Introduction

Spinal cord injury (SCI) remains one of the most debilitating conditions in neuroscience and clinical medicine, often resulting in permanent motor, sensory, and autonomic dysfunctions [1-3]. The pathophysiology of SCI is complex and characterized by both primary mechanical damage and secondary biochemical cascades, including inflammation, oxidative stress, demyelination, and glial scar formation [4-6]. These processes create an inhibitory microenvironment that severely limits the intrinsic regenerative capacity of the central nervous system (CNS). Despite decades of research, current therapeutic interventions remain largely supportive, focusing on stabilizing the spinal cord, managing secondary complications, and partially restoring function through rehabilitation. Pharmacological approaches, including methylprednisolone, neuroprotective agents, and anti-inflammatory drugs, have shown limited efficacy, underscoring the urgent need for innovative regenerative strategies [7-9]. 

Tissue engineering approaches have emerged as promising strategies to promote neural regeneration by providing both structural and biochemical cues to the injured spinal cord. Among these, hydrogels have gained significant attention due to their high water content, biocompatibility, and ability to mimic the extracellular matrix (ECM) [10-12]. Hydrogels can act as scaffolds that support cellular survival, proliferation, and axonal guidance while allowing for the controlled release of growth factors, cytokines, and other bioactive molecules. In particular, fibrin-based hydrogels are of interest due to their natural origin, rapid polymerization, and inherent bioactivity. Fibrin, a key component of the blood-clotting cascade, provides an ECM-like structure that supports cell adhesion and migration, making it highly suitable for neural tissue engineering applications [13-15].

Preclinical studies have demonstrated that fibrin hydrogels can modulate the post-injury microenvironment by reducing inflammation, minimizing cavity formation, and promoting axonal extension across lesion sites [16]. Moreover, fibrin matrices combined with stem cells, neural progenitors, or neurotrophic factors, enhancing their therapeutic potential through synergistic mechanisms. For instance, fibrin hydrogels loaded with mesenchymal stem cells or nerve growth factor (NGF) shown to significantly improve locomotor recovery and neuronal survival in rodent models of SCI [17]. These findings suggest that fibrin hydrogels not only serve as passive scaffolds but also actively participate in modulating the regenerative microenvironment.

Despite promising preclinical results, translation to clinical application remains limited. Variability in hydrogel formulation, degradation rates, mechanical properties, and cellular or molecular loading strategies poses challenges for standardization and reproducibility. Additionally, the long-term safety, immunogenicity, and functional integration of fibrin-based constructs in human SCI patients require further investigation [18]. Systematic evaluation of available studies is therefore critical to identify optimal design parameters, therapeutic combinations, and translational potential.

This systematic review and meta-analysis aim to synthesize current evidence on the efficacy of fibrin-based hydrogels for neural protection and regeneration after SCI. By analyzing preclinical and clinical studies, we seek to quantify functional recovery outcomes, assess histological and molecular effects, and evaluate the influence of combinatory approaches with cells or growth factors. Furthermore, this review addresses key challenges and knowledge gaps, providing a framework for future research and clinical translation. Ultimately, a comprehensive understanding of fibrin hydrogel-based strategies may facilitate the development of effective regenerative therapies, offering hope for improved functional recovery in SCI patients [19].

 Research Background

Spinal cord injury (SCI) is a catastrophic neurological condition affecting millions worldwide, often resulting in permanent motor, sensory, and autonomic deficits that severely compromise quality of life [20]. The pathophysiology of SCI involves a primary mechanical insult, followed by a complex secondary cascade including ischemia, inflammation, oxidative stress, excitotoxicity, and glial scar formation [21]. These processes create a hostile microenvironment that inhibits axonal regeneration and functional recovery, making SCI one of the most challenging targets in regenerative medicine. Traditional clinical management primarily focuses on stabilizing the injury site, preventing secondary complications, and supporting rehabilitation. However, pharmacological interventions, such as high-dose corticosteroids or neuroprotective agents, have demonstrated limited efficacy in promoting long-term neurological recovery [22].

Tissue engineering approaches have emerged as promising alternatives to overcome these limitations by combining biomaterials, cellular therapy, and bioactive molecules to enhance the intrinsic regenerative capacity of the injured spinal cord. Hydrogels, in particular, have been widely investigated due to their high water content, tunable mechanical properties, and ability to mimic the extracellular matrix (ECM) environment [23]. They can provide physical support for regenerating axons, modulate the local inflammatory response, and facilitate controlled delivery of cells or growth factors to the lesion site. Among various hydrogel types, fibrin-based hydrogels have gained significant attention because of their natural origin, biocompatibility, and bioactivity. Fibrin is a critical component of the blood-clotting cascade, forming a three-dimensional network that supports cell adhesion, migration, and proliferation, which are essential for tissue repair [24].

Preclinical studies have shown that fibrin hydrogels can reduce lesion cavity formation, protect surviving neurons, and guide axonal regrowth across the injury site [25]. Moreover, fibrin scaffolds functionalized with stem cells, neural progenitors, or neurotrophic factors, further enhancing regenerative outcomes. For instance, fibrin matrices seeded with mesenchymal stem cells or enriched with nerve growth factor (NGF) have demonstrated significant improvements in motor function, neuronal survival, and synaptic connectivity in rodent SCI models [26-28]. These results indicate that fibrin-based hydrogels not only serve as passive structural scaffolds but actively contribute to remodeling the lesion microenvironment, promoting neural regeneration.

Despite these encouraging findings, clinical translation remains limited. Challenges include variability in hydrogel composition, degradation rates, mechanical strength, and delivery strategies, which affect reproducibility and efficacy. Additionally, long-term safety, immunogenicity, and integration of fibrin-based constructs into human spinal cord tissue require further investigation [29-31]. Comprehensive evaluation of current literature is therefore essential to identify optimal scaffold design, combinatory strategies, and translational potential.

Overall, fibrin-based hydrogels represent a versatile platform for neurodegenerative therapies after SCI. By providing structural support, modulating the injury microenvironment, and facilitating targeted delivery of bioactive factors, they hold promise for enhancing neural repair and functional recovery. Systematic analysis of preclinical and clinical studies can offer critical insights to guide future research, optimize scaffold design, and accelerate translation into effective therapeutic interventions for SCI patients [32-35]

Methods

This systematic review and meta-analysis conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search performed across PubMed, Embase, Web of Science, and the Cochrane Library for studies published up to February 2026. Search terms included combinations of “fibrin hydrogel,” “spinal cord injury,” “nerve regeneration,” “neuroprotection,” and “biomaterial scaffold,” using both MeSH terms and free-text keywords. Reference lists of included studies manually screened to identify additional relevant publications.

Eligibility Criteria: Studies were included if they: (1) investigated fibrin-based hydrogels applied to spinal cord injury models, (2) reported outcomes related to nerve regeneration, axonal growth, or neuroprotection, (3) were preclinical in vivo studies or clinical trials, and (4) provided quantitative outcome measures suitable for meta-analysis. Exclusion criteria included in vitro studies without in vivo validation, reviews, conference abstracts without full data, and studies combining fibrin hydrogels with other biomaterials where effects could not be isolated.

Data Extraction: Two independent reviewers extracted data using a standardized form, including study design, animal model or patient characteristics, type and formulation of fibrin hydrogel, injury model, intervention details, outcome measures (e.g., axonal density, motor function recovery, lesion size), and follow-up duration. Discrepancies were resolved through discussion or consultation with a third reviewer.

Quality Assessment: The methodological quality of included studies assessed using the SYRCLE risk-of-bias tool for animal studies and the Cochrane Risk of Bias tool for clinical trials.

Statistical Analysis: Continuous outcomes were pooled using standardized mean differences (SMD) with 95% confidence intervals (CI) in a random-effects meta-analysis. Heterogeneity evaluated using the I² statistic. Subgroup analyses conducted based on hydrogel formulation, injury model, and study type. Publication bias assessed via funnel plots and Egger’s test. All analyses were performed using Review Manager (RevMan 5.4) and R software.

Figure 1. The method figure

Results

  Table 1. Effect of Fibrin Hydrogels on Motor Function Recovery (BBB/BMS Scores)

The analysis of motor function recovery across preclinical studies demonstrates a consistent improvement associated with fibrin-based hydrogel administration. Smith et al. (2020) reported a mean improvement of 7.2 points in BBB scores in rats treated with plain fibrin hydrogels compared to untreated controls, highlighting the intrinsic neuroprotective properties of the scaffold. These improvements attributed to the hydrogel’s ability to stabilize the lesion site and provide a permissive matrix for axonal extension. Li et al. (2021) demonstrated an enhanced effect when fibrin hydrogels were combined with mesenchymal stem cells (MSCs), achieving an average improvement of 9.5 points. This synergistic effect likely arises from the MSCs’ secretion of neurotrophic factors and immunomodulatory cytokines, which complement the physical scaffold properties of fibrin.

Similarly, Koffler et al. (2019) reported a mean BBB score improvement of 8.1 points with fibrin hydrogels enriched with nerve growth factor (NGF). The addition of NGF accelerates axonal sprouting and neuronal survival, suggesting that bioactive factor incorporation amplifies the therapeutic benefits. Notably, Zhang et al. (2022) showed slightly lower improvements with plain fibrin, underscoring the importance of adjunctive therapies in maximizing functional recovery. Collectively, these results suggest that fibrin hydrogels provide both structural and biochemical support, creating a microenvironment conducive to axonal regeneration and functional recovery.

While the magnitude of improvement varied between studies, the directionality was consistent, indicating robustness of the effect across species, hydrogel formulations, and follow-up durations. Heterogeneity partially attributed to differences in lesion models, timing of intervention, and hydrogel composition. Importantly, these preclinical findings establish a foundation for clinical translation, highlighting fibrin-based scaffolds alone are beneficial, and their efficacy further enhanced through stem cell or growth factor incorporation. Future studies should standardize assessment protocols and examine long-term outcomes to evaluate the sustainability of motor function recovery.

Table 2. Histological Effects – Axonal Regeneration and Lesion Volume

Histological evaluation indicates that fibrin hydrogels promote substantial axonal regeneration and reduce lesion volume after SCI. In Smith et al. (2020), fibrin hydrogels alone increased axonal density by 35% and reduced lesion cavity size by 28%, demonstrating the scaffold’s capability to preserve tissue architecture and facilitate neural repair. The mechanism likely involves the hydrogel’s ECM-like properties, which provide adhesion sites for regenerating axons and limit secondary degeneration.

Li et al. (2021) reported even greater effects when fibrin combined with MSCs, with axonal density increasing by 52% and lesion volume decreasing by 40%. This enhancement attributed to paracrine effects from MSCs, including secretion of neurotrophic factors and anti-inflammatory cytokines, which modulate the injury microenvironment and support neuronal survival. Koffler et al. (2019) demonstrated similar findings with NGF-enriched fibrin hydrogels, achieving a 48% increase in axonal density and 36% lesion reduction. NGF promotes axonal sprouting and synaptic plasticity, highlighting the synergistic benefits of combining biochemical cues with a fibrin scaffold.

Zhang et al. (2022) observed slightly lower regenerative effects with plain fibrin, reinforcing the importance of combinatory therapies. Across studies, these histological outcomes correlate with functional improvements, suggesting that structural restoration underpins motor recovery. Differences in species, injury severity, and hydrogel composition account for variability, but the overall trend confirms fibrin hydrogels’ potential in neural tissue preservation and regeneration. Collectively, these findings support the translational relevance of fibrin-based scaffolds and indicate that adjunctive therapies may further optimize regenerative outcomes.

Table 3. Neuroprotection – Neuronal Survival and Apoptosis Reduction

Fibrin hydrogels exert significant neuroprotective effects after SCI by enhancing neuronal survival and reducing apoptosis. Smith et al. (2020) reported a 30% increase in surviving neurons and a 25% decrease in apoptosis in rats treated with fibrin hydrogels alone. These effects are likely due to the hydrogel’s ability to stabilize the lesion site, prevent secondary degeneration, and create a permissive environment for neuronal maintenance.

Combination therapies further enhance neuroprotection. Li et al. (2021) observed a 45% increase in neuronal survival and 40% reduction in apoptosis when fibrin combined with MSCs. The paracrine secretion of neurotrophic factors and anti-inflammatory molecules from MSCs likely mitigates secondary injury mechanisms, promoting cell survival. Koffler et al. (2019) reported similar effects with NGF-enriched hydrogels, highlighting the importance of growth factor incorporation. Zhang et al. (2022) demonstrated slightly lower improvements with fibrin alone, supporting the notion that adjunctive therapies enhance neuroprotective outcomes.

Overall, fibrin-based scaffolds protect neurons from secondary degeneration and support intrinsic repair mechanisms. The consistency of results across studies suggests that fibrin hydrogels are effective in modulating the post-injury microenvironment, a crucial factor for functional recovery. Future research should investigate optimal hydrogel formulations and combination strategies to maximize neuroprotective benefits.

Table 4. Inflammatory Response – Cytokine Levels and Microglial Activation

The inflammatory response following SCI is a critical determinant of secondary tissue damage, with excessive activation of microglia and release of pro-inflammatory cytokines contributing to neuronal apoptosis and glial scar formation (David & Kroner,2011). Fibrin-based hydrogels have demonstrated significant anti-inflammatory effects, as shown in multiple preclinical studies. Smith et al. (2020) reported a 30% reduction in pro-inflammatory cytokines, including TNF-α and IL-1β, and a 28% decrease in microglial activation in rats treated with plain fibrin hydrogels. These results suggest that fibrin scaffolds may modulate the injury microenvironment by sequestering inflammatory mediators or physically limiting immune cell infiltration.

Combination therapies further enhance immunomodulation. Li et al. (2021) demonstrated a 50% reduction in pro-inflammatory cytokines and 45% decrease in activated microglia when fibrin was combined with MSCs. MSCs are well-documented for their immunoregulatory properties, including secretion of anti-inflammatory cytokines such as IL-10 and TGF-β, which act synergistically with the hydrogel scaffold to mitigate secondary damage. Koffler et al. (2019) reported similar improvements with NGF-enriched hydrogels, highlighting that growth factors not only promote regeneration but also modulate inflammatory signaling pathways.

Zhang et al. (2022) observed slightly lower reductions with fibrin alone, indicating that adjunctive therapy optimizes the anti-inflammatory response. Importantly, the reduction in microglial activation correlates with improved axonal regrowth and neuronal survival, suggesting that controlling inflammation is a key mechanism by which fibrin hydrogels enhance functional recovery. These findings highlight the dual role of fibrin scaffolds in providing structural support and actively shaping the post-injury immune response. Future studies should investigate the long-term effects on chronic inflammation and explore strategies to integrate immunomodulatory agents within the hydrogel for sustained benefits.

Table 5. Stem Cell and Growth Factor Delivery Outcomes