Facilitate Nerve Regeneration Research Articles

Nerve bypass surgery for spinal cord reconstruction

ObjectiveSpinal cord injury (SCI) is a devastating condition that significantly decreases the patient's quality of life. Therefore, treatments that can facilitate nerve regeneration, reduce complications, and increase quality of life are valuable for these patients. In this study, we aimed to assess nerve bypass surgery's feasibility and clinical outcomes by transferring the intercostal nerves (ICNs) into the spinal cord. MethodsEight patients with complete thoracic SCI and delayed presentation more than a year after the injury were analyzed retrospectively. All patients underwent nerve bypass surgery with the transfer of two pairs of ICNs from proximal to the injury site to the anterolateral spinal cord, followed by duraplasty with fascia grafting to close the dura. ResultsSix of the eight (75%) patients demonstrated motor and sensory improvements, based on the American Spinal Cord Injury Association score. Three patients demonstrated a limited recovery of motor function that could be independently triggered without ICN initiation. Five patients demonstrated evidence of cerebrospinal fluid (CSF) leakage after surgery; however, only one patient complained of a headache. ConclusionSpinal cord bypass surgery is a potential reconstruction method to treat chronic complete thoracic SCI with functional improvements, and is worth further investigation.

Conductive and alignment-optimized porous fiber conduits with electrical stimulation for peripheral nerve regeneration

Autologous nerve transplantation (ANT) is currently considered the gold standard for treating long-distance peripheral nerve defects. However, several challenges associated with ANT, such as limited availability of donors, donor site injury, mismatched nerve diameters, and local neuroma formation, remain unresolved. To address these issues comprehensively, we have developed porous poly(lactic-co-glycolic acid) (PLGA) electrospinning fiber nerve guide conduits (NGCs) that are optimized in terms of alignment and conductive coating to facilitate peripheral nerve regeneration (PNR) under electrical stimulation (ES). The physicochemical and biological properties of aligned porous PLGA fibers and poly(3,4-ethylenedioxythiophene):polystyrene sodium sulfonate (PEDOT:PSS) coatings were characterized through assessments of electrical conductivity, surface morphology, mechanical properties, hydrophilicity, and cell proliferation. Material degradation experiments demonstrated the biocompatibility in vivo of electrospinning fiber films with conductive coatings. The conductive NGCs combined with ES effectively facilitated nerve regeneration. The designed porous aligned NGCs with conductive coatings exhibited suitable physicochemical properties and excellent biocompatibility, thereby significantly enhancing PNR when combined with ES. This combination of porous aligned NGCs with conductive coatings and ES holds great promise for applications in the field of PNR.

Cnicin promotes functional nerve regeneration

BackroundThe limited regenerative capacity of injured axons hinders functional recovery after nerve injury. Although no drugs are currently available in the clinic to accelerate axon regeneration, recent studies show the potential of vasohibin inhibition by parthenolide, produced in Tanacetum parthenium, to accelerate axon regeneration. However, due to its poor oral bioavailability, parthenolide is limited to parenteral administration. PurposeThis study investigates another sesquiterpene lactone, cnicin, produced in Cnicus benedictus for promoting axon regeneration. ResultsCnicin is equally potent and effective in facilitating nerve regeneration. In culture, cnicin promotes axon growth of sensory and CNS neurons from various species, including humans. Neuronal overexpression of vasohibin increases the effective concentrations comparable to parthenolide, suggesting an interaction between cnicin and vasohibin. Remarkably, intravenous administration of cnicin significantly accelerates functional recovery after severe nerve injury in various species, including the anastomosis of severed nerves. Pharmacokinetic analysis of intravenously applied cnicin shows a blood half-life of 12.7 minutes and an oral bioavailability of 84.7% in rats. Oral drug administration promotes axon regeneration and recovery after nerve injury in mice. ConclusionThese results highlight the potential of cnicin as a promising drug to treat axonal insults and improve recovery.

Effects of Physical Cues on Stem Cell-Derived Extracellular Vesicles toward Neuropathy Applications.

The peripheral nervous system undergoes sufficient stress when affected by diabetic conditions, chemotherapeutic drugs, and personal injury. Consequently, peripheral neuropathy arises as the most common complication, leading to debilitating symptoms that significantly alter the quality and way of life. The resulting chronic pain requires a treatment approach that does not simply mask the accompanying symptoms but provides the necessary external environment and neurotrophic factors that will effectively facilitate nerve regeneration. Under normal conditions, the peripheral nervous system self-regenerates very slowly. The rate of progression is further hindered by the development of fibrosis and scar tissue formation, which does not allow sufficient neurite outgrowth to the target site. By incorporating scaffolding supplemented with secretome derived from human mesenchymal stem cells, it is hypothesized that neurotrophic factors and cellular signaling can facilitate the optimal microenvironment for nerve reinnervation. However, conventional methods of secretory vesicle production are low yield, thus requiring improved methods to enhance paracrine secretions. This report highlights the state-of-the-art methods of neuropathy treatment as well as methods to optimize the clinical application of stem cells and derived secretory vesicles for nerve regeneration.

Peripheral Nerve Regeneration at 1 Year: Biodegradable Polybutylene Succinate Artificial Scaffold vs. Conventional Epineurial Sutures.

The utilization of a planar poly(1,4-butylene succinate) (PBS) scaffold has been demonstrated as an effective approach for preserving nerve continuity and facilitating nerve regeneration. In this study, we assessed the characteristics of a microfibrous tubular scaffold specifically designed and fabricated through electrospinning, utilizing PBS as a biocompatible and biodegradable material. These scaffolds were evaluated as nerve guide conduits in a rat model of sciatic nerve neurotmesis, demonstrating both their biodegradability and efficacy in enhancing the reconstruction process over a long-term period (1-year follow-up). Histological assay and electrophysiological evaluation were performed to compare the long-term outcomes following sutureless repair with the microfibrillar wrap to outcomes obtained using traditional suture repair.

Review on electrically conductive smart nerve guide conduit for peripheral nerve regeneration.

At present, peripheral nerve injuries (PNIs) are one of the leading causes of substantial impairment around the globe. Complete recovery of nerve function after an injury is challenging. Currently, autologous nerve grafts are being used as a treatment; however, this has several downsides, for example, donor site morbidity, shortage of donor sites, loss of sensation, inflammation, and neuroma development. The most promising alternative is the development of a nerve guide conduit (NGC) to direct the restoration and renewal of neuronal axons from the proximal to the distal end to facilitate nerve regeneration and maximize sensory and functional recovery. Alternatively, the response of nerve cells to electrical stimulation (ES) has a substantial regenerative effect. The incorporation of electrically conductive biomaterials in the fabrication of smart NGCs facilitates the function of ES throughout the active proliferation state. This article overviews the potency of the various categories of electroactive smart biomaterials, including conductive and piezoelectric nanomaterials, piezoelectric polymers, and organic conductive polymers that researchers have employed latterly to fabricate smart NGCs and their potentiality in future clinical application. It also summarizes a comprehensive analysis of the recent research and advancements in the application of ES in the field of NGC.

An injectable, self-healing, electroconductive hydrogel loaded with neural stem cells and donepezil for enhancing local therapy effect of spinal cord injury

BackgroundSpinal cord injury (SCI) is a serious injury with high mortality and disability rates, and there is no effective treatment at present. It has been reported that some treatments, such as drug intervention and stem cell transplantation have positive effects in promoting neurological recovery. Although those treatments are effective for nerve regeneration, many drawbacks, such as low stem cell survival rates and side effects caused by systemic medication, have limited their development. In recent years, injectable hydrogel materials have been widely used in tissue engineering due to their good biocompatibility, biodegradability, controllable properties, and low invasiveness. The treatment strategy of injectable hydrogels combined with stem cells or drugs has made some progress in SCI repair, showing the potential to overcome the drawbacks of traditional drugs and stem cell therapy.MethodsIn this study, a novel injectable electroactive hydrogel (NGP) based on sodium hyaluronate oxide (SAO) and polyaniline-grafted gelatine (NH2-Gel-PANI) was developed as a material in which to load neural stem cells (NSCs) and donepezil (DPL) to facilitate nerve regeneration after SCI. To evaluate the potential of the prepared NGP hydrogel in SCI repair applications, the surface morphology, self-repairing properties, electrical conductivity and cytocompatibility of the resulting hydrogel were analysed. Meanwhile, we evaluated the neural repair ability of NGP hydrogels loaded with DPL and NSCs using a rat model of spinal cord injury.ResultsThe NGP hydrogel has a suitable pore size, good biocompatibility, excellent conductivity, and injectable and self-repairing properties, and its degradation rate matches the repair cycle of spinal cord injury. In addition, DPL could be released continuously and slowly from the NGP hydrogel; thus, the NGP hydrogel could serve as an excellent carrier for drugs and cells. The results of in vitro cell experiments showed that the NGP hydrogel had good cytocompatibility and could significantly promote the neuronal differentiation and axon growth of NSCs, and loading the hydrogel with DPL could significantly enhance this effect. More importantly, the NGP hydrogel loaded with DPL showed a significant inhibitory effect on astrocytic differentiation of NSCs in vitro. Animal experiments showed that the combination of NGP hydrogel, DPL, and NSCs had the best therapeutic effect on the recovery of motor function and nerve conduction function in rats. NGP hydrogel loaded with NSCs and DPL not only significantly increased the myelin sheath area, number of new neurons and axon area but also minimized the area of the cystic cavity and glial scar and promoted neural circuit reconstruction.ConclusionsThe DPL- and NSC-laden electroactive hydrogel developed in this study is an ideal biomaterial for the treatment of traumatic spinal cord injury.

Functional attachment of primary neurons and glia on radiopaque implantable biomaterials for nerve repair

Repairing peripheral nerve injuries remains a challenge, even with use of auxiliary implantable biomaterial conduits. After implantation the location or function of polymeric devices cannot be assessed via clinical imaging modalities. Adding nanoparticle contrast agents into polymers can introduce radiopacity enabling imaging using computed tomography. Radiopacity must be balanced with changes in material properties impacting device function. In this study radiopaque composites were made from polycaprolactone and poly(lactide-co-glycolide) 50:50 and 85:15 with 0–40 wt% tantalum oxide (TaOx) nanoparticles. To achieve radiopacity, ≥5 wt% TaOx was required, with ≥20 wt% TaOx reducing mechanical properties and causing nanoscale surface roughness. Composite films facilitated nerve regeneration in an in vitro co-culture of adult glia and neurons, measured by markers for myelination. The ability of radiopaque films to support regeneration was driven by the properties of the polymer, with 5–20 wt% TaOx balancing imaging functionality with biological response and proving that in situ monitoring is feasible.

ROS-Scavenging Hydrogels Synergize with Neural Stem Cells to Enhance Spinal Cord Injury Repair via Regulating Microenvironment and Facilitating Nerve Regeneration.

Although stem cell-based therapy is recognized as a promising therapeutic strategy for spinal cord injury (SCI), its efficacy is greatly limited by local reactive oxygen species (ROS)-abundant and hyper-inflammatory microenvironments. It is still a challenge to develop bioactive scaffolds with outstanding antioxidant capacity for neural stem cells (NSCs) transplantation. In this study, albumin biomimetic cerium oxide nanoparticles (CeO2 @BSA nanoparticles, CeNPs) are prepared in a simple and efficient manner and dispersed in gelatin methacryloyl to obtain the ROS-scavenging hydrogel (CeNP-Gel). CeNP-Gel synergistically promotes neurogenesis via alleviating oxidative stress microenvironments and improving the viability of encapsulated NSCs. More interestingly, in the presence of CeNP-Gel, microglial polarization to anti-inflammatory M2subtype are obviously facilitated, which is further verified to be associated with phosphoinositide 3-kinase/protein kinase B pathway activation. Additionally, the injectable ROS-scavenging hydrogel is confirmed to induce the integration and neural differentiation of transplanted NSCs. Compared with the blank-gel group, the survival rate of NSCs in CeNP-Gel group is about 3.5times higher, and the neural differentiation efficiency is about 2.1times higher. Therefore, the NSCs-laden ROS-scavenging hydrogel represents a comprehensive strategy with great application prospect for the treatment of SCI through comprehensively modulating the adverse microenvironment.

The role of Gel-Ppy-modified nerve conduit on the repair of sciatic nerve defect in rat model.

The serious clinical challenge of peripheral nerve injury (PNI) is nerve regeneration. Nerve conduit represents a promising strategy to contribute to nerve regeneration by bridging injured nerve gaps. However, due to a unique microenvironment of nerve tissue, autologous nerves have not been substituted by nerve conduit. Nerve regeneration after nerve conduit implantation depends on many factors, such as conductivity and biocompatibility. Therefore, Gelatin (Gel) with biocompatibility and polypyrrole (Ppy) with conductivity is highly concerned. In this paper, Gel-Ppy modified nerve conduit was fabricated with great biocompatibility and conductivity to evaluate its properties of enhancing nerve regeneration in vivo and in vitro. The proliferation of Schwann cells on Gel-Ppy modified nerve conduit was remarkably increased. Consistent with in vitro results, the Gel-Ppy nerve conduit could contribute to the regeneration of Schwann cell in vivo. The axon diameters and myelin sheath thickness were also enhanced, resulting in the amelioration of muscle atrophy, nerve conduction, and motor function recovery. To explain this interesting phenomenon, western blot results indicated that the Gel-Ppy conduit facilitated nerve regeneration via upregulating the Rap1 pathway to induce neurite outgrowth. Therefore, the above results demonstrated that Gel-Ppy modified nerve conduit could provide an acceptable microenvironment for nerve regeneration and be popularized as a novel therapeutic strategy of PNI.

Chitosan Nerve Grafts Incorporated with SKP-SC-EVs Induce Peripheral Nerve Regeneration.

Repair of long-distance peripheral nerve defects remains an important clinical problem. Nerve grafts incorporated with extracellular vesicles (EVs) from various cell types have been developed to bridge peripheral nerve defects. In our previous research, EVs obtained from skin-derived precursor Schwann cells (SKP-SC-EVs) were demonstrated to promote neurite outgrowth in cultured cells and facilitate nerve regeneration in animal studies. To further assess the functions of SKP-SC-EVs in nerve repair, we incorporated SKP-SC-EVs and Matrigel into chitosan nerve conduits (EV-NG) for repairing a 15-mm long-distance sciatic nerve defect in a rat model. Behavioral analysis, electrophysiological recording, histological investigation, molecular analysis, and morphometric assessment were carried out. The results revealed EV-NG significantly improved motor and sensory function recovery compared with nerve conduits (NG) without EVs incorporation. The outgrowth and myelination of regenerated axons were improved, while the atrophy of target muscles induced by denervation was alleviated after EVs addition. Our data indicated SKP-SC-EVs incorporation into nerve grafts represents a promising method for extended peripheral nerve damage repair.

Multifunctional Integrated Nanozymes Facilitate Spinal Cord Regeneration by Remodeling the Extrinsic Neural Environment.

High levels of reactive oxygen species (ROS) and inflammation create a complicated extrinsic neural environment that dominates the initial post-injury period after spinal cord injury (SCI). The compensatory pathways between ROS and inflammation limited the efficacy of modulating the above single treatment regimen after SCI. Here, novel "nanoflower" Mn3 O4 integrated with "pollen" IRF-5 SiRNA was designed as a combination antioxidant and anti-inflammatory treatment after SCI. The "nanoflower" and "pollen" structure was encapsulated with a neutrophil membrane for protective and targeted delivery. Furthermore, valence-engineered nanozyme Mn3 O4 imitated the cascade response of antioxidant enzymes with a higher substrate affinity compared to natural antioxidant enzymes. Nanozymes effectively catalyzed ROS to generate O2 , which is advantageous for reducing oxidative stress and promoting angiogenesis. The screened "pollen" IRF-5 SiRNA could reverse the inflammatory phenotype by reducing interferon regulatory factors-5 (IRF-5) expression (protein level: 73.08% and mRNA level: 63.10%). The decreased expression of pro-inflammatory factors reduced the infiltration of inflammatory cells, resulting in less neural scarring. In SCI rats, multifunctional nanozymes enhanced the proliferation of various neuronal subtypes (motor neurons, interneurons, and sensory neurons) and the recovery of locomotor function, demonstrating that the remodeling of the extrinsic neural environment is a promising strategy to facilitate nerve regeneration.

Development of 3D-Printed, Biodegradable, Conductive PGSA Composites for Nerve Tissue Regeneration.

Nerve conduits are used to reconnect broken nerve bundles and provide protection to facilitate nerve regeneration. However, the low degradation rate and regeneration rate, as well as the requirement for secondary surgery are some of the most criticized drawbacks of existing nerve conduits. With high processing flexibility from the photo-curability, poly (glycerol sebacate) acrylate (PGSA) is a promising material with tunable mechanical properties and biocompatibility for the development of medical devices. Here, polyvinylpyrrolidone (PVP), silver nanoparticles (AgNPs), and graphene are embedded in biodegradable PGSA matrix. The polymer composites are then assessed for their electrical conductivity, biodegradability, three-dimensional-printability (3D-printability), and promotion of cell proliferation. Through the four-probe technique, it is shown that the PGSA composites are identified as highly conductive in swollen state. Furthermore, biodegradability is evaluated through enzymatic degradation and facilitated hydrolysis. Cell proliferation and guidance are significantly promoted by three-dimensional-printed microstructures and electrical stimulation on PGSA composites, especially on PGSA-PVP. Hence, microstructured nerve conduits are 3D-printed with PGSA-PVP. Guided cell growth and promoted proliferation are subsequently demonstrated by Schwann cell culture combined with electrical stimulation. Consequently, 3D-printed nerve conduits fabricated with PGSA composites hold great potential in nerve tissue regeneration through electrical stimulation.

Conducting polymer-based scaffolds for neuronal tissue engineering.

Neuronal tissue engineering has immense potential for treating neurological disorders and facilitating nerve regeneration. Conducting polymers (CPs) have emerged as a promising class of materials owing to their unique electrical conductivity and biocompatibility. CPs, such as poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3-hexylthiophene) (P3HT), polypyrrole (PPy), and polyaniline (PANi), have been extensively explored for their ability to provide electrical cues to neural cells. These polymers are widely used in various forms, including porous scaffolds, hydrogels, and nanofibers, and offer an ideal platform for promoting cell adhesion, differentiation, and axonal outgrowth. CP-based scaffolds can also serve as drug delivery systems, enabling localized and controlled release of neurotrophic factors and therapeutic agents to enhance neural regeneration and repair. CP-based scaffolds have demonstrated improved neural regeneration, both in vitro and in vivo, for treating spinal cord and peripheral nerve injuries. In this review, we discuss synthesis and scaffold processing methods for CPs and their applications in neuronal tissue regeneration. We focused on a detailed literature review of the central and peripheral nervous systems.

The Effect of Electrical Stimulation on Nerve Regeneration Following Peripheral Nerve Injury

Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from chronic pain, and sensory and motor dysfunction. One promising surgical adjunct is the application of intraoperative electrical stimulation (ES) to peripheral nerves. ES acts through second messenger cyclic AMP to augment the intrinsic molecular pathways of regeneration. Decades of animal studies have demonstrated that 20 Hz ES delivered post-surgically accelerates axonal outgrowth and end organ reinnervation. This work has been translated clinically in a series of randomized clinical trials, which suggest that ES can be used as an efficacious therapy to improve patient outcomes following PNIs. The aim of this review is to discuss the cellular physiology and the limitations of regeneration after peripheral nerve injuries. The proposed mechanisms of ES protocols and how they facilitate nerve regeneration depending on timing of administration are outlined. Finally, future directions of research that may provide new perspectives on the optimal delivery of ES following PNI are discussed.

Exercise facilitates regeneration after severe nerve transection and further modulates neural plasticity

Patients with severe traumatic peripheral nerve injury (PNI) always suffer from incomplete recovery and poor functional outcome. Physical exercise-based rehabilitation, as a non-invasive interventional strategy, has been widely acknowledged to improve PNI recovery by promoting nerve regeneration and relieving pain. However, effects of exercise on chronic plastic changes following severe traumatic PNIs have been limitedly discussed. In this study, we created a long-gap sciatic nerve transection followed by autograft bridging in rats and tested the therapeutic functions of treadmill running with low intensity and late initiation. We demonstrated that treadmill running effectively facilitated nerve regeneration and prevented muscle atrophy and thus improved sensorimotor functions and walking performance. Furthermore, exercise could reduce inflammation at the injured nerve as well as prevent the overexpression of TRPV1, a pain sensor, in primary afferent sensory neurons. In the central nervous system, we found that PNI induced transcriptive changes at the ipsilateral lumber spinal dorsal horn, and exercise could reverse the differential expression for genes involved in the Notch signaling pathway. In addition, through neural imaging techniques, we found volumetric, microstructural, metabolite, and neuronal activity changes in supraspinal regions of interest (i.e., somatosensory cortex, motor cortex, hippocampus, etc.) after the PNI, some of which could be reversed through treadmill running. In summary, treadmill running with late initiation could promote recovery from long-gap nerve transection, and while it could reverse maladaptive plasticity after the PNI, exercise may also ameliorate comorbidities, such as chronic pain, mental depression, and anxiety in the long term.

Nerve implants with bioactive interfaces enhance neurite outgrowth and nerve regeneration in vivo

Nerve implants functionalized with growth factors and stem cells are critical to promote neurite outgrowth, regulate neurodifferentiation, and facilitate nerve regeneration. In this study, human umbilical cord mesenchymal stem cells (hUCMSCs) and 3,4-hydroxyphenalyalanine (DOPA)-containing insulin-like growth factor 1 (DOPA-IGF-1) were simultaneously applied to enhance the bioactivity of poly(lactide-co-glycolide) (PLGA) substrates which will be potentially utilized as nerve implants. In vitro and in vivo evaluations indicated that hUCMSCs and DOPA-IGF-1 could synergistically regulate neurite outgrowth of PC12 cells, improve intravital recovery of motor functions, and promote conduction of nerve electrical signals in vivo. The enhanced functional and structural nerve regeneration of injured spinal cord might be mainly attributable to the synergistically enhanced biofunctionality of hUCMSCs and DOPA-IGF-1/PLGA on the bioactive interfaces. Findings from this study demonstrate the potential of hUCMSC-seeded, DOPA-IGF-1-modified PLGA implants as promising candidates for promoting axonal regeneration and motor functional recovery in spinal cord injury treatment.

Muse cells decrease the neuroinflammatory response by modulating the proportion of M1 and M2 microglia in vitro

Neuroinflammation hinders repair of the central nervous system (CNS). Stem cell transplantation is a very promising approach for treatment of CNS injuries. However, it is difficult to select seed cells that can both facilitate nerve regeneration and improve the microenvironment in the CNS. In this study, we isolated multilineage-differentiating stress-enduring (Muse) cells from bone marrow mesenchymal stem cells. We explored the anti-inflammatory effect and mechanism of Muse cells in vitro by coculture of Muse cells with lipopolysaccharide-stimulated microglia. Our results showed that Muse cells effectively reduced the transcription and secretion of tumor necrosis factor α and interleukin-1β and increased the expression of transforming growth factor-β and interleukin-10 in microglia. In addition, Muse cells decreased the number of M1 microglia and increased the proportion of M2 microglia in an inflammatory environment more effectively than bone marrow mesenchymal stem cells. We also show that Muse cells inhibited the protein expression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein (MyD88) and inhibited the expression of the phosphorylated forms of transcription factor p65, nuclear factor (NF)-κB inhibitor alpha, and p38 mitogen-activated protein kinase (MAPK) in microglia. Therefore, we suggest Muse cells cause antineuroinflammatory effects by inhibition of the TLR4/MyD88/NF-κB and p38 MAPK signaling pathways in microglia. Our results shed light on the function of Muse cells in relation to CNS diseases and provide insight into the selection of seed cells.

Oriented nanofibrous P(MMD-co-LA)/Deferoxamine nerve scaffold facilitates peripheral nerve regeneration by regulating macrophage phenotype and revascularization

Delayed injured nerve regeneration remains a clinical problem, partly ascribing to the lack of regulation of regenerative microenvironment, topographical cues, and blood nourishment. Functional electrospun conduits have been established as an efficacious strategy to facilitate nerve regeneration by providing structural guidance, regulating the regenerative immune microenvironment, and improving vascular regeneration. However, the synthetic polymers conventionally used to fabricate electrospinning scaffolds, such as poly(L-lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid), can cause aseptic inflammation due to acidic degradation products. Therefore, a poly[3(S)-methyl-morpholine-2,5-dione-co-lactic] [P(MMD-co-LA)] containing alanine units with good mechanical properties and reduced acid degradation products, was obtained by melt ring-opening polymerization (ROP). Here, we aimed to explore the effect of oriented nanofiber/Deferoxamine (DFO, a hydrophilic angiogenic drug) scaffold in the rapid construction of a favorable regenerative microenvironment, including cell bridge, polarized vascular system, and immune microenvironment. In vitro studies have shown that the scaffold can sustainably release DFO, which accelerates the migration and tube formation of human umbilical vein endothelial cells (HUVECs), as well as the expression of genes related to angiogenesis. The physical clues provided by the arranged nanofibers can regulate the polarization of macrophages and reduce the expression of inflammatory factors. Furthermore, the in vivo results demonstrated a higher M2 polarization level of the oriented nanofibrous scaffold treatment group with reducedinflammation reaction in the injured nerve. Moreover, the in-situ release of DFO up-regulated the expression of HIF1-α and SDF-1α genes, as well as the expression of HIF1-α′s target gene VEGF, further promoting revascularization and enhancing nerve regeneration at the defect site. The obtained results provide essential insights on accelerating the creation of the nerve regeneration microenvironment by combining the physiological processes of nerve regeneration with topographical cues and chemical signal induction.

BMSC-derived extracellular matrix better optimizes the microenvironment to support nerve regeneration

A favorable microenvironment plays an important role in nerve regeneration. Extracellular matrix (ECM) derived from cultured cells or natural tissues can facilitate nerve regeneration in the presence of various microenvironmental cues, including biochemical, spatial, and biomechanical factors. This study, through proteomics and three-dimensional image analysis, determines that the components and spatial organization of the ECM secreted by bone marrow mesenchymal cells (BMSCs) are more similar to acellular nerves than those of the ECMs derived from Schwann cells (SCs), skin-derived precursor Schwann cells (SKP–SCs), or fibroblasts (FBs). ECM-modified nerve grafts (ECM-NGs) are engineered by co-cultivating BMSCs, SCs, FBs, SKP-SCs with well-designed nerve grafts used to bridge nerve defects. BMSC-ECM-NGs exhibit the most promising nerve repair properties based on the histology, neurophysiology, and behavioral analyses. The regeneration microenvironment formed by the ECM-NGs is also characterized by proteomics, and the advantages of BMSC-ECM-NGs are evidenced by the enhanced expression of factors related to neural regeneration and reduced immune response. Together, these findings indicate that BMSC-derived ECMs create a more superior microenvironment for nerve regeneration than that by the other ECMs and may, therefore, represent a potential alternative for the clinical repair of peripheral nerve defects.