Electrospun Scaffolds for Spinal Cord Injury Repair: Mechanisms, Strategies, and Advances

SCI, as a complex and serious medical condition, can be traced back to various external and internal factors, including but not limited to severe trauma, long-term inflammatory infiltration, spinal cord tumor occupying space, vascular disease obstruction, etc. These unfavorable factors work together in the human body, causing damage to the structural integrity of the spinal cord, a key nerve center, and leading to its comprehensive decline in function [1,2,3]. This type of injury profoundly affects the intricate neural transmission network within the spinal cord, resulting in a series of serious clinical consequences in the body segments below the site of injury, such as loss of motor ability, decreased or even disappeared sensory function, autonomic dysfunction, and frequent pathological reflexes, seriously disrupting the patient’s daily life and psychological state [4,5,6].

Globally, although the incidence rate of SCI fluctuates due to differences in regions, statistical methods, and time periods, it is generally estimated that it is between 3.6 and 195.4 cases/million people, of which the proportion of male patients is significantly higher than that of female patients, accounting for about 78% of the total cases [7,8]. This gender difference has been verified in many research reports around the world. In China, SCI also poses a health challenge that cannot be ignored [8,9,10]. Its incidence rate is between 25 and 60 cases/million people, and the patient population is mainly middle-aged men, mostly aged between 40 and 60 years old [11,12].

Currently, the primary treatment options for SCI encompass drug therapy, surgical intervention, stem cell transplantation, as well as the utilization of electrospinning techniques [13,14,15]. The specific implementation methods and their respective advantages and disadvantages are shown in Table 1. According to the comparison in the table, although there are many treatment methods for SCI, neither medication nor surgery has been able to cure it completely. Electrospinning technology can customize nanofiber scaffolds [16,17], accurately simulate the spinal cord microenvironment [18,19], and promote nerve cell repair and regeneration. Moreover, its high porosity, adjustable pore size, and high surface volume ratio [20,21,22] facilitate cell migration, proliferation, and differentiation. And by selecting biocompatible materials [23,24], immune reactions and toxicity can be avoided, protecting the spinal cord. In addition, its fiber morphology resembles ECM [24,25,26], promoting the growth and regeneration of nerve cells and supporting SCI repair [27,28].

As illustrated in Figure 1, substantial efforts have been devoted to understanding the roles of electrospinning parameters and their applications in SCI repair [8,9,10]. Current studies primarily focus on the design of electrospun nanofibrous scaffolds—such as conduit-based systems, multifunctional scaffolds, and microenvironment-responsive immunomodulatory platforms—as well as their integration with complementary strategies including cell therapy, growth factor delivery, and other biomaterials [11,12]. These advances have significantly propelled scaffold-based approaches for SCI repair [32,33].

However, electrospun scaffolds should be regarded not as direct therapeutic agents, but as structural and functional platforms that regulate the cellular microenvironment and guide tissue regeneration. In this context, increasing attention has been paid to the relationship between scaffold design parameters and biological outcomes. Nevertheless, two major challenges remain: (i) the synergistic effects of electrospinning parameters (e.g., fiber diameter, alignment, and degradation kinetics) on SCI repair are not yet fully understood, and (ii) the integration of multiple functionalities—such as immunomodulation, controlled drug release, and mechanical support—within a single scaffold system remains difficult.

Concurrently, emerging biofabrication approaches are beginning to address intrinsic limitations of conventional electrospun scaffolds, particularly the restricted cell infiltration within densely packed fibrous networks. Among these, cell electrospinning (C-ES) represents a shift from post-seeding strategies toward in situ cell incorporation. Since its initial demonstration in 2006, C-ES has evolved from proof-of-concept studies to a developing platform capable of controllable cell encapsulation, fiber alignment, and multilayer scaffold construction [34]. Although its application in SCI remains at an early stage, its ability to integrate structural guidance with cellular delivery suggests significant potential for next-generation neural scaffolds.

The research approach is illustrated in Figure 2. The initial focus is on analyzing the core mechanism of electrospinning for SCI treatment, followed by examining the dose-response relationship between material parameters and biological effects. Based on different parameters, five groups are identified: fiber diameter, arrangement method, biocompatibility and degradability, surface activity and biological activity, and nanostructure. Multi-parameter optimization has been analyzed. The key scientific challenge lies in applying electrospinning to SCI treatment and integrating it with other advanced technologies to achieve better outcomes. This study provides a detailed overview of how electrospinning parameters influence SCI, their application, and integration with other cutting-edge technologies, aiming to address current issues in electrospinning for SCI treatment.

According to Table 1, it can be learned that the influence of various characteristic parameters of electrospinning is difficult to accurately control at present; the existing literature lacks a systematic review and relatively few reference experience in clinical treatment, leading to the lack of targeted guidance in practical application. This paper reveals the core mechanism of electrospinning technology for SCI, systematically reviews the current application progress of the technology in SCI treatment, clarifies the influence of characteristic parameters on the repair effect, and summarizes the broad prospect of electrospinning technology combined with other advanced technologies. Finally, the challenges of SCI clinical treatment strategies based on electrospinning technology and the future directions are explored and discussed. It aims to provide technical guidance and theoretical support for the clinical application of electrospinning for SCI, and jointly promote the innovative development of electrospinning technology in the field of SCI therapy.

Electrospun scaffolds promote SCI repair through a coordinated set of mechanisms rather than a single isolated effect. Their therapeutic value arises from the ability to mimic the extracellular matrix, provide directional guidance for axonal extension, regulate cellular responses through mechanical and biochemical cues, and deliver bioactive factors in a controlled manner. These mechanisms are interdependent: physical architecture establishes the initial structural niche, surface chemistry and topology modulate cell–material interactions, and drug-loading strategies further reshape the post-injury microenvironment. Therefore, the function of electrospun scaffolds in SCI should be understood as a hierarchical repair process that integrates structural support, biological signaling, and local microenvironmental regulation.

A central advantage of electrospun scaffolds is their ability to approximate the fibrous architecture of the native ECM while providing temporary mechanical support across the lesion site. In SCI, tissue continuity is disrupted not only at the level of neuronal pathways but also at the level of the extracellular scaffold that normally organizes cells, molecules, and mechanical forces. Electrospun fibers can partially restore this lost architecture by creating a porous and anisotropic network that supports cell adhesion, migration, and tissue bridging. Compared with bulk materials, electrospun structures more closely resemble the nanoscale organization of the spinal cord microenvironment, thereby offering a more permissive substrate for regeneration [35,36].

Among the structural parameters that determine scaffold performance, fiber diameter and porosity are particularly important. Nanoscale fibers offer a large surface area-to-volume ratio and increase the density of cell-contact sites, which is favorable for adhesion and early neurite attachment. At the same time, pore size and inter-fiber spacing determine whether cells can infiltrate deeply into the scaffold and whether nutrients and metabolites can diffuse effectively. If the scaffold is too dense, the network may act as a barrier to cellular penetration; if it is too open, the scaffold may lose mechanical integrity and fail to provide stable guidance [37,38,39,40]. Therefore, scaffold design must balance structural mimicry with mass transport and mechanical robustness rather than maximizing any single parameter in isolation.

Mechanical support is another essential function of electrospun scaffolds. After SCI, the lesion cavity is exposed to mechanical instability, inflammatory infiltration, and secondary tissue collapse, all of which can further aggravate neural loss [41]. Electrospun conduits and three-dimensional fiber constructs can fill part of the defect space, reduce cavity collapse, and provide a temporary bridge for regenerating axons. In addition, the elastic modulus and overall compliance of the scaffold influence how host cells perceive the material. A scaffold that is too stiff may trigger a foreign-body-like response, whereas one that is too soft may collapse before tissue integration occurs. For this reason, mechanical matching with the spinal cord environment is a key design consideration in translational scaffold engineering [42,43]. As shown in Figure 3, electrospun scaffolds mimic the native extracellular matrix and provide mechanical support across the SCI lesion site, thereby creating a permissive microenvironment for tissue bridging and axonal regeneration.

Beyond structural support, electrospun fibers exert a profound influence on cell behavior through contact guidance and receptor-mediated signaling. In the injured spinal cord, neurons, glial cells, and stem/progenitor cells encounter a hostile microenvironment characterized by inflammation, inhibitory ECM components, and poor alignment of regenerative cues [44,45]. Electrospun fibers can partially counteract these barriers by presenting anisotropic topography that directs cell orientation and by providing an adhesive surface that supports cell attachment and spreading. In this sense, the scaffold does not merely occupy the lesion cavity; it actively instructs how cells organize and respond [46,47,48].

One of the most studied phenomena is fiber alignment. Aligned electrospun fibers can guide neurite extension along a preferred axis, thereby mimicking the longitudinal organization of nerve tissue [49]. This contact-guidance effect is especially relevant in SCI, where directed axonal growth is required to reconnect discontinuous neural pathways. In contrast, random fibers may support general cell attachment but usually provide weaker directional cues. The difference between aligned and random architectures highlights an important point: a scaffold’s biological function is determined not only by its material composition, but also by the spatial organization of its micro- and nano-topology [50,51,52].

Surface chemistry further modulates cell behavior. Functional groups, peptide motifs, and ECM-derived ligands can be incorporated onto fiber surfaces to enhance the interaction between cells and the scaffold. Such modifications may improve adhesion, promote cytoskeletal reorganization, and activate signaling pathways related to survival, migration, and differentiation. For example, biomimetic ligands can enhance integrin engagement and trigger downstream responses that support neurite outgrowth and progenitor cell fate commitment. In SCI repair, these effects are particularly valuable because the lesion environment is typically unfavorable for spontaneous cell attachment and extension [53,54].

As shown in Figure 4, the biological responses of cells to electrospun scaffolds are governed by fiber alignment, surface functionalization, and receptor-mediated signaling, which collectively regulate adhesion, polarity, and neurite extension.

Importantly, cell–material interactions should be interpreted in a context-dependent manner. A design strategy that works well for one cell type or one injury phase may not be optimal for another. For instance, a scaffold that promotes early adhesion may not necessarily support long-term maturation or remyelination. Similarly, the needs of transplanted stem cells may differ from those of resident glial cells or regenerating neurons. Therefore, a critical review of electrospun scaffolds must move beyond simply listing “good effects” and instead discuss how topography, chemistry, and cell type jointly determine biological outcomes.

Electrospun scaffolds are particularly attractive because they can integrate multiple regulatory cues within a single platform. In SCI, tissue repair is governed by a complex interplay of mechanical injury, inflammatory cascades, glial scarring, and impaired axonal regeneration. A successful scaffold must therefore do more than provide passive support; it must also participate in shaping the biochemical and biophysical environment of the damaged tissue. Electrospun systems can achieve this by combining mechanical guidance, biochemical functionalization, and, in some cases, electrically or thermally responsive behavior [55,56,57].

Mechanical and topographical cues are the most immediate signals delivered by electrospun scaffolds. Fiber diameter, surface roughness, and alignment all influence how cells spread, migrate, and polarize. These cues can regulate the morphology of astrocytes, the directional growth of axons, and the behavior of stem cells within the damaged tissue. The significance of these effects lies in the fact that SCI repair depends not only on cell survival, but also on the restoration of organized tissue architecture. By offering a defined physical template, electrospun scaffolds help convert a disordered lesion into a more structured regenerative niche [17,58,59].

Biochemical cues can be introduced by loading growth factors, cytokines, small molecules, or immunomodulatory agents into the fibers. Such functionalization allows the scaffold to interact with inflammatory and regenerative processes in a stage-dependent manner. During the acute phase of SCI, anti-inflammatory signals may help limit secondary damage and reduce glial scar formation. During later phases, neurotrophic or pro-regenerative cues can promote neuronal survival, neurite extension, and remyelination. This temporal dimension is important: the ideal scaffold is not static but rather adapts its influence to the changing biological needs of the lesion [60].

As shown in Figure 5, electrospun scaffolds can integrate mechanical, biochemical, and electrical/thermal cues to modulate the post-injury microenvironment and enhance SCI repair.

In some studies, electrospun scaffolds are further combined with electrical, photothermal, or piezoelectric components to create more sophisticated multimodal systems. These designs aim to provide additional levels of control over cell behavior and material performance. However, such complexity should not be introduced for its own sake. In a review focused on SCI, it is more useful to emphasize how multimodal regulation helps reproduce the dynamic, heterogeneous, and evolving nature of the post-injury microenvironment. The value of electrospinning in this context is its ability to integrate several cues into one material platform without losing the basic structural function of a scaffold.

Architectural design and material composites enable multi-phase, stimuli-responsive release of bioactive molecules, precisely matching the evolving therapeutic demands of SCI repair . Electrospun scaffolds also function as local delivery systems for drugs and growth factors. This capability transforms them from passive conduits into active therapeutic platforms that modulate inflammation, support cell survival, and promote regeneration over extended time periods. In SCI, where pathological processes unfold in stages, controlled release is especially important because the biological needs of the tissue change over time. An agent that is useful in the acute phase may not be sufficient in the chronic phase, and vice versa .

Various electrospinning strategies have been developed to regulate release behavior. Core–shell fibers are particularly effective for protecting sensitive cargo and extending release duration. Nanoparticle incorporation, multilayer structures, and stimulus-responsive systems can further tailor the temporal profile of delivery. These approaches allow electrospun scaffolds to deliver anti-inflammatory compounds early after injury, followed by neurotrophic factors or other pro-regenerative molecules during later stages. Such sequential delivery is conceptually well suited to SCI because it mirrors the transition from inflammation control to tissue reconstruction [61].

Controlled release also has an important structural implication. A scaffold that merely loads a therapeutic agent without preserving fiber architecture may fail to provide the intended physical guidance. Conversely, a structurally robust scaffold without therapeutic cargo may not sufficiently modulate the hostile injury environment. The strength of electrospun systems lies in their ability to combine these two functions. This dual role is especially relevant in SCI, where regeneration depends on both creating a permissive microenvironment and physically directing new tissue growth [62,63]. As shown in Figure 6, electrospun scaffolds can serve as controlled delivery platforms for drugs and growth factors, enabling staged release in accordance with the evolving phases of SCI pathology.

Nevertheless, the design of drug-loaded electrospun scaffolds should be evaluated critically. Not every release profile is clinically meaningful, and not every drug benefits from encapsulation in a fibrous matrix. Factors such as burst release, degradation kinetics, bioactivity retention, and manufacturing reproducibility must be considered. For this reason, an effective review should not simply enumerate loaded molecules, but should explain how the release strategy relates to the injury stage, the target cell population, and the intended biological effect.

Taken together, electrospun scaffolds support SCI repair through a layered mechanism that combines ECM mimicry, directional cell guidance, multimodal regulation, and controlled therapeutic release. The earliest and most fundamental contribution of these scaffolds is structural: they provide a fibrous framework that can bridge the lesion and guide cell organization. On this basis, surface chemistry, topography, and cargo delivery further amplify biological responses by influencing cell adhesion, migration, survival, and differentiation. The resulting repair effect is therefore not the product of any single material property, but of the coordinated interaction between scaffold architecture and the evolving post-injury microenvironment.

This mechanistic understanding also explains why electrospun scaffold design remains challenging. A scaffold optimized for one function may compromise another, and the best-performing system in vitro may not necessarily translate into durable in vivo repair. For this reason, future research should focus on integrated design strategies that balance structure, mechanics, bioactivity, and degradation behavior. Such a perspective is essential for developing electrospun platforms that are not only scientifically interesting but also genuinely relevant to clinical SCI repair.

The core advantage of electrospinning lies in its capacity to precisely reconstruct the spinal cord’s native microenvironment by tuning fiber-level structural parameters. These intrinsic scaffold properties—fiber diameter, alignment, biocompatibility, and degradation rate, and surface nanotopography—act in concert across multiple dimensions of mechanical support, cell-adhesion guidance, and multimodal signal regulation to direct tissue repair. In particular, structural parameters (diameter and alignment) define the scaffold’s physical topology and thus establish the foundation for cell–material interactions, while chemical functionalization (bioactive-molecule loading and surface-group modification) endows the scaffold with dynamic control over the local microenvironment. By delineating a systematic “design window” that spans single-parameter optimization to multiparameter synergy, this chapter provides clear, quantitative guidelines for the engineering of electrospun scaffolds.

Among the various electrospinning parameters, fiber diameter represents a fundamental structural dimension that directly influences cell–material interactions by modulating surface area, mechanical cues, and topographical scale [64,65].

Small diameter fibers (200–500 nm) promote the differentiation of neural stem cells (NSC): Christopherson et al. [66] demonstrated that 200–500 nm electrospun fibers significantly enhanced neural stem cell (NSC) adhesion and neuronal differentiation by increasing specific surface area, as evidenced by SEM imaging of rNSCs exhibiting superior attachment and axial alignment on 283 nm fibers compared to flat cells, As shown in Figure 7. This study quantitatively validated the “200–500 nm” diameter range as a critical determinant for early NSC differentiation. However, limitations included: Polymer specificity confined to PES systems, with unverified universality in alternative materials (e.g., PLCL, PCL); Exclusive focus on in vitro short-term assays, lacking long-term in vivo validation in chronic injury models or clinical samples; and omission of systematic analysis on the impact of fiber diameter distribution heterogeneity (e.g., standard deviation) on cellular responses. While advancing mechanistic understanding, these constraints restrict translational applicability.

Medium diameter fibers (800–1200 nm) support astrocyte (AC) function: Zhang et al. [67] found that fibers with diameters of 800–1200 nm were more conducive to the elongation of astrocytes (AC), which helped to form supportive glial networks. As shown in Figure 8A–D, GFAP, positive cells (green) are significantly stretched along the fiber direction on the SF:PLCL nanofiber scaffold with a diameter of approximately 900 nm, forming a mesh-like structure. In contrast, similar cells in the control group (glass substrate) exhibit a classic star-like pattern without directional extension. This figure intuitively demonstrates that nanofibers in the range of 800–1200 nm facilitate the elongation of AC along the fiber direction, thereby constructing a supportive glial network. By precisely regulating the electrospinning parameters, a quantitative relationship between fiber diameter and biological function was established, which provided an important paradigm for the design of neural tissue engineering scaffolds. This work clarifies the biological effects of medium diameter fibers in “glial scaffolds”, but additional in vivo experiments are needed to verify their practical significance for functional recovery.

Liu et al. [68] prepared collagen nanofibers with an average diameter of 208.2 ± 90.4 nm using electrospinning technology and found that fibers of this size can effectively inhibit the over-activation of astrocytes. In vitro experiments showed that oriented collagen fibers significantly promoted the directed growth of dorsal root ganglion (DRG) axons compared to randomly arranged fibers. Additionally, after in vivo implantation, the scaffold’s helical structure remained intact for 30 days, supporting continuous nerve fiber regeneration. As shown in Figure 9, the average diameter of the electrospun collagen nanofibers is 208.2 ± 90.4 nm (Figure 9a,b), and their ordered arrangement (aligned fibers) promotes DRG axon growth along the fiber axis through contact guidance mechanisms (Figure 9c). This diameter range has been proven to inhibit astrocyte activation (reduced GFAP expression by 72%) while supporting neuronal adhesion and differentiation. This case is a breakthrough in natural biomaterials, but it still needs to be combined with more complex models to examine long-term degradation and immune compatibility.

Johnson et al. [69] research shows that 808 nm large-diameter fibers enhance the morphological polarity and GLT-1 expression of astrocytes, while optimizing axon guidance efficiency and neuroprotective capabilities, providing crucial parameter references for the design of spinal cord injury repair scaffolds. Figure 10 displays scanning electron microscope images of two electrospun fibers, showing diameters of 386 nm and 808 nm, respectively. The consistency in fiber surface roughness and pore structure indicates that the diameter difference is the only variable. The conclusion that 808 nm large diameter promotes glial cell polarity and neuroprotection is innovative, but there are deficiencies in in vivo verification and parameter optimization.

Chen et al.^.[70] found that Gelatin methacryloyl (GelMA) fiber scaffolds with a diameter of 1.1 ± 0.13 μm have better orientation and mechanical properties than Gelatin scaffolds with a diameter of 1.4 ± 0.13 μm, As shown in Figure 11. This study provides important data for the diameter optimization of GelMA-based electrospun scaffolds, but further breakthroughs are needed in material diversity, mechanism depth, and transformation validation to promote its clinical application potential in spinal cord injury repair.

A comparative summary is provided in Table 2, which links diameter ranges to cellular behavior and clinical relevance. While fiber diameter governs the cellular interface at the microscale, it is the spatial organization—or alignment—of these fibers that determines the directionality of axonal regrowth, which is critical for functional neural circuit reconstruction [71,72,73]. This leads to the next key parameter: fiber orientation.

Following the determination of fiber diameter, the next critical parameter is fiber alignment, as it directly regulates axon guidance, directional mechanical properties, and scaffold anisotropy [74].

Orientation fibers promote axonal orientation and extension: Hurtado et al. [39] placed randomly arranged and directionally arranged electrospun left-handed PLLA nanofibers in a rat spinal cord transection model, and found that after 4 weeks of implantation, the directionally arranged group (2055 μm ± 150 μm) had a longer protrusion extension distance compared to the randomly arranged group (1162 μm ± 87 μm), and the difference was statistically significant. As shown in Figure 12, the immunofluorescence imaging of aligned and random fiber groups visually compared the growth of NF H labeled axons on the two scaffolds. “It has been widely accepted that high orientation significantly improves axon regeneration and functional recovery”, but further optimization is needed in large size preparation and multi-directional mechanical matching.

Random fiber induced multi-directional differentiation: Xia et al. [75] found that in polymethyl methacrylate (PMMA) electrospun nanofibers, astrocytes cultured in the oriented arrangement group formed longer, highly oriented protrusions along the matrix fiber axis compared to the randomly arranged group, As shown in Figure 13. This study provides important experimental evidence for the regulation of astrocyte behavior by oriented nanofiber scaffolds, but it needs to be deepened in the aspects of material degradability, multi-cell interaction and transformation verification, so as to break through the gap between the current “cell-scaffold” binary model and the complex SCI microenvironment.

Subramanian et al. [76] developed a collector-based method to fabricate oriented PLGA-PCL nanofibers (230 ± 63 nm) and quantified alignment via fiber angle distribution. Compared to random fibers, oriented scaffolds exhibited significantly reduced pore size, Young’s modulus, and degradation rate (p < 0.05). In vitro evaluation demonstrated that axial alignment enhanced Schwann cell adhesion and proliferation (p < 0.05), As shown in Figure 14. Although there are shortcomings in in vivo validation and mechanism elucidation, the systematic material design and cell behavior research have laid a solid foundation for subsequent translational applications.

Key distinctions between aligned and random fiber effects are summarized in Table 3. Although alignment provides structural guidance, its effectiveness is greatly enhanced when combined with appropriate biochemical signals. Therefore, the next section explores how surface chemistry and nanotopography can further modulate cellular responses through ligand presentation and topographical cues.

Beyond physical parameters, the biochemical landscape of electrospun fibers—such as surface ligand functionalization and nanoscale texture—plays a pivotal role in directing cell fate, particularly via integrin signaling and cytoskeletal reorganization.

Nanotube structure regulates cell behavior: Sánchez et al. [77] added curcumin dissolved in dimethyl sulfoxide (DMSO) to the electrospinning solution and functionalized the PLA electrospun membrane during the electrospinning process, altering the surface morphology of the nanofibers, guiding and supporting axonal elongation in neuronal culture, and providing neuroprotection and enhanced neuroplasticity when implanted into a half cut spinal cord in vivo. In Figure 15, functionalized PLA-curcumin nanofibers showed enhanced neuroplasticity. This study is the first to integrate “nano-topology + drug”, but it needs to be strengthened in terms of drug release timing and long-term stability.

Micropores promote angiogenesis: Liao et al. [78] found that Tubastatin A (TUBA) is a stable and efficient selective histone deacetylase 6 (HDAC6) inhibitor, with much higher selectivity than any other isoenzymes, which can accelerate cell autophagy and apoptosis. Loading TUBA into multi-channel bioactive silk nanofiber conduits can pharmacologically inhibit HDAC6, enhance axonal regeneration, and restore functionality in mice that have undergone injury. Reducing inflammation stabilizes the damaged microenvironment, promoting neuronal regeneration and functional recovery. The role of multi-channel stents loaded with bioactive agents is illustrated in Figure 16. Its core value lies in the close combination of basic research and clinical needs to confirm that local sustained release TUBA can reshape the damaged microenvironment and promote functional recovery.

Johnson et al. [44] Several pure physical morphologies have been compared, but the results are consistent with Maria et al. at the pure surface topology level. Topographical regulation mechanisms are summarized in Table 4, detailing cell responses to nanoscale surface features.

However, for long-term therapeutic efficacy, scaffolds must also undergo controlled biodegradation and sustained bioactive release. The following section thus addresses how material biocompatibility and degradation dynamics modulate the inflammatory microenvironment and scaffold longevity.

The in vivo performance of electrospun scaffolds depends not only on their initial structure and function but also on their degradation profile, which affects immune responses, drug delivery, and tissue integration over time.

Degradation rate regulates inflammatory response: Wu et al. [79] fabricated aligned electrospun poly(vinylidene fluoride-trifluoroethylene) (PVDF-TrFE) scaffolds and demonstrated that their intrinsic piezoelectric properties enable the conversion of mechanical stimulation into electrical signals. This electroactive behavior significantly promoted Schwann cell alignment, neurite extension, and myelination in vitro, As shown in Figure 17. These findings indicate that PVDF-TrFE scaffolds can regulate neural cell behavior through an electro-mechanical coupling mechanism, providing an alternative strategy to enhance neural regeneration that is fundamentally different from degradation-mediated bioactivity in conventional biodegradable scaffolds.

Extended factor activity of the sustained release system: Sun et al. [80] studies have shown that the electroactive scaffold based on hydroxyapatite/carbon nanofibers (HAp/CNF) achieves controlled degradation through the following mechanisms: the carbonization of PVDF releases HF, which causes slight expansion of the fibers (Figure 18g), increasing the specific surface area and accelerating medium permeation; during physiological activities (such as spinal movement), the piezoelectric effect generates microcurrents in the scaffold, promoting local ROS production and accelerating material decomposition; HAp doping provides a continuous release function for Ca²⁺, with its lattice defects (Figure 18i) enhancing the charge distribution on the material surface, promoting osteoblast adhesion and differentiation. Scanning electron microscopy reveals that the scaffold has three-dimensional interconnected pores (with pore sizes of about 500 nm) and a high aspect ratio structure (Figure 18a–e), and the HAp/CNF composite design significantly upregulates the expression of osteogenic markers such as Runx2 and OCN. This scaffold holds potential for multi-trauma repair but requires further validation through the synergistic effects of multiple mechanisms and targeted verification for pure spinal cord injury.

For a comparison of degradation cycles and immune effects, refer to Table 5. As degradation progresses, scaffold porosity and mechanical properties evolve [81,82]. Hence, a thorough understanding of porosity and modulus matching is essential to support vascularization and maintain structural integrity, which is the focus of the next section.

Porosity and mechanical compliance are key characteristics of electrospun scaffolds. By regulating nutrient diffusion gradients, cell migration kinetics, and host-scaffold interface mechanical matching, the microenvironment for angiogenesis and axonal regeneration can be synergistically optimized, significantly promoting spinal cord injury repair [83].

Cnops et al. [40] found that high-density fiber scaffolds have good host integration performance. Fiber density has no effect on cell infiltration, and effective vascular growth may require larger gaps between fibers or faster fiber degradation, offering an optimal environment for nerve regeneration post-SCI.SEM and vascular infiltration data are shown in Figure 19, where scaffold gap size influences host integration. The “density-vascularization” mechanism was quantitatively analyzed, but to truly guide the design of SCI stents, the coupling evaluation of “vascular maturity-neurological function” should be supplemented.

Zhao et al. [84] through a spinal cord injury rat model, the PHBV/PLA+COL electrospun scaffold loaded with AC significantly improved biocompatibility. After implantation, the inflammatory response was reduced, the area of spinal cord cavities shrank, glial scar formation was inhibited, and neuronal regeneration capacity was enhanced, ultimately promoting the recovery of hind limb motor function (Figure 20). Cell experiments showed an increased cell proliferation rate on the scaffold surface, indicating its ability to support cell adhesion and expansion. Although degradability was not explicitly mentioned, the copolymer structure of PHBV/PLA typically has controllable degradation properties, potentially degrading gradually through hydrolysis to meet tissue repair needs. The study explored the “synthetic + natural composite” synergistic approach.

Zheng et al. [85] through live and dead cell staining and cell counting kit-8 (CCK-8) experiments, confirmed that 0.5% and 1.0% ceria nanofiber scaffolds (NS@COP) Nanofiber scaffolds have good biocompatibility, no obvious cytotoxicity, and do not affect cell proliferation. In vivo, 0.5%, 1.0% by h&e staining NS@COP The nanofiber scaffolds did not cause pathological tissue changes to the important organs of the body at 8 weeks after surgery, indicating its good biological safety. Nanofiber scaffold NS@COP It not only has degradability, but also has good biosafety, slow-release of loaded nanoparticles, simple preparation process, high feasibility and low cost. As shown in Figure 21.

Given the interdependence among diameter, alignment, chemistry, degradation, and porosity, the final section integrates these parameters into a synergistic strategy, outlining how multi-parameter optimization can be achieved in practice.

To move beyond single-parameter tuning, this section synthesizes the preceding findings into an integrative framework, identifying optimal combinations and trade-offs among electrospinning variables to design functionally robust scaffolds [86,87].

Optimization and regeneration of diameter-oriented composite stent: He et al. [88] created a unique electrospun PLLA scaffold (oriented and randomly oriented) with a diameter range of 300–900 nanometers and increments of 200 nanometers. C17.2 cells cultured on a scaffold with an average fiber diameter of 500 nm induced the longest neuroinflammation elongation and the maximum neuronal differentiation. Unlike previous studies, C17.2 differentiation is highly dependent on fiber arrangement, as there are more cells differentiating into neuronal lineages on arranged fibers regardless of fiber diameter. This result led He et al. to conclude that fibers with a diameter of 500 nm are optimal for guiding neuroinflammation. However, the researchers acknowledge that their observations may result from the high neuronal differentiation of C17.2 cells, as neuroinflammation is longest on scaffolds with the highest neuronal differentiation. Diameter-alignment combinations and their influence on neuronal differentiation are illustrated in Figure 22. “500 nm + high orientation” has been established as the optimal unit for early neuronal differentiation, but to build a truly “globally optimal” scaffold, more dimensional parameters and in vivo validation are needed.

Topological-drug synergistic enhancement of functional recovery: Singh et al. [89] developed a novel method of delivering a UA locally from biomaterials and demonstrated that the Uric acid (UA)-PCL fibers successfully protected excitotoxic lesions in an in vitro spinal cord tissue injury model. Both fibers protected neurons and reduced the reactive oxygen species (ROS) produced by Glutamate-induced excitotoxicity (GIE) in organospinal cord slice cultures. Its findings have implications for the treatment of SCI and further support the feasibility of UA as an effective therapeutic agent. Topological–pharmacological synergy effects are shown in Figure 23. The research shows high scientific value in parameter design, mechanism interpretation, and function verification, but some key links still need to be further deepened.

In summary, the influence of key electrospinning parameters on spinal cord injury repair can be understood through a hierarchical, multiparametric framework. Fiber diameter exerts a first-order effect: nanoscale fibers (200–500 nm) maximize specific surface area to cluster integrins, activate FAK/ERK signaling, and thereby promote neural stem cell adhesion and early axonal extension, whereas larger fibers (800–1200 nm) favor astrocyte elongation and glial network formation to support later-stage tissue stabilization. Fiber alignment (<10° deviation) provides contact-guidance tracks that double axonal outgrowth relative to random mats, while simultaneously tuning directional stiffness without compromising porosity. Surface chemical functionalization—through RGD peptide or antibody grafting—and nanotopographical features (pits, pores) synergistically regulate integrin–MAPK pathways, reduce GFAP expression, and encourage neurite branching. Scaffold composition and molecular weight govern degradation kinetics (e.g., ~35% mass loss at 28 days), synchronizing mechanical support with sustained release of bioactive agents; degradation byproducts further modulate macrophage polarization from M1 to M2, extending the regenerative window. Finally, scaffold porosity (70–95%) and elastic modulus (0.1–1 MPa) must be co-optimized to facilitate vascular ingrowth and minimize interfacial shear stress. By integrating these single-parameter effects into a consolidated “design window” matrix, researchers can rationally engineer electrospun scaffolds that faithfully recapitulate spinal cord microarchitecture and dynamically orchestrate the repair milieu [90,91].

To visually consolidate the relationships described above, Figure 24 presents a schematic overview of the five principal electrospinning parameters, their optimized design ranges, biological effects, and interdependencies. This diagram captures both the direct cellular responses elicited by individual parameters (e.g., fiber alignment enhancing axonal extension) and the synergistic interactions required to balance structural, biochemical, and immunological functions in vivo. As such, it serves as a strategic framework for scaffold design, guiding the rational integration of multiple fiber-level cues into a unified, biomimetic solution for spinal cord injury repair. Table 6 summarizes the experimental validation of the effect of electrospinning parameters on therapeutic spinal cord injury.

Electrospun scaffolds have been explored in SCI repair from a translational perspective because they can simultaneously provide physical bridging, directional guidance, and a platform for biochemical functionalization. Compared with single-component biomaterials, electrospun systems are especially attractive in SCI because they can be engineered at multiple levels: macroscopically, they can fill lesion cavities and reconstruct continuity across the injury site; microscopically, they can regulate cell adhesion, migration, and axonal extension; and functionally, they can be combined with drugs, cells, growth factors, and hydrogels to reshape the hostile post-injury microenvironment. Nevertheless, the reported studies differ widely in scaffold geometry, material composition, cell-loading strategy, and animal model, making direct comparison difficult and highlighting the need for critical synthesis rather than simple enumeration.

Physical scaffolds are the most direct and foundational application of electrospinning in SCI repair. Their core purpose is to reconstruct a permissive bridge across the lesion cavity and to provide a structural template that can support axonal extension, host-cell infiltration, and tissue integration. In this category, the central design logic is relatively consistent across studies: electrospun conduits or three-dimensional fiber constructs are used to recreate the anisotropic architecture of the spinal cord ECM, while the specific implementation varies in terms of conduit geometry, pore structure, material composition, and degree of structural hierarchy. As a result, the reported systems differ substantially in translational maturity, even when they share a similar regenerative intent [17].

Single- and multichannel conduits are designed to provide a macroscale physical bridge across the injury site and to convert the lesion cavity into a more organized regeneration space. The common rationale is that a channelized scaffold can reduce collapse of the injured region, restrict fibrotic invasion, and guide axons along a preferred direction. In practice, however, the biological benefit of such constructs depends not only on the presence of a conduit but also on whether the conduit maintains sufficient porosity, wall stability, and internal organization to support host integration over time.

Among the reported examples, Wang et al. [92] developed a 3D-printed bionic scaffold incorporating plant-derived exosomes extracted from Lycium barbarum L. and loaded with isoliquiritigenin (ISL). The authors showed that the plant-derived exosomes possessed anti-inflammatory activity and promoted neuronal differentiation, and that ISL-loaded plant-derived exosomes (ISL@PE) further enhanced these effects compared with exosomes derived from ectomesenchymal stem cells. By combining ISL@PE with a biomimetic 3D-printed scaffold, the study aimed to modulate the inflammatory response after spinal cord injury, facilitate axonal restoration, and improve neurological function，As shown in Figure 25. This work is notable because it introduces a novel plant-exosome-based delivery route for an insoluble drug and demonstrates a composite 3D-bioprinted strategy for SCI repair, although further mechanistic clarification and long-term translational validation are still needed.

A different design strategy was used by Li et al. [42], who combined gas foaming with electrospinning to fabricate three-dimensional PCL/PPDO nanofiber sponge scaffolds with controllable hierarchical structure and high porosity. Their study emphasized that the value of a conduit lies not merely in filling the lesion space, but in reproducing a native ECM-like fiber profile while allowing tissue ingrowth and exogenous neural stem cell support, As shown in Figure 26. This work is important because it addresses a major limitation of many densely packed electrospun mats, namely, insufficient three-dimensional infiltration. However, the clinical relevance of this approach still depends on whether the scaffold degradation rate and structural persistence can be matched to the dynamic phases of SCI repair.

The translational potential of channel-based scaffolds was further strengthened by Zeng et al. [93], who evaluated a three-dimensional gelatin sponge scaffold in a non-human primate SCI model. In this study, the scaffold supported robust tissue remodeling, with evidence of cell migration into the regenerated tissue, matrix deposition, nerve fiber regeneration, myelination, vascularization, and electrophysiological improvement, As shown in Figure 27. This is one of the most clinically relevant studies in the present review because it moves beyond rodent-only evidence and demonstrates that a cell-supportive scaffold can also perform in a primate model. Nevertheless, the system is not without limitations: although the tissue response was encouraging, additional work is still needed to determine whether the scaffold can sustain long-term biomechanical integrity and whether similar outcomes can be achieved in more severe or chronic injuries.

Taken together, these studies suggest that single- and multichannel conduits are best understood as lesion-bridging platforms whose value depends on the balance between geometry, porosity, degradation, and biological loading. The main advancement in this subfield is no longer simply whether a conduit can be fabricated, but whether it can be engineered to maintain internal organization, support cell retention, and remain mechanically competent long enough to influence meaningful regeneration.

Once the overall conduit architecture is established, fiber diameter and alignment are the key variables that determine how effectively the scaffold guides cell behavior and axonal regrowth. These two parameters act together: diameter influences surface area, compliance, and cell-contact density, whereas alignment determines whether the scaffold provides directional cues for neurite extension and cellular polarity. The major message from the literature is that physical guidance is not a binary property; rather, it is a graded response that depends on the interactions among topography, mechanics, and the specific cell types present in the lesion environment [94].

A representative body of work has established fiber alignment as a key determinant of axonal guidance in electrospun scaffolds. Hurtado et al. [39] provided a classic demonstration of the importance of orientation by implanting aligned PLLA electrospun microfibers into a rat complete spinal cord transection model. Their results showed that aligned fibers promoted axonal regeneration along the fiber axis through contact guidance, with axonal extension reaching 2055 ± 150 μm, compared with 1162 ± 87 μm for random fibers and 413 ± 199 μm for the film control,As shown in Figure 28. This study remains highly influential because it clearly established that aligned electrospun fibers can provide a directional track for regenerating axons and can partially reconstruct the ordered architecture required for functional recovery. However, the work also illustrates a recurring limitation in the field: while directional growth was evident histologically, translating that structural success into durable long-term functional restoration remains challenging.

Building on this foundation, subsequent studies have expanded the role of alignment beyond neuronal guidance to include glial regulation and mechanical adaptation. Subramanian et al. [76] extended this logic by developing a directed PLGA-PCL nanofiber scaffold that mimicked the Büngner-band structure of peripheral nerves. In vitro, Schwann cells aligned longitudinally on the oriented fibers, with their cytoskeleton organized in the same direction as the scaffold, and in vivo, the scaffold promoted axonal regeneration and accelerated myelination, As shown in Figure 29. This study is important because it shows that alignment affects not only neurons but also glial cells that are essential for regeneration and remyelination. It also highlights a more nuanced design principle: the best scaffold is not simply the one with the highest alignment, but the one whose mechanical properties and cell response are compatible with the tissue it aims to reconstruct. The measured reduction in Young’s modulus compared with the random scaffold indicates that structural alignment can be accompanied by a softer, more nerve-like mechanical profile. Even so, the field still lacks sufficient comparative data to determine the optimal level of alignment under different injury conditions and scaffold compositions.

Additional studies reinforce the same conclusion from different material systems. For example, Tai et al. [41] collagen-based aligned electrospun fibers were reported to be more suitable for SCI repair than random counterparts, and dECM-derived aligned versus random fibers have been investigated for mesenchymal stem cell-based SCI treatments. These studies collectively show that the directional effect is not material-specific, but rather emerges from the interaction between anisotropic geometry and cell adhesion dynamics, As shown in Figure 30. This also means that alignment should not be discussed as an isolated structural feature; instead, it should be considered together with diameter, porosity, and surface chemistry when evaluating scaffold performance.

Overall, the physical scaffold literature shows a clear trend toward increasingly sophisticated architectures, moving from simple conduits to hierarchical, cell-supportive, and clinically more realistic systems. The remaining challenge is to establish design rules that connect scaffold geometry to reproducible biological outcomes across models, species, and injury stages.

Biochemical functionalization represents the transition of electrospun scaffolds from passive structural supports to active therapeutic platforms. In SCI repair, this strategy is used to localize pharmacological agents, regulate inflammatory signaling, and provide spatiotemporally controlled release that matches the evolving phases of injury. Compared with purely physical scaffolds, chemically functionalized electrospun systems can more directly modulate the post-injury microenvironment; however, their effectiveness depends strongly on cargo stability, release kinetics, and the degree to which the biochemical function remains coupled to scaffold architecture rather than being added as an afterthought.

A foundational step in this field was the demonstration that electrospun fibers can serve as localized, sustained delivery systems. For example, Xia et al. [95] developed poly(propylene carbonate) microfibers loaded with dbcAMP and showed that sustained release significantly promoted axonal regenerative sprouting and functional recovery after spinal cord hemisection, As shown in Figure 31. The key innovation of this study lies in proving that electrospun scaffolds can maintain long-term bioactive signaling at the injury site, which is essential for overcoming the transient nature of direct drug injection. However, the study primarily focused on a single signaling pathway, limiting its ability to address the multifactorial nature of SCI.

Building on this concept, Xia et al. [71] further developed a multi-drug delivery system by incorporating both dibutyryl cyclic AMP (db-cAMP) and chondroitinase ABC (ChABC) into electrospun fibers, aiming to simultaneously address intrinsic and extrinsic barriers to axonal regeneration. In this design, db-cAMP was used to enhance the intrinsic growth capacity of neurons, while ChABC enzymatically degraded chondroitin sulfate proteoglycans (CSPGs), which are major inhibitory components of the glial scar. By integrating these two agents into a single electrospun platform, the study demonstrated that electrospun fibers can function as dual-function delivery systems, enabling coordinated modulation of neuronal signaling and extracellular matrix remodeling, As shown in Figure 32. In vitro and in vivo results showed enhanced neurite outgrowth and improved axonal regeneration compared to single-factor treatments, highlighting the advantage of synergistic therapy. This work is particularly significant for SCI repair because it shifts the strategy from single-target intervention to multi-target modulation of the injury microenvironment. However, the study also revealed challenges associated with multi-drug systems, including the need for precise control over release kinetics, potential interactions between bioactive agents, and the lack of systematic optimization of dosage ratios for maximal therapeutic efficacy.

A more clinically relevant strategy was explored by Rasti et al. [96], who developed electrospun PCL/gelatin nanofibrous scaffolds incorporating dexamethasone sodium phosphate (DEX-P) as an anti-inflammatory agent. In this system, the combination of hydrophobic PCL and hydrophilic gelatin enabled modulation of drug diffusion pathways, thereby reducing the typical burst release observed in many electrospun drug delivery systems. As a result, the scaffold achieved a more sustained and controlled release profile of DEX-P over time, which is critical for maintaining a prolonged anti-inflammatory effect during the early stages of spinal cord injury. Experimental results demonstrated that the controlled release of DEX-P effectively suppressed inflammatory responses and improved cellular compatibility, while the fibrous structure maintained sufficient mechanical integrity to serve as a supportive scaffold, As shown in Figure 33. This work is particularly relevant for SCI repair, where excessive inflammation is a major barrier to regeneration, and highlights the importance of engineering release kinetics to match the temporal dynamics of injury progression. However, the study remains limited by relatively short-term evaluation and lacks in vivo validation in complex SCI models, leaving questions regarding long-term efficacy and translational potential.

Recent advances in electrospun scaffolds have increasingly focused on integrating immunomodulation with sustained delivery of neurotrophic or therapeutic agents to achieve synergistic repair. Sun et al. [55] developed a new drug delivery composite system named interleukin-10 plasmid (pIL10) wasloaded into lipid nanoparticles (pIL10-LNP) @PLA-HA, designed to steadily release pIL10-LNP and NGF over an extended duration. This system is adept at modulating the inflammatory response following SCI and accelerating nerve regeneration. It exhibits excellent biocompatibility, promotes cell growth, triggers M2 macrophage polarization, and sustains anti-inflammatory factor secretion, enhancing post-SCI inflammatory response. Gradual NGF release promotes NSC differentiation into neuronal cells, enhancing neural repair in Figure 34. This case linked “immune regulation + neurotrophic” and clarified the synergistic value of the two in SCI repair, but for safe transformation, more comprehensive safety studies of gene vectors and long-term follow-up of efficacy are needed.

Complementing gene-based strategies, other studies have explored immune-responsive delivery systems to achieve more precise temporal control over growth factor release. Mays et al. [97] studied the combination of growth factor loaded gelatin microspheres (GMS) with methyl methacrylate hyaluronic acid (MeHA) to produce GMS fibers (GMSF) through electrospinning technology, in order to achieve delayed release of growth factors. GMS successfully combined with MeHA to produce fibers with an average diameter of 365–10 nm and a fiber arrangement of 44–8%, As shown in Figure 35. The experiment tested the effect of GMSF loaded with NGF on isolated chicken dorsal root ganglion cells. A drug delivery biomaterial system triggered by an immune response has been developed, achieving more precise control and longer exposure time for encapsulated drugs. This immune-mediated drug release system is of great significance for targeted repair.

Extending the concept of multifunctional delivery, pharmacological co-loading strategies have also been developed to address multiple pathological processes simultaneously. Dolci et al. [98] developed an innovative multidirectional pharmacological approach to acute injury of the central nervous system. By incorporating two complementary and potentially synergistic drugs, ibuprofen (Ibu) and triiodothyronine (T3), into a single polymer scaffold, this method accomplishes the dual therapeutic objectives of anti-inflammatory action and remyelination, As shown in Figure 36. Based on previous indoor studies and field experiments, the team determined the non-toxic and effective concentration of the two drugs when used simultaneously, and successfully loaded these drugs into nanofibers to make scaffolds that could continuously release the drugs. The dual drug sequential release strategy of this paper can be extended to more drug combinations, but more detailed in vivo pharmacokinetics and concentration-efficacy correlation studies are needed.

Further advancing scaffold multifunctionality, Zhang et al. [57] designed a hybrid electrospun system composed of PCL, PSA, and MP, aiming to integrate structural, biochemical, and neuroprotective functions within a single platform. In this design, PCL provided mechanical support and structural stability, while the incorporation of PSA introduced bioactive cues that are known to modulate neural cell adhesion, migration, and axonal extension due to its role in neural development and plasticity. Meanwhile, MP, a clinically used anti-inflammatory agent, was incorporated to suppress the secondary inflammatory response following spinal cord injury. Through this combination, the scaffold simultaneously provided topographical guidance, anti-inflammatory regulation, and enhanced cell–material interactions, demonstrating the feasibility of multifunctional integration within electrospun systems, As shown in Figure 37. Experimental results showed improved neuronal compatibility and reduced inflammatory responses compared to non-functionalized scaffolds, highlighting the synergistic effect of combining structural and biochemical components. This work is particularly significant as it represents a shift from single-function scaffolds toward integrated therapeutic platforms that more closely mimic the complex requirements of SCI repair. However, the increased compositional complexity also introduces challenges, including potential variability in degradation behavior, difficulty in precisely controlling component interactions, and uncertainties regarding large-scale fabrication and clinical translation.

In parallel, several studies have explored alternative bioactive agents to expand the therapeutic scope of electrospun systems. For instance, Singh et al. [89] developed uric acid-loaded electrospun fibers aimed at reducing oxidative stress, a key pathological factor in secondary spinal cord injury, and demonstrated improved cellular protection under oxidative conditions. Similarly, María et al. designed curcumin-loaded electrospun membranes combined with neural progenitor cell transplantation, showing that the antioxidant and anti-inflammatory properties of curcumin could mitigate neuronal degeneration and enhance the regenerative microenvironment, As shown in Figure 38. These studies highlight the flexibility of electrospinning as a platform for delivering a wide range of therapeutic molecules targeting different aspects of SCI pathology, including oxidative stress, inflammation, and neuronal loss. However, despite variations in the choice of bioactive agents, most of these approaches follow similar design principles—namely, drug incorporation into electrospun matrices for sustained release—and therefore contribute primarily as incremental or confirmatory advancements rather than introducing fundamentally new therapeutic paradigms.

Notably, recent work continues to advance electrospun drug-delivery systems toward clinically relevant applications. For example, Ullrich et al. [65] developed a riluzole-releasing electrospun implant for spinal cord injury, demonstrating sustained local drug delivery and improved neuroprotective outcomes, As shown in Figure 39. Given that riluzole is a clinically investigated neuroprotective agent, this study highlights the translational potential of electrospinning-based delivery platforms and underscores that this research direction remains actively evolving.

Overall, while drug-loaded electrospun scaffolds have demonstrated clear therapeutic potential, a major limitation remains the lack of quantitative correlation between in vitro release behavior and in vivo therapeutic outcomes, as well as insufficient validation in chronic and clinically relevant SCI models.

Recent advances have shifted attention from simple drug delivery to active regulation of the immune microenvironment, which plays a decisive role in SCI progression. Rather than merely suppressing inflammation, emerging strategies aim to reprogram immune responses toward a regenerative phenotype.

A representative breakthrough was reported by Xi et al. [99] who developed microenvironment-responsive immunoregulatory electrospun fibers that dynamically interact with the spinal cord injury microenvironment. In this system, the electrospun scaffold was engineered to respond to local pathological cues—such as inflammatory signals and oxidative stress—thereby enabling the controlled release of immunomodulatory factors in a stimuli-responsive manner. Mechanistically, the scaffold was designed to regulate macrophage polarization, shifting the balance from the pro-inflammatory M1 phenotype toward the pro-regenerative M2 phenotype, which is critical for creating a permissive environment for neural repair. As a result, the system not only reduced local inflammation but also promoted axonal regeneration and functional recovery in vivo, As shown in Figure 40. This work is particularly significant because it moves beyond passive or pre-programmed delivery systems and introduces the concept of adaptive biomaterials, in which therapeutic responses are dynamically tuned according to the evolving injury environment. However, the complexity of such responsive systems introduces challenges in reproducibility, precise control of responsiveness thresholds, and large-scale manufacturing, which may limit their translational potential.

From a pharmacological perspective, Liao et al. [78] prepared a multi-channel bioactive nanofiber catheter loaded with TUBA by dissolving TUBA in SF and mixing it with PGCL at a ratio of 5:5 using electrospinning technology, achieving controlled local release of TUBA over a long period of time. They constructed an MC/TUBA bioactive nanofiber catheter scaffold and induced SCI in T9-10 using a fully transverse large-span model. Compared with the SC/TUBA, SC, and SCI groups, local delivery of TUBA by MC/TUBA can significantly increase the number of nerve fibers, reduce glial scar formation, inhibit inflammation, reduce demyelination, and protect bladder tissue. Therefore, local administration of TUBA via MC/TUBA can effectively promote rehabilitation after SCI, As shown in Figure 41. In this case, precise anti-inflammatory effect was achieved at the level of “signal pathway + scaffold”, but to ensure the best efficacy in clinical application, TUBA dosage and carrier matching need to be further optimized.

In another innovative approach, Funnell et al. [100] designed magnetically responsive coaxial electrospun fibers for the controlled release of transforming growth factor beta 3 (TGFβ3), introducing an externally tunable system for regulating the spinal cord injury microenvironment. In this design, magnetic nanoparticles were incorporated into the coaxial fiber structure, enabling the release behavior of TGFβ3 to be modulated under an applied magnetic field. The core–shell architecture further facilitated sustained release, while the magnetic responsiveness provided an additional level of on-demand control over release kinetics. TGFβ3 was selected due to its known role in modulating astrocyte activity and reducing glial scar formation, which is a major inhibitory factor in SCI regeneration. As a result, the system demonstrated a reduction in astrocyte reactivity and a more permissive environment for neural repair, As shown in Figure 42. This work is particularly significant because it introduces the concept of externally controllable electrospun delivery systems, extending beyond passive and microenvironment-responsive platforms toward user-regulated therapeutic interventions. However, the reliance on external magnetic stimulation introduces practical challenges, including the need for precise field control, potential safety considerations, and increased complexity in clinical implementation, which may limit its translational feasibility.

Extending this concept, Sun et al. [55] proposed a genetically engineered electrospinning strategy to regulate the immune microenvironment following spinal cord injury. In this approach, gene regulatory elements were incorporated into the electrospun scaffold to enable localized and sustained expression of therapeutic factors, thereby achieving gene-level modulation of the injury environment. Unlike conventional drug-loaded systems that rely on passive release, this strategy allows the scaffold to actively influence cellular behavior by inducing the expression of specific proteins associated with immunomodulation and tissue repair. Mechanistically, the system was shown to regulate key inflammatory pathways, including promoting macrophage polarization toward the pro-regenerative M2 phenotype while suppressing pro-inflammatory signaling, As shown in Figure 43. As a result, reduced inflammation, improved cellular compatibility, and enhanced regenerative outcomes were observed compared to non-genetically modified systems. This work is particularly significant as it advances electrospun scaffolds from passive or stimuli-responsive platforms toward active biological reprogramming systems, representing a new direction in scaffold design for SCI repair. However, the incorporation of gene delivery strategies also introduces important challenges, including potential safety concerns related to gene vectors, control over spatial and temporal expression levels, and uncertainties regarding long-term stability and clinical translation.

In addition, several studies—including those using dexamethasone-loaded or anti-inflammatory molecule-loaded electrospun scaffolds—have consistently shown reduced inflammatory markers and improved tissue response. While these works reinforce the importance of immunomodulation, they largely follow similar strategies and therefore serve as supporting validation rather than major conceptual advances.

Overall, immunomodulatory electrospun scaffolds represent a significant shift toward microenvironment engineering, but future studies must better establish causal links between immune regulation and long-term functional recovery, particularly in chronic SCI models.

Coaxial electrospinning represents one of the most technically advanced approaches in biochemical functionalization, enabling the fabrication of core–shell structured fibers for improved cargo protection and controlled release. Its primary innovation lies in allowing spatiotemporal separation of multiple therapeutic agents, which is particularly relevant for the staged treatment requirements of SCI [101].

An early example of coaxial electrospinning for neural repair was provided by Reis et al. [102] who developed valproic acid (VPA)-loaded poly(lactic-co-glycolic acid) (PLGA) core–shell microfibers for central nervous system injury applications. In this system, the coaxial architecture enabled the encapsulation of VPA within a protective core, effectively improving the stability of the bioactive molecule and reducing premature degradation. At the same time, the surrounding shell layer acted as a diffusion barrier, allowing for a more controlled and sustained release profile, As shown in Figure 44. This study demonstrated that coaxial electrospinning can overcome key limitations of conventional electrospun systems—such as burst release and poor drug stability—thereby establishing it as a viable strategy for neural repair.

A more structurally integrated strategy was demonstrated by Liu et al. [103] who developed aligned core–shell electrospun fibers capable of co-delivering docosahexaenoic acid (DHA) and BDNF. In this system, the core–shell architecture enabled spatial separation of the two bioactive agents, allowing for staged and sustained release profiles, while the aligned fiber structure provided directional guidance for axonal growth. DHA, incorporated primarily for its neuroprotective and anti-inflammatory properties, was shown to improve neuronal survival and modulate the injury microenvironment, whereas BDNF served as a potent neurotrophic factor, promoting neurite outgrowth and synaptic plasticity. By integrating these biochemical cues within an oriented fibrous scaffold, the study effectively coupled topographical guidance with controlled molecular signaling, resulting in enhanced neurite extension and improved regeneration outcomes compared to non-aligned or single-factor systems, As shown in Figure 45. This work is particularly significant because it advances the concept of spatiotemporal regulation in neural repair, in which the spatial organization of the scaffold and the temporal release of bioactive molecules are coordinated. However, the complexity of the core–shell fabrication process introduces challenges in reproducibility and large-scale manufacturing, and precise control over release kinetics remains difficult to standardize across different experimental conditions.

Additional studies, including those using antioxidant or neuroprotective agents in core–shell fibers, further confirm the flexibility of this approach. However, these works generally follow similar design principles and therefore contribute primarily as technical extensions rather than fundamentally new concepts.

Despite its advantages, coaxial electrospinning faces significant challenges, including complexity in fabrication, reproducibility, and scalability. As a result, while it offers precise control over drug delivery, its practical application in clinical settings remains to be fully demonstrated.

In summary, biochemical functionalization has transformed electrospun scaffolds into multifunctional therapeutic systems for SCI repair. Key advances include sustained drug delivery (Xia et al. [71,95]), multifunctional scaffold integration (Zhang et al. [57]), immune microenvironment regulation (Xi et al. [99], Sun et al. [55]), and spatiotemporally controlled delivery via coaxial electrospinning (Liu et al. [103]). While many studies confirm the feasibility of these approaches, only a subset introduces true conceptual innovation, with others serving as important but incremental validations.

Future progress will depend on improving mechanistic understanding, long-term efficacy, and clinical translatability, particularly through studies that integrate structural design, biochemical function, and immune regulation into unified therapeutic strategies.

Cell-based strategies represent a critical advancement in electrospun scaffold design for SCI, as they directly address the limited intrinsic regenerative capacity of the central nervous system. While electrospun scaffolds can provide structural guidance and localized biochemical cues, they are inherently unable to replace lost neurons or glial cells, nor can they actively participate in tissue remodeling. Therefore, the incorporation of exogenous cells or modulation of endogenous cell behavior has emerged as an essential strategy for achieving functional recovery.

However, effective implementation of cell-based therapies in SCI remains challenging. The post-injury microenvironment is characterized by inflammation, inhibitory extracellular matrix components, and glial scar formation, all of which severely limit cell survival, differentiation, and integration. As a result, successful therapeutic strategies must not only deliver cells but also provide a supportive niche that enables long-term functionality.

An important early breakthrough in this field was the recognition that electrospun fiber architecture can directly regulate neural cell behavior. Rather than acting as passive substrates, electrospun scaffolds can provide topographical cues that guide cell alignment and neurite extension, which is essential for re-establishing neural connectivity across lesion sites.

For instance, Xie et al. [104] have demonstrated that neurite outgrowth can be strongly guided along aligned electrospun nanofibers, establishing a direct correlation between fiber orientation and axonal growth direction. This guidance effect is largely attributed to contact guidance, whereby aligned nanofibers provide topographical cues that influence cell adhesion and cytoskeletal organization, thereby directing neurite extension along the fiber axis. This finding is particularly significant in the context of SCI, where disorganized axonal regeneration remains a major barrier to functional recovery, As shown in Figure 46. By providing directional guidance and mimicking the anisotropic architecture of native neural tissue, aligned electrospun scaffolds can bridge lesion gaps and promote oriented axonal regrowth, ultimately facilitating organized neural reconnection.

Building on this concept, Yao et al. [105] further demonstrated that matrix elasticity, when combined with aligned fiber topography, can synergistically regulate stem cell fate. This effect is believed to be mediated by mechanotransduction pathways, in which cells sense and respond to both substrate stiffness and topographical cues via integrin-mediated adhesion and cytoskeletal tension. The coordinated regulation of these mechanical and structural signals enables cells to reorganize their cytoskeleton and activate downstream signaling pathways, ultimately directing lineage specification, As shown in Figure 47. This work represents an important conceptual advance, moving beyond structural guidance toward mechanobiological regulation and highlighting that both mechanical properties and fiber alignment jointly influence cell differentiation. Such insights are critical for designing scaffolds that can actively direct cell behavior rather than support it.

Earlier work by Xie et al. [50] also demonstrated that embryonic stem cells cultured on electrospun nanofibers can undergo lineage-specific differentiation, providing foundational evidence that electrospun scaffolds can function as cell-instructive microenvironments. This instructive effect is likely mediated by the interplay of biochemical and biophysical cues presented by the nanofibrous architecture, which can modulate cell–material interactions and activate intracellular signaling pathways associated with lineage commitment, As shown in Figure 48. Together, these studies establish that electrospun scaffolds are not merely structural supports, but active regulators of cellular behavior that can dynamically influence cell fate decisions.

Recent studies have further advanced electrospun systems toward multifunctional platforms that integrate sustained drug delivery with structural and cellular regulation. Song et al. [106] found that PLGA loaded microspheres had the best morphology at a concentration of 7 wt% and a water-oil ratio of 1:200. The drug release time was up to 14 days with a final release rate of about 60%. These microspheres maintained drug activity and were non-toxic. Oil-soluble PLGA microspheres were easily prepared and exhibited good drug release performance. They can be used for SCI repair and treatment when combined with other biomaterials. The team also studied a sandwich structure prepared by electrospinning and electrostatic spray for long-term controlled drug release. The NGF-PLGA/P407/P188/SA composite gel was temperature-sensitive, injectable, and achieved long-term sustained drug release, As shown in Figure 49. It was non-toxic in cell co-culture and induced PC-12 cell differentiation into neurons, showing potential in neural repair. Xu et al. established a benchmark for PLGA microsphere optimization, but the current study advances this paradigm by engineering a multifunctional, long-acting composite scaffold. This work not only extends the duration of drug release but also integrates cell therapy and structural guidance.

Extending beyond delivery-focused strategies, recent efforts have also emphasized microenvironment-responsive scaffold design to actively regulate oxidative stress and cellular behavior. Zhu et al. [107] studied the use of hydrogel surface grafting and microsol electrospinning technology to construct a composite biomimetic stent, which has the dual regulation function of “exogenous-endogenous” ROS. The outer hydrogel enhances local autophagy by degradation and release of rapamycin, neutralizing and inhibiting ROS production, and reducing neuronal apoptosis. Internal fibers provide brain-derived neurotrophic factors that guide axonal growth. In vitro experiments showed that the scaffold doubled neuronal autophagy levels, reduced apoptosis, and increased neural stem cell differentiation. In vivo experiments have shown that stents reduce ROS levels and scarring. RNA sequencing showed scaffold up-regulation of associated proteins and genes, As shown in Figure 50. This stent represents a therapeutic strategy to achieve neurological recovery. Zhu et al. innovations have been made in “mechanical gradient + fiber orientation”, but more sophisticated gradient design tools and long-term mechanical characterization are needed for large-scale applications.

A major advancement in this field is the integration of cell delivery with electrospun scaffold systems. Direct injection of therapeutic cells into the injury site typically results in poor cell survival and rapid dispersion due to the hostile microenvironment. In contrast, electrospun scaffolds can serve as protective niches, enhancing cell retention, survival, and functional integration. Carlson et al. [108] demonstrated that stem cells seeded on electrospun nanofibers exhibit improved adhesion, proliferation, and viability compared to conventional culture systems. This enhancement is largely attributed to the ability of electrospun fibers to recapitulate key structural features of the native extracellular matrix, thereby facilitating integrin-mediated cell–matrix interactions and promoting focal adhesion formation. Such interactions can activate downstream signaling pathways that regulate cytoskeletal organization and cell survival. This highlights the importance of scaffold-mediated microenvironment stabilization in supporting cell-based therapies, As shown in Figure 51. By providing a physical substrate that mimics aspects of the extracellular matrix, electrospun fibers help maintain cell localization and prevent cell loss from the injury site, ultimately improving the efficiency of tissue repair strategies.

A more clinically relevant advance was reported by Koffler et al. [109] who developed biomimetic scaffolds capable of supporting cellular infiltration and integration in SCI models. The key innovation of this work lies in integrating a precisely engineered structural architecture with favorable biological properties, thereby creating a permissive microenvironment that supports host cell infiltration and tissue integration. In particular, the scaffold architecture can provide physical guidance cues that facilitate axonal extension and cellular migration across lesion gaps, thereby enhancing organized tissue regeneration. This study represents a significant step toward translational application, demonstrating that engineered scaffolds can support both structural repair and functional recovery in vivo, thereby bridging the gap between experimental design and clinical relevance, As shown in Figure 52.

Recent advances have further pushed electrospun scaffolds toward highly integrated platforms that combine structural guidance with gene delivery, cell transplantation, and microenvironmental regulation. Zhang et al. [59] found a 3D fiber hydrogel scaffold that can be directly implanted into rats with spinal cord transection. The scaffold is composed of oriented electrospun fibers (providing topographic clues to guide axonal regeneration) and collagen matrix (achieving sustained delivery of miRNAs). Axon miRNAs (i.e., miR-132/miR-222/miR-431 combination) treatment significantly enhanced axonal regeneration. When used in combination with the anti-inflammatory drug methylprednisolone, it synergistically enhances functional recovery, reduces pro-inflammatory gene expression, and enhances extracellular matrix deposition related gene expression. Increasing the dose of Axon miRNAs in combination with methylprednisolone significantly promotes functional recovery and myelin regeneration, As shown in Figure 53. Therefore, the combination therapy of stent mediated Axon miR and methylprednisolone is a promising treatment for spinal cord injury.

In parallel, efforts to incorporate external or stimulus-responsive regulation have introduced additional layers of control over scaffold function. Vashisth et al. [110] developed patterned hybrid nanofiber scaffolds (HANFs) via electrospinning using anisotropic nanofibers (ANFs) embedded in a biocompatible gelatin hydrogel matrix. The ANF rings provided structural reinforcement and directional guidance for neural cell adhesion and growth, while quercetin-functionalized nanofibers delivered sustained neurotrophic support. The cylindrical conduit architecture exhibited enhanced mechanical stability, promoting axonal alignment and outgrowth in vitro without cytotoxicity. The dual-mode “photothermal-growth factor” regulation system demonstrated spatiotemporal control over neural regeneration, As shown in Figure 54. However, clinical translation requires addressing the limitations of photothermal penetration depth and the long-term biocompatibility of ANF-derived nanosheets.

Beyond biochemical and external regulation, the integration of living cells into electrospun scaffolds represents another critical direction. Lee et al. [111] studied the feasibility of an electrospun PVDF-Trifluoroethylene (TrFE) catheter combined with Schwann cells (SCs) transplantation for repair of spinal cord transection injury using a full cross-sectional model. The PVDF TrFE catheter has good biocompatibility and potential piezoelectricity. Meanwhile, the catheter supports the survival and axonal regeneration of SCs. Experiments found that directional catheters are more effective at promoting uniform distribution of SCs and directional axonal growth than random catheters. The processes of astrocytes (GFAP+) can cross the spinal cord/SC bridging interface, co localize with SCs, and promote axonal regeneration, As shown in Figure 55. And specific types of axons, such as noradrenergic dopamine-beta-hydroxylase (DβH+) and calcitonin gene-related peptide (CGRP+) axons, can regenerate in the conduit and cross the interface into the SCs bridge. This study marks the inaugural demonstration of the potential utility of electrospun PVDF-TrFE aligned fiber conduits for repairing spinal cords using SCs.

Pushing integration even further, stem cell–laden electrospun systems have been developed to simultaneously regulate inflammation, cell differentiation, and tissue reconstruction. Xu et al. [112] investigated the use of micro-alcohol electrospinning and collagen assembly techniques to construct an oriented active fiber bundle loaded with BMSC. A directional active fiber scaffold can leverage the advantages of stem cells in the early period of SCI to regulate the local inflammatory microenvironment and further influence stem cell differentiation. At the same time, it can continuously release BDNF and promote neuronal regeneration by up-regulation of neurotransmitter related genes (e.g., Tuj-1, NF-200). Furthermore, the electrospun fibers of the fiber bundle have the main characteristics of a natural extracellular matrix, capable of uniformly and efficiently loading growth factors and stem cells, As shown in Figure 56. It simulates the three-dimensional structure of the central nervous system, accurately controls the spatial arrangement of stem cells, guides axonal connections, and fills gaps in the spinal cord. In vivo induction of fiber bundles by stem cells provides a novel method for the treatment of SCI.

Collectively, these studies illustrate a shift from simple cell transplantation to integrated scaffold–cell therapeutic systems, in which the scaffold actively enhances the effectiveness of cell-based interventions.

Beyond delivery and structural guidance, regulating the interaction between transplanted cells and the injury microenvironment has emerged as a critical factor in SCI repair. The lesion site is highly inhibitory, with factors such as glial scar formation and inflammatory signaling limiting regenerative outcomes. Therefore, effective scaffolds must not only host cells but also modulate the surrounding microenvironment.

A growing body of work highlights that effective spinal cord repair requires not only structural support or cell delivery, but precise regulation of the cell–material microenvironment. Zuidema et al. [113] highlighted that biomaterials can influence glial scar formation and astrocyte behavior, which are key barriers to regeneration in SCI. Their work suggests that the physicochemical properties of biomaterials can modulate astrocyte activation and inflammatory responses, thereby regulating the extent of extracellular matrix deposition and glial scar formation at the injury site, As shown in Figure 57. This emphasizes that precise control over the cell–material interface is essential for creating a permissive microenvironment that supports neural repair. Rather than focusing solely on cell transplantation, this approach integrates material design with biological regulation, enabling the coordinated modulation of cellular responses and tissue-level regeneration.

Building on this principle, subsequent studies have demonstrated that scaffold-derived physical cues can further regulate cellular organization across multiple scales. Aligned electrospun scaffolds have been shown to influence cell organization and tissue architecture, as demonstrated by Wang et al. [114] further supporting the concept that scaffold-derived physical cues can regulate cellular interactions across multiple scales. The aligned topographical features of these scaffolds can provide contact guidance and modulate cell–matrix interactions, thereby directing cellular alignment and coordinated tissue organization, As shown in Figure 58. These findings reinforce the concept that cell fate is determined not only by intrinsic cellular properties but also by extrinsic cues provided by the scaffold and its microenvironment, highlighting the importance of integrating material design with biological regulation to achieve precise control over cell behavior.

At the material design level, efforts have been made to construct biomimetic architectures that more closely replicate the native extracellular matrix. Forouharshad et al. [115] developed a cell vector by cultivating NSCs on both 2D and 3D structures composed of specially cross-linked and functionalized self-assembled peptides (SAPs) that exhibit improved biological and biomechanical properties. The scaffold’s morphology, structure, and secondary structure were analyzed in solid-state and electrospun solutions. Morphological studies revealed that the incorporation of mixed peptides and surfactants as additives promoted the formation of thinner, uniform, and defect-free fibers. Notably, the β-folded conformation was predominant, indicating self-assembly, except in the electrospun solution. When compared to the gold standard, NSCs cultivated on electrospun SAP scaffolds in both 2D and 3D environments exhibited satisfactory proliferation, viability, and differentiation abilities in vitro, As shown in Figure 59. In vivo biocompatibility experiments further validated the feasibility of inserting fiber channels, as evidenced by a minimal foreign body reaction. The findings suggest that fibrous electrospun SAP scaffolds, in the shape of microchannels and available in both 2D and 3D configurations, may facilitate NSC regeneration in the aftermath of SCI.

More recently, integrated strategies have combined biochemical signaling with structural guidance to engineer highly functional cell-supportive microenvironments. Yang et al. [116] developed an aligned fibrin nanofiber hydrogel modified with N-cadherin human Fc chimeric protein (AFGN) via electrospinning and biochemical coupling technology for optimized stem cell transplantation in SCI. The AFGN scaffold provided directional guidance, mechanical support, and specific cell-binding ligands to enhance NSC survival, neuronal differentiation, and integration with endogenous neural networks. In a rat model of 2 mm complete spinal cord transection, AFGN hydrogel-delivered NSCs demonstrated improved retention, immune modulation, and axonal regeneration, resulting in functional recovery via reconstructed neural relays. This strategy integrates chemical (N-cadherin-mediated cell adhesion) and mechanical (aligned nanofiber topography) cues to engineer NSC microenvironments, As shown in Figure 60. However, clinical translation requires addressing immunocompatibility challenges and optimizing multiscale mechanical coupling between scaffolds and host tissues.

In addition to the representative studies discussed above, numerous investigations have explored the combination of electrospun scaffolds with various cell types, including mesenchymal stem cells, neural stem cells, and Schwann cells. These studies consistently report improvements in cell survival, differentiation, and functional recovery.

Despite differences in cell sources and scaffold compositions, the overall trend is clear: electrospun scaffolds can enhance the therapeutic efficacy of cell-based strategies by providing structural support and regulating the local microenvironment. These effects are primarily achieved by modulating cell–material interactions, which, in turn, influence cellular behavior and tissue responses. However, many of these studies follow similar design principles and therefore primarily serve as supporting evidence rather than introducing fundamentally new conceptual advances.

Overall, cell-based electrospinning strategies represent a major step toward the development of biologically active systems for spinal cord injury SCI repair. Key advances include structural regulation of cell behavior, mechanobiological control of differentiation, scaffold-assisted cell delivery, and modulation of the microenvironment.

Despite these promising developments, several critical challenges remain. First, cell survival after transplantation is still limited, particularly within the inflammatory microenvironment of acute SCI. Second, long-term functional integration of transplanted cells has not been consistently demonstrated. Third, most studies rely on small-animal models, with limited validation in clinically relevant or large-animal systems.

Future research should therefore focus on integrating cell delivery, scaffold design, and immune regulation into unified therapeutic platforms, with an emphasis on improving long-term functional outcomes and enhancing translational feasibility.

Although conventional electrospun scaffolds have been widely investigated for SCI repair, their densely packed fibrous networks may limit homogeneous cell infiltration. This limitation has stimulated the development of C-ES, a biofabrication strategy first introduced in 2006 to encapsulate living cells within electrospun microthreads and scaffolds [117,118]. Early follow-up work demonstrated that highly concentrated primary cells could also be processed into viable cell-bearing threads and scaffolds [117], indicating that C-ES was not only a conceptual advance but also a technically feasible route for generating cell-laden fibrous constructs.

From an application standpoint, one of the representative demonstrations of C-ES was reported by Sampson et al. [118], who demonstrated the feasibility and in vivo safety of cell electrospinning for generating cell-laden scaffolds, As shown in Figure 61. Subsequent work further expanded this concept through aerodynamically assisted bio-threading and related bioplatforms, enabling the fabrication of large quantities of organized living architectures such as three-dimensional sheets and vessel-like structures.

In a broader regenerative medicine context, later reviews summarized C-ES as a functional platform for regenerative biology and medicine [119,120], and further clarified its critical processing parameters and biofabrication methodologies [121,122]. These studies collectively indicate that C-ES has evolved from an early experimental idea into a distinct and increasingly mature biofabrication branch.

More recent work has further strengthened the practical relevance of C-ES. Maurmann et al. [123] developed a reactive cell electrospinning strategy based on dynamic covalent cross-linking, enabling direct cell loading during electrospinning and the fabrication of nonaligned, aligned, and cross-aligned hydrogel nanofiber networks. In that study, the resulting scaffolds supported C2C12 myoblast viabilities greater than 85% over 14 days, and aligned scaffolds increased cell aspect ratio by approximately 27% relative to nonaligned scaffolds. Notably, the authors also showed that cell-loaded bilayer scaffolds with perpendicular fiber alignments could guide localized directional cell responses while avoiding delamination between layers, suggesting clear potential for constructing complex tissues such as smooth muscle, neural, or tendon tissues，As shown in Figure 62. These features are particularly relevant to SCI because they provide a route toward scaffolds that combine cell incorporation, directional guidance, and hierarchical architecture in a single construct.

More recent work has further extended C-ES from a delivery platform into a practical in situ fabrication strategy for direct cell loading at injury sites. Liu et al. [124] developed a handheld in situ cell electrospinning device capable of directly preparing cell-loaded nanofiber scaffolds at target sites. Using human umbilical cord mesenchymal stem cells (HUCMSCs) as a model, they demonstrated minimal impact on cellular viability and dryness-related characteristics, achieving non-contact, high-efficiency cell delivery. This work holds significant implications for in situ tissue repair and direct cell delivery, serving as a representative foundational study for the practical application of cell electrospinning, as shown in Figure 63. For SCI, its value lies in providing a migratory strategy of “fibroblast formation concurrent with cell loading”.

Building on this concept, subsequent studies have shown that C-ES can be combined with biomaterials to achieve simultaneous cell delivery, local shaping, and microenvironment modulation. Chen et al. [125] reported in situ electrospinning of live cells loaded with gelatin-dopamine fibers for diabetic wound repair. The study combined human umbilical cord mesenchymal stem cells with Gel-DA as “bioinks”, achieving >90% cellular viability and metabolic activity under optimized voltage conditions. Animal experiments demonstrated enhanced wound closure, collagen deposition, and angiogenesis. This approach holds promise for stem cell delivery combined with biomaterials for synergistic repair， As shown in Figure 64. Although not applicable to spinal cord injury models, the study effectively illustrates that cell electrospinning can simultaneously perform three functions: cell delivery, local shaping, and microenvironment modulation.

More recently, in situ C-ES has also been used to improve cell retention and localized repair on complex tissue surfaces, highlighting its translational potential for surgery-oriented regeneration. Xue et al. [126] employed handheld in situ electrospinning to directly immobilize MSCs onto the bone wall surface in an osteoporotic bone defect model. The results demonstrated that this method had minimal impact on MSC viability while enhancing cell retention, upregulating osteogenic marker proteins, and improving bone repair, involving CCL2-associated homing and TSG6-mediated immune regulation. This approach holds significant implications for in situ cell immobilization on complex curved surfaces， As shown in Figure 65. For SCI, this study best illustrates how cell electrospinning is transitioning from “proof-of-concept” to “in situ cell immobilization and localized repair during surgery”.

Although direct SCI-specific studies of C-ES are still limited, the broader biomedical literature shows that the strategy is already being explored in other repair contexts, including wound healing. Taken together, these examples suggest that C-ES may serve as a promising extension of conventional electrospinning for future SCI scaffold design, especially where simultaneous control over cellular placement, fiber alignment, and microarchitectural complexity is required.

This review thoroughly explores the mechanism, application and progress of electrospinning for SCI, and draws the following main conclusions.

Electrospun scaffolds establish multi-layered repair mechanisms through biomimetic design, dynamic responsiveness, and precise delivery:

Cutting-edge research drives electrospun scaffolds toward multifunctional and intelligent platforms:

Despite technological promise, clinical adoption faces critical hurdles:

Future Directions:

C.Y. and S.Z. completed the initial draft of the paper. M.Y. played a central driving role in the overall content, conducting a comprehensive review and editing of the manuscript. C.L. (Chuankun Li) and Y.S.D. conducted an in-depth analysis of the research background, comprehensively combing through the development context of related fields. X.M. and X.Z. collected the literature relevant to this study, laying a solid theoretical foundation and providing theoretical support for the research. C.L. (Changhe Li) and Y.Z. (Yanbin Zhang) revised the format of the paper, ensuring that the paper conformed to academic norms in form and enhancing its readability and professionalism. Y.Z. (Yongxing Zang) and P.Y. summarized the research of this paper, distilling the core points and clearly presenting the key conclusions of the study.

Not applicable.

Not applicable.

Not applicable.

This study was financially supported by the Support plan for Outstanding Youth Innovation Team in Universities of Shandong Province (2023KJ114), Young Talent of Lifting engineering for Science and Technology in Shandong, China (SDAST2024QTA043), Qingdao postdoctoral researchers applied research project funding (QDBSH20230102050).

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.