Smart-responsive electrospun scaffolds (SRES) for neural repair: Recent advances and future prospects

Abstract

Neurological injuries trigger complex, multi-stage pathological cascades, while traditional clinical interventions such as drug therapy and surgical decompression can only alleviate symptoms rather than reconstruct damaged neural circuits. Conventional repair approaches face multiple limitations, including the inherently weak regenerative ability of central nervous neurons, glial scar formation post-injury, shortage of autologous nerve grafts, donor site secondary trauma and tissue size mismatch, which urgently demand novel regenerative therapeutic strategies. Tissue-engineered artificial nerve implants have opened new avenues for neural repair, among which smart-responsive electrospun scaffolds (SRES) stand out for their unique biomimetic advantage of actively sensing pathological microenvironment signals and dynamically modulating local repair conditions, greatly expanding the development of neural regenerative medicine. Benefiting from electrospinning technology, SRES have been developed targeting traumatic brain injury (TBI), spinal cord injury (SCI) and peripheral nerve injury (PNI), which realize spatiotemporally controllable drug release, biomimetic extracellular matrix construction and in-situ neuromodulation. However, a comprehensive and systematic review that integrates these scattered advancements to provide guidance for researchers remains absent. This review firstly elaborates the pathological characteristics of three typical neural injuries (TBI, SCI, PNI) and the endogenous self-repair defects of neural tissues. Afterwards, it systematically summarizes the classification of electrospinning technologies, fabrication methodologies, responsive mechanisms, and classifications of SRES, further focuses on their recent application progress in neural regeneration via bibliometric big data analysis over the past decade, critically analyzes current limitations and prospective research trends, and underscores the necessity of developing tailored electrospun smart-responsive materials, thereby offering an authoritative reference for advancing neural regeneration engineering and regenerative medicine.

Graphical abstract

Highlights

• •Fabrication, response mechanisms and categories of smart-responsive electrospun scaffolds (SRES) are summarized.
• •Application progress in neural regeneration, including SCI, TBI and PNI of SRES for neural regeneration are emphasized and discussed.
• •The current limitations and prospective research directions of SRES in nerve regeneration are highlighted.
• •The review will provide important reference for SRES in advancing neural regeneration engineering and regenerative medicine.

1. Introduction

Nerve injury refers to structural and functional damage to the central nervous system (CNS) and peripheral nervous system (PNS) resulting from external forces, diseases, or other causes [1]. Such injuries can result in permanent impairments in patient sensation, functional movement, cognition, and autonomic functions, severely compromising patients’ quality of life [2,3]. Clinically, prevalent neurological injuries encompass traumatic brain injury [4](TBI), spinal cord injury [5](SCI), and peripheral nerve injury [6,7](PNI). Owing to their intricate pathophysiological processes, current pharmacological and surgical methods are only partially effective and fail to achieve the desired curative outcomes [8]. Therefore, traditional therapeutic approaches have limitations in addressing the complexity of the regeneration of different neural tissues, urgently demanding innovative solutions.

Tissue-engineered artificial nerve scaffolds have inaugurated novel avenues for nerve repair and regeneration [9]. Artificial nerve scaffolds serve a critical role in nerve regeneration and repair as an alternative therapy, by providing structural support, enhancing cellular attachment and directed motility, and guiding nerve growth, obviating the need for secondary surgeries and donor nerve tissue [10]. Among these, various fabrication techniques for tissue-engineered nerve grafts exist, such as 3D printing [11], freeze-drying [12], micromolding [13], and electrospinning [14]. Notably, electrospun scaffolds constructed via electrospinning technology have attracted significant attention due to the precise control this technique offers over mechanical properties, biocompatibility, and surface micro-topography to mimic the cellular microenvironment. These elements collectively orchestrate an ideal microenvironment conducive to neural tissue regeneration [15]. The fibrous arrays generated by the electrospinning process possess an extensive specific surface area. This characteristic substantially enhances the loading density of bioactive factors, thereby influencing fundamental cellular functions, including adhesion and migration. Coupled with the remarkable versatility demonstrated by electrospinning polymer materials, which are capable of delivering a broad spectrum of therapeutic agents ranging from small-molecule drugs to macromolecular proteins, this synergy enables the rapid advancement of tailored intervention strategies to accelerate nerve repair and regeneration while concurrently mitigating the initiation and progression of wound inflammation, thereby attracting extensive interest [16]. Furthermore, electrospinning technology has been widely applied in various biomedical fields beyond neural tissue engineering [17], including wound dressings [18], drug delivery [19], bone tissue engineering [20], and cardiovascular repair [21]. These diverse applications demonstrate the versatility of electrospinning technology in fabricating nanofibrous scaffolds with tunable porosity, high specific surface area, and biomimetic extracellular matrix structures, thereby offering new insights into its application in neural tissue repair [22,23], as illustrated in Fig. 1.

Fig. 1.

Smart-responsive electrospun scaffolds (SRES) for neural repair and application.

However, traditional electrospun fibrous scaffolds possess inherent drawbacks including limited drug loading capacity, uncontrollable drug release behavior for neural injury treatment, and passive responsive therapy [24]. The above limitations render the scaffolds unable to actively adapt to the dynamic microenvironment demands at different stages of neural regeneration [25,26]. Notably, regardless of the biomimetic topological structure or fabrication process adopted, various neural scaffolds lacking smart-responsive regulation capability exhibit limited repair efficacy in the repair of different types of long-duration nerve injuries, failing to achieve the expected therapeutic outcomes [27]. Given that the aforementioned passive release strategies struggle to realize spatiotemporal precise regulation of therapeutic factors at different stages of neural regeneration, it is urgent to construct a dynamic delivery system capable of actively sensing and responding to microenvironment changes. Smart-responsive electrospun materials refer to a class of materials that can sense and respond to external environmental changes, thereby producing corresponding changes in structure, property, or function [28]. Combining this characteristic with electrospinning technology can create dynamic, biomimetic smart scaffolds for neural tissue engineering to address the shortcomings of traditional static scaffolds [29]. It upgrades neural scaffolds from static structures to dynamic smart-responsive systems, capable of actively responding to and regulating the local microenvironment, thereby holding promise to precisely match the complex demands at different stages of neural regeneration [28]. The application of smart responsiveness of scaffold materials in tissue engineering can significantly improve the adaptability of tissue engineering scaffolds, making them more suitable for the complex in vivo environment and promoting tissue regeneration and repair [29]. Therefore, adjusting their chemical and mechanical properties in response to changes in physiological parameters and exogenous stimuli, and responding to biological, chemical, and physical cues, various types of neural scaffolds based on smart responsiveness have garnered widespread attention and research exploration [29,30]. The main types adopted include: magnetically-controlled smart-responsive, temperature smart-responsive, light-controlled smart-responsive, electrical smart-responsive, ultrasound-controlled smart-responsive, and other novel smart-responsive tissue-engineered neural scaffolds with multifunctional synergy, which, through smart control response, actively sense and respond to microenvironment changes, thereby achieving the effect of promoting neural tissue regeneration [31,32]. However, to date, reviews concerning electrospinning-related smart-responsive neural scaffolds for neural regeneration have been rarely reported [14,33]. Therefore, this review outlines the different types of nerve injuries, nerve injury repair methods, principles and classifications of different electrospinning techniques, construction methods of biomimetic anisotropic topography and the importance of their rational application, as well as the advantages, disadvantages, and selection principles of natural or synthetic electrospun materials. It emphatically introduces the challenges and cutting-edge advances of various SRES for different types of nerve injuries, and based on big data analysis, discusses the current deficiencies and future research directions of SRES applied in the field of neural regeneration. (Fig. 1).

Furthermore, the literature search strategy and selection criteria of this review are as follows. A systematic literature search was performed using the PubMed, Web of Science, and Scopus databases up to December 2026. The search strategy combined the following keywords and their synonyms using Boolean operators: “Electrospinning,” “Nerve Regeneration,” “Smart-Responsive,” “Tissue Engineering,” “Scaffolds,” “smart-responsive electrospun scaffolds,” “neural tissue engineering,” “spinal cord injury,” “peripheral nerve injury,” “traumatic brain injury,” “piezoelectric,” and “magnetoelectric.” Only peer-reviewed original research articles and reviews written in English were considered. Inclusion criteria were: (i) studies focusing on electrospun scaffolds with defined smart-responsive properties (e.g., piezoelectric, magnetoelectric, thermally responsive, or photo-responsive) for neural repair applications (including SCI and TBI); (ii) in vitro and/or in vivo investigations reporting functional outcomes related to nerve regeneration. Exclusion criteria comprised non-English articles, conference abstracts, book chapters, patents, and studies without explicit smart-responsive mechanisms.

2. Neural tissue and injury

2.1. TBI

The CNS is composed of the brain and spinal cord, serving as the primary regulatory center for various bodily functions [34]. The brain is located within the cranial cavity and protected by the skull [35]. It is a soft organ that works in coordination with the spinal cord, which connects the brain to the rest of the body and extends from the brainstem to the lumbar vertebrae [36,37]. Both the brain and the spinal cord are composed of white matter and gray matter: white matter is made up of bundles of myelinated axons, while gray matter consists of neuronal cell bodies and dendrites [38]. The distribution positions of white matter and gray matter in the brain and spinal cord are different: as shown in Fig. 2A, the organizational structure of the CNS includes the brain and spinal cord, the histology and main parts of the brain, the cross-section of the spinal cord shows sensory and motor pathways, as well as the main neurons and glial cells in the CNS tissues [39]. In the brain, white matter is located in the inner part, while gray matter is distributed on the outer surface; in the spinal cord, by contrast, gray matter lies in the inner part and white matter is situated on the outer surface [37]. TBI refers to brain tissue damage caused by impact or blow to the head [41]. TBI can be categorized into primary injury and secondary injury based on the time of occurrence [37]. The fundamental cause of primary injury is the direct impact of external mechanical force, which leads to conditions such as concussion, cerebral contusion and laceration, diffuse axonal injury, primary intracranial hematoma (e.g., some cases of epidural hematoma), and skull fracture [30,37]. Primary injury is irreversible and can only be avoided through preventive measures. In contrast, secondary injury refers to a series of subsequent pathological processes, including cerebral edema, cerebral ischemia, increased intracranial pressure, excitotoxicity, calcium overload, free radical damage, inflammatory response, and mitochondrial dysfunction [42].

Fig. 2.

Nerve Tissues (A) Schematic diagram of the organizational structure of the CNS composed of the brain and spinal cord [39]. Copyright 2024, Elsevier. (B) Schematic diagram of the biological events occurring after SCI and the methods for nerve injury repair [40]. Copyright 2024, Wiley. (C) Distribution of peripheral nerves of the PNS in the human body, including the cross-section of the spinal cord connected to DRG, the connective tissue of peripheral nerves, the cross-section of the perineurium showing blood vessels, endoneurium and axons, and the main components of axons [39]. Copyright 2024, Elsevier.

2.2. SCI

SCI and TBI both belong to central nervous system injuries, but SCI, in terms of anatomical structure, post-injury pathological evolution, and repair obstacles, exhibits both commonalities and significant differences [43,44]. The spinal cord is a key structure of the CNS, responsible for transmitting information between the brain and peripheral nerves and executing reflex activities [45,46]. SCI refers to damage to the structure or function of the spinal cord due to various causes, resulting in motor, sensory, and autonomic nervous dysfunction below the level of injury. Its main causes can be divided into two broad categories: traumatic causes are the most common etiological factors, typically triggered by events such as traffic accidents, high falls, violent impacts, and sports injuries, leading to vertebral fractures or dislocations that compress or damage the spinal cord. Non-traumatic causes include tumor compression, vascular diseases such as arteriovenous malformations or infarction, infectious diseases, degenerative spinal disorders, and congenital malformations. Among the global annual new cases of spinal cord injury, young and middle-aged adults account for the majority, with approximately 40% of patients injured due to traffic accidents [47]. After the spinal cord tissue is damaged, in addition to the lack of nutritional support and the inherently limited self-repair ability of the CNS, secondary events that occur post-injury—such as vascular injury, inflammation and scar formation—further hinder the reconstruction of original axonal connections, thus precluding the possibility of spontaneous regeneration [48]. In addition, studies on SCI animal models have confirmed that the cascade of primary and secondary injuries following traumatic SCI in adult mammals gradually alters the cellular composition and structural architecture of the injured spinal cord tissue, ultimately creating a non-permissive microenvironment at the lesion site that inhibits axonal regeneration [49]. As illustrated in Fig. 2B of the biological events occurring after SCI. Therefore, there is an urgent need to explore effective alternative approaches that can enhance the regenerative capacity of the injured spinal cord [50].

2.3. PNI

The PNS is composed of multiple branches that originate from cranial nerves, spinal nerves, and ganglia, innervating all regions of the body [[51], [52], [53]]. Functionally, its neurons can be classified into sensory neurons, motor neurons, and mixed neurons [54]. The cell bodies of sensory neurons are located adjacent to the dorsal root ganglia (DRG) of the spinal cord or within cranial ganglia, whereas the cell bodies of motor neurons reside in the CNS [55,56]. As shown in Fig. 2C of the distribution of peripheral nerves in the human body, the cross-section of the spinal cord connected to the DRG, the connective tissue of peripheral nerves, the cross-section of the perineurium showing blood vessels, endoneurium, and axons, as well as the main components of axons including SCs, nodes of Ranvier, and myelin sheaths [39,[56], [57], [58]].

Therefore, the health of the PNS is particularly crucial for maintaining normal bodily functions [59]. PNI refers to damage to nerves outside the CNS, which may lead to sensory and motor dysfunction and sometimes involve autonomic nerve function [60]. The more refined extended Sunderland classification further subdivides these injuries into five grades. Among them, Grade Ⅰ (conduction block) and Grade Ⅱ (axonal disruption with intact endoneurium) correspond to the first two types in the Seddon classification, with favorable prognosis [61]. In contrast, Grade Ⅲ (endoneurial disruption), Grade Ⅳ (perineurial disruption with only intact epineurium), and Grade Ⅴ (complete nerve transection) are associated with difficult regeneration due to internal scarring or complete severance, often necessitating surgical intervention [60,62]. For peripheral nerve defects, conventional direct surgical suture repair can be applied to treat short-segment defects. However, directly suturing large nerve defect gaps will result in excessive tension at the suture line and poor surgical outcomes, failing to achieve the desired therapeutic effect [63]. The treatment of PNI has long been a tough and challenging problem in clinical practice [64]. Autologous nerve transplantation is regarded as the gold standard for repairing peripheral nerve defects [65]. To date, autologous nerve grafts have demonstrated the best nerve regeneration efficacy. Nevertheless, the application of autologous nerve transplantation is subject to multiple limitations, such as insufficient donor sources, secondary trauma caused by the additional surgery required to harvest the graft tissue, and potential discrepancies in tissue size and structure [66]. There is an urgent need to develop new therapeutic approaches to replace autologous nerve transplantation [67].

3. Repair of nerve tissue injury

3.1. Repair of TBI

TBI is a life-threatening neurological trauma caused by external factors [68]. Following injury, the central nervous system possesses an intrinsic, yet extremely limited and inefficient, self-repair mechanism, which involves the activation of endogenous neural stem/progenitor cells in the subventricular zone and the dentate gyrus of the hippocampus [69]. After injury occurs, the proliferation rate of cells in these regions accelerates, and the newly generated neural precursor cells attempt to migrate toward the injured area and differentiate into neurons or glial cells to replace some of the damaged cells [70]. Meanwhile, angiogenesis and glial cell responses are initiated locally at the injury site: microglia and astrocytes aggregate to form a “glial scar”. This structure exhibits dual properties—its physical barrier effect and secreted inhibitory molecules can restrict the expansion of injury in the short term, but in the long run, they severely impede axonal regeneration and the reconstruction of neural connections. In addition, the injured area transiently upregulates a variety of neurotrophic factors, attempting to support neuronal survival.

However, this entire set of self-repair mechanisms has fundamental flaws: the number of newly generated neurons is extremely small, and their long-distance migration efficiency is low, making it difficult for them to accurately reach and integrate into the damaged complex neural circuits. In the harsh post-injury microenvironment such as persistent inflammation, ischemia, and excitotoxicity, the vast majority of newborn cells cannot survive long-term or mature into functional neurons. More critically, mature central neurons inherently possess extremely weak axonal regeneration ability. Therefore, despite the aforementioned endogenous repair attempts, the brain cannot effectively reconstruct the damaged neural structures relying solely on its own capacity, leading to extremely limited functional recovery and essentially no self-regeneration ability [71]. In the United States, more than 500,000 hospitalizations annually are attributed to acquired brain injury, with patients afflicted by disabilities caused by TBI [72]. Patients with TBI often suffer from impairments in memory, motor function, and cognition. In severe cases, TBI can be fatal [73]. Due to the inability of mature neurons to regenerate, restoring function after TBI is usually extremely challenging. Numerous studies have focused on neural stem cell (NSC) transplantation, fetal tissue explantation, and more recently, brain organoids [[74], [75], [76]]. Nevertheless, these research endeavors frequently encounter issues such as immune rejection, low cell viability, insufficient neuronal differentiation, and significant batch-to-batch variability [[74], [75], [76]]. Adult neurogenesis has been identified in the subventricular zone (SVZ), which lines the lateral ventricles, offering substantial therapeutic promise for regenerating lost tissue. Following brain injury, the proliferation rate of SVZ cells increases, and newly generated neurons actively migrate to the TBI-affected area, indicating the potential for intrinsic repair [77,78]. However, relying solely on endogenous repair is insufficient. Among various therapeutic strategies, artificial nerve scaffolds in tissue engineering are designed to mimic the extracellular matrix (ECM) of tissues [79], provide mechanical support and chemical cues, and avoid immune rejection, thus holding great potential for clinical application. For instance, Li et al. [80] developed an interpenetrating polymer network scaffold containing collagen (Coll), which was combined with two glycosaminoglycans commonly found in the brain: chondroitin sulfate (CS) and/or hyaluronic acid (HA). These results indicate that Coll-HA and Coll-CS-HA scaffolds can selectively promote neurogenesis, which has positive implications for the tissue engineering-based treatment of TBI [80]. In addition, as illustrated in Fig. 3A, Li et al. [76] developed a dual-enzyme cross-linked gelatin hydrogel via the combination of horseradish peroxidase (HRP) and cholesterol oxidase (ChOx), and simultaneously loaded it with bone marrow mesenchymal stem cells (BMSC) for the treatment of TBI. As shown in Fig. 3B and C, compared with BMSC cultured alone, the GH hydrogel significantly promoted neuronal differentiation and the secretion of neurotrophic factors under three-dimensional culture conditions, with the combination of 1 U HRP and 0.25 U ChOx yielding the optimal efficacy. Implantation of the GH/MSC hydrogel markedly improved motor, learning and memory abilities in TBI mice. Furthermore, as presented in Fig. 3D, An et al. [81] fabricated an electrospun scaffold loaded with copper oxide (CuO@PCL/gelatin), which achieved slow, continuous and low-dose copper delivery to the local brain region, thereby providing a favorable regenerative microenvironment for the imbalance of brain copper homeostasis after TBI.

Fig. 3.

Nerve tissue injury and repair. (A) Coll-CS induces a higher expression of GFAP⁺ [80]. Copyright 2020, Elsevier. (B) Implantation of GH/MSC hydrogel scaffolds can promote neurogenesis and functional reconstruction in TBI mice [76]. Copyright 2021, Elsevier. (C) Camera and MRI imaging of the brains of TBI mice at 35 dpi for the analysis of lesion areas [76]. Copyright 2021, Elsevier. (D) Electrospun nanofibrous scaffolds loaded with copper oxide repair TBI by restoring copper homeostasis and regulating the pyroptosis pathway [81]. Copyright 2023, Oxford Academic. (E) (i) Schematic diagram of the injured spinal cord and the injury/implantation site; (ii) Innervation at the injury site at 8 weeks post SCI [82], showing the immunostaining imaging area. Copyright 2021, Elsevier. (F) Spinal cord tissue engineering via covalent interaction between biomaterials and cells [83]. Copyright 2023, Wiley. (H) Micropatterned scaffolds with grooves of anisotropic topological structures for peripheral nerve regeneration [84]. Copyright 2023, Elsevier. (G) Effect of anisotropic topological structures on SCs [85]. Copyright 2023, Elsevier.

In summary, TBI repair is confronted with fundamental challenges including the hostile post-injury microenvironment characterized by inflammation and glial scar formation, the inability of mature neurons to regenerate, and the extreme complexity of reconstructing functional neural circuits [86]. Future research directions will focus on developing SRES that can dynamically respond to pathological changes, combining gene-edited neural cells or brain organoid technologies to enhance cell integration efficiency, and advancing multimodal combination therapies of “scaffold + cells + drugs + rehabilitation”. Meanwhile, advanced imaging, neuroelectro-physiological technologies or brain-computer interface technologies will be leveraged to achieve precise evaluation of the repair process and personalized treatment.

3.2. Repair of SCI

SCI is a severe neurological disorder that can cause impairment or loss of sensory and motor functions, usually associated with a poor prognosis and potentially leading to paralysis or even life-threatening conditions [87]. The biological efficacy of self-repair following SCI is extremely limited. Neuronal axons in the central part of the spinal cord are barely able to regenerate effectively after injury, due to their intrinsically weak regenerative capacity. Meanwhile, the injured microenvironment rapidly forms inhibitory glial scars and triggers inflammation, which further hinders the repair process [88]. Current research has revealed that the so-called “self-repair” mainly refers to limited axonal sprouting in the peripheral region, synaptic remodeling, and functional compensation of partial neural circuits. However, these spontaneous processes are insufficient to restore severe motor or sensory dysfunction [89]. In addition, most SCI patients face the predicament of lifelong paralysis and prolonged bedridden status, which not only results in exorbitant costs for treatment and nursing care, but also imposes a heavy burden on their families and society at large [90]. At present, the outcomes of clinical treatments are still far from satisfactory [87,91]. Therefore, developing effective therapeutic methods and repair strategies for SCI remains an extremely significant challenge faced by the global clinical community. As an important branch of regenerative medicine, tissue engineering offers new opportunities for SCI repair. Current research on tissue-engineered scaffolds for SCI repair mainly focuses on creating a favorable microenvironment for the survival of seed cells, bridging the injured site, inhibiting glial scar formation, and providing essential contact guidance for axonal regeneration [92,93]. These scaffolds also serve to restrict local inflammatory responses, suppress cell apoptosis, and promote nerve regeneration as well as axonal growth [94,95]. Zhang et al. [96] fabricated a hyaluronic acid/collagen hydrogel nerve scaffold loaded with magnetic-electric core-shell structured Fe₃O₄@BaTiO₃ nanoparticles (NPs). This scaffold incorporates a considerable number of key features of both magnetic-electric materials and natural neural extracellular matrix. Their findings demonstrated that the application of an external pulsed magnetic field could enhance neurogenesis at the cellular level and in in vivo SCI models [96]. In addition, as shown in Fig. 3E, Ma et al. [82] found that a mechanically reinforced decellularized spinal cord (DSC) scaffold with a poly (lactic-co-glycolic acid) (PLGA) outer shell could meet the requirements for effective in-situ neural engineering following SCI. Using chemical extraction and electrospinning methods, they constructed a PLGA thin-shell encapsulated DSC scaffold (PLGA-DSC scaffold). Furthermore, the PLGA-DSC scaffold displayed mild immunogenicity while possessing a prominent ability to polarize macrophages from the M1 to the M2 phenotype, leading to significant tissue regeneration and functional recovery post-SCI [82]. In Fig. 3F, Sun et al. [97] combined microfluidic and electrospinning technologies to fabricate a genetically engineered electrospun scaffold, which achieved long-term immunomodulation and neural repair, effectively promoting the repair and regeneration of neural tissue and improving motor function in rats with SCI.

In summary, current tissue engineering research for SCI repair adopts synergistic strategies of sophisticated material design to regulate the injured microenvironment. For instance, the magnetoelectric core-shell nanoparticle composite hydrogel developed above can effectively enhance neurogenesis under pulsed magnetic field stimulation. The constructed mechanically reinforced decellularized spinal cord scaffold not only resists fibrotic infiltration and provides a conducive niche for NSC differentiation, but also drives macrophage polarization toward the reparative phenotype [98]. Moreover, the genetically engineered scaffold prepared by integrating microfluidic and electrospinning technologies realizes long-term immunomodulation and neural repair. The common advantage of these studies lies in the coupling of biomimetic structures with active biological functions, which simultaneously promotes axonal regeneration, immune remodeling, and partial functional recovery in animal models [99]. However, the limitations of current research still include the insufficient simulation of highly heterogeneous human chronic SCI by engineering strategies, the relatively low efficiency of functional neural circuit reconstruction, and the need for further verification of the long-term biointegrity, safety, and clinical translation of the developed materials. The profound challenges of SCI repair stem from the extremely inhibitory microenvironment formed after injury and the insufficient intrinsic regenerative capacity of central neurons. This requires future research to move beyond the concept of static scaffolds and instead develop SRES systems that can real-time sense and dynamically respond to pathological changes. It is also necessary to deeply integrate neural interface technologies, precise immune regulation, and patient-specific organoid models to ultimately achieve a clinical translational breakthrough from structural connection to functional recovery.

3.3. Repair of PNI

Complete regeneration following PNI remains remarkably challenging, and functional reconstruction after long-distance nerve injury persists as a global challenge [100]. There is an essential difference in regenerative capacity between the peripheral and CNS after injury, the PNS has a significantly stronger intrinsic self-repair potential [101]. For short-distance defects in SD rat models, the body's self-repair mechanisms can usually lead to effective functional recovery [102,103]. SCs dedifferentiate, proliferate, and form Büngner bands, which provide critical physical channels and neurotrophic support for regenerating proximal axons, thus enabling target-oriented reinnervation of nerves. However, for long-distance defects, this self-repair process fails to achieve satisfactory regeneration. Regenerating axons struggle to cross large physical gaps, often resulting in disordered growth and the formation of traumatic neuromas. Meanwhile, distal SCs atrophy due to prolonged lack of axonal contact, leading to denervation of target organs and ultimately, failure of functional recovery. As a strategy that can compensate for the shortcomings of autologous nerve transplantation, tissue-engineered artificial grafts have provided a new perspective for addressing this challenge. Nevertheless, the repair efficacy of most current nerve grafts is still inferior to that of autologous nerve grafts, especially for long-distance PNI [104]. This is because such nerve grafts lack a suitable microenvironment, as well as physical, chemical, and biological cues to induce rapid nerve regeneration [64,105]. The surface micro-nano topography of tissue-engineered nerve guidance conduits (NGCs) can affect the behaviors of different neural cells, such as their growth rate, migration, and secretion of nutrients [106]. The ECM exists in all tissues and organs, providing physical support as well as biological and chemical cues for cells. Native ECM possesses a unique topological structure, which exhibits anisotropy in neural tissues [107]. As shown in Fig. 3G–H, from the perspective of natural biomimicry, mimicking the anisotropic topological structure of autologous nerve ECM to construct a biomimetic neural regeneration microenvironment is considered more conducive to neural tissue regeneration, and has been extensively investigated in the field of neural regeneration [84,85]. It has been established that native ECM has a distinctive structure, which varies among different tissues according to their specific functions. Mimicking these structures is expected to enhance the repair efficacy of artificial nerve grafts [108]. Studies have confirmed that anisotropic topological structures can promote the proliferation of SCs, and also improve the directional extension of neurites in PC12 cells and DRG [109]. Fibrous scaffolds with anisotropic topological structures can be fabricated via electrospinning technology [110]. The advantages of electrospun artificial nerve scaffolds lie in their high specific surface area and small fiber diameter; in addition, they can morphologically mimic native ECM [111]. Research has found that electrospun scaffolds provide structural support for cells, facilitating cell adhesion, migration and differentiation [112].

In summary, considering that regeneration following PNI requires cell recruitment, proliferation, and differentiation, and involves multiple cell types and growth factors jointly accelerating nascent nerve regeneration [113]. In recent years, research in the field of PNI repair has shifted from passive structural bridging toward active microenvironmental regulation and functional regeneration [114]. However, current technologies for constructing artificial nerve grafts still face severe challenges [114,115]. The directional accuracy and rate of regenerating axons remain insufficient to fully prevent distal muscle atrophy [116]. The immunogenicity and long-term stability of implanted materials have not yet been completely resolved [117]. The survival, expansion, and functional maintenance efficiency of SCs after transplantation are limited [118]. Furthermore, significant discrepancies exist in clinical translation from animal models to human patients [119,120].

4. Electrospinning

4.1. Definition and classification of electrospinning

Electrospinning is a technology that processes polymer solutions into fibers with micro- or nanoscale diameters by means of a high-potential electric field [121]. Its equipment structure is relatively simple, mainly consisting of a positive electrode, a negative electrode, a power supply, a syringe driving device and a conductive collector [16]. Under the action of a high-voltage electrostatic field, the polymer liquid is drawn and transformed into ultra-fine fibers, while the solvent evaporates rapidly in the air and the fibers solidify subsequently [122]. During the electrospinning process, a Taylor cone is formed from the polymer liquid in the air, and fibers are ultimately deposited on the collector [122]. Electrospun fibrous scaffolds offer the advantages of a high specific surface area and small fiber diameter [122,123]. Additionally, they can morphologically mimic the natural ECM [111]. Meanwhile, electrospun scaffolds provide structural support for cells, which facilitates cell adhesion, migration and differentiation [112]. The underlying principle lies in suppressing jet instability and achieving programmable direct-writing control over the deposition path of the charged polymer jet by drastically reducing the distance between the nozzle and the collector to the millimeter or even micrometer scale, while precisely controlling the spinning voltage, solution flow rate, and collection process [124]. First, a high-voltage direct current is applied to the spinneret to generate the required electric field [125]. A higher electric field intensity enhances the electrostatic forces acting on the polymer jet, thereby facilitating the formation of finer fibers [126]. Conversely, insufficient field intensity may result in inadequate stretching, leading to the formation of thicker fibers or beaded structures [127]. Variations in voltage affect the charge distribution density, electrostatic repulsion, and the interaction between the jet and the electric field [127]. Generally speaking, a higher voltage can enhance electrostatic stretching forces and promote the production of finer fibers, yet an excessively high voltage may cause an increase in solution ejection volume, which leads to fiber thickening [125,128]. Therefore, voltage adjustment should be conducted within an optimal range that enables effective control of fiber diameter. Another critical parameter is the flow rate of the electrospinning dope, which is controlled by a syringe pump to ensure the stable and adjustable delivery of the dope through the spinneret [129]. An increased flow rate leads to a larger volume of delivered dope, which may result in the formation of coarser fibers [129]. Thus, optimizing the flow rate is essential for obtaining fibers with a uniform and fine structure [130]. The distance between the spinneret and the collector, which determines the travel distance of the jet prior to deposition, is also a critical parameter [129]. Increasing the working distance typically reduces the fiber diameter by allowing greater jet stretching, yet the resultant changes in electric field strength and solution flow rate must be taken into account [131].

Based on the state of the polymer used and the specific conditions during the spinning process, electrospinning can be mainly classified into the following types: (1) Dry electrospinning [132]: In this method, the polymer solution is extruded through a nozzle, and the solvent evaporates rapidly in the air, leaving solid fibers. Dry electrospinning is typically suitable for polymers soluble in low-volatility solvents. (2) Wet electrospinning [133] involves the solidification of polymer solution in a coagulation bath. The polymer solution is extruded through a nozzle into the air and then solidifies in a coagulation bath to form fibers [134]. This technique facilitates the fabrication of fibers with tailored structures, such as hollow fibers or porous structures [135]. (3) Melt electrospinning [136], the polymer is extruded through a nozzle in a molten state and then solidifies into fibers during cooling. This solvent-free method is therefore applicable to polymers with good thermal stability. (4) Near-field direct-write electrospinning [137], as an emerging micro/nano fabrication technology, near-field direct-write electrospinning integrates the high precision of electrohydrodynamic printing with the fiber-forming capability of conventional electrospinning. Its principle lies in suppressing jet instability and whipping by drastically shortening the distance between the spinneret and the collector to the millimeter or even micrometer scale, while precisely controlling the spinning voltage, solution flow rate and collector movement trajectory [138]. This enables programmable direct-write control over the deposition path of charged polymer jets, allowing the direct fabrication of micro/nanofibrous scaffolds with precisely designed 2D or 3D structures, featured by highly ordered fiber alignment and programmable pore structures (Fig. 4A–B) for different fabrication methods of electrospun scaffolds). In practical research and applications, the selection of a suitable electrospinning method depends on the desired fiber properties, as well as the availability and spinnability of raw materials.

Fig. 4.

Different Fabrication Methods of Electrospun Scaffolds. (A) ((i) Uniaxial electrospinning, (ii) Coaxial electrospinning, (iii) Electrospinning combined with electrospraying [27]. Copyright 2022, Springer Nature. (B) Post-treatment via physical adsorption and covalent immobilization [27]. Copyright 2022, Springer Nature. (C) The development history of electrospinning techniques [139]. Copyright 2025, Wiley. (D) Fabrication of electrospun scaffolds with diverse compositions, structures, and functions for advanced applications [139]. Copyright 2025, Wiley.

4.2. Dry electrospinning

In dry electrospinning, the polymer solution is placed in a container such as a syringe [140,141]. By applying a high-voltage electrostatic field, a Taylor cone is formed by the solution at the nozzle [140]. Owing to the volatility of the solvent, a solution jet is ejected from the tip of the Taylor cone under the action of the electrostatic force [142]. As the jet travels toward the collector, the solvent evaporates rapidly [140]. With the evaporation of the solvent, the concentration of the solution gradually increases, and the polymer ultimately solidifies to form fibers [143]. Depending on the number and design of nozzles, dry electrospinning can be classified into uniaxial electrospinning, coaxial electrospinning, triaxial electrospinning and other types [144].

4.2.1. Uniaxial electrospinning

Uniaxial electrospinning is the most fundamental form, which uses a single nozzle to eject the spinning dope [145,146]. In this configuration, the spinning dope forms a cone at the nozzle tip and is stretched into fibers under the action of an electric field [146]. Capable of fabricating fibers with different morphologies, uniaxial electrospinning is a relatively simple electrospinning technique that is easy to set up and operate [147]. Kim et al. [148] prepared bioactive and biodegradable fibrous conduits composed of structurally ordered microfibers with longitudinal grooves on the surface via uniaxial electrospinning, which are suitable for the application of NGCs. Tubular structures with unidirectionally aligned topographical features exhibit significant potential in promoting axonal regeneration, especially for bridging large defects between the proximal and distal nerves [148]. In addition, this conduit exhibited an excellent pro-regenerative effect in a sciatic nerve injury model. Furthermore, Wei et al. [149] developed a biomimetic, aligned and electroactive scaffold composed of polypyrrole (PPy), polydopamine (PDA) and poly-L-lactic acid (PLLA) via electrospinning combined with a dual in-situ polymerization process. This scaffold significantly improved cell adhesion capacity and reactive oxygen species (ROS) scavenging efficiency, and effectively induced the differentiation of mesenchymal stem cells into Schwann-like cells, which is of great significance for neural regeneration [149]. In summary, the advantage of uniaxial electrospinning lies in its low cost and scalable production of anisotropic fibers, but its limitations are equally evident: it is difficult to achieve spatially partitioned loading of multi-components, nor can it precisely control the temporal release of different drugs. Therefore, for application scenarios that require synergistic delivery of multiple therapeutic factors or mimicking complex microenvironments, coaxial or triaxial electrospinning becomes a superior choice [150].

4.2.2. Coaxial electrospinning

Coaxial electrospinning employs two or more nested nozzles to eject solutions containing distinct core and shell materials [151]. This method enables the formation of composite fibers with a core-shell structure in a single fiber, thus achieving the encapsulation of different materials or functional components [152]. Coaxial electrospinning exhibits extensive application potential in fields such as drug delivery systems and multilayer composite materials [153].

Existing studies have demonstrated that coaxial electrospinning technology can effectively encapsulate chemically unstable bioactive molecules into electrospun fibers [154]. During the coaxial electrospinning process, the core spinning dope composed of biomolecules and the shell spinning dope composed of polymers form two independent jets through a coaxial needle, thus fabricating core-shell structured nanofibers. Compared with the traditional uniaxial electrospinning method, the preparation of coaxial nanofibers can significantly reduce the interaction between organic polymer solutions and water-based biomolecules, thereby effectively preserving the biological activity of unstable biomolecules [155,156]. In addition, in comparison with uniaxial blend electrospinning, coaxial electrospinning can reduce the initial release rate of drugs, enable the simultaneous loading of hydrophilic and hydrophobic drugs, and avoid the biotoxicity caused by the late cross-linking of hydrophilic polymers [157]. Since coaxial electrospinning can be used to prepare electrospun fibers with a core-shell structure, different drugs or bioactive molecules can be loaded into the core and shell layers separately. Drugs released from the core layer need to penetrate the shell layer, resulting in a relatively slow release rate [156,158]. For example, an in vitro release study showed that the cumulative release of matrix metalloproteinase-2 from the core layer reached only approximately 50% within 960 h [159]. In our previous study [29], a novel three-dimensional suspended fibrous scaffold was constructed via coaxial electrospinning technology, with PCL as the outer layer and ovalbumin (OVA) as the core, aiming to promote SCs myelination. Magnetic nanoparticles loaded with curcumin and cholesterol were encapsulated in the core, enabling remote, non-invasive, precisely controllable drug release, thus mimicking the complex microenvironmental changes during nerve repair [29].

In summary, coaxial electrospinning technology provides a highly biomimetic strategy for fabricating fibrous scaffolds for nerve regeneration [160]. By constructing core–shell structured fibers ranging from nanoscale to microscale, it enables precise recapitulation of the topological structure of the native nerve basement membrane. The essence of this technology lies in its capacity to achieve spatially ordered integration and temporally controlled release of functional components, which is particularly critical for the dynamic regulation of the neural microenvironment. The shell layer of the fibers offers stable mechanical support and directs the oriented migration of SC, whereas the core layer is capable of loading and sustainably releasing neurotrophic factors, anti-inflammatory agents, or gene carriers, thereby continuously establishing a pro-regenerative microenvironment at the injury site [160,161]. However, the fabrication process is highly sensitive to the parameters of coaxial electrospinning. Achieving SRES regulation, along with precise control over fiber mechanical properties and degradation kinetics, remains challenging. Moreover, current efforts are largely confined to laboratory-scale nerve conduits featuring complex three-dimensional architectures and cell-loading capabilities for long-distance defects, with no relevant reports yet available regarding clinical translation outcomes [162].

4.2.3. Triaxial electrospinning

Based on coaxial electrospinning, triaxial electrospinning further introduces an intermediate layer, achieving gradient release of multi-drug compartments. Triaxial electrospinning is a more sophisticated technology involving three or more nozzles, which enables the fabrication of multilayered structures within fibers. This method is suitable for preparing composite fibers with specific functions, such as gradient-functional sensors, catalyst carriers or drug delivery systems. Triaxial electrospinning technology exhibits unique value in the fields of neural tissue engineering scaffolds and their drug delivery applications [163]. Studies have shown that Yang et al. [164] employed a triaxial hybrid electrospinning device composed of three concentric nested needles to fabricate three-layer core-shell nanofibers with discrete drug distribution using cellulose acetate (CA) as the key filament-forming polymer matrix and ketoprofen as the model drug. Compared with conventional core-shell nanofibers, the three-layer nanofibers with discrete drug distribution offered an improved biphasic drug release profile in terms of the precise release content during the first stage and the more prolonged release during the second stage [164]. Since the number of nanofiber layers increases with the number of injection systems, triaxial electrospinning neural scaffolds demonstrate great potential in the design and development of controlled drug release compared with single hybrid electrospinning and coaxial electrospinning devices [165]. As shown in Fig. 4C, triaxial electrospinning is applicable for poorly water-soluble drugs [166]. Therefore, triaxial electrospinning has also been adopted to achieve personalized control of drug release from electrospun neural scaffolds. However, triaxial electrospinning is more difficult to translate into clinical practice due to the increased complexity of the spinning solution system, the more complicated device setup, and the greater number of influencing electrospinning parameter conditions.

4.3. Wet electrospinning

Dry electrospinning can produce micro/nanofibers, but some materials are difficult to process under high viscosity or heat-sensitive conditions [167]. Wet electrospinning provides an alternative route for the fibrillation of such materials by introducing a coagulation bath wet electrospinning is a composite material preparation method that combines wet spinning and electrospinning technologies [168]. It is a composite material preparation method that combines wet spinning and electrospinning technologies [169]. In the wet electrospinning process, polymer solutions are typically stretched into nanofibers under a high-voltage electrostatic field and then solidified into fibers in a specific coagulation bath [170]. Compared with traditional electrospinning, wet electrospinning enables better control over fiber morphology and structure, as the environment in the coagulation bath can affect the fiber solidification process and the final microstructure [171]. Isotropic structure is also a key factor limiting the application of electrospun nanofiber scaffolds in tissue engineering [170]. Therefore, Dong et al. [172] fabricated a micro/nanofiber composite scaffold composed of PLA and PCL materials in a water bath environment. This composite scaffold is jointly constituted by aligned microfibers and randomly distributed nanofibers, exhibiting a distinct three-dimensional anisotropic structure. In-situ surface functionalization achieved via wet electrospinning allows the introduction of bioadhesive components to improve neural cell adhesion [173]. Chen et al. [174] prepared a wet electrospun blend of PCL and PEO to obtain an anisotropic and in-situ functionalized scaffold (GF/pNE). The cell survival status and neurite outgrowth were compared and analyzed, and the results showed that the GF/pNE fibrous scaffold had good nutrient transport and cell infiltration capabilities, which effectively promoted neurite extension.

Wet electrospinning circumvents the limitations of conventional electrospinning, namely the difficulty in spinning from highly viscous solutions [175]. It enables the fabrication of well-aligned fibers with high modulus. In addition, wet electrospinning allows for better control over fiber morphology and structure, doping or surface modification, and yarn preparation, thereby expanding its application prospects [176]. A advantage of this technique is that fiber morphology—including fiber diameter, surface roughness and internal structure—can be tailored by adjusting the composition and conditions of the coagulation bath [177]. Furthermore, wet electrospinning is suitable for materials that cannot be directly prepared by melt or dry electrospinning, especially heat-sensitive polymeric materials. Nevertheless, wet electrospinning has limitations associated with complex process control: it requires the precise regulation of spinning parameters and coagulation bath conditions, which may increase process complexity, and it also faces potential solvent residue issues. Although wet electrospinning facilitates solvent removal, complete elimination of solvents must be ensured to avoid adverse effects on the final in vivo applications.

4.4. Melt electrospinning

All the above-mentioned electrospinning methods require the use of organic solvents [178,179]. Solvent residues may be toxic to cells or tissues. Melt electrospinning requires no solvent, directly prepares fibers from polymer melts, fundamentally eliminating this risk [179]. In melt electrospinning, the polymer is heated above its melting point to form a melt and, under a high-voltage electrostatic field, is extruded from a nozzle to generate a jet [180]. Owing to the viscoelasticity of the melt, the jet undergoes stretching under the interplay of electric field forces and its own viscous forces, a rheological behavior that influences jet stability and fiber diameter during the process [180]. Meanwhile, as the melt jet travels from the nozzle to the collector, heat is continuously dissipated due to the temperature difference with the surrounding environment, causing the melt to gradually cool and solidify into fibers [181]. Melt electrospinning is suitable for polymers with good thermal stability, as such polymers do not undergo chemical changes such as decomposition under high-temperature conditions [182]. For instance, biodegradable polymers such as polylactic acid (PLA) can be processed into fibers via melt electrospinning above their melting points, which are applied in biomedical fields including tissue engineering scaffolds [183]. Lecina-Tejero et al. [184] fabricated auxiliary PCL fiber scaffolds based on melt electrospinning writing (MEW) technology and constructed a systematic design framework for tuning scaffold mechanical properties by integrating mechanical performance testing with finite element method (FEM) simulations. Additionally, successful cell adhesion and proliferation were observed within seven days, further demonstrating their potential applicability in tissue repair [184]. In addition, Mueller et al. [185] fabricated small-diameter vascular graft scaffolds with helical ultrafine fibrous structures from polymers via melt electrospinning writing technology, whose compliance can be programmed on demand. By adjusting the fiber winding angle, the relationship between the mechanical properties and functions of MEW scaffolds was effectively utilized, thereby obtaining customized compliance performance covering the physiological ranges of arteries and veins.

In summary, melt electrospinning, as an emerging fabrication technique, exhibits unique value in the fabrication of neural tissue engineering scaffolds [186,187]. Its advantage lies in the direct spinning of molten polymers without the use of organic solvents, which not only completely avoids the potential cytotoxicity of solvent residues on cell viability but also facilitates the loading of solvent-sensitive bioactive molecules. Moreover, melt-electrospun fibers typically demonstrate superior mechanical strength and structural stability, providing durable physical support for nerve regeneration [188]. However, this technique faces inherent limitations, including a relatively narrow range of applicable materials, fiber diameters generally in the micrometer range that make it difficult to precisely mimic the nanoscale topography of the extracellular matrix, and the challenge of preserving the activity of heat-sensitive biological macromolecules due to the high-temperature processing conditions [189]. These limitations, to some extent, restrict its application in constructing highly biomimetic and bioactive scaffold conduits [186,189].

4.5. Near-field direct-write electrospinning

Near-field direct-write electrospinning enables the programmable fabrication of complex two-dimensional and three-dimensional fibrous structures with micron-scale resolution through the precise control of the stable deposition of jets in the near-field region, serving as a revolutionary tool for neural interface engineering [190]. Li et al. [191] successfully developed a novel multifunctional wound dressing via near-field direct-write electrospinning, using calf skin type I collagen (CSC-I) and PCL as the matrix materials, Hexafluoroisopropanol (HFIP) as the solvent system, and adding erythromycin (ERY) as the antibacterial pharmaceutical component [191]. This demonstrated that near-field direct-write electrospinning can simply regulate the porosity of dressings, realize the compounding of multiple functional materials and the optimization of their distribution, thus effectively addressing the drawbacks of traditional dressings such as poor air permeability, weak moisturizing performance and single functionality. Notably, Chen et al. [192] optimized the process parameters for preparing PCL scaffolds by using near-field direct-write melt electrospinning, and constructed PCL scaffolds with different thicknesses, gaps and structural characteristics based on these parameters, while characterizing their hydrophilic properties. Subsequently, the modified PCL scaffolds were used as cell culture carriers, and fluorescence microscopy observations revealed that the cells presented a good morphology and uniform distribution, indicating that the scaffolds had excellent biocompatibility. Compared with conventional random electrospinning, the advantage of near-field direct writing electrospinning lies in its structural controllability, enabling the fabrication of biomimetic aligned fiber bundles to guide directional cell migration and complex three-dimensional micropatterns. However, this technique also has limitations, including a typically slow deposition rate that restricts large-scale production, stringent requirements for ink properties that necessitate balancing conductivity, viscoelasticity, and volatility to achieve a stable Taylor cone and continuous direct writing, and the potential for electrostatic charge accumulation in underlying fibers to interfere with the precise deposition of overlying fibers during the construction of three-dimensional structures.

Based on the aforementioned different types of electrospinning technologies, electrospinning is recognized as a highly efficient approach for achieving neural tissue regeneration. Its advantages include tunable nanofiber dimensions, strong material bonding, low cost, simple operation, and easy scalability for industrial production [193]. Most crucially, the micro/nanofibers in electrospun neural scaffolds can provide a biomimetic microenvironment for neural regeneration, which can be loaded with bioactive materials to guide the directional growth of nerves and simultaneously promote cell proliferation, thereby accelerating tissue regeneration [194]. In addition, neural scaffolds fabricated via electrospinning enable the blend spinning of multiple materials to achieve smart responsive regulation, effectively load poorly soluble drugs, and provide personalized drug controlled-release functions for the design of different types of smart responses in smart responsive neural scaffolds [195]. Over time, the electrospinning technique has undergone continuous evolution—driven by successive advances in engineering technology—to expand its functionality and adaptability across diverse applications [139](Fig. 4C–D). Table 1.

Table 1.

Applications of different electrospinning types in tissue engineering.

Electrospun Materials	Types of Electrospinning	Tissue Types	Results	References
CNT/gelatin methacryloyl (GelMA) hydrogel fibers	Uniaxial Electrospinning	SCI	This material enhanced the mechanical properties and biocompatibility of the fibers and promoted the regeneration of brain tissue.	[196]
PLGA-GNP nanofibers	Coaxial Electrospinning	SCI	The scaffold improved the survival rate of transplanted neural progenitor cells, inhibited the inflammatory response, and promoted nerve regeneration.	[197]
Collagen nanofibers	Conventional electrospinning (unless otherwise specified)	SCI	These nanofibers promoted functional recovery, reduced inflammation, and improved tissue repair.	[198]
Poly (glycolic acid-ε-caprolactone)/silk fibroin (PGCL/SF) nanofibrous channels (loaded with Tubastatin A)	Random electrospinning	SCI	The PGCL/SF channels promoted axonal regeneration, reduced glial scar formation, and inhibited inflammation.	[199]
GelMA-coated PLLA microgel electrospun fibers (containing SDF-1α and BDNF)	Coaxial Electrospinning	SCI	It promoted the recovery of neurological function and improved local angiogenesis and maturation by regulating the inflammatory response and recruiting NSCs.	[200]
Magnetic coaxial fibers (TGFβ3-loaded)	Coaxial Electrospinning	SCI	These magnetic coaxial fibers reduced astrocyte reactivity and promoted nerve regeneration and functional recovery.	[201]
3D Injectable Short Nanofibers (3D-ISN)	3D Injectable Short Nanofibers (3D-ISN)	SCI	The 3D-ISN inhibited glial cell proliferation, promoted neurological function recovery, suppressed the inflammatory response, and facilitated nerve regeneration.	[202]
Aligned Nanofibers	Coaxial Electrospinning	SCI	The aligned nanofibers promoted the directional growth and differentiation of MSCs into neurons and improved tissue regeneration and neural repair.	[203]
Direct Jet Co-electrospun Fibers (DJ-co-ES)	Direct jet co-electrospinning	SCI	The DJ-co-ES fibers mimicked the microstructure of spinal white matter, enabled MRI imaging validation, and provided reliable microstructural information.	[204]
Genetically Engineered Electrospun Fibers (GEES)	Microfluidics-assisted Electrospinning	SCI	The GEES fibers modulated the immune response, promoted nerve regeneration, and improved motor function recovery.	[205]
PU/C/FK-PDA Nanofibrous Membrane	Uniaxial Electrospinning	PNI	This nanofibrous membrane promoted nerve fiber density, myelin regeneration, axonal growth, and functional recovery, and optimized the immune microenvironment.	[206]
PLCL/hydroxyethyl cellulose (HEC)-poly (3,4-ethylenedioxythiophene) (PEDOT) Nanofibrous Membrane	Uniaxial Electrospinning	PNI	The membrane significantly enhanced the adhesion and proliferation of SCs and PC12 cells, and promoted nerve regeneration and functional recovery.	[207]
HE-NGC (Aligned NGCsFabricated by E-jet 3D Printing)	Uniaxial Electrospinning	PNI	The HE-NGC promoted SCs and PC12 cell proliferation and migration and accelerated nerve regeneration and functional recovery.	[208]
PCL/ZnO Nanofibrous Membrane	Uniaxial Electrospinning	PNI	Under piezoelectric stimulation, this membrane significantly promoted nerve regeneration and shortened the time to functional recovery (within 4 weeks).	[209]
PCL/PA Nanofibrous Membrane	Uniaxial Electrospinning	PNI	The PCL/PA membrane enhanced neural cell growth and alignment and promoted nerve regeneration.	[210]
3D Aligned Fibrous Scaffold	Coaxial Electrospinning	PNI	The 3D aligned fibrous scaffold promoted nerve regeneration and enhanced directional nerve fiber growth and neurological function recovery.	[211]
YR/DFO@DCNT-Functionalized Micro-nano Composite Topological Structure	Coaxial Electrospinning	PNI	This composite structure accelerated long-distance nerve regeneration, promoted vascularization, suppressed the inflammatory response, and restored neurological function.	[212]
P (MMD-co-LA)/DFO Nanofibrous Channel	Conventional electrospinning (unless otherwise specified)	PNI	The nanofibrous channel alleviated iron overload and organelle stress and promoted nerve regeneration.	[213]
PLGA Electrospun Fibrous Nerve Conduit (with Optimized Alignment and Conductive Coating)	Conventional electrospinning (unless otherwise specified)	PNI	The PLGA conduit significantly promoted nerve regeneration and improved neurological function recovery under electrical stimulation.	[15]
PLGA/CS Nanofibers (Modified with PDA and Loaded with bFGF)	Conventional electrospinning (unless otherwise specified)	PNI	The PLGA/CS nanofibers provided immunomodulation and antioxidation and promoted nerve regeneration and functional recovery.	[214]
Ibuprofen-Loaded PLLA/PCL Copolymer Nanofibers	Uniaxial Electrospinning	PNI	In a rat model of sciatic nerve compression injury, the nanofibers significantly accelerated the rates of axonal growth and sensory recovery, and the sustained release of ibuprofen ameliorates nerve regeneration.	[215]
PLLA-PPSB Composite Nanofibrous Nerve Conduit	Uniaxial Electrospinning	PNI	The conduit promoted the proliferation and myelin expression of SCs in vitro, and facilitated angiogenesis, myelination and axonal regeneration in vivo, with a functional recovery effect comparable to that of autologous nerve transplantation.	[216]
Conductive NGCsBased on Shape Memory Polymers (P/G-RGO)	Uniaxial Electrospinning	PNI	The conductive NGCs promoted nerve regeneration, improved neurological function recovery, and were applicable to nerve injuries with long gaps and large diameters.	[217]
Magnetoresponsive Coaxial Fibers (MeHAPB/PPy)	Uniaxial Electrospinning	PNI	These magnetoresponsive fibers promoted nerve regeneration, reduced muscle atrophy, and accelerated neurological function recovery.	[218]
Engineered Regenerative Isolated Peripheral Nerve Interface (eRIPEN)	Uniaxial Electrospinning	PNI	The eRIPEN promoted nerve regeneration and muscle contraction, alleviated neuropathic pain, and improved motor function.	[219]
Ultrasound-Responsive Piezoelectric Nanofiber-Derived Hydrogel Conduit (BTNPs/P(VDF-TrFE))	Coaxial Electrospinning	PNI	This hydrogel conduit promoted nerve regeneration, accelerated functional recovery, and achieved controllable drug release.	[220]
PLGA/Mxene Composite Membrane	Uniaxial Electrospinning	PNI	The PLGA/Mxene composite membrane exhibited excellent antibacterial properties, electrical conductivity, and hydrophilicity, and promoted cell growth.	[221]
GDNF@GO-ICA@PLGANanofiber	Coaxial Electrospinning	PNI	The nanofiber achieved the phased release of the anti-inflammatory drug ICA and the neurotrophic factor GDNF, promoted nerve regeneration after sciatic nerve injury, and improved the recovery of neurological function.	[153]
Collagen-Modified Anisotropic PLA Electrospun Scaffold	Uniaxial Electrospinning	PNI	The scaffolds possessed favorable mechanical properties and hydrophilicity, promoted axonal regeneration, and accelerated peripheral nerve repair by regulating the YAP molecular pathway.	[204]
PCNB (PCL-Collagen Fibers Loaded with Bacopa Monnieri Extract and MWCNTs)	Uniaxial Electrospinning	PNI	PCNB combined the antioxidant and neurotrophic properties of Bacopa Monnieri with the mechanical and electrical properties of MWCNTs, promoted the adhesion, proliferation and differentiation of neural cells, and accelerated peripheral nerve regeneration.	[222]
PLGA Nanofibers	Emulsion Electrospinning	Treatment of Multiple Sclerosis (MS)	The PLGA nanofibers alleviated EAE symptoms by regulating the immune response and protected the intestinal barrier and microbiota.	[223]
Collagen Nanofibers (Fabricated via Coaxial Electrospinning)	Coaxial Electrospinning	Repair of Traumatic Muscle Injury	In animal models, progressive stretching significantly improved myotube formation and polarized elongation, and promoted the recovery of muscle tissue.	[224]
Collagen/PLGA Fibers	Coaxial Electrospinning	Dural repair	The fiber enhanced the mechanical properties and biocompatibility of the fibers and promoted brain tissue regeneration.	[225]
Pt/CeO2 nanofibers	Uniaxial Electrospinning	TBI	The Pt/CeO2 nanofibers mitigated secondary injury after brain injury by scavenging excessive ROS and reducing the inflammatory response.	[226]

5. Electrospun materials

5.1. Natural polymers

A large body of previous research in neural tissue engineering has demonstrated that the rational and appropriate selection of biomaterials can effectively maintain cellular integrity, facilitate regeneration, and provide a favorable regenerative microenvironment [227,228], while avoiding the induction of inflammation [229]. The materials adopted for artificial nerve conduits need to provide a suitable physical, chemical and biological microenvironment for neurons and glial cells [230]. Both natural and synthetic biopolymers have been applied in the fabrication of artificial nerve conduits [30]. Natural polymers have become common carriers in tissue engineering due to their various properties similar to those of native tissues [231]. Natural materials including collagen [232], silk fibroin [233], chitosan [234], gelatin [235], alginate [236], cellulose nanofibers [237], hyaluronic acid [232,238], OVA [239] and others exhibit excellent biocompatibility and inherent bioactivity. They can effectively promote cell adhesion, neural differentiation and angiogenesis, with non-toxic degradation products that cause no side effects. However, most of these natural materials generally possess poor mechanical properties, an excessively fast degradation rate and insufficient processing stability, and require strong solvents or additives during electrospinning, which limits their application in the repair of long-segment nerve defects [175,240]. Such materials are more suitable for short-term repair or regenerative scenarios of the CNS with high bioactivity requirements. For example, as a structural protein widely present in connective tissues, collagen is often used as a natural polymeric material for artificial nerve conduits by virtue of its ideal properties such as high biocompatibility [230]. Chitosan, silk fibroin and ECM components are also commonly used natural materials in neural scaffolds [241]. Wang et al. [242] demonstrated that the combined transplantation of amniotic epithelial cells with silk fibroin scaffolds could effectively promote the repair of SCI, where the silk fibroin scaffolds created a favorable microenvironment for neural regeneration for amniotic epithelial cells [242]. Experimental results showed that rats exhibited mild local immune responses, reduced inflammatory cell infiltration and moderate rejection between the host and the graft after transplantation, with a significant improvement in motor function. These findings further verified the positive effect of this combined transplantation strategy in spinal cord repair and also indicated that silk fibroin scaffolds are conducive to constructing a microenvironment favorable for neural regeneration. Secondly, Zheng et al. [243] fabricated natural material OVA implants with membranous, fibrous and freeze-dried porous structures by employing casting, electrospinning and freeze-drying technologies, respectively. Furthermore, Gong et al. [244] developed a multi-channel nerve guidance conduit integrating immunomodulatory drugs and gradient cues to promote peripheral nerve regeneration. In addition, this anisotropic topological conduit could promote the ordered arrangement of nerve fibers, enhance myelination, and achieve nerve function recovery close to that of autologous transplantation [244] (Fig. 5A). The research findings of Millesi et al. [250] indicated that natural spider silk was comparable to laminin coating, as it allowed cell attachment and proliferation and supported the characteristic behaviors of all tested cell types. Axonal outgrowth of DRG neurons occurred along longitudinally aligned SCs, which formed continuous fascicular structures similar to the Bungner bands present in regenerating nerves [250].

Fig. 5.

Electrospun Materials (A) Bioinspired conductive oriented nanofiber felt with efficient ROS clearance and anti-inflammation for inducing M2 macrophage polarization and accelerating SCI repair [245]. Copyright 2025, Elsevier. (B) Porous aligned conduits reinforced with GDNF-loaded composite microspheres for enhanced peripheral nerve regeneration [246]. (C) Representative natural biopolymers utilized in neural tissue engineering [247]. Copyright 2025, Elsevier. (D) Conductive multi-scale neural guidance conduits with layered fibers fabricated by combining electrospinning and 3D printing for peripheral nerve regeneration [248]. Copyright 2023, Wiley. (E) Conductive and anti-inflammatory neural conduits based on chitosan/hydroxyethyl cellulose hydrogels for enhanced peripheral nerve regeneration [237]. Copyright 2025, Elsevier. (F) PDA-modified hydrogel nanofibers for sustained release of SFRP2: synergistic promotion of angiogenesis and neural regeneration [249]. Copyright 2025, Nature.

Be that as it may, the application of only natural biopolymers in electrospinning is currently subject to certain limitations, including unstable mechanical properties, low environmental tolerance, and potential infection risks [241,251,252].

5.2. Synthetic polymers

Compared with natural biopolymers, synthetic materials can be engineered to achieve higher mechanical strength and rigidity, and their production processes feature high controllability, which ensures material consistency [253,254]. Silicone is one of the earliest materials used for fabricating synthetic nerve conduits, mainly owing to its excellent elasticity [255]. However, it has certain limitations in practical applications, such as low nutrient transport efficiency, a high tendency to induce fibrotic host responses, irritation to surgical sites, and the need for scar tissue debridement [252]. With the in-depth research on synthetic polymeric materials for artificial nerve conduits, an increasing number of such materials have been widely adopted in the fabrication of nerve conduits. Synthetic materials including PCL [248], PLGA, PLA, polyethylene glycol (PEG) and polyvinyl alcohol (PVA) offer the advantages of tailorable mechanical properties and degradation cycles, ease of processing and functionalization, as well as the ability to provide stable physical support. Nevertheless, their main drawbacks are the lack of bioactivity, poor cell affinity, and the potential of acidic degradation products from some materials to trigger inflammatory responses [256]. Such materials hold greater application value in the repair of long-segment peripheral nerve defects, especially in scenarios that require mechanical load-bearing. They have been further explored in several clinical trials and demonstrated promising application prospects. Yalikun et al. [246] fabricated aligned multi-channel CH-CO1:1/PLGA conduits using PLGA as the electrospinning material and CH-CO as the filler via electrospinning. These conduits exhibited excellent morphology, biocompatibility and mechanical strength, and maintained a sufficiently long tubular structure to guide the alignment of SCs and the extension of axons [246]. (Fig. 5B). Hu et al. [257] developed a biomimetic bilayer electrospun membrane with neurovascular coupling. The outer layer is composed of PCL fibers, and the inner layer is a PCL membrane doped with L-arginine-whitlockite nanoparticles (ArgWH) with an anisotropic topological structure (pPCL@AW). Future research should focus not only on single nerve regeneration, but also on the organic integration of multiple fields to synergistically promote regeneration—much like the coordinated operation of various organs and tissues in the human body to maintain normal bodily functions. This also represents an intriguing research direction for biomimetic tissue engineering (Fig. 5C). Fang et al. [248] fabricated a conductive multi-scale filled nerve guidance conduit (MF-NGC) structure with electroconductive properties by integrating 3D printing and electrospinning technologies. This conduit possesses both favorable mechanical stability and electroactivity, providing the necessary physical support and electrical stimulation environment for neural tissue regeneration [248] (Fig. 5D).

However, many synthetic polymers currently suffer from a prominent drawback: it is difficult for cells to effectively adhere to their surfaces, and material-induced inflammatory responses also limit their further clinical translation. In addition, highly rigid biomaterials may induce mechanical damage, fistula formation, and tissue compression at the injury site, which has thus spurred research into modifying the structural properties of such materials, aimed at developing more flexible synthetic biomaterials.

5.3. Hybrid materials

Given that natural and synthetic biomaterials each possess distinct advantages, combining the two may represent an ideal solution, achieving a balance among biocompatibility, mechanical properties, and degradation characteristics through their synergistic effects [252]. For example, the incorporation of natural polymers into composite scaffolds can further enhance the biocompatibility and biodegradability of hybrid materials by promoting biochemical interactions between cells and the scaffolds [258]. Another approach is the surface coating of synthetic scaffolds with certain natural polymers, which can improve cell adhesion efficiency, as the surface layer of scaffolds plays a pivotal role in cell adhesion. Currently reported hybrid materials for neural regeneration research include PPy-PLCL-PLGA [259], decellularized ECM (dECM)-PCL [260], PLGA-gelatin [261], chitosan/hydroxyethyl cellulose [237] and PDA-GelMA [249] conduits. By integrating the components of natural and synthetic materials, these hybrids achieve a balance of mechanical support, bioactivity, and functional properties (e.g., electrical conductivity and magnetic responsiveness), and have thus become the mainstream research direction in the field of SRES [262]. However, their preparation processes are complex and costly, and the introduction of multiple components may lead to issues of interface stability and uncertainties in long-term biosafety. Future development will focus on developing smart hybrid material systems that realize precise neural regeneration through the synergistic action of multimodal cues, while the combination of multiple technologies can be adopted to achieve the diversification of material functions in a simple and feasible manner. Song et al. [237] developed a hydrogel with both electrical conductivity and anti-inflammatory properties, which was introduced into neural conduits via injection and exhibited the potential to regulate local inflammatory responses and promote neural regeneration. After the in-situ polymerization of PEDOT in CHP and CHPS hydrogels, the materials exhibited superior and stable electrical conductivity, which effectively enhanced the proliferative capacity of SCs and PC12 cells under electrical stimulation [237](Fig. 5E). In addition, Zhang et al. [249] developed a PDA-modified GelMA hydrogel nanofiber as an effective delivery platform for the sustained release of secreted frizzled-related protein 2 (SFRP2). This platform was designed to promote neurite outgrowth, improve neurological function recovery, and enhance neovascularization by activating the Wnt signaling pathway [249](Fig. 5F).

Overall, natural polymeric materials in SRES offer optimal bioactivity but insufficient mechanical properties. Synthetic materials provide controllable mechanical properties and degradation characteristics yet lack bioactivity. Hybrid materials achieve performance complementation through combination strategies, and have emerged as the mainstream development trend for the future. Future research should focus on addressing issues such as interface stability, long-term biosafety, and large-scale preparation processes of hybrid materials, while developing more spatiotemporally ordered and smart responsive multifunctional electrospun material systems. Finally, the applications of different materials used in electrospinning in tissue engineering are summarized in Table 2.

Table 2.

Applications of materials used in electrospinning in tissue engineering.

Electrospun Materials	Type	Form	Effect	References
PLCL/HEC-PEDOT	Synthetic polymer (PLCL), conductive polymer (PEDOT), natural polymer (HEC)	Spiral-structured catheter with aligned nanofibers filled inside and random nanofibers on the outside	This catheter enhanced the adhesion and proliferation of SCs and PC12 cells, and promoted nerve regeneration, angiogenesis, and functional recovery.	[207]
GelMA/COL PCL	Natural polymers (GelMA/COL), synthetic polymer (PCL), growth factor drug (1400W, a highly selective inducible nitric oxide synthase (iNOS) inhibitor)	Multichannel Catheter	The multichannel catheter modulated M1-to-M2 macrophage polarization, promoted SCs migration, axonal elongation, and myelination, and achieved functional recovery approaching that of autologous transplantation.	[263]
CH-CO/PLGA GDNF-CP-MSs	Natural polymers (chitosan/collagen), synthetic polymer (PLGA), growth factor microspheres	Dual-layer catheter with CH-CO porous core and PLGA outer shell, combined with GDNF microspheres	The sustained release of GDNF promoted axonal growth, myelination, and functional recovery, and outperformed traditional catheters.	[264]
GelMA-PDA-SFRP2	Natural polymer (GelMA), biomimetic coating (PDA), growth factor (SFRP2)	Hydrogel nanofiber catheter for curly wrapping of nerves	This hydrogel nanofiber catheter stably released SFRP2, promoted SCs migration, angiogenesis, nerve repair, and muscle functional recovery.	[265]
PU/MWCNTs/FK506-PDA Nanofiber Membrane	Synthetic polymer (PU), carbon nanotube drug	Composite Nanofiber Membrane (Scaffold Alone)	This composite nanofiber membrane promoted nerve regeneration, immune regulation (M2 polarization), and ROS scavenging.	[206]
TPU/PEO/tannic acid (TA)/PDA-Fe-BTi Nanofiber Scaffold	Synthetic polymers (TPU/PEO), magnetoelectric nanoparticles	Composite Electrospun Scaffold (Scaffold Alone)	This composite electrospun scaffold provided magnetically controlled electrical stimulation, promoted axon growth, and improved the SCI microenvironment.	[266]
PLGA/PCL double-layer nerve catheter dECM hydrogel Extracellular Vesicles (EVs)	Synthetic polymers (PLGA/PCL), natural hydrogel (dECM), cell-derived EVs	Composite catheter (scaffold + hydrogel)	The composite catheter promoted the repair of 12 mm nerve defects, functional recovery, and remyelination.	[267]
PCL/PDA/ELP/TCS Nanofiber Membrane	Synthetic polymer (PCL), elastin-like polypeptide (ELP) + antibacterial agent (TCS)	Modified Electrospun Membrane (Scaffold Alone)	The modified electrospun membrane exhibited antibacterial activity against MRSA, promoted angiogenesis/neurogenesis, and induced a low inflammatory response.	[268]
Electrospun gelatin/PCL nanofibers with a “sandwich” layered structure	Natural polymer (gelatin), synthetic polyester (PCL)	Electrospun nanofiber tube alone Three-layer sandwich nanofiber tube	The sandwich-structured nanofiber tube enhanced mechanical strength, promoted BMSC proliferation, increased axonal outgrowth, induced M2 macrophage polarization, and improved sciatic nerve function.	[269]
PLLA micro-yarns + electrospun PLLA/SF/tetrahydroquinoline nanofibers → knitted scaffold	Synthetic polyester (PLLA) + natural protein (silk fibroin) + small molecule drug	Composite Knitted Scaffold (Micro-yarn Core + Nanofiber Sheath)	The composite knitted scaffold inhibited excessive fibroblast proliferation, promoted M2 macrophage polarization, reduced inflammation, increased collagen deposition, and enhanced tendon regeneration.	[270]
Electrospun PCL fibers	Synthetic polyester (PCL) Inorganic nanoparticles (Fe3O4) Conductive two-dimensional material (graphene)	Double-layer Conductive Electrospun Catheter	The double-layer conductive electrospun catheter generated inductive current wirelessly in an alternating magnetic field, which promoted SCs proliferation/migration, enhanced axonal outgrowth and myelin sheath thickness, and achieved motor function recovery comparable to that of autologous transplantation.	[271]
Mg-sputtered collagen	Natural polymer	Collagen scaffold alone (CPL@3 Mg)	The collagen scaffold (CPL@3 Mg) significantly promoted axonal regeneration and SCs migration at 2 weeks; the recovery of the sciatic nerve function index (SFI) approached that of autologous transplantation at 12 weeks; the level of muscle reinnervation was comparable to that of autologous transplantation with attenuated muscle atrophy; precise control of Mg2+ release (≈10 mmol) avoided hypermagnesemia toxicity and hydrogen accumulation.	[272]
PEDOT:PSS-coated PLGA electrospun fibers	Synthetic polymer Conductive polymer	Fiber scaffold alone	The conductive coating (0.017 wt% PEDOT:PSS) endowed the fibers with an electrical conductivity of 0.07 S cm−1 along the parallel direction; the oriented arrangement combined with electrical stimulation (ES, 100 mV, 20 Hz) synergistically promoted neurite outgrowth and myelin regeneration; after 3 months, the CMAP amplitude showed no significant difference from that of autologous transplantation, and the SFI was significantly superior to that of the uncoated group; the surface porous structure enhanced cell adhesion and reduced inflammation.	[15]
L-Zein/BBR Hollow Catheter + ZPGM Hydrogel	Natural polymer (zein)Polysaccharide (pectin)	Hollow fiber catheter Hydrogel composite filled inside	The hollow fiber catheter with hydrogel composite inhibited LPS-induced NO production and improved the viability of Raw264.7 cells; it restored the mitochondrial function of RSC96 cells under TBHP-induced oxidative stress; electrical stimulation at 250 mV for 36 h doubled the OD value of RSC96 cells and promoted the formation of axonal networks.	[273]

6. Electrospun neural scaffolds with different surface morphologies

6.1. Different topological structure types for neural tissue engineering

The surface morphology of scaffold materials is extremely crucial in regulating cellular behaviors and differentiation processes [274]. These topological features are mainly categorized into three types: continuous topological structures, discontinuous topological structures, as well as anisotropic and isotropic topological structures, which are classified based on the structural symmetry and consistency of physical properties of materials or scaffolds in different spatial directions [275].

A variety of top-down and bottom-up technologies are adopted to fabricate structured surface topographies on biomaterials, including nanolithography, etching, deposition, laser ablation, template-assisted synthesis, and nanotransfer printing [276]. In addition, topological structures can be manufactured using polymer composites via techniques such as electrospinning, layer-by-layer assembly, sol-gel processing, in-situ polymerization, 3D printing, template-assisted methods, and spin coating [274]. Existing studies have demonstrated that the micro- and nano-scale surface morphology of tissue-engineered NGCs can affect the behaviors of different neural cells, such as their growth rate, migration, and nutrient secretion [106]. The ECM exists in all tissues and organs, providing physical support and biological/chemical cues for cells. Native ECM possesses a unique topological structure, which exhibits anisotropy in neural tissues [107]. Isotropic structures have essentially consistent physical properties (e.g., pore size, fiber arrangement, and mechanical strength) in all directions of three-dimensional space and do not provide specific directional guidance [277]. As the fundamental form of scaffolds for neural tissue engineering, such structures primarily function to offer a 3D space for cell adhesion, proliferation, and early migration, as well as to permit the free diffusion of nutrients and metabolic waste [278]. In addition, anisotropic topological structures can guide the directional growth of nerve axons and the formation of nerve fascicles [279]. Characterized by distinct directional features [280], anisotropic structures are designed to mimic the parallel-arranged nerve fascicle architecture of native neural tissues, providing contact guidance cues for regenerating axons, facilitating their ordered and long-distance extension, and reducing neuroma formation.

In addition, anisotropic topological structures are also widely applied in scaffolds fabricated via electrospinning technology. Relevant studies [[281], [282], [283]] have demonstrated that various types of viable cells exhibit extremely high sensitivity to the morphological orientation of scaffolds both in vivo and in vitro. The topological structure of scaffolds significantly affects cellular growth characteristics, particularly cell proliferation, differentiation, and migration. It has been reported that Li et al. [284] found that the inner hydrogel with adequate mechanical support, linear topological structure, and bioactive cues promoted the migration and neuronal differentiation of endogenous NSCs in the late stage of SCI treatment, thereby facilitating the recovery of motor function in SCI rats. Gao et al. [106] discovered that the prepared biomimetic functional topological scaffold with aligned ridge/groove structures, favorable mechanical properties, and biocompatibility could effectively promote the proliferation, migration, and elongation of SCs, and significantly upregulate the expression of genes related to proliferation, apoptosis, migration, and axonal regeneration, thus accelerating regeneration after PNI. Existing studies have indicated that Wallerian degeneration occurring after PNI, namely the autonomous degeneration of distal axons, can induce iron homeostasis disorders, which in turn lead to iron overload and trigger oxidative stress. Researchers [285] designed an electrospun scaffold with iron-chelating function, highlighting the critical role of constructing a suitable microenvironment in neural repair. The results showed that the PDPLA/DFO membrane could alleviate the glutathione redox state disorder and loss of glutathione peroxidase 4 activity caused by iron overload, while reducing ROS levels, alleviating endoplasmic reticulum and mitochondrial stress, and inhibiting cell apoptosis [285]. In the in vivo environment, the PDPLA/DFO conduit created an anti-inflammatory microenvironment by relieving iron overload and organelle stress, thereby enhancing cell viability [285](Fig. 6A).

Fig. 6.

Effects of Electrospun Scaffolds with Topological Structures on Neural Tissue Regeneration (A) Enhancement of sciatic nerve regeneration via nanofibrous P (MMD-co-LA)/DFO conduits through alleviating iron overload and organelle stress [285]. Copyright 2022, Elsevier. (B) Immunomodulatory fibrous membranes loaded with FK506 promote peripheral nerve regeneration [206]. Copyright 2025, Elsevier. (C) Core-shell structured nanofibers mediate staged anti-inflammatory and proneurogenic activities for peripheral nerve repair [153]. Copyright 2024, Iopscience. (D) Aligned and random electrospun fibers derived from porcine acellular ECM for mesenchymal stem cell-based SCI therapy [203]. Copyright 2024, MDPI. (E) A biomimetic multi-channel nanofibrous conduit loaded with tubastatin A for repairing injured spinal cord [199]. Copyright 2022, Elsevier. (F) BMSC in hydrogel/nanofibrous composite scaffolds enhance the activity of the PI3K/AKT signaling pathway by inhibiting miR-206-3p expression, exerting superior pro-angiogenic and neuroprotective effects after ischemic brain injury [286]. Copyright 2023, Elsevier.

6.2. Disordered neural scaffolds with isotropic structure

As the fundamental form of scaffolds for neural tissue engineering, isotropic structures primarily function to provide a three-dimensional space for cell adhesion, proliferation, and early migration, as well as to allow the free diffusion of nutrients and metabolic waste [287]. They are fabricated via techniques such as random-collection electrospinning, phase separation, or freeze-drying. These scaffolds mimic the random fibrous network of the ECM and feature high porosity and specific surface area. An et al. [81] developed an isotropic electrospun scaffold loaded with copper oxide (CuO@PCL/gelatin, abbreviated as CuO@PG), which enables localized administration of low-dose drugs and effectively avoids systemic toxic side effects. Their study demonstrated that CuO@PG can inhibit delayed neuronal apoptosis induced after TBI. Meanwhile, this material can significantly downregulate the expression levels of pyroptosis-related proteins. In addition, CuO@PG also exerts the effects of alleviating cerebral edema and acute-phase neurodegeneration, exhibiting potential neuroprotective functions. Previous studies have prepared electrospun fibrous scaffolds based on PLGA and PCL, which are applied to guide axonal growth, inhibit glial scar formation, and promote neural remyelination after SCI [288,289]. Studies have shown that aligned and random polyethersulfone (PES) nanofibers fabricated via electrospinning. Human induced pluripotent stem cells (hiPSC) cultured on aligned pure nanofibers exhibited neurite extension along the fiber orientation, as well as higher expression levels of Tuj-1 and microtubule-associated proteins, compared with those cultured on random nanofibers [290]. In addition, Xing et al. [206] developed an innovative drug delivery system based on an isotropic structure, which enables the local sustained release of FK506 and enhances substance exchange, thereby improving its immunomodulatory efficacy and promoting peripheral nerve regeneration. In a rat model of sciatic nerve crush injury repair, the PDA-modified nanofibrous membrane loaded with FK506 significantly increased nerve fiber density, the degree of myelin regeneration, axonal growth rate, and functional recovery outcomes [206](Fig. 6B). Inflammatory responses can significantly interfere with the neural regeneration mechanism during PNI repair; therefore, creating an anti-inflammatory microenvironment is crucial for promoting nerve regeneration. Lin et al. [153] innovatively employed core-shell structured nanofibers with sequential anti-inflammatory and proneurogenic functions to repair peripheral nerve injuries. Specifically, icariin (ICA), a compound renowned for its anti-inflammatory properties, was mixed with PLGA to form the spinning solution for the shell layer; meanwhile, the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) combined with graphene oxide (GO) constituted the spinning solution for the core layer [153] (Fig. 6C).

Although isotropic scaffolds have occupied a historical position in early research, they are limited by their disordered structure and have inherent drawbacks in guiding precise neural regeneration and functional recovery. For example, in 3D organoids or in vitro disease models designed to simulate the layered structure of the cerebral cortex or the arrangement of spinal nerve tracts, the disordered structure fails to meet the requirements for the specific spatial arrangement of cells, which limits their application in high-throughput drug screening or pathological mechanism research. Compared with engineered scaffolds with precisely controllable structural parameters, isotropic structures have limited regulatory capabilities in terms of mechanical signal and electrical signal transmission, making it difficult to construct standardized disease or regeneration models in vitro. In the future, the focus of research should be on developing anisotropic scaffolds that can mimic the ordered structure of natural nerves, integrating multimodal regulatory signals to achieve structural order, temporal order, and spatial order.

6.3. Anisotropic topological neural scaffolds

Anisotropic topological structures provide a highly biomimetic physical guidance strategy for the repair of central and PNS injuries by simulating the naturally ordered microenvironment of neural tissues [291,292]. In the repair of peripheral nerve injuries, highly oriented fibrous or grooved structures have been widely demonstrated to effectively guide the alignment of SCs and the directional extension of axons [108]. Similarly, in the field of SCI, anisotropic hydrogels or scaffolds are designed to bridge injury cavities and provide linear pathways for regenerating axons to traverse lesion areas [293]. In TBI, anisotropic structures have been explored to guide neuronal migration and neural network reconstruction [291]. The advantage of this strategy lies in its ability to exert a distinct contact guidance effect, directly regulating cytoskeleton arrangement and cell migration direction at the cellular level, thereby overcoming the common challenge of disordered neural regeneration. Hence, it has been extensively investigated in the field of neural regeneration. Anisotropic topological structures can effectively guide the directional growth of nerve axons and the formation of nerve fascicles. Studies have confirmed that anisotropic topological structures promote the proliferation of SCs, and improve the directional extension of neurites in PC12 and DRG [109]. Furthermore, Daeschler et al. [294] encapsulated tacrolimus into coaxial electrospun polycarbonate-urethane nanofibers via coaxial electrospinning technology to fabricate implantable nerve wraps, which can release therapeutically active doses of tacrolimus over 31 days. Tai et al. [203] fabricated an aligned nanofibrous scaffold using porcine decellularized spinal cord matrix (DSC) to induce the differentiation of mesenchymal stem cells for SCI treatment. The results demonstrated that the DSC component in the scaffolds might create a more favorable microenvironment for mesenchymal stem cells to secrete neuroprotective factors [203]. In this experiment, the aligned scaffold group exhibited superior therapeutic outcomes compared with the other two groups. Tissue and cellular damage often lead to an adverse local microenvironment—such as glial scar formation—which inhibits neural regeneration after SCI (Fig. 6D). This phenomenon further confirms the critical role of the microenvironment in neural repair. Therefore, in the treatment of SCI, constructing a favorable microenvironment is of great significance for promoting the formation of new neural pathways and improving the recovery of motor function [295]. Liao et al. [199] developed a biomimetic multi-channel tubastatin A (TUBA)-loaded nanofibrous conduit (SC-TUBA(+)) via random electrospinning combined with triple-network crosslinking technology, which was designed for the targeted inhibition of histone deacetylase 6 (HDAC6) and the promotion of axonal regeneration. The TUBA-loaded nanofibers significantly reduced glial scar formation, increased the number of nerve fibers, inhibited inflammation, alleviated demyelination, and protected bladder tissue in SCI [199](Fig. 6E). In addition, Pei et al. [286] constructed a rigid-flexible composite scaffold composed of electrospun nanofibers and an adaptive injectable hydrogel, with BMSC seeded on it. In vitro experiments showed that compared with BMSC cultured in normal saline, BMSC loaded in the composite scaffold exhibited superior cell viability, migration capacity, neurite outgrowth, angiogenic potential, and paracrine function. In animal models, BMSC in the composite scaffold significantly reduced cerebral edema and infarct volume, improved neurological deficits, inhibited the abnormal activation of microglia and astrocytes, and simultaneously promoted neuronal proliferation and neovascularization (Fig. 6F).

Base on the aforementioned, the current topological structure design of electrospun scaffolds for neural tissue engineering is trending toward personalization, refinement, functionalization, hybridization, and more realistic biomimicry. Isotropic structures can serve as the foundation, providing a critical cell-supporting microenvironment and channels for substance exchange. Whereas anisotropic structures focus on guiding the ordered regeneration of axons. Future research could lie in the smart integration of these two types of topological structures, as well as physical, chemical, and biological cues, into hierarchical and functional composite scaffolds, so as to more effectively simulate the complex microenvironment of natural neural tissues and thus significantly improve the speed and quality of neural regeneration. Potential future research directions include the following, (1) Construction of composite and hierarchical topological structures based on electrospinning technology: Harnessing the synergistic advantages of isotropic and anisotropic properties, the latest research trend is strongly directed toward the design of composite and hierarchical topological structures—i.e., internal anisotropy combined with external isotropic/protective layers—coupled with SRES, due to the limitations of single topological structures. (2) Gradient topological structures: Within the scaffold, the topological structure exhibits a gradient variation from one end to the other or from the center to the periphery, so as to simulate the transition from the nerve stump to the regenerative region, or to guide the shift of cell/axon migration from random movement to directional extension. This design requires advanced manufacturing technologies. (3) Microenvironment-biomimetic topology: Moving beyond simple parallel alignment, attempts should be made to simulate the more complex fascicular structures of natural nerves, such as the hierarchy of epineurium, perineurium, and endoneurium, or the branched structures of nerve endings (e.g., for peripheral nerve-muscle interfaces). This relies on further innovations in ultra-high-precision electrospinning biomanufacturing technologies and biomaterials. The applications of electrospun scaffolds with different topological structures in neural tissue engineering are summarized in Table 3.

Table 3.

Applications of electrospun scaffolds with different topological structures in neural tissue engineering.

Alignment	Structural Type	Injured Neural Tissue Type	Therapeutic Effects	Reference
Anisotropic (multi-scale aligned structures such as fibers and grooves)	Composite nanofibers	PNI	The composite nanofiber scaffold provided immunomodulation, ROS scavenging, promoted axonal growth, and enhanced SCs function.	[234]
Anisotropic (aligned poly (lactic acid) electrospun fibers)	Composite nanofibers	PNI	The aligned PLA electrospun fibers promoted axonal regeneration, provided enhanced mechanical support, and modulated the YAP signaling pathway.	[296]
Anisotropic (micro-/nano-composite topography incorporating functionalized multi-walled carbon nanotubes)	Micro-/nano-composite topography	PNI	The micro-/nano-composite topography promoted vascularization, suppressed the inflammatory response, accelerated long-distance nerve regeneration, and achieved favorable functional recovery.	[212]
Anisotropic (biomimetic micro-/nano-structures)	Tubular structure (SDCHC) and lamellar structure (SDCHP)	PNI	These biomimetic structures provided biocompatibility, anisotropic architecture, electroactivity, mechanical durability, and permeability, leading to enhanced cell functionalization and tissue repair.	[297]
Anisotropic (core of aligned microfiber mesh and sheath of randomly oriented nanofibers)	Composite structure (inner aligned microfiber mesh core and outer random nanofiber sheath)	PNI	The composite structure demonstrated superior regenerative capacity compared to sheath-only constructs and commercial Neurolac nerve conduits in a canine model, resulting in significantly improved nerve regeneration and functional muscle recovery.	[298]
Anisotropic, with surface microtopography	Anisotropic topography fabricated by micromolding	PNI	The anisotropic topography regulated directional SCs growth and promoted axonal extension from DRG via the piezoelectric effect, accompanied by upregulation of genes associated with myelination and axonal growth.	[239]
Radially and longitudinally aligned fiber architecture	3D aligned fiber scaffolds and shape-memory multichannel conduits	PNI	The 3D aligned fiber architecture significantly enhanced directional cell migration and differentiation, promoted nerve regeneration and motor functional recovery, with outcomes approaching those of autologous nerve grafting.	[299]
Hierarchically anisotropic	Silk fibroin-based hollow conduits filled with aligned porous silk fibroin nanofibers	PNI	The hierarchically anisotropic structure significantly promoted cell proliferation and migration, elevated neurotrophic factor secretion, and achieved remarkable nerve regeneration, approaching the efficacy of autografts.	[300]
Aligned fibers conferred by 30 μm microgrooves on the chitosan film surface	Micropatterned surface	PNI	The micropatterned surface successfully induced directional cell alignment, upregulated nerve regeneration-associated gene expression, enhanced paracrine effects, and promoted primary SCs proliferation/migration and motor neuron axonal growth.	[301]
Aligned and random	Includes nanofibers, 3D architectures, and micro-/nano-structures with varying dimensions and shapes	SCI	These scaffolds enhanced nerve regeneration through modulation of NSC fate determination, promoted neurogenesis, guided axonal growth, and regulated inflammatory responses.	[302]
Aligned fiber architecture	Nanofiber/hydrogel composite	TBI	The nanofiber/hydrogel composite supported BMSCs, prolonged their in vivo retention in the brain, enhanced neuroprotective and pro-angiogenic effects, mitigated brain edema and infarct volume, and ameliorated neurological deficits.	[286]
Aligned	PLGA aligned nanofiber scaffolds functionalized with LysoGM1 via amide bonds	TBI	The PLGA aligned nanofiber scaffolds functionalized with LysoGM1 promoted nerve regeneration.	[303]
Aligned fibers	PCN and PCNB nanofibers	PNI	These aligned nanofibers promoted axonal growth, myelination, and motor/sensory functional recovery; demonstrated good biocompatibility and biodegradability; effectively mitigated oxidative stress and facilitated nerve regeneration.	[304]
Anisotropic	Microsolvent-electrospun GelMA hydrogel fibers	SCI	The anisotropic GelMA hydrogel fiber scaffold improved neurological functional recovery through modulation of the immune microenvironment, promoted NSC migration and differentiation, and exhibited favorable biocompatibility, mechanical properties, and biodegradability.	[305]
Random	CuO@PCL/gelatin nanofiber hydrogel	TBI	This nanofiber hydrogel inhibited TBI-induced neuronal pyroptosis, attenuated brain edema and neurodegeneration, improved neurological functional recovery, and showed good antibacterial properties and sustained copper ion release.	[81]
Aligned	PLGA-GNP aligned nanofibers	SCI	The PLGA-GNP aligned nanofibers significantly enhanced transplanted neural progenitor cell (NPC) survival, suppressed inflammatory signaling pathways, augmented the neuronal differentiation rate, and promoted hindlimb motor function recovery in spinal cord-injured rats.	[197]
Random	Tubastatin A-loaded PGCL/SF nanofibers	SCI	The Tubastatin A-loaded PGCL/SF nanofibers significantly reduced glial scar formation, increased the nerve fiber count, suppressed inflammation, attenuated demyelination, and protected bladder tissue.	[199]
Aligned	CNT/GelMA hydrogel fibers	SCI	The CNT/GelMA hydrogel fibers induced nerve fiber regeneration, enhanced remyelination and axonal regeneration, significantly restored motor function, and ameliorated pain perception in rats.	[306]
Aligned	Nanofibrous dressing	TBI	This nanofibrous dressing reduced secondary brain injury through ROS scavenging and calcium channel modulation, offering advantages such as non-invasiveness, cost-effectiveness, and environmental friendliness.	[226]
Aligned	Electrospun nanofibrous channels	PNI	These electrospun nanofibrous channels alleviated iron overload and organellar stress, promoted nerve regeneration, improved the distal microenvironment, and reduced inflammatory responses and apoptosis.	[285]
Aligned (inner tube) and random (outer tube)	Multi-channel structure with inner tubes of GelMA/collagen fibers and outer tube of PCL fibers	PNI	The multi-channel structure significantly enhanced nerve regeneration, promoted remyelination, and improved functional recovery via modulation of the immune response (facilitating M1-to-M2 macrophage polarization) and provision of bioactive gradient cues.	[263]
Aligned	Electrospun nanofibrous membrane	PNI	The electrospun nanofibrous membrane promoted increased nerve fiber density, remyelination, axonal growth, and functional recovery through the synergistic action of FK506 and PDA, optimizing the local immune microenvironment.	[206]

7. Classification and applications of SRES

7.1. Classification of SRES

Materials that mimic the stimulus-responsive capabilities of living organisms are generally referred to as smart responsive biomaterials [31]. These materials can sense and respond to the surrounding environment, thereby achieving smart regulation to enhance therapeutic efficacy. Currently, tissue engineering and drug delivery systems utilize stimulus-responsive materials to control bio-surface interactions or the administration of pharmaceutical compounds, for both in vivo and in vitro applications [[307], [308], [309]]. A range of developed materials and technologies enable the modulation of material properties according to local environmental cues—such as pH, temperature, photothermal effects—or via the application of remotely delivered stimuli (electrical stimulation [310], ultrasound, magnetic fields), so as to regulate drug delivery and promote neural tissue regeneration [31,32,311].

SRES are defined as electrospun scaffolds capable of actively and reversibly altering their physicochemical properties (e.g., shape, surface wettability, drug release rate, or electrical conductivity) in response to external or internal stimuli (such as magnetic fields, thermal stimulation, electric fields, light, pH, ionic, etc). Compared with conventional electrospun scaffolds, SRES are capable of actively and reversibly altering their own physicochemical properties, thereby enabling on-demand modulation of cellular behavior and tissue repair [312]. This distinguishes them from conventional functional electrospun scaffolds, which typically provide passive support or sustained drug release without real-time adaptability to external signals [313]. Conventional scaffolds may incorporate bioactive molecules or conductive polymers, but lack the dynamic, stimulus-triggered response characteristics inherent to smart scaffolds [314].

With the continuous improvement in the demand for material functionality in the fields of tissue engineering and controlled drug release, research related to SRES has developed rapidly. These scaffolds not only possess the high specific surface area and tunable porosity of traditional electrospun materials, but also can undergo reversible physicochemical property changes in response to specific external stimuli, thereby achieving precise personalized therapy characterized by “on-demand treatment”. The design of SRES is based on the stimulus-response mechanisms that are ubiquitous in living organisms. For instance, infected wound sites exhibit a slightly acidic microenvironment, while inflammatory regions are accompanied by ROS bursts [315]. By integrating functional molecules sensitive to these biological signals into electrospun fibers, an “smart” scaffold system that can autonomously sense the pathological microenvironment and make adaptive responses can be constructed. Such materials show great potential in the field of neural regeneration in the future.

7.1.1. pH-responsive

In recent decades, pH-responsive polymeric fibers have attracted extensive research attention due to their wide range of applications [316,317]. This class of smart fibrous materials can exhibit specific responses to changes in environmental pH values, such as morphological alterations, volume expansion or contraction, and color changes [318]. Encapsulating pH-responsive dyes in hydrogel fibers can not only prevent the dyes from diffusing into the wound area, but also form a biocompatible interface with the wound site [319]. Core-shell structured pH-responsive polymeric fibers can regulate the rate and dosage of drug release by virtue of their micro-morphological responses to pH variations [320]. Yang et al. [316] prepared pH-responsive ZnS/SF composite fibrous membranes by loading zinc sulfide nanoparticles into SF fibrous membranes via in-situ polymerization. Under optimized process conditions, the composite membranes achieved uniform loading of nanoscale ZnS particles, exhibiting a dense network structure, excellent water absorption capacity, as well as favorable biocompatibility and hemostatic efficacy. When the wound is in an acidic microenvironment, ZnS can react with hydrogen ions to continuously release hydrogen sulfide (H₂S) and zinc ions (Zn²⁺). Furthermore, Zhang et al. [317] constructed a multifunctional fibrous membrane (PCSNP) integrated with pH-smart responsive drug release to achieve on-demand antibacterial activity. The PCSNP is composed of three layers of electrospun fibers: a rapid bactericidal inner layer, a pH-responsive coaxial middle layer, and a self-powered outer layer [317]. Electrical performance tests showed that the PCSNP generates an electrical stimulation of 1.6 V, which is conducive to promoting cell growth. The PCSNP can change color to indicate wound status and facilitate rapid drug release upon contact with diabetic wounds [317]. Guo et al. [321] fabricated nanoparticles without the need for chemical cross-linking agents by utilizing β-sheet structure-driven physical cross-linking technology, with gelatin and SF serving as the core protein materials. This co-assembly strategy not only ensures the structural stability of the nanoparticles, but also endows them with enzyme- and pH-smart responsive degradation properties, as well as enabling narrow particle size distribution and precise size regulation.

In summary, pH-responsive biomaterials provide an smart strategy for the precise, on-demand delivery of drugs and bioactive factors by sensing the characteristic acidic microenvironment at nerve injury sites [322]. In the acute phase of TBI and SCI, the damaged tissues develop local acidosis due to ischemia, hypoxia and inflammatory responses. Under such conditions, pH-responsive hydrogels or nanofibrous scaffolds can undergo swelling, dissociation or charge reversal, thereby releasing anti-inflammatory drugs, neurotrophic factors or inhibitory molecule neutralizers in a site-specific manner, aiming to alleviate secondary injury and modulate the immune microenvironment. For peripheral nerve defects, such materials have also been explored to respond to microenvironmental changes in the early stage of Wallerian degeneration, so as to optimize the repair process. The advantage of this strategy lies in its ability to achieve targeted release of therapeutics that is spatiotemporally synchronized with pathophysiological changes, which improves treatment efficacy and may reduce systemic side effects. However, the limitations of this strategy are also quite obvious: the pH distribution in the injured area is heterogeneous and dynamic, making it difficult for simple threshold-responsive systems to match such complexity. The response rate, degradation behavior and drug release kinetics of the materials are hard to precisely control in vivo. More critically, single pH responsiveness cannot cover the multiple signals necessary for nerve regeneration, such as physical guidance and the establishment of an electrophysiological micro-environment. The challenge in current nerve repair is how to expand this kind of response targeting a single pathological marker into a dynamic, synergistic regulatory system that can adapt to the complex multi-stage demands of regeneration. Therefore, future development is bound to move toward the smart design of multi-functional coupling systems. For example, developing pH/enzyme dual-responsive or pH/reduction potential dual-responsive material systems, which can not only release anti-inflammatory agents in response to the acidic environment of early inflammation, but also switch to releasing axon growth-promoting factors in the subsequent regeneration stage. Meanwhile, integrating pH-responsive modules with conductive materials and anisotropic topological structures to construct next-generation nerve scaffolds that can both provide chemical responses and offer physical and electrical signal guidance, thereby realizing smart, adaptive regulation throughout the entire process of nerve regeneration.

7.1.2. Temperature-responsive

Temperature governs nearly all physical, chemical, and biological reactions, and is also a critical regulatory parameter of the human body [323]. Temperature governs nearly all physical, chemical, and biological reactions, and is also a critical regulatory parameter of the human body [324,325]. Guo et al. [325] fabricated collagen-mimetic hydrogel nanofibers using GelMA and PLLA via coaxial electrospinning technology. Subsequently, the thermoresponsive polymer poly (N-vinylcaprolactam) (PNVCL) was grafted onto these nanofibers through dehydration condensation reaction, thereby endowing the materials with temperature-dependent mechanical properties. The incorporation of PLLA significantly enhanced the mechanical strength of GelMA hydrogel nanofibers, while PNVCL grafting effectively reduced the swelling capacity and porosity of the materials. When the ambient temperature exceeds the lower critical solution temperature (LCST), PNVCL undergoes phase separation and spontaneous shrinkage, forming strong hydrogen bonds with GelMA and expelling water from the polymer network, which further reinforces the overall mechanical performance. This dynamic mechanical stimulation can promote cytoskeleton remodeling of mouse skin fibroblasts (MSF) without compromising their proliferation and migration capabilities; additionally, it can induce the transformation of fibroblasts into myofibroblasts, thereby enhancing ECM secretion. Axonal regeneration is slow and difficult to achieve precise docking after PNI. Thermoresponsive shape memory polymers (SMP) can maintain their initial morphology within the body temperature range and exhibit excellent structural durability. Song et al. [217] developed a temperature-coupled conductive NGC fabricated via electrospinning, which can maintain a stable tubular configuration at physiological temperature and enhance electrical conductivity. The physicochemical properties and biocompatibility of four types of conductive NGCs (P, P/G, P/G-GO, and P/G-RGO) were evaluated through in vitro experiments. Meanwhile, these conduits were implanted in the dorsal region and sciatic nerve subcutaneous area of rats, and their biocompatibility and efficacy in promoting peripheral nerve regeneration were verified by histological and immunofluorescence analyses. At the same time, Qian et al. [326] successfully prepared curcumin nanoparticles (Cur-NPs) sensitive to both pH and temperature to enhance the bioavailability of curcumin. In vitro experiments demonstrated that Cur-NPs not only significantly improved the bioavailability of the drug, but also achieved smart responsive drug release in response to temperature changes in the injury microenvironment, thereby optimizing physiological effects [326].

Temperature-responsive biomaterials, represented by poly-N-isopropylacrylamide and its copolymers, provide a unique spatiotemporal manipulation tool for neural repair through their phase transition behavior [327]. In the repair of peripheral nerve defects, the typical “low-temperature sol–body-temperaturegel” property of these materials renders them ideal injectable in-situ forming scaffolds, which can non-invasively fill irregular defect cavities and provide physical support. In the fields of SCI and TBI treatment, their phase transition characteristics have been explored to achieve thermally triggered on-demand release of neurotrophic factors, or to encapsulate therapeutic cells via localized low-temperature-induced gelation. The advantage of this strategy lies in its reversible and rapid physical state response, which creates favorable conditions for minimally invasive implantation and spatiotemporally controlled delivery of local therapeutic agents. However, existing systems face significant limitations: first, most materials have a narrow and difficult-to-precisely regulate phase transition temperature window, which results in poor compatibility with the complex in-vivo physiological environment. Second, cyclic thermal stimulation may exert potential adverse effects on sensitive neural tissues. Third, a single physical state change cannot actively provide the multiple biochemical and topological cues necessary to guide the directional regeneration of nerves. Therefore, future development directions will focus on developing new biocompatible materials with broader and more precisely tunable temperature response thresholds, and striving to construct composite systems that synergize temperature responsiveness with other smart response mechanisms. For example, integrating temperature responsiveness with conductive polymers or anisotropic topological structures to create a multifunctional neural interface that can not only trigger drug release or alter stiffness via external mild thermal fields, but also provide electrical stimulation or contact guidance simultaneously. The ultimate goal is to realize SRES capable of adaptively adjusting their physical properties and bioactive signal output according to the demands of the repair stage, thereby dynamically matching the microenvironmental requirements at different periods during nerve regeneration, achieving an effect that fully biomimics the autologous nerve.

7.1.3. Light-controlled smart responsive

Near-infrared (NIR) light, featuring the advantages of long-distance transmission and stronger tissue penetration, has been increasingly adopted as a light source in drug release-assisted tissue regeneration [327,328]. By incorporating photothermal agents or light-responsive particles, electrospun fibers can be endowed with excellent photothermal properties, thus enabling efficient delivery of nutrients and drugs [[329], [330], [331]]. Studies have shown that the nanofibrous membrane fabricated via coaxial electrospinning technology consists of a core structure composed of quercetin-stabilized selenium nanoparticles (Qu@SeNPs) and electrochemically synthesized molybdenum disulfide nanosheets, with a matrix of PVA and α-lipoic acid (LA) cross-linked network [329]. This core-shell structured nanofibrous membrane (PMLQS) exhibits excellent air permeability and NIR light-responsive photothermal effects, achieving highly efficient antibacterial activity [329]. Furthermore, Li et al. [332] constructed a photothermally responsive N-isopropylacrylamide (PNIPAM) hydrogel loaded with SCs through surface modification and in-situ free-radical polymerization technology, in which multi-walled carbon nanotubes were modified with dopamine hydrochloride. The multi-walled carbon nanotubes treated with dopamine at a concentration of 2 mg/mL (abbreviated as 2 DM) demonstrated the strongest photothermal response performance, along with excellent dispersibility and stability [332]. The PNIPAM hydrogel modified with 2 DM possesses a porous structure, favorable hydrophilicity, and reversible photothermal response characteristics [332].

Light-controlled SRES introduce a new dimension of remote and precise regulation with high spatiotemporal resolution to neural regeneration by integrating photosensitive components with biological scaffolds [333]. In peripheral nerve repair, oriented fibers loaded with photothermal agents can generate localized thermal effects under near-infrared light irradiation, enabling on-demand release of neurotrophic factors or dynamic modulation of fiber topology to guide axonal extension. For SCI, photoresponsive hydrogels can not only achieve light-triggered drug release to modulate inflammation, but their photocurable property also facilitates minimally invasive in-situ molding and filling of irregular injury cavities. In the field of TBI, upconversion nanomaterials can convert near-infrared light— which has strong tissue penetration capability—into visible light or ultraviolet light, thereby activating photosensitive molecules to regulate NSC differentiation or inhibit glial scarring in a spatiotemporally controlled manner. The advantage of this strategy lies in its non-contact manipulation mode and nearly unlimited spatiotemporal regulation precision, which allows non-invasive directional intervention of specific cellular or molecular events in complex living organisms. However, its development faces inherent challenges: the limited tissue penetration depth of light, especially in the deep spinal cord and brain tissues, potential local thermal damage or phototoxicity caused by long-term or high-intensity light irradiation and the fact that most existing systems rely on single photothermal or photochemical reactions, making it difficult to synergistically regulate the multiple signals required for neural regeneration. The fundamental difficulty in neural repair lies in achieving dynamic and precise multi-stage, multi-target intervention throughout the lengthy and ordered regeneration process. Therefore, thereafter, novel deep-tissue optical control technologies based on multiphoton absorption or upconversion mechanisms can be developed, and efforts devoted to constructing smart material systems with multi-wavelength orthogonal response or multimodal synergy. For example, a scaffold can be designed that independently controls the release of immunomodulatory factors and the enhancement of conductivity using different wavelengths of light, thereby coordinating inflammation regulation and electrical signal guidance in a time- and region-dependent manner, realizing a biointerface that seamlessly integrates with neural tissue and is amenable to external optical programming, by which the regenerative microenvironment can be remotely regulated, propelling nerve repair from static substitution toward dynamic reconstruction.

7.1.4. Electrically smart responsive

Electrically SRES construct an electroactive microenvironment using conductive polymers, piezoelectric materials, or carbon-based nanomaterials [334,335]. They generate controllable electrical signals under external electric fields or mechanical stress to mimic the electrophysiological activities of nerves and promote neural regeneration [336,337]. Among them, piezoelectric materials generate charges or electrical potentials upon mechanical stress, enabling non-invasive electrical stimulation to promote nerve repair without the need for implanted electrodes [338]. Magnetoelectric materials convert external magnetic fields into electrical signals, allowing remote and deep-tissue stimulation across biological barriers [279]. This technology enables wireless remote regulation, allowing for precise spatiotemporal control over neural regeneration. Tang et al. [336] combined electrospinning and electrospraying to fabricate a biomimetic scaffold with conductive and aligned fibrous structures. The highly aligned PCL microfiber scaffold, co-sprayed with collagen and conductive polypyrrole nanoparticles, exhibited favorable bioactivity [336]. In addition, Song et al. [207] adopted a combination of HEC and PEDOT to enhance the conductivity of NGCs. Through electrospinning, they prepared spiral-structured conductive PLCL/HEC-PEDOT NGCs filled with aligned nanofibers (F-P/H-P). These electrospun F-P/H-P NGCs displayed excellent electrical conductivity, which significantly enhanced the adhesion and proliferation of SCs and PC12 [207](Fig. 7A). Furthermore, Jeon et al. [339] developed an ultrasound-responsive, highly oriented piezoelectric nanofiber nerve guidance conduit (APNF-NGC) for promoting peripheral nerve regeneration. The conduit was composed of PLLA nanofibers fabricated via electrospinning, featuring an anisotropic aligned structure and a shear piezoelectric effect, which enabled it to provide structural support while achieving electrical stimulation functionality [339](Fig. 7B).

Fig. 7.

Applications of smart responsive electrospun scaffolds in neural tissue engineering (A) Conductive F-P/H-P NGCs promote nerve regeneration under electrical ES [207]. Copyright 2025, Elsevier. (B) Wireless sonopiezoelectric conduit with aligned nanofibers for nerve regeneration [339]. Copyright 2025, Wiley. (C) Noninvasive method for achieving the regeneration of damaged nerves via ultrasonic nasal drops [340]. Copyright 2025, Elsevier. (D) A Magnetically controlled drug-loaded coaxial electrospun suspended fiber scaffold promotes SCs myelination [341]. Copyright 2025, Elsevier. (E) Magnetic-topological multistage synergy: anisotropic OVA scaffold loaded with magnetically responsive neural cells for remote peripheral nerve regeneration [100]. Copyright 2026, Elsevier. (F) DRG and RSC 96 cells cultured on OVA scaffolds: topology significantly enhances axonal orientation and connection; magnetic smart regulation of magnetized cells followed by coordinated magnetic field stimulation further facilitates axonal elongation; The synergy of both improves axonal alignment and elongation by approximately 30% [100]. Copyright 2026, Elsevier.

Current electrically SRES, including conductive polymers, piezoelectric and triboelectric materials, provide a regulatory strategy combining endogenous and exogenous modalities for neural repair by simulating or modulating the electrophysiological microenvironment of the nervous system [342]. In the repair of peripheral nerve defects, conductive nerve conduits not only provide topological structures for contact guidance of regenerating axons, but their inherent conductivity can also directly guide the directional migration of SCs and accelerate axonal extension via locally generated electrical signals with the assistance of external electric fields [343]. Their passive systems can continuously stimulate regeneration through piezoelectric signals generated by limb movements. For SCI, multifunctional scaffolds based on conductive polymers can not only bridge the injured area to transmit bioelectrical signals, but also induce the directional differentiation of loaded NSCs into neurons through electrical stimulation. In TBI models, microelectrode arrays combined with conductive hydrogels have been used to record neural activity and deliver precise electrical stimulation, aiming to reconstruct damaged neural network connections. The advantage of this strategy lies in its natural compatibility with the nervous system, allowing direct utilization of electricity, a native signal of the nervous system, to intervene in cell behavior, and it is particularly suitable for promoting neurogenesis, synapse formation, and functional circuit reconstruction. However, the long-term electrochemical stability of materials in complex bodily fluid environments, the ability for effective and safe charge injection, and how to translate external electrical stimulation parameters into precisely controllable in vivo biological effects remain technical challenges. In the future, biomimetic conductive composite materials with higher biostability and charge-carrying capacity can be developed, and efforts should be devoted to constructing a fully biomimetic, smart, integrated closed-loop neural interface system.

7.1.5. Acoustically controlled smart responsive

Ultrasound (US) exhibits mechanical, cavitation, and thermal effects, which can exert diverse biological effects on organs, tissues, and cells [344]. US stimulation induces the phosphorylation of signaling proteins in multiple pathways, such as PI3K/AKT/mTOR, Rho/ROCK/ERK, and MEK/ERK1/2/CyclinD1, thereby regulating a variety of biological responses including cell survival, proliferation, adhesion, migration, and differentiation [345,346]. Its mechanism lies in the use of precisely tunable ultrasound frequencies—typically ranging from low frequencies of 20–100 kHz to middle-high frequencies of 0.5–3 MHz—to interact with biological tissues or pre-implanted smart materials [347,348]. Through such frequency-dependent mechanical forces and cavitation effects, this technology can reversibly open the blood-brain barrier to enable targeted delivery of neuroprotective drugs to TBI regions, effectively modulate microglia-mediated neuroinflammatory responses, and provide guiding stimulation for axonal regeneration after SCI [349,350]. In peripheral nerve repair, specific ultrasound frequency gradients have been demonstrated to physically guide the migration of SCs and accelerate the myelination process [351]. Acoustically controlled smart responsive biomaterials are mainly used for the controlled release of drugs. Via acoustic response systems, they alter the carrier structure upon exposure to high- or low-frequency ultrasound, achieving efficient drug release. In addition, low-intensity pulsed ultrasound (LIPUS) has been widely applied in treatment centers and research to promote the differentiation and proliferation of stem cells [352]. Tiwari et al. [353] demonstrated that under ultrasound stimulation, ultrasound-responsive antibacterial silk composite scaffolds can respond to mechanical signals such as low-frequency ultrasound, thereby guiding the differentiation of seeded human mesenchymal stem cells toward specific lineages. Wireless ultrasound stimulation not only eliminates the need for cumbersome wired circuit design, but also has been proven to activate intracellular calcium ion channels. Zhu et al. [340] demonstrated that under ultrasound stimulation, intracranially delivered LTO@TB nanomaterials achieved non-invasive, targeted electrical modulation of injured neurons via an electro-pharmacological coupling effect. Whereas MS@LTO@TB further regulated microglial polarization toward an anti-inflammatory phenotype, restored the aberrantly disrupted electrical signal transmission between neurons, remodeled the local inflammatory microenvironment, markedly inhibited neuronal apoptosis, and activated the PI3K/AKT signaling pathway, thereby effectively promoting axonal regeneration (Fig. 7C).

In short, acoustically controlled smart responsive materials—especially ultrasound-responsive microbubbles, nanoparticles, or phase-change electrospun scaffolds—provide a non-invasive, remote-controlled tool with excellent tissue penetration capability for the field of neural repair. In the repair of TBI and SCI, focused ultrasound can trigger the targeted release of nanocarriers loaded with neurotrophic factors or anti-inflammatory drugs at specific injured sites, or transiently open the blood-brain barrier via mechanical effects to enhance delivery efficiency. For long-segment peripheral nerve defects, ultrasound-sensitive nerve conduits have been explored to achieve spatiotemporally controlled release of neurotrophic factors, so as to dynamically match the regeneration process. The advantages of this strategy lie in its strong deep tissue penetration and precise spatiotemporal regulation potential, which enable non-invasive intervention in deep lesions in vivo, and flexible control of treatment intensity and range by adjusting ultrasound parameters. However, its development faces a series of key challenges: the absorption and scattering effects of ultrasound energy in biological tissues may affect positioning accuracy and uniformity. The energy conversion efficiency, biosafety, and long-term stability of acoustically sensitive materials need systematic verification. More importantly, single-mode acoustic-controlled drug release or physical effects are difficult to meet the complex demand for multi-dimensional signal synergistic regulation during neural regeneration. What is urgently needed now is how to smartly adapt efficient external energy stimulation to the dynamically changing pathophysiological state within the injury site, thereby driving ordered functional regeneration. Looking to the future, in the direction of acoustically controlled smart responsive materials, novel sonosensitive materials with higher biocompatibility and energy conversion efficiency can be developed. This system, by integrating real-time ultrasound imaging and biosensing feedback, can automatically adjust ultrasound stimulation parameters according to the dynamic changes of the injury microenvironment, thereby achieving a leap from passive response to adaptive regulation.

7.1.6. Magnetically smart responsive

In cells and tissues within living organisms, magnetic stimulation has received widespread attention due to its characteristics of being non-invasive, painless, high precision, high penetrability, and low energy loss [354]. By integrating superparamagnetic nanoparticles, magnetically SRES can achieve regulated performance under the action of an external magnetic field [355]. The unique advantage of magnetically controlled smart responsive biomaterials lies in the fact that they can not only be applied in targeted drug delivery systems to regulate drug release rates and precisely control the delivery location and speed of drugs in vivo, but also exert mechanical or thermal stimulation on target regions under the action of an external magnetic field. Such materials usually contain magnetic nanoparticles and possess both favorable biocompatibility and magneto-responsive properties. In addition, Hu et al. [356] developed a magnetic nanochain-induced assembly method for anisotropic neural structures, which was applied for SCI repair. Under the action of a magnetic field, silica-coated magnetic nanoparticles self-assemble into stable and ordered nanochains. Through the smart responsive regulation of an external magnetic field, directional nanoarray structures are constructed in three-dimensional space, enabling the temporal regulation of the scaffold's spatial architecture. In vitro experiments demonstrated that these anisotropic nanochain arrays possess excellent biocompatibility and can effectively guide the oriented extension of neural cells and neuronal growth. In animal models, transplantation of the arrays into the spinal cord defect area (approximately 2 mm in length) of rats successfully stimulated the regeneration of newborn neurons and axons, and significantly improved motor function recovery. Furthermore, Sun et al. [341] fabricated a novel three-dimensional suspended fibrous scaffold using coaxial electrospinning technology. The scaffold has a PCL outer layer and an OVA inner, with the core loaded with magnetic nanoparticles carrying curcumin and cholesterol. Non-invasive, smartly responsive drug release can be achieved via an external magnetic field, thereby mimicking the complex microenvironmental changes during the neural repair process (Fig. 7D). Guan et al. [100] achieved remote and smart regulation of peripheral nerve regeneration through the synergy of magnetic smart responsive regulation and topological multistage coordination, based on an anisotropic OVA scaffold loaded with magnetically responsive neural cells. Their results further indicated that culturing magnetized and smartly responsive DRG and RSC 96 cells on the OVA scaffold showed that magnetic stimulation facilitated axonal elongation, while topological cues significantly enhanced axonal orientation and connection. The synergy of both improved axonal alignment and elongation by approximately 30%. In the 6% PEG + MAG group, cells exhibited an elongated and tightly connected morphology, and the BDNF secretion level was 1.5 times that of the control group. These findings suggested that the smart responsive magnetic field switch-mediated co-stimulation can enhance the secretion of neurotrophic factors and promote neural regeneration (Fig. 7E and F).

Magnetically smart responsive materials introduce a novel approach of remote, non-invasive, and spatiotemporally precise regulation to the field of neural repair by combining magnetic nanoparticles with biocompatible matrices. In SCI repair, magnetoelectric composite scaffolds can generate localized microelectric fields under stimulation by external alternating magnetic fields, effectively guiding the directional differentiation of NSCs and axonal growth. For peripheral nerve defects, oriented nerve conduits loaded with magnetic particles can remotely direct the ordered arrangement of SCs along the magnetic field direction via static magnetic fields, thereby enhancing their contact guidance effect. In TBI models, magnetic nanoparticles can serve as carriers to cross the blood-brain barrier under magnetic field navigation, enabling targeted delivery of neurotrophic factors or drugs. The advantage of this SRES lies in its excellent spatiotemporal manipulability and deep tissue penetrability, enabling non-invasive dynamic regulation of cell behavior and molecular delivery, thereby overcoming the limitations of traditional biochemical stimulation, including restricted diffusion and short duration of action. However, its development remains constrained by the complexity of the material system, including the potential biosafety concerns associated with long-term retention of magnetic components, the unclear quantitative relationship between magnetic field parameters and biological effects, and the difficulty in constructing a uniform and potent magnetically responsive microenvironment within complex three-dimensional injury sites. The current challenge lies in how to achieve seamless integration and synergistic amplification between this precise external physical manipulation and the intrinsically complex biological repair process. Therefore, subsequent research will enable the development of biodegradable smart materials with tunable magnetic response properties, and the construction of a closed-loop controlled nerve repair platform integrating biomaterials, magnetic fields, and microenvironmental regulation, which can dynamically adjust magnetic field parameters through real-time biofeedback, thereby synchronously regulating cell fate, guiding precise axonal projection, and modulating the local immune microenvironment, ultimately achieving a paradigm shift from passive support to active intervention.

7.2. Applications of SRES in neural tissue engineering

SRES constructed based on multiple electrospinning techniques have attracted widespread attention due to their tunable topography that mimics the regenerative microenvironment, appropriate mechanical support, drug loading capacity, and smart responsiveness [161,200]. Extensive studies have been conducted on SRES for TBI, SCI, and PNI [112]. Current SRES have achieved precise spatiotemporal regulation of the regenerative microenvironment in the field of neural tissue engineering by integrating a variety of advanced functional materials, such as thermosensitive PNIPAM, magnetically responsive Fe₃O₄ nanoparticles [355], conductive polypyrrole [357], and photosensitive titanium dioxide. These scaffolds can respond to external physical stimuli (e.g., magnetic fields, near-infrared light, electric fields) or changes in the pathological microenvironment (e.g., decreased pH value, specific enzyme expression) [358].

Currently, existing SRES are achieving integrated sensing-response-therapy functions through biomimetic design, leading biomaterials toward an smart interactive evolution. With the deepening convergence of multidisciplinary technologies, such SRES are expected to play a transformative role in tissue engineering and precision medicine. Thus, subsequent research directions can be based on constructing multi-level spatiotemporally ordered degradation to better match the process of nerve regeneration, avoiding excessive degradation or excessively slow degradation that affects nerve growth and development. The scaffold can self-curl from a two-dimensional membrane into a three-dimensional tubular structure at body temperature, precisely matching tissue defects. Machine learning-driven design employs large smart agent models to predict fiber morphology-performance relationships; by inputting polymer solution parameters (viscosity, conductivity) and processing conditions (voltage, humidity, etc.), the final fiber diameter and modulus can be predicted, substantially reducing experimental trial-and-error costs. With synergistic breakthroughs in material innovation and manufacturing technologies, SRES are gradually moving from laboratory research toward clinical applications. On the path to clinical and practical translational application, three major issues need to be prioritized: large-scale standardized production, long-term biosafety evaluation, and individualized precise matching. In addressing the above issues, high-precision electrospinning equipment combined with online quality monitoring can be developed in the future to achieve continuous large-scale standardized production of fibrous scaffolds for industrial applications. Long-term biosafety evaluation can be performed by establishing accelerated aging models to predict the long-term degradation behavior of materials, with a focus on assessing the accumulation of nanomaterials in lymph nodes and the liver, as well as their potential impact on the immune system. Individualized precise matching can be achieved by customizing the size of nerve grafts based on future AI large model clinical data, fabricating scaffolds that perfectly match the morphology of the patient's defect.

7.2.1. Applications in TBI

Due to the brain's limited self-repair capacity, the treatment of TBI has long been a critical challenge in modern medicine [359]. There is an urgent need to develop biofunctional scaffolds capable of promoting neuronal growth, guiding axonal extension, and reconstructing damaged brain tissue. After severe TBI, controlling secondary injury is of great significance for protecting neural tissue and function, especially when imbalanced neuroimmune responses trigger excessive inflammation [360]. However, effective therapeutic strategies for regulating neuroimmunity are still lacking. Bao et al. [361] discovered that fibroblast growth factor 21 (FGF21) is a promising candidate immunomodulatory drug, and constructed a bilayer electrospun scaffold to achieve efficient delivery of FGF21 to the brain. FGF21 was stably encapsulated in a PLA matrix, and its binding properties were verified via molecular docking. The FGF21-loaded PLA matrix was embedded in the inner layer of PLA/glyceryl monostearate (PT) nanofibers, enabling controlled release through pH-responsive matrix metalloproteinase 9 (MMP-9). Cross-linked zein/gelatin (CZG) was added to the outer layer to facilitate dural repair. Yin et al. [318] developed a barium titanate-reduced graphene oxide composite piezoelectric electrospun nanopatch that can adhere to the surface of NSC membranes for an extended period. This nanopatch regulates the generation of piezoelectric potential via an ultrasound-responsive switch. Driven by ultrasound, the piezoelectric stimulation generated by the nanopatch directly acts on voltage-gated calcium channels on the cell membrane, activating the calmodulin-dependent protein kinase II/cyclic adenosine monophosphate response element-binding protein (CaMKII/CREB) signaling pathway [318]. This significantly enhances the efficiency and maturation rate of NSC differentiation into functional neurons, and promotes the formation of biologically functional neural networks. In addition, the nanopatch is not endocytosed by cells, thereby avoiding the generation of ROS in lysosomes and the consequent cell death, achieving efficient and safe wireless regulation. Meanwhile, Liang et al. [362] developed an immune-piezoelectric sensor that can guide the polarization of microglia toward the anti-inflammatory M2 phenotype and promote the release of anti-inflammatory factors, significantly inhibiting inflammatory responses and creating an optimal environment for NSC survival. The sensor mainly regulates ultrasound-excited electrical stimulation via an smart responsive switch to induce NSC differentiation into glutamatergic and GABAergic neurons, enhance the complexity of neurites, upregulate the expression of synaptic proteins in the injured area, and improve neural network integration capability. In a rat model of TBI, the combined therapy exhibited excellent efficacy, not only restoring structural integrity but also improving functional performance and enhancing behavioral activities.

In summary, the practical application of SRES in the field of TBI repair remains in its early exploratory stage, facing a series of bottlenecks and difficulties that urgently need to be overcome [363]. First, most existing studies focus on a single response mode and a single therapeutic target, whereas the pathological process after TBI is a complex network of intertwined multiple signaling pathways with spatiotemporal dynamic evolution [364]. Second, brain tissue is extremely soft and highly heterogeneous, and the long-term compatibility and biocompatibility of the mechanical properties and degradation behavior of current electrospun scaffolds with the host brain tissue still require systematic optimization to avoid unnecessary foreign body reactions or secondary injuries caused by mechanical mismatch. Third, the translation rate from animal models to clinical applications is extremely low. Most studies are conducted under controllable laboratory conditions, whereas clinical TBI is highly heterogeneous, with great variability in the injury site, extent, severity, and individual physiological differences among patients, imposing extremely stringent requirements on personalized scaffold design and implantation methods. Moreover, how to implant these scaffolds non-invasively or minimally invasively into deep brain injury regions and ensure their long-term stable and reliable function in the dynamic brain microenvironment represents a major engineering challenge. Looking forward, future breakthroughs in this field will depend on deep interdisciplinary convergence and the integration of next-generation neural graft construction technologies. Simultaneously, it is essential to strengthen the close integration of basic neuroscience and clinical medicine, utilizing advanced models such as organoids and organs-on-chips to deeply investigate the mechanisms of scaffold interactions with the complex neuroimmune-vascular unit, thereby establishing a solid biological foundation for clinical translation. Ultimately, these smart biomaterials can be transformed from highly conceptual laboratory prototypes into safe, effective, and innovative clinical therapeutic tools capable of truly addressing the major clinical challenge of TBI.

7.2.2. Applications in SCI

As a vital component of the CNS, the spinal cord is often accompanied by exacerbated inflammatory responses following injury [365]. These responses further aggravate tissue damage, impair the structural integrity of the spinal cord, create a microenvironment unfavorable to regeneration, and ultimately lead to permanent sensory and motor dysfunction below the level of injury [366]. At present, there remains a lack of effective clinical treatment options for this condition [366]. To address this complex challenge, researchers have begun to explore the potential value of immunomodulators in therapy. Electrospinning technology enables the fabrication of nanofibrous structures mimicking the ECM, providing an ideal biomimetic platform for cell adhesion, proliferation, and controlled drug release. Fan et al. [367] developed an electrospun nanofiber scaffold with excellent mechanical properties, using thermoplastic polyurethane (TPU) and polyethylene oxide (PEO) as the base materials and incorporating TA. Dopamine-modified Fe₃O₄-BaTiO₃ (PDA/Fe-BTi) nanoparticles were embedded into the scaffold, which can generate electrical effects and electrical stimulation through remote magnetic field-responsive regulation to modulate neural function. Meanwhile, under the action of an external magnetic field, the scaffold maintained cell morphology, exhibited favorable biocompatibility, and effectively promoted axonal growth. Implanting the scaffold at the injury site and applying a magnetic field significantly optimized the local microenvironment, facilitated neural regeneration, and thus markedly improved motor function in rats (Fig. 8A). Regulating inflammatory immune responses and NSC function represents a key strategy for promoting functional recovery of the CNS. Tang et al. [200] innovatively integrated a hydrogel “perfusion” system with electrospinning technology to develop a composite scaffold material for neural injury repair. This composite scaffold smartly responds to changes in the neural regenerative microenvironment to achieve controlled release of stromal cell-derived factor-1α (SDF-1α) and brain-derived neurotrophic factor (BDNF). These factors increased the recruitment of NSCs by approximately 4-fold and enhanced neuronal differentiation efficiency by around 2-fold, respectively. The fibrous structure not only modulated the local immune-inflammatory status, but also promoted the recruitment of endogenous NSCs, stimulated the formation and maturation of new blood vessels, and significantly improved neural function recovery in a rat model of SCI (Fig. 8B). Furthermore, Gao et al. [370] developed a redox-responsive mechanism based on pH-responsive regulation for the controlled release of reduced nicotinamide adenine dinucleotide (NADH) via biodegradable mesoporous silica nanocarriers containing bioactive diselenide bonds (Se@NADH). The NADH encapsulated in these nanocarriers can be precisely released through the cleavage of diselenide bonds in environments containing ROS or glutathione (GSH). The released NADH reacts with harmful ROS to regenerate NAD⁺, thereby alleviating mitochondrial dysfunction, enhancing ATP production efficiency, and promoting axonal regeneration in the SCI area. This nanosystem not only prolonged the circulation time of NADH in vivo, enhanced its stability, and reduced its clearance rate, but also exhibited significant anti-inflammatory and neuroprotective effects, and improved the recovery of electrophysiological conduction ability in the injured area. Most notably, Se@NADH inhibited glial scar formation, stimulated neuronal neogenesis, and guided the growth of long axons across the scar region. Ultimately, it significantly improved motor function recovery in mice with SCI, yielding superior therapeutic outcomes. Chen et al. [368] constructed an ECM-mimetic nanofiber scaffold integrated with pH-responsive metal-phenolic network nanoparticles, which released Mg²⁺ to block Ca²⁺ influx, thereby alleviating excitotoxicity, and suppressed neuroinflammation by reducing pro-inflammatory mediators (Fig. 8C).

Fig. 8.

Applications of smart responsive electrospun scaffolds in neural tissue engineering. (A) A high-strength nanofiber scaffold loaded with PDA-modified magnetoelectric nanoparticles for SCI repair [367]. Copyright 2025, Sciopen. (B) Engineered fibrous composites ameliorate local inflammatory responses, promote nerve regeneration via a hydrophilic programmed cytokine delivery system, and improve and complement the immune response mechanisms regulated by the inherent properties of biomaterials [200]. Copyright 2023, Wiley. (C) pH-responsive triggered release of Mg²⁺, achieved via ECM-mimetic nanofibers incorporating metal-phenolic network nanoparticles, mediated neuroprotection and axonal regeneration, leading to SCI repair [368]. Copyright 2025, Wiley. (D) Piezoelectric stimulation of electrospun composite nanofibers for rapid peripheral nerve regeneration [209]. Copyright 2022, Elsevier. (E) Biomimetic piezoelectric OVA/BaTiO₃ combined with anisotropic topology synergistically regulates the behaviors of SCs and DRG [239]. Copyright 2024, Elsevier. (F) A thermoresponsive self-coiling multichannel NGC, composed of shape-memory PLMC, SF, and rGO, enables scarless regeneration and provides personalized nerve matching [369]. Copyright 2025, Elsevier.

In the field of neural tissue engineering, the development of SRES is advancing SCI repair strategies from passive structural support toward active dynamic microenvironmental regulation [371]. Their design concept lies in integrating multiple responsive modules into a biomimetic fibrous matrix to construct a functional interface capable of sensing and responding to specific biophysical or biochemical signals. Such scaffolds not only provide topographical cues to guide axonal regeneration but also enable, upon smart-responsive triggering by external physical fields or endogenous pathological signals, the temporally controlled release of neurotrophic factors, local modulation of inflammatory responses, or directed guidance of stem cell fate, thereby theoretically achieving stage-specific intervention in the complex repair process. However, current systems still face significant challenges: most smart-responsive behaviors have been validated in controllable in vitro or acute animal models, whereas their responsiveness efficiency and reliability remain questionable in the complex environment characteristic of human SCI, including chronic inflammation, dense glial scar formation, and cavitation; the synergistic mechanisms among different smart-responsive systems remain unclear, making it difficult to systematically recapitulate the ordered signaling network necessary for physiological repair; more critically, functional recovery depends on long-distance, target-specific neural circuit reconstruction, whereas current preset logic-based paradigms fail to meet the stringent requirements for precise spatiotemporal coordination of multiple signals in this process. Therefore, a future direction may shift from single responsive materials toward adaptive systems endowed with biofeedback capacity. By deeply integrating smart fibrous structures with flexible biosensing elements and microfluidics, it is expected to develop next-generation interactive neural interfaces capable of real-time monitoring of local microenvironmental changes and dynamically adjusting therapeutic outputs. This direction aims to propel repair platforms from static implants toward dynamic regulators, thereby offering new possibilities for promoting functional integration of neural circuits.

7.2.3. Applications in PNI

Peripheral nerves are distributed throughout the human body and serve as crucial communication bridges connecting the CNS to other parts of the body [14,371]. Nerve injury typically leads to motor and sensory impairments, and the rapid reconstruction of structural integrity is essential for optimizing repair outcomes [372,373]. SRES can dynamically adjust themselves in response to environmental changes, thereby mimicking the microenvironment of nerve regeneration in a more biomimetic manner. Chen et al. [374] designed a composite scaffold loaded with melatonin (MLT) and Fe₃O₄ magnetic nanoparticles (Fe₃O₄-MNPs), which enables sustained, magnetically responsive, and smartly controlled drug release via a magnetic field switch, thus creating a microenvironment conducive to nerve regeneration. This scaffold exhibited favorable mechanical properties and biocompatibility in vitro, and significantly promoted the recovery of neural structure, function, and electrophysiological characteristics in a sciatic nerve defect model. In addition, Mao et al. [209] fabricated PCL/zinc oxide nanofibers (abbreviated as PZNF) using electrospinning technology, constructing nerve conduits with piezoelectric properties. This material can generate stable endogenous electrical stimulation through smart response to mechanical stimuli, which remarkably accelerates the regeneration of sciatic nerves. Their experiments demonstrated that PZNF outperformed pure PCL nanofibers and traditional in situ nerve bridging methods in sciatic nerve repair, exhibiting faster and superior repair efficacy. Furthermore, this piezoelectric property can also significantly upregulate the expression levels of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), thereby accelerating the recovery of nerve function and shortening the rehabilitation cycle (Fig. 8D). Gao et al. [239] developed a piezoelectric topological scaffold loaded with barium titanate (BTO) nanoparticles, which possesses excellent mechanical strength and hydrophilicity. Moreover, it can smartly respond to and regulate mechanical triggers to maintain piezoelectric performance, thereby providing in-situ and non-invasive electrical stimulation for tissues and cells. This scaffold can promote the early proliferation and migration of SCs, and continuously guide cell elongation; meanwhile, the synergistic effect of piezoelectric signals and surface topography regulates the growth direction and extension of dorsal root ganglion axons (Fig. 8E).

To overcome the challenge of “inflammation-oxidative stress-ischemia-delayed regeneration” in the repair of long-distance peripheral nerve defects, Dong et al. [375] innovatively proposed a triple synergistic strategy consisting of “chemical signals (nitric oxide) + micro/nano-structured hydrogels + electrical stimulation (electroactive conduits)". They designed ROS (ROS)-responsive nitric oxide (NO) nanodrug donor particles (PTKNO NPs), which undergo phase transition and rapidly release NO when triggered by excessive ROS at the injury site. This process inhibits the NF-κB/TNF inflammatory pathway, activates the PI3K/AKT/eNOS and cGMP/PKG pro-angiogenic pathways, improves mitochondrial dynamics and ATP synthesis, and comprehensively optimizes the regenerative microenvironment. At the structural level, a secondary crosslinking process of covalently photocrosslinked gelatin-lipoic acid/selenolipoic acid (Gel-LA-SA) microgels was adopted to construct hydrogel chambers with multiscale interconnected macropores, which significantly enhances cell migration ability and long-distance axonal growth. In terms of physical regulation, the outer layer of the conduit was wrapped with Ag@P (MMD-CL) spiral coils, which realize non-invasive electrical stimulation via induced current from alternating magnetic fields, thus promoting neural cell migration and the secretion of neurotrophic factors (e.g., BDNF, NGF). The multi-module synergy endows the conduit with anti-inflammatory and antioxidant capabilities in the early in-vivo stage, rapidly forms a vascular network to provide nutritional support. After 12 weeks, it exhibits larger axon diameter, thicker myelin sheath, higher nerve conduction velocity, and greater compound muscle action potential (CMAP) amplitude. Gao et al. [369] developed a thermoresponsive adaptive multichannel NGC composed of a shape-memory polyester (poly (lactide-co-trimethylene carbonate), PLMC), SF, and reduced graphene oxide (rGO), which exhibited both scarless regeneration capability and personalized anatomical conformability. The electrospun PLMC/SF-rGO conduit featured an axially aligned intraluminal fibrous architecture that provided directional topographical guidance cues, while leveraging the thermoresponsive property of PLMC to enable intraoperative on-demand shaping and morphological stability during the regeneration process. Histological analysis further confirmed enhanced axonal regeneration, with levels of NF200 and S100β expression approaching those of autologous nerve grafts, demonstrating excellent neuroregenerative performance (Fig. 8F). The applications of SRES in neural tissue engineering are summarized in Table 4.

Table 4.

Applications of SRES in neural tissue engineering.

Electrospinning Material	Electrospinning Type	Stimuli-Responsive Modality	Tissue Type	Therapeutic Effects	Reference
PCL-RGP-Fe3O4	Anisotropic	Magnetically responsive	Nerve injury repair	This magnetic scaffold promoted axonal extension, enhanced cellular activity, upregulated BDNF and NGF expression, and improved motor function in animal models.	[376]
PCL/Fe3O4	Anisotropic	Magnetically responsive	PNI	This magnetic composite guided and promoted directional axonal extension, upregulated gene expression associated with adhesion, proliferation, and magnetoreceptor function.	[14]
Magnetic graphene hybrid (MGH) with PLGA	Aligned coaxial nanofiber scaffold	Magnetically responsive	Optic nerve regeneration	This aligned coaxial nanofiber scaffold improved directional neurite extension of retinal ganglion cells (RGCs), restored optic nerve function, and inhibited RGC apoptosis.	[377]
PCL/Gelatin/iron oxide nanoparticles	Three-dimensional (3D) magnetic nanofiber scaffold	Magnetically responsive	Neural differentiation of stem cells	This 3D magnetic nanofiber scaffold enhanced mesenchymal stem cell neural differentiation, promoted cell proliferation, and enhanced cell infiltration.	[378]
PCL/BaTiO3 and PLLA-PAG-CS-Gel	Bilayer fibrous conduit	Piezoelectrically responsive	Neural tissue engineering	This bilayer fibrous conduit significantly promoted sciatic nerve regeneration and improved neurological functional recovery. At 4 weeks post-operation, nerve regeneration in rats was superior to that in the control group, with a significantly improved sciatic nerve function index and increased axon count facilitating nerve repair.	[379]
PLCL/HEC-PEDO	Helically structured conductive conduit	Piezoelectrically responsive	PNI	This helically structured conductive conduit accelerated peripheral nerve regeneration, neurovascularization, and functional recovery; significantly enhanced SCs and PC12 cell adhesion and proliferation; promoted nerve regeneration-associated protein expression; in vivo, significantly promoted peripheral nerve tissue regeneration and angiogenesis, with markedly improved nerve conduction velocity and compound muscle action potential amplitude, yielding functional recovery outcomes approaching those of autografts.	[207]
PCL/ZnO	Composite nanofibers	Piezoelectrically responsive	PNI	This composite nanofiber scaffold facilitated rapid sciatic nerve repair and shortened functional recovery time. In vivo, it significantly promoted sciatic nerve functional recovery and physical continuity within 4 weeks post-operation, accompanied by a marked increase in myelin sheath number, via activation of the RET signaling pathway and its downstream protein GRB2 to promote nerve regeneration.	[209]
PVDF and P(VDF-TrFE) fibrous scaffolds	Electrospinning	Piezoelectrically responsive	Neural tissue engineering	These piezoelectric fibrous scaffolds promoted osteoblast and neural cell adhesion, proliferation, and differentiation; enhanced NSC differentiation and axonal growth.	[380]
Thermoresponsive drug-loaded nanofibrous membrane (PNLA/PLLA)	Blend electrospinning (PNLA and PLLA blend)	Thermoresponsive	Controlled drug release system (potential for tissue engineering applications)	This thermoresponsive membrane allowed drug release rate to be tunable via PNLA content and molecular weight, as well as environmental temperature.	[381]
Magnetic composite conduit (PHB and Fe3O4−CA based)	Magnetic composite conduit (PHB and Fe3O4−CA based)	Magnetically responsive	Peripheral nerve repair	This magnetic composite conduit supported rat bone marrow mesenchymal stem cell (rMSC) and SH-SY5Y cell proliferation under a magnetic field. In vivo, the conduit successfully functioned as a barrier and promoted nerve regeneration.	[382]
BTNPs/P(VDF-TrFE) nanofibers and pNIPAM thermoresponsive hydrogel	Aligned piezoelectric nanofibers integrated with a hydrogel	Ultrasound-triggered electrical stimulation and thermoresponsive controlled release	Peripheral nerve regeneration	This integrated system accelerated functional recovery and axonal regeneration, significantly promoting repair of long sciatic nerve defects in a rat model.	[383]
SF/PVDF-HFP/MXene composite	Composite scaffold	External ultrasound mechanical stimulation (piezoelectric effect))	Peripheral nerve regeneration	This composite scaffold enhanced SCs proliferation, promoted axonal elongation and myelination, and enabled robust recovery of motor and sensory function, allowing safe and effective nerve repair.	[384]
PLGA fibers with PEDOT:PSS coating	Porous aligned electrospun neural conduit	Electrically responsive	PNI repair	This porous aligned neural conduit significantly enhanced hindlimb functional recovery in rats, improving the therapeutic efficacy of nerve regeneration.	[15]
PLA/KNN@PDA nanofibers	Electrospun nanofibers	Ultrasound-driven wireless electrical signal	SCI repair	These electrospun nanofibers accelerated motor functional recovery and promoted SCI repair.	[385]
PVA/MoS2/LA/Qu@SeNPs coaxial nanofibrous membrane	Coaxial electrospun nanofibrous membrane	NIR light responsive	Anti-drug-resistant bacterial infection	This coaxial nanofibrous membrane exhibited effective bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and other bacteria, showed low cytotoxicity, and promoted endogenous neural differentiation and angiogenesis.	[329]
Coaxial electrospun mat (shell: AVT-loaded, core: ZnO-loaded)	Coaxial electrospinning	Piezoelectrically responsive	Vascularized bone regeneration	This coaxial electrospun mat enhanced vascularization, promoted bone regeneration in critical-sized bone defects, and facilitated osteogenic differentiation via activation of calcium signaling pathways.	[386]

In summary, SRES, as next-generation neural interface materials, are providing spatiotemporally precise regulatory strategies for nerve repair through their dynamic responsiveness to external physical or chemical cues. According to their response mechanisms, they can be mainly classified into magneto-responsive, electro-responsive, photo-responsive, and a range of microenvironment-responsive types. In SCI repair, magnetoelectric-responsive fibers can be induced by external magnetic or electric fields to respectively direct the differentiation of neural stem cells or guide axonal regeneration. For peripheral nerve defects, photothermal-responsive scaffolds enable remotely triggered on-demand release of neurotrophic factors. In the complex environment of TBI, reactive oxygen species-responsive fibers can specifically degrade at the injury site and release anti-inflammatory drugs. The advantage of such smart materials lies in their ability to transform static physical support into a dynamic and tunable biological functional interface, thereby achieving active regulation of the regenerative microenvironment. Nevertheless, existing systems still face numerous challenges: the synergistic integration mechanisms among different response systems remain unclear; the quantitative relationship between the intensity and frequency of external energy stimulation and in vivo biological effects lacks systematic investigation; moreover, most smart-responsive behaviors are still at the stage of in vitro validation, and their long-term stability, biosafety, and ultimate repair efficacy in the complex in vivo environment remain to be confirmed. Therefore, a future direction is to deeply integrate the hierarchical structures of systematized SRES with flexible electronic sensing technologies, developing scaffolds with “sensing-feedback-therapy-monitoring” capabilities that can real-time monitor local biochemical markers and automatically adjust drug release or physical properties. The ultimate goal is to construct bio-fused smart implants capable of bidirectional information exchange with the host nervous system, truly moving from replacing the autologous nerve graft to surpassing it, realizing bionic limb replacement, and comprehensively improving patient quality of life and lifespan.

8. Big data analysis

To more comprehensively analyze the research landscape and frontier dynamics of SRES in the field of nerve regeneration, we conducted a bibliometric analysis based on 496 relevant research articles from the past decade indexed in the Web of Science database, using VOS-viewer to generate visualization maps. The network visualization analysis (Fig. 9A) clearly reveals the primary modes of responsiveness in this field: first, electrical stimulation, as the regulatory modality most directly coupled to the inherent electrophysiological activity of the nervous system, exhibits the largest node and densest connections in related research, indicating that applying external electric fields or constructing bioelectric potential gradients using conductive electrospun fibers to guide axonal regeneration and promote neural differentiation of stem cells has become a well-established therapeutic strategy. Second, technologies such as magnetic stimulation, light stimulation, and ultrasound response, leveraging their unique advantages of non-invasiveness, deep tissue penetration, and high spatiotemporal resolution, have demonstrated substantial potential for achieving remote and precise drug release as well as manipulating cell behavior, complementing electrical stimulation strategies. Finally, smart materials such as magnetic nanoparticles and upconversion nanoparticles, serving as the carriers for realizing the aforementioned physical responses, have emerged as a hub connecting fundamental materials science with neurobiological applications. The density visualization analysis (Fig. 9B) further quantifies research hotspots, confirming that “stimuli-responsiveness” and “stem cells” are the most frequently co-occurring keywords, reflecting the current dominant paradigm—namely, constructing dynamic microenvironments through smart materials to regulate and recruit endogenous stem cells, thereby driving nerve regeneration. However, this mapping also highlights a non-negligible issue: despite the substantial number of fundamental research articles in this field, nodes such as “clinical trial” and “translational medicine” are almost entirely absent from the keyword network, which aligns with our in-depth literature review—no smart-responsive electrospun scaffold has yet entered the clinical stage. In the field of SCI, the only commercially available artificial nerve scaffold that has been applied clinically is a collagen-based scaffold-NeuroRegen [387,388]. On one hand, this reveals the clinical feasibility of biomaterial bridging and indicates the great potential of this direction; on the other hand, it also highlights the translational gap that current smart scaffolds face in terms of complexity, safety, standardization, and large-scale production [389]. The temporal overlay network visualization (Fig. 9C) further reveals another challenge from the perspective of researcher collaboration: although multiple global teams (for example, active teams from China, the United States, Europe, etc.) are making efforts in this field, the collaboration network among teams remains sparse, exhibiting a certain decentralized research landscape, which may delay the progress in tackling key common technical difficulties.

Fig. 9.

Visualized Analysis of Research Progress on SRES in the Field of Neural Regeneration(A)Network visualization analysis.(B)Density visualization analysis.(C)Timeline diagram of visualized analysis on the collaborative network of research teams focusing on the application of SRES in neural regeneration over the past decade.

Focusing on the specific applications in different neural tissues, SRES exhibit distinct developmental trajectories and challenges. In PNI repair, the research is the most advanced, with a clear goal centered on providing contact guidance and directional stimulation through electro-/magneto-responsive scaffolds, synergizing with Schwann cells to promote rapid, orderly, and long-distance axonal extension. The advantages lie in the relatively favorable PNI microenvironment and straightforward functional assessment. However, most current studies are limited to rat sciatic nerve defect models of <15 mm, and effective solutions remain lacking for more clinically challenging scenarios, including lengthy defects of large-diameter nerves, precise alignment of mixed sensory and motor fascicles, and reversal of chronic denervation muscle atrophy. In SCI repair, the regulatory approaches are more complex and diverse, requiring simultaneous management of multiple obstacles such as glial scar, inflammatory outburst, and neural circuit disruption. The role of SRES here is not only bridging but also microenvironmental modulation. Moreover, the complexity of SCI models is far greater than that of PNI. Most reports of significant functional recovery based on SRES are limited to acute hemisection models in mice/rats, whereas their repair efficacy for chronic, complete transection, and cavitated injuries that more closely resemble human SCI is extremely limited, and functional reconstruction of fine sensorimotor circuits remains difficult to validate. In TBI repair, the application is still in an early exploratory stage, primarily using photo-/ultrasound-responsive systems to achieve targeted drug delivery across the blood–brain barrier for alleviating neuroinflammation or edema. The core difficulty lies in the high complexity and functional plasticity of the brain. SRES must not only morphologically adapt to irregular injury cavities but also functionally intervene in the sophisticated processes of neurogenesis, angiogenesis, and neural network remodeling, a depth that current research is far from reaching.

In summary, although the field of SRES holds promise, its development is facing a series of difficulties. First, the issue of multimodal signal coordination: nerve regeneration is a multi-stage, multi-factor process, yet most current smart scaffolds can only respond to a single physical field, such as only electricity or only light, making it difficult to simulate the spatiotemporal synergistic symphony of multiple signals in vivo. Second, insufficient dynamic adaptability: the injury microenvironment changes dynamically with the repair process, whereas the response logic of existing materials is often simple and static, lacking the smart responsiveness to adaptively adjust their physical properties and bioactive output according to the regeneration stage. Third, the lack of integration from single device to system. An ideal neural repair should be a closed-loop system incorporating sensing, decision-making, and execution, whereas current scaffolds are mostly open-loop “stimulus-response” devices, unable to sense local biomarkers (such as neurotransmitter and inflammatory cytokine concentrations) in real time and make feedback adjustments. Fourth, clinical translation barriers. In addition to the aforementioned issues of biosafety and scalable manufacturing, for TBI/SCI, how to integrate smart scaffolds with existing surgical procedures and how to perform long-term in vivo functional monitoring and regulation of them remain insufficiently explored. Finally, the research approach should shift from independent and fragmented efforts to collaborative networking. As shown in the temporal overlay network visualization, deepening the deep integration and cross-disciplinary collaboration among materials scientists, neurobiologists, clinicians, and application engineers, and jointly establishing standardized performance evaluation systems and clinical translation pathways for nerve regeneration, represents the pathway to ultimately push this highly promising laboratory technology to the clinic and achieve a breakthrough from 0 to 1 in the field of nerve repair.

Furthermore, to demonstrate the research trends and major progress of SRES over the past decade, we have drawn a development timeline of smart responsive electrospun scaffolds for nerve repair (2016–2026), illustrating the process of strategy optimization from single stimulus response to multimodal smart responsive regulation of nerve regeneration over the ten years (Fig. 10).

Fig. 10.

Development timeline of SRES for nerve repair from 2016 to 2026: over the decade, from single stimulus response to multimodal smart responsive regulation of nerve regeneration.

9. Current problems and future prospects

Electrospinning technology has demonstrated significant advantages in numerous fields, including batteries [390], wearable devices [391],bone regeneration [392],and sensors [393], and its application in neural regeneration exhibits great potential, particularly in achieving post-implantation smart responsive regulation, long-term visualizable monitoring, precise control of nerve regeneration rate, and ensuring long-term efficacy [394]. However, due to the inherent limitations of electrospun scaffolds, cautious consideration is still required [33]. First, although the aligned architecture of electrospun fibers can mimic the anisotropy of the native extracellular matrix, its biomimetic fidelity remains insufficient compared with the highly ordered, multi-scale hierarchical structure within native nerve fascicles. Second, the temporal coordination between scaffold degradation rate and axonal growth rate has not been systematically optimized; excessively rapid degradation may lead to premature loss of mechanical support, whereas overly slow degradation may impede new tissue remodeling. Furthermore, functional modules introduced to confer smart responsive properties, such as conductive coatings, temperature-responsive coatings, or magnetic nanoparticles, may compromise the mechanical integrity of the scaffold or provoke potential inflammatory responses or cytotoxicity, thereby offsetting their intended benefits. Therefore, the safety of their application needs to be further validated in different animal models and injury models. Significant deficiencies still exist. Therefore, before future research is conducted, it is necessary to start from the fundamental goals of material design; for example, smart responsive electrospun scaffolds need to maintain stable and reliable performance responses in the complex in vivo physiological environment while simultaneously meeting high biosafety requirements.

Moreover, although current hybrid strategies that combine natural and synthetic materials can achieve complementary performance, the construction of smart responsive systems is often accompanied by increased complexity in structure and regulatory mechanisms, which may pose additional challenges for their clinical translation [395]. Hence, the design of electrospun scaffolds for neural regeneration should pay more attention to the balance among functional practicality, system simplicity, and clinical translatability. Research focus could be on achieving intelligent and biomimetic functional upgrades while simplifying the material system or manufacturing process. For example, one could explore the design of biomaterials whose degradation products themselves possess neurotrophic or neuroprotective functions, thereby constructing scaffold systems that more closely recapitulate the physiological repair process, rather than merely pursuing excessive structural complexity or methodological novelty.

At the level of clinical translation, smart responsive scaffolds must undergo systematic validation of their biocompatibility, long-term safety, and response efficiency in complex, dynamic physiological environments, with full consideration of interindividual differences in patients' anatomical structures and physiological microenvironments. Existing studies have shown that pH fluctuations in the local injured microenvironment may affect the targeted release efficiency of pH-responsive materials, while the distribution and enrichment behaviors of magnetic nanoparticles in vivo also exhibit interindividual variability. In addition, the standardization and quality control of electrospun scaffolds during large-scale production, the standardized setting of response parameters, and the adaptability of regulatory review pathways are all key bottlenecks restricting their clinical translation. Currently, only a few systems such as thermosensitive hydrogels have entered the clinical trial phase, and the vast majority of SRES remain in the preclinical research stage. In the future, there is an urgent need to achieve real-time monitoring and feedback of material behaviors through the in-depth integration of materials science, biology, clinical medicine, and engineering, combined with advanced in vivo imaging and sensing technologies [247]. It is also necessary to establish animal models that are more closely aligned with the pathological characteristics of human diseases, so as to systematically evaluate and accelerate their clinical translation process.

Although significant preclinical progress has been made in smart responsive electrospun scaffolds, that is, SRES, for nerve repair, several obstacles remain to be addressed in clinical application [396]. First, regulatory pathways need to be clearly defined. Most SRES belong to combination products, that is, device plus biological or drug components. Under the FDA's guidance framework for combination products, the preclinical data package required for an Investigational Device Exemption (IDE), should include stimulation control functionality, biocompatibility, sterility, and stability verification of responsive components. Second, the engineering challenges of scale-up production require systematic solutions. Major issues include batch-to-batch consistency of fiber alignment, uniformity of stimulus-responsive material coating, and development of sterilization methods that maintain smart responsive functionality, such as ethylene oxide or low-temperature plasma instead of autoclaving. Third, clinical trial design considerations deserve special attention. It is necessary to conduct dose-finding studies to establish the relationship between stimulation parameters, such as magnetic field intensity, electrical pulse frequency, and light intensity, and therapeutic effects. Long-term biocompatibility endpoints should be evaluated in large animal models within clinically relevant timeframes, for example, exceeding six months, with particular attention paid to chronic inflammation, implant stability, and potential off-target effects of the applied stimulation. In addition, adaptive trial designs that can account for inter-individual variability in responsiveness are recommended. Addressing these issues will transform the current technology inventory into an actionable clinical translation roadmap.

Furthermore, to advance the transformation of SRES toward interactive and adaptive systems, the development of integrated systems capable of responding to multiple stimuli and acting synergistically has become a major trend. By integrating composite response mechanisms such as magnetic field-temperature and photothermal-pH responsiveness, it is possible to better match the dynamic requirements of different stages during neural regeneration. Nevertheless, for such multi-signal programmed systems, it is imperative to carefully evaluate the spatiotemporal control precision of each trigger signal, the coupling effects between signals, and their potential biological impacts. In addition, computational simulation modeling and artificial intelligence methods can be combined to optimize the regulation strategies. For instance, the parameters of magnetic field stimulation need to be precisely regulated to avoid non-specific cellular effects or tissue thermal damage.

In summary, although SRES face multiple challenges in the field of neural regeneration, including material design, system integration, process scale-up, and clinical validation, it can be predicted that this research direction holds great promise and enormous potential [397]. Its future development will inevitably rely on the in-depth collaboration of basic research, engineering innovation, and clinical needs. By continuously optimizing the biomimetic properties of biomaterials themselves through emerging technologies such as in vivo bioprinting and induced pluripotent stem cell technologies, integrating multiple smart response modalities while ensuring their reliability, developing smartly responsive active regulation systems that possess both multifunctionality and simplicity, and establishing a comprehensive clinical outcome-oriented evaluation system, this technology is expected to become a key driving force for advancing the field of neural repair toward active, precise, and dynamic therapies, thus opening up new avenues for breakthroughs in tissue engineering and regenerative medicine.

Notes

The copyright of all the images cited form published literatures is provided in the Supplementary File.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

Not applicable.

CRediT authorship contribution statement

Huoyun Shen: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft. Mingzhu Jia: Formal analysis, Investigation, Methodology, Resources, Software. Hui Zhu: Data curation, Formal analysis, Investigation, Methodology, Software. Yuqing Shang: Formal analysis, Investigation, Methodology. Lele Wang: Project administration, Software, Validation. Hongxia Gao: Methodology, Resources, Validation. Yaqiong Liu: Data curation, Formal analysis, Software. Chunsheng Xiao: Resources, Software, Visualization. Yumin Yang: Project administration, Resources, Supervision, Validation. Qi Han: Project administration, Resources, Software, Supervision. Guicai Li: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following is the Supplementary data to this article: