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Attenuation of gastrocnemius muscle atrophy after ECH treatment. (A) Gross images of the isolated gastrocnemius muscles in each group. (B) The crosssectional view of the ipsilateral muscles highlighted by Masson's trichrome stain. (C-E) Statistical analysis of the (C) wet weight ratio of the gastrocnemius muscle, (D) percentage of muscle fiber, and (E) percentage of collagen deposits area (n = 3) (*p < 0.05, **p < 0.01, and ***p < 0.001).
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Conductive scaffolds have been shown to exert a therapeutic effect on patients suffering from peripheral nerve injuries (PNIs). However, conventional conductive conduits are made of rigid structures and have limited applications for impaired diabetic patients due to their mechanical mismatch with neural tissues and poor plasticity. We propose the de...
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... muscle atrophy can serve as an indicator of functional regeneration after a sciatic nerve injury [15]. Gross views of the gastrocnemius muscle revealed that the muscle of the injured side significantly atrophied in comparison to that of the contralateral side, especially in the PNI group (Fig. 7A). A histological examination was performed using MTS to conduct a gross observation of the target gastrocnemius muscle. Evident signs of atrophy, such as disordered muscle fibers and the existence of hyperplastic collagen fibers around them, were observed in the PNI group. However, these signs were significantly attenuated by the ...
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... signs of atrophy, such as disordered muscle fibers and the existence of hyperplastic collagen fibers around them, were observed in the PNI group. However, these signs were significantly attenuated by the improved nerve reinnervation in the ECH group, which demonstrated larger muscle fibers and smaller collagen deposits than the other groups (Fig. 7B). Greater muscle weight and fiber density further confirmed that the implantation of the ECH in the PNI model facilitated the recovery of muscle fibers (Fig. 7C and D). The percentage of collagen fiber area in the ECH group (5.9 ± 1.9%) was lower than that in the PNI group (14.3 ± 2.7%) (Fig. 7E). These results indicated that the ECH ...
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... these signs were significantly attenuated by the improved nerve reinnervation in the ECH group, which demonstrated larger muscle fibers and smaller collagen deposits than the other groups (Fig. 7B). Greater muscle weight and fiber density further confirmed that the implantation of the ECH in the PNI model facilitated the recovery of muscle fibers (Fig. 7C and D). The percentage of collagen fiber area in the ECH group (5.9 ± 1.9%) was lower than that in the PNI group (14.3 ± 2.7%) (Fig. 7E). These results indicated that the ECH treatment restored muscle function and morphology, in addition to reducing ...
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... and smaller collagen deposits than the other groups (Fig. 7B). Greater muscle weight and fiber density further confirmed that the implantation of the ECH in the PNI model facilitated the recovery of muscle fibers (Fig. 7C and D). The percentage of collagen fiber area in the ECH group (5.9 ± 1.9%) was lower than that in the PNI group (14.3 ± 2.7%) (Fig. 7E). These results indicated that the ECH treatment restored muscle function and morphology, in addition to reducing ...
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Over the years, electroconductive hydrogels (ECHs) have been extensively applied for stimulating nerve regeneration and restoring locomotor function after peripheral nerve injury (PNI) with diabetes, given their favorable mechanical and electrical properties identical to endogenous nerve tissue. Nevertheless, PNI causes the loss of locomotor functi...
Peripheral nerve injury is a challenging orthopedic condition that can be treated by autograft transplantation, a gold standard treatment in the current clinical setting. Nevertheless, limited availability of autografts and potential morbidities in donors hampers its widespread application. Bioactive scaffold‐based tissue engineering is a promising...
Schwann cells (SCs) dominate the regenerative behaviors after peripheral nerve injury by supporting axonal regrowth and remyelination. Previous reports also demonstrated that the existence of SCs is beneficial for nerve regeneration after traumatic injuries in central nervous system. Therefore, the transplantation of SCs/SC-like cells serves as a f...
Peripheral nerve regeneration after injury is still a clinical problem. The application of autologous nerve grafting, the gold standard treatment, is greatly restricted. Acellular nerve allografts (ANAs) are considered promising alternatives, but they are difficult to achieve satisfactory therapeutic outcomes, which may be attributed to their compa...
Peripheral nerve injury (PNI) is one of the public health concerns that can result in a loss of sensory or motor function in the areas in which injured and non-injured nerves come together. Up until now, there has been no optimized therapy for complete nerve regeneration after PNI. Exosome-based therapies are an emerging and effective therapeutic s...
Citations
... The protein expression that related to nerve regeneration, including NF200, NF-H, and S100 for sciatic nerves was analyzed with immunohistochemical and immunofluorescence staining. NF200 is a marker of myelinated A fiber neurons in rodent dorsal root ganglions (DRGs) [39,40], which represents regenerated neurofilaments and axons [41] and is expressed in all DRG neurons in humans [42]. S100-β is a calcium-binding protein found in glial cells [43], which has various homeostatic activities, including the regulation of cell proliferation and differentiation [44]. ...
Peripheral nerve injury (PNI) is a common and severe clinical disease worldwide, which leads to a poor prognosis because of the complicated treatments and high morbidity. Autologous nerve grafting as the gold standard still cannot meet the needs of clinical nerve transplantation because of its low availability and limited size. The development of artificial nerve conduits was led to a novel direction for PNI treatment, while most of the currently developed artificial nerve conduits was lack biochemical cues to promote nerve regeneration. In this study, we designed a novel composite neural conduit by inserting decellularized the rat sciatic nerve or kidney in a poly (lactic-co-glycolic acid) (PLGA) grooved conduit. The nerve regeneration effect of all samples was analyzed using rat sciatic nerve defect model, where decellularized tissues and grooved PLGA conduit alone were used as controls. The degree of nerve regeneration was evaluated using the motor function, gastrocnemius recovery, and morphological and histological assessments suggested that the combination of a grooved conduit with decellularized tissues significantly promoted nerve regeneration compared with decellularized tissues and PLGA conduit alone. It is worth to note that the grooved conduits containing decellularized nerves have a promotive effect similar to that of autologous nerve grafting, suggesting that it could be an artificial nerve conduit used for clinical practice in the future.
Graphical Abstract
... Увага багатьох сучасних дослідників спрямована на вдосконалення методів лікування та регенерації периферичних нервів після травм [16,17]. ...
Aim: to analyze modern professional literature and summarize data on treatment methods for peripheral nerve injuries, taking into account the mechanisms of positive effects.
The article presents an overview of possible methods for treatment of peripheral nerve injuries, fundamental classifications of peripheral nerve injuries, their differences are considered, pathophysiological mechanisms and the probability of spontaneous recovery depending on the degree of injury, general principles and conditions for successful regeneration of the peripheral nerve. Options, combinations, advantages and disadvantages of such surgical methods for peripheral nerve injury treatment as neurorrhaphy, autotransplantation and allotransplantation are described in detail, such terms as “small”, “large” and “critical” gaps between the nerve stumps are specified. Classifications and characteristics of conduits are described, types of synthetic conduits are considered. The use of drugs, Schwann cells, growth and neurotrophic factors, neural, embryonic and mesenchymal stem cells of various origins, exosomes of mesenchymal stem cells in the so-called “stem cell-free therapy” in treating this pathology is mentioned. Genetically modified mesenchymal stem cells, optokinetics are also noted, such physical methods for peripheral nerve injury treatment as short-term low-frequency electrical stimulation of the nerve, magnetic stimulation, low-intensity ultrasound, photobiomodulation therapy, photochemical bonding are discussed, indicating some mechanisms of their positive effects.
Conclusions. Improving the quality of life and reducing the degree of disability in patients with injuries of the main nerve trunks depends on the combined use of a number of surgical, bioengineering and regenerative technologies. These involve the restoration of the anatomical continuity of the nerve, including through the use of natural or artificial elements, cellular technologies and the management of regenerative processes. Therefore, every time, a surgeon is facing a major challenge to create a combination of various means from the indicated basic components for the treatment of nerve damage in managing a particular patient. However, such a treatment approach requires proper competences of surgeons as well as specific material and technical bases in order to bring down the level of social tension in patients with injuries of the main nerve trunks.
... Peripheral nerve injury (PNI) is still a major cause of physical disability that may lead to different sensory and motor dysfunction levels, resulting in a reduced quality of life and a heavy burden on the healthcare system [1,2]. Peripheral nerve repair is often more challenging in diabetics attributed to long-term insulin resistance, hyperglycemia, and microvessel complications exacerbating axon degeneration, segmental demyelination, delayed regeneration of impaired nerves, and even denervated muscle atrophy [1,3,4]. Different approaches are indicated depending on the type and extent of PNI, including pharmaceuticals, decompression, neurorrhaphy, and grafting (allografts and autografts) [5][6][7][8]. ...
... The past few years have witnessed a burgeoning interest in biocompatible electroconductive hydrogels (ECHs) with electroconductive and soft mechanical properties compatible with endogenous nerve tissue to enhance neuronal differentiation and axonal regeneration [3,[13][14][15]. It is widely acknowledged that electrical signals are crucial for nerve regrowth, remyelination and maturation in the innate nervous system [3,[13][14][15][16]. ...
... The past few years have witnessed a burgeoning interest in biocompatible electroconductive hydrogels (ECHs) with electroconductive and soft mechanical properties compatible with endogenous nerve tissue to enhance neuronal differentiation and axonal regeneration [3,[13][14][15]. It is widely acknowledged that electrical signals are crucial for nerve regrowth, remyelination and maturation in the innate nervous system [3,[13][14][15][16]. Combining electrically conductive components with a hydrophilic matrix into the extracellular environment is able to promote the intercellular transduction of electric signals [3,[13][14][15]. ...
In recent years, electroconductive hydrogels (ECHs) have shown great potential in promoting nerve regeneration and motor function recovery following diabetic peripheral nerve injury (PNI), attributed to their similar electrical and mechanical characteristics to innate nervous tissue. It is well-established that PNI causes motor deficits and pain, especially in diabetics. Current evidence suggests that ropivacaine (ROP) encapsulated in poly lactic-co-glycolic acid (PLGA) microspheres (MSs) yield a sustained analgesic effect. In this study, an ECH electroconductive network loaded with MS/ROP (ECH-MS/ROP) was designed as a promising therapeutic approach for diabetic PNI to exert lasting analgesia and functional recovery. This dual delivery system allowed ROP's slow and sequential release, achieving sustained analgesia as demonstrated by our in vivo experiments. Meanwhile, this system was designed like a lamellar dressing, with desirable adhesive and self-curling properties, convenient for treating injured nerve tissues via automatically wrapping tube-like structures, facilitating the process of implantation. Our in vitro assays verified that ECH-MS/ROP was able to enhance the adhesion and motility of Schwann cells. Besides, both in vitro and in vivo studies substantiated that ECH-MS/ROP stimulated myelinated axon regeneration through the MEK/ERK signaling pathway, thereby improving muscular denervation atrophy and facilitating functional recovery. Therefore, this study suggests that the ECH-MS/ROP dressing provides a promising strategy for treating diabetic PNI to facilitate nerve regeneration, functional recovery and pain relief.
... Conductive hydrogels are multifunctional biomaterials that have a number of advantages as nerve regeneration scaffolds, including a three-dimensional porous network suitable for cells adhesion, proliferation and migration, adjustable electrical and mechanical properties, high water absorption capacity, biodegradability, biocompatibility, and low immunogenicity (80,(97)(98)(99)(100). Bu et al. fabricated electroconductive hydrogel of carboxymethyl chitosan (CMC), sodium alginate (SA), and PPy via the chemical cross-linking method. ...
Recent Progress in Conductive Biomaterials for Tissue Engineering. Intrinsically conducting polymers and their derivatives are being employed in tissue engineering due to their promising electrical conductivity as bioactive scaffolds for tissue regeneration (i.e., bone, nerve, muscle and cardiac tissue engineering and wound healing). Nevertheless, their mechanical brittleness and poor processability limit their applications, resulting in the development of composites, which are based on conductive polymers. The main objective of this book is to summarize and review the preparation methods; physicochemical and mechanical properties; biological properties; and latest advances of both conductive polymers and their composites for tissue engineering applications. Researchers, scientists, and upper level students working in the areas of biomedical engineering, polymers, and biomaterials science will find Electrically Conducting Polymers and Their Composites for Tissue Engineering to be an essential reference.
... PPy can be synthesized chemically or electrochemically, and it has good biocompatibility and a noninflammatory response after long-term implantation in the body [42,43]. Liu et al. [44] developed a soft, viscous CH film with good biocompatibility. The hydrogel dressing was constructed by crosslinking PPy and tannic acid (TA) under the action of an oxidation initiator (FeCl 3 ) (Fig. 1A). ...
... (E) Morphology and self-healing properties of hydrogels at different temperatures and application to zebrafish brain injury for treatment. Reused with permission [44]. Copyright, Elsevier Ltd. (2021). ...
Peripheral nerve injury (PNI) is a complex disease that often appears in young adults. It is characterized by a high incidence, limited treatment options, and poor clinical outcomes. This disease not only causes dysfunction and psychological disorders in patients but also brings a heavy burden to the society. Currently, autologous nerve grafting is the gold standard in clinical treatment, but complications, such as the limited source of donor tissue and scar tissue formation, often further limit the therapeutic effect. Recently, a growing number of studies have used tissue-engineered materials to create a natural microenvironment similar to the nervous system and thus promote the regeneration of neural tissue and the recovery of impaired neural function with promising results. Hydrogels are often used as materials for the culture and differentiation of neurogenic cells due to their unique physical and chemical properties. Hydrogels can provide three-dimensional hydration networks that can be integrated into a variety of sizes and shapes to suit the morphology of neural tissues. In this review, we discuss the recent advances of engineered hydrogels for peripheral nerve repair and analyze the role of several different therapeutic strategies of hydrogels in PNI through the application characteristics of hydrogels in nerve tissue engineering (NTE). Furthermore, the prospects and challenges of the application of hydrogels in the treatment of PNI are also discussed.
... Peer review under responsibility of KeAi Communications Co., Ltd. patients due to persistent hyperglycemia, insulin resistance, and microvascular complications aggravating segmental axon demyelination, slow regeneration of damaged nerves, and even muscular atrophy [3][4][5]. The current clinical treatments for PNI include pharmacological and surgical methods (mainly decompression, neurorrhaphy and nerve grafting) [2,[6][7][8][9][10]. ...
... It has been established that electrical signals in the nervous system play a vital role in neural regeneration, development, remyelination and maturation [5,[15][16][17][18]. In recent years, biocompatible electroconductive hydrogels with soft mechanical properties and electroconductive characteristics similar to native nerve tissue have been designed and shown great potential in promoting neuronal differentiation and axonal regrowth by providing a favorable three-dimensional (3D) biomimetic extracellular matrix (ECM) [5,[15][16][17]. ...
... It has been established that electrical signals in the nervous system play a vital role in neural regeneration, development, remyelination and maturation [5,[15][16][17][18]. In recent years, biocompatible electroconductive hydrogels with soft mechanical properties and electroconductive characteristics similar to native nerve tissue have been designed and shown great potential in promoting neuronal differentiation and axonal regrowth by providing a favorable three-dimensional (3D) biomimetic extracellular matrix (ECM) [5,[15][16][17]. Accordingly, combining a hydrophilic matrix with electroconductive components into the extracellular microenvironment can enhance the transmission of intercellular electrical signals [5,[15][16][17]. ...
Over the years, electroconductive hydrogels (ECHs) have been extensively applied for stimulating nerve regeneration and restoring locomotor function after peripheral nerve injury (PNI) with diabetes, given their favorable mechanical and electrical properties identical to endogenous nerve tissue. Nevertheless, PNI causes the loss of locomotor function and inflammatory pain, especially in diabetic patients. It has been established that bone marrow stem cells-derived exosomes (BMSCs-Exos) have analgesic, anti-inflammatory and tissue regeneration properties. Herein, we designed an ECH loaded with BMSCs-Exos (ECH-Exos) electroconductive nerve dressing to treat diabetic PNI to achieve functional recovery and pain relief. Given its potent adhesive and self-healing properties, this laminar dressing is convenient for the treatment of damaged nerve fibers by automatically wrapping around them to form a size-matched tube-like structure, avoiding the cumbersome implantation process. Our in vitro studies showed that ECH-Exos could facilitate the attachment and migration of Schwann cells. Meanwhile, Exos in this system could modulate M2 macrophage polarization via the NF-κB pathway, thereby attenuating inflammatory pain in diabetic PNI. Additionally, ECH-Exos enhanced myelinated axonal regeneration via the MEK/ERK pathway in vitro and in vivo, consequently ameliorating muscle denervation atrophy and further promoting functional restoration. Our findings suggest that the ECH-Exos system has huge prospects for nerve regeneration, functional restoration and pain relief in patients with diabetic PNI.
... In this material, PUAO is a highly porous cryogel with sustained oxygen releasing properties and can reduce oxidative stress. Liu C et al. (2021) developed a biocompatible conductive hydrogel (ECH) that can promote axonal regeneration and myelin regeneration through the MEK/ERK pathway, as well as the proliferation of Schwann cells, which provide metabolic support to regenerating axons. The results demonstrated that this type of hydrogel is an effective treatment for nerve regeneration in diabetic nerve injury. ...
Due to recalcitrant microangiopathy and chronic infection, traditional treatments do not easily produce satisfactory results for chronic diabetic ulcers. In recent years, due to the advantages of high biocompatibility and modifiability, an increasing number of hydrogel materials have been applied to the treatment of chronic wounds in diabetic patients. Research on composite hydrogels has received increasing attention since loading different components can greatly increase the ability of composite hydrogels to treat chronic diabetic wounds. This review summarizes and details a variety of newly loaded components currently used in hydrogel composites for the treatment of chronic diabetic ulcers, such as polymer/polysaccharides/organic chemicals, stem cells/exosomes/progenitor cells, chelating agents/metal ions, plant extracts, proteins (cytokines/peptides/enzymes) and nucleoside products, and medicines/drugs, to help researchers understand the characteristics of these components in the treatment of diabetic chronic wounds. This review also discusses a number of components that have not yet been applied but have the potential to be loaded into hydrogels, all of which play roles in the biomedical field and may become important loading components in the future. This review provides a “loading component shelf” for researchers of composite hydrogels and a theoretical basis for the future construction of “all-in-one” hydrogels.
... Schiff base bond N,O-carboxymethyl chitosan (N,O-CMCS)-guar gum-base 2021 anticancer drug delivery [23] chitosan-aniline tetramer (CS-AT) and PEG double aldehyde PEG-DA 2016 cardiac cell therapy [24] glycol chitosan and telechelic difunctional poly(ethylene glycol) (DF-PEG) 2015 zebrafish embryo neural injury model CNS injury treatment [25] Catechol-conjugated chitosan (CHI-C) and dialdehyde cellulose nanocrystal (DACNC) 2021 mouse liver injury model, mouse tail amputation model, and rabbit ilium bone defect model. bone defect treatment [26] Diels-Alder bond HA, furylamine amine groups and adipic dihydrazide (ADH) 2015 cartilage engineering [27] Coordination interaction HA-BP, acrylated bisphosphonate (Ac-BP), and MgCl 2 2017 osteogenesis stem cell therapy [28] 3-carboxy-phenylboronic acid, gelatin, and vancomycin-conjugated silver nanoclusters 2021 mouse hemorrhaging liver model, chronically infected wound in a diabetic mouse model wound treatment [29] hyaluronic acid-graft-dopamine (HA-DA) and reduced graphene oxide (rGO) 2019 mouse full-thickness wound model wound treatment [30] tannic acid, TA, PPy, and Fe3+ 2021 diabetic sciatic nerve injury model peripheral nerve injury [31] isoguanosine-borate-guanosine (isoGBG) 2020 OSCC xenograft mouse model cancer therapy [32] Dynamic imine bond glycol chitosan and poly(N-isopropylacrylamide)-co-poly(acrylic acid) (DF poly(NIPAM-co-AA)) 2016 drug delivery and 3D cell cultivation [33] Π-π stacking interactions Fmoc-grafted chitosan (FC) and Fmoc peptidelaminin-derived peptide IKVAV (FI) 2021 spinal cord transection rat model spinal cord injury treatment [34] Hydrogen bonds supramolecular ureido-pyrimidinone (UPy) and (PEG) chains 2013 chronic myocardial infarction pig model infarcted myocardium treatment [35] Hydrogen bonding, hydrophobic and coordination interaction poly(glycerol sebacate)-co-poly(ethylene glycol) (PEGSD)and UPy-HDI synthon modified gelatin (GTU) 2020 rabbit ear artery bleeding model; full-thickness rat skin incision model wound treatment [36] Schiff base and coordination interaction (Fe), protocatechualdehyde (PA) and quaternized chitosan (QCS) 2021 rat skin incision model and infected full-thickness skin wound model [37] aminated gelatin (AG)-oxidized hyaluronic acid (OD-Fe(III)) 2021 ...
... The highly aligned porous microstructures and interfacial interaction promoted cell attachment such that Schwann cells could spread out in good stretching state with strong interconnectivity and distribute to the denuded area. The biocompatible electroconductive hydrogel led to significant improvement in nerve regeneration and muscle function retention in peripheral nerve-injured animals [31]. ...
A hydrogel is a three-dimensional structure that holds plenty of water, but brittleness largely limits its application. Self-healing hydrogels, a new type of hydrogel that can be repaired by itself after external damage, have exhibited better fatigue resistance, reusability, hydrophilicity, and responsiveness to environmental stimuli. The past decade has seen rapid progress in self-healing hydrogels. Self-healing hydrogels can automatically self-repair after external damage. Different strategies have been proposed, including dynamic covalent bonds and reversible noncovalent interactions. Compared to traditional hydrogels, self-healing gels have better durability, responsiveness, and plasticity. These features allow the hydrogel to survive in harsh environments or even to be injected as a drug carrier. Here, we summarize the common strategies for designing self-healing hydrogels and their potential applications in clinical practice.
... For solving this problem, Liu et al. successfully prepared a self-coiling conductive hydrogel by compounding PPy for diabetic nerve repair. 61 The hydrogel exhibited both ionic and electronic conductivity because of the introduction of PPy and Fe 3+ and it was crosslinked through physical interaction. The flexible conductive hydrogel has good adhesion and self-healing to the damaged nerve and can spontaneously twist into a tubular structure, and thus the nerve repair material can easily adhere to the damaged nerve perfectly. ...
Conductive hydrogels have recently attracted considerable attention as a class of soft medical materials with high water content to mimic the electrophysiological environment of biological tissues for tissue repair applications.
... However, it is still difficult to achieve similar effects to those of autologous implants [10]. Therefore, it is necessary to conduct further explorations on peripheral nerve implants with optimal performance for nerve repair and regeneration [11,12]. ...
Background
Anisotropic topologies are known to regulate cell-oriented growth and induce cell differentiation, which is conducive to accelerating nerve regeneration, while co-culture of endothelial cells (ECs) and Schwann cells (SCs) can significantly promote the axon growth of dorsal root ganglion (DRG). However, the synergistic regulation of EC and SC co-culture of DRG behavior on anisotropic topologies is still rarely reported. The study aims to investigate the effect of anisotropic topology co-cultured with Schwann cells and endothelial cells on dorsal root ganglion behavior for promoting peripheral nerve regeneration.
Methods
Chitosan/artemisia sphaerocephala (CS/AS) scaffolds with anisotropic topology were first prepared using micro-molding technology, and then the surface was modified with dopamine to facilitate cell adhesion and growth. The physical and chemical properties of the scaffolds were characterized through morphology, wettability, surface roughness and component variation. SCs and ECs were co-cultured with DRG cells on anisotropic topology scaffolds to evaluate the axon growth behavior.
Results
Dopamine-modified topological CS/AS scaffolds had good hydrophilicity and provided an appropriate environment for cell growth. Cellular immunofluorescence showed that in contrast to DRG growth alone, co-culture of SCs and ECs could not only promote the growth of DRG axons, but also offered a stronger guidance for orientation growth of neurons, which could effectively prevent axons from tangling and knotting, and thus may significantly inhibit neurofibroma formation. Moreover, the co-culture of SCs and ECs could promote the release of nerve growth factor and vascular endothelial growth factor, and up-regulate genes relevant to cell proliferation, myelination and skeletal development via the PI3K-Akt, MAPK and cytokine and receptor chemokine pathways.
Conclusions
The co-culture of SCs and ECs significantly improved the growth behavior of DRG on anisotropic topological scaffolds, which may provide an important basis for the development of nerve grafts in peripheral nerve regeneration.
