional recovery in mice operated on for transient middle cerebral artery occlusion (tMCAO). Besides, MR-409 can stimulate endogenous neurogenesis and improve the tMCAO-induced loss of neuroplasticity. MR-409 also enhances the proliferation and inhibits apoptosis of neural stem cells treated with oxygen and glucose deprivation–reperfusion. The neuroprotective effects of MR-409 are closely related to the activation of AKT/CREB and BDNF/TrkB pathways. In conclusion, the present study demonstrates that GHRH agonist MR-409 has remarkable neuroprotective effects through enhancing endogenous neurogenesis in cerebral ischemic mice.