Chitosan conduits for peripheral nerve repair: a systematic review of animal studiesAbstract
Peripheral nerve injuries are major causes of disability worldwide. The current standard treatment, autologous nerve grafting, puts the donor region at risk and has limited availability. A systematic search of MEDLINE, EMBASE, and Web of Science databases for studies published between January 1, 2008, and September 04, 2024, was performed to compare interventions using chitosan tubes with non-intervention or autologous nerve grafts in rats with artificially injured sciatic nerves. Twenty-one experimental studies including 738 animals were selected. Nerve repair using chitosan conduits resulted in a higher sciatic functional index compared to non-intervention. Higher conduction velocity and a greater number of myelinated fibers were observed in nerve fibers treated with chitosan compared to the no intervention or primary repair groups. However, compound muscle action potentials and somatosensory evoked potentials were superior in the latter compared to nerves treated with the polymer.
Keywords:
nerve regeneration; biomaterials avaliability; animal model; suture; eletrical stimulation
Resumo
Lesões de nervos periféricos são as principais causas de incapacidade em todo o mundo. O tratamento padrão atual, enxerto autólogo de nervo, pode colocar em risco a região doadora e tem disponibilidade limitada. Uma pesquisa sistemática nas bases de dados MEDLINE, EMBASE e Web of Science publicadas entre 1º de janeiro de 2008 e 31 de dezembro de 2020 foi realizada para encontrar estudos comparando intervenções empregando tubos de quitosana com enxertos nervosos autólogos ou sem intervenção em ratos com nervo ciático artificialmente ferido. Foram selecionados 21 estudos experimentais, incluindo 738 animais. O uso do conduto de quitosana para reparo do nervo resultou em maior índice funcional do ciático em comparação à não intervenção. A velocidade de condução e maior número de fibras mielinizadas foram observados nas fibras nervosas tratadas com quitosana quando comparadas aos grupos sem intervenção ou reparo primário. Os potenciais de ação muscular compostos e os potenciais evocados somatossensoriais foram superiores nestes últimos em comparação aos nervos tratados com o polímero.
Palavras-chave:
regeneração nervosa; biomateriais; modelo animal; sutura; estimulação elétrica
1. Introduction
Peripheral nerve injuries are major causes of disability worldwide, posing challenges for care and having a significant economic impact. An estimated 2.8% of trauma patients experience disability related to these injuries (Noble et al., 1998). When a nerve is transected, the goal is to perform a tensionless, primary neurorrhaphy for gaps <5 mm. For gaps >5 mm that preclude primary repair, the current gold standard treatment is bridging the nerve defect with an autologous sensory nerve graft. However, these grafts have limited supply, are associated with donor site morbidities, and often result in disappointing clinical outcomes despite the best repair techniques (Andrès et al., 2019; Mohammadi et al., 2013). Consequently, clinicians and scientists have developed nerve allografts and conduits, using both biologic and artificial materials, to serve as axonal guidance channels and correct misalignments.
Repairing nerve injuries using conduits has potential advantages over primary repair or autologous nerve grafts (ANG). It avoids the need for a second procedure on the donor site and shows superior regenerative results compared to ANG. These conduits can reduce the possibility of neuroma formation and help guide axons from the proximal to the distal stump without interference from degenerate fascicles (Castañeda and Kinne, 2002; Mohammadi et al., 2013; Wang et al., 2007).
Biological polymers have emerged as an alternative for manufacturing these scaffolds. Chitosan, derived from chitin (an element widely found in exoskeletons and fungal cell walls), is one such material. Chitosan tubes can be manipulated by surgeons to achieve a desired configuration. This material does not appear to induce significant inflammatory responses or neuroma formation (Madihally and Matthew, 1999). With its low toxicity profile and adsorptive properties, chitosan is suitable for peripheral nerve regeneration (Marcol et al., 2011). Chitosan polymers, including their nanoformulations, have broad medical applications, such as controlling obesity and dyslipidemia by inhibiting adipogenesis and improving hepatic lipid metabolism. This makes them promising for treating metabolic syndromes and hypertension (Abd El‐Hack et al., 2023). Additionally, they exhibit effective antimicrobial activity against bacterial and fungal pathogens, as demonstrated in silkworm larvae treatment, showing potential for antimicrobial therapies under laboratory conditions (El-Adly et al., 2022).
Adjuncts such as solutions containing thyroid hormones or nerve growth factors can be incorporated into chitosan conduits to improve nerve regeneration efficiency (Wang et al., 2012). Chitosan may serve as a support for various filling materials that can further enhance regeneration. Some studies have reported less infiltration of fibrous scar tissue and maximized accumulation of soluble factors produced by nerve stumps. A limitation of currently available synthetic material ducts is their insufficient filling of long gaps due to their short length.
Recent years have seen growing interest in these synthetic materials. However, most studies evaluating the efficacy of chitosan tubes for peripheral nerve repair are experimental, using animal models. A detailed systematic study of nerve repair in rats can stimulate the development of primary studies in humans using these materials. This systematic review aims to investigate the efficacy of conduits built using chitosan scaffolds in repairing artificially created gaps in rat sciatic nerves.
2. Material and Methods
A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations. The research protocol was registered in PROSPERO (CRD42020162842). Two investigators (T.F. and D.C.C.) independently searched MEDLINE and EMBASE via OVID SP and Web of Science databases for works published from January 2008 to September 2024. The search was limited to English, Portuguese, and Spanish languages.
The questions were structured according to the PICOS format: P: Rats weighing 200 g or more, with artificially transected sciatic nerves creating a gap of at least 10 mm between endings I: Interposition of chitosan conduits C: Other interventions (including control, ANG, or no intervention) O: Results in walking track analysis, electroneuromyography, and histological parameters. The selection process is shown in Figure 1.
PRISMA Flow Diagram for Study Selection in Sciatic Nerve Repair Review. This diagram illustrates the study identification and selection process for a review on chitosan conduits in sciatic nerve repair.
The research question was: “Is there experimental evidence that the use of a chitosan nerve tube improves nerve repair in rats?”
The search strategies were (Table 1):
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“Peripheral Nerve Injuries/rh,su,th, [Rehabilitation, Surgery, Therapy] AND Chitosan/tu [Therapeutic Use]”
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“Peripheral nerve injury/ dt, rh, su, th [Drug Therapy, Rehabilitation, Surgery, Therapy] AND chitosan nanoparticle/ or chitosan/ or chitosan acetate/ or chitosan derivative”
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“(chitos) AND [(nerve repair) OR nerve regeneration OR peripheral nerve injury OR nerve injury)] AND (surg)”
Reference lists of included studies were also searched for eligible studies not retrieved by the initial strategy. Grey literature was included through database searches. Two investigators (T.F and U.C) independently screened studies by title and abstract, then read the full text of those selected. All discrepancies were resolved through discussion or by consulting a third investigator.
2.1. Inclusion criteria
Randomized comparative animal studies performed on rats weighing 200 g or more, with artificially transected sciatic nerves creating a gap of at least 10 mm between endings. Only studies comparing interposition of chitosan conduits with other interventions (including control, ANG, or no intervention) were included.
2.2. Exclusion criterias
tudies in animals other than rats, in vitro studies, studies evaluating chitosan tubes for the repair of other nerves or structures, and reviews. Human studies were not selected for this systematic review.
2.3. Intervention
Surgical interventions in sciatic nerve gaps using various chitosan-based formulations were considered (e.g., tubes, adhesives, drug-soaked materials, and others).
2.4. Primary outcomes
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Improvement in the walking track analysis of sciatic functional index (SFI), which requires coordinated activity involving sensory input, motor response, and cortical integration;
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Evidence of electromyographic improvement in nerve conduction velocity (NCV), compound muscle action potentials (CMAPs), and/or somatosensory evoked potentials (SSEPs);
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Histological improvement by microscopic inspection of the number and size of myelinated fibers, myelin sheath thickness, axon count and diameter, and/or neuroma formation.
2.5. Bias risk analysis
The SYRCLE Risk of Bias tool was used to assess the quality of the included preclinical studies. This tool identifies potential biases in animal studies that could affect the reliability and validity of study outcomes, particularly in studies investigating sciatic nerve regeneration in rats using various chitosan-based interventions. It assesses critical domains for ensuring internal validity of animal research, including sequence generation, allocation concealment, blinding, and handling of incomplete outcome data.
Two reviewers independently applied the SYRCLE Risk of Bias tool to each study. Discrepancies were resolved through discussion or consultation with a third reviewer. Each study was evaluated across multiple domains, with judgments made regarding the risk of bias as “low,” “high,” or “unclear.”
Scoring/Rating: The criteria for scoring each domain included the adequacy of randomization in sequence generation, maintenance of blinding throughout the study, and handling of incomplete outcome data. The presence or absence of these features determined the risk of bias for each study.
3. Results
The main results of the twelve experimental studies included in this review are summarized in Table 2. A total of 738 rats were studied, comprising 391 animals treated with or included in chitosan tube groups and 274 rats in control groups. The control groups were managed with autologous nerve grafts (ANG), no intervention, transected nerve control group (TC), or with isolated chitosan tubes (when comparing to chitosan tubes filled with any substance).
Functional outcomes, such as walking track or Sciatic Functional Index (SFI), were assessed in six studies. In four experiments, a higher SFI was observed in rats treated with chitosan conduits compared to animals that had no intervention or primary repair after four, eight, and 12 weeks (Azizi et al., 2014, 2015; Ilkhanizadeh et al., 2017; Raisi et al., 2012). Another study found no statistically significant differences in SFI between both groups 90 days post-intervention (Shapira et al., 2016). Liu et al. compared different formulations of chitosan conduits (chitosan alone or associated with polypeptide-based hydrogel (MPEG-PELG), NGF/IM, or both) to ANG and demonstrated a significant improvement in SFI using chitosan tubes associated with NGF/mPEG-PELG (Liu et al., 2019).
Electrophysiological improvement was typically evaluated through nerve conduction velocity (NCV), somatosensory evoked potentials (SSEPs), and compound muscle action potentials (CMAPs). Four studies suggested an improvement in NCV when compared to ANG or no intervention (Azizi et al., 2014, 2015; Raisi et al., 2012; Zhang et al., 2008). However, no electrophysiological improvement was observed in three studies that evaluated SSEPs and NCV (Haastert-Talini et al., 2013; Liu et al., 2019; Shapira et al., 2016). Four studies found worse CMAPs in animals managed with chitosan grafts compared to the control group (Dietzmeyer et al., 2019; Duda et al., 2014; Sun et al., 2019; Zhang et al., 2008). Conversely, three other studies showed higher values of CMAPs and NCV in animals treated with ANG compared to rats managed with chitosan materials (Azizi et al., 2014, 2015; Raisi et al., 2012).
Histological and morphometric analyses were performed in all included studies. The evaluated parameters were myelinated fiber number and size, axon count and diameter, myelin sheath thickness, and/or neuroma formation. Six studies demonstrated an improvement in histological parameters in chitosan-based interventions, finding a greater number (Haastert-Talini et al., 2013; Raisi et al., 2012) and/or diameter (Aydemir and Ulusu, 2020) of myelinated fibers (Azizi et al., 2014, 2015; Ilkhanizadeh et al., 2017; Raisi et al., 2012) or myelin sheath thickness (Azizi et al., 2014, 2015; Ilkhanizadeh et al., 2017) in the chitosan intervention group compared to the control and primary repair arms. Conversely, in four experiments, the number of regrown axons in ANG groups was superior to chitosan groups (Carvalho et al., 2018; Dietzmeyer et al., 2019; Duda et al., 2014; Zhang et al., 2008). Shapira et al. and Liu et al. failed to demonstrate a difference in the myelinated fiber number and size between ANG and treatment groups (Liu et al., 2019; Shapira et al., 2016). Haastert-Talini et al. studied chitosan nerve conduit (CNC) arms displaying low, medium, and high degrees of acetylation (DAI: ~2%, DAII: ~5%, DAIII: ~20%) and consequently different degradability and microenvironments for the regenerating nerve. They found no difference in axon and fiber diameters and myelin thickness between chitosan and ANG groups (Haastert-Talini et al., 2013). However, the absolute count of myelinated fibers distal to DAI-chitosan tubes was found to be significantly superior compared to the ANG group.
Recent studies have expanded our understanding of chitosan-based interventions for peripheral nerve repair. Sun et al. (2024), Zhang et al. (2024), and Jafarisavari et al. (2024) demonstrated improvements in myelin sheath thickness, axon diameter, and SFI using various chitosan-based conduits. Al-Haideri and Al-Timmemi (2024) and Xue et al. (2024) reported increased NCV and axon numbers. Li et al. (2024) and Zhang et al. (2023) showed enhanced CMAP amplitude and NCV using chitosan conduits with growth factors. Jiang et al. (2023), Qi et al. (2023), Wang et al. (2023), and Li et al. (2023) all observed improvements in myelin thickness and myelinated fiber count using different chitosan-based approaches. Collectively, these studies consistently reported significant improvements in SFI compared to control groups, further supporting the potential of chitosan-based interventions in peripheral nerve repair.
The SYRCLE Risk of Bias assessment revealed that several studies had a high risk of bias in certain domains (Table 3). For instance, the sequence generation process was inadequately reported in most studies, leading to a “high risk” or “unclear risk” rating in this domain. Similarly, blinding of outcome assessors was not consistently reported, which may have introduced bias in the assessment of outcomes. On the other hand, most studies adequately addressed incomplete outcome data, leading to a “low risk” of bias in this domain.
Risk of Bias Assessment in Studies on Chitosan Conduits for Sciatic Nerve Repair using SYRCLE tool.
4. Discussion
4.1. Summary of main results
This review of animal studies indicates that rats receiving chitosan nerve conduits for the primary repair of nerve gaps of at least 10 mm demonstrated promising results in walking track analysis, electroneuromyography, and histological parameters compared to rats treated with primary repair, autologous nerve grafts (ANG), or control interventions. Nerve conduits were assessed alone or filled with substances, including alpha-lipoic acid (with antioxidant effects) (Azizi et al., 2015), pyrroloquinoline quinone (PQQ) (Azizi et al., 2014), vitamin E (Azizi et al., 2014), bone marrow-derived mast cells (BMMCs) (Ilkhanizadeh et al., 2017), Gellan Gum (GG) (Carvalho et al., 2018), polypeptide-based hydrogel (MPEG-PELG), and nerve growth factor (NGF) (Liu et al., 2019). To the authors' knowledge, this is the first systematic review comparing the performance of chitosan-based conduits with primary repair, control interventions, or ANG in managing sciatic nerve gaps in rat experimental models.
Six studies analyzed the Walking Track or Sciatic Functional Index (SFI) test. Only one study showed no significant difference between chitosan conduits and no intervention or primary repair for peripheral nerve repair. Four studies evaluating neurophysiological parameters yielded controversial results: one-third favored chitosan-related interventions, one-third showed no superiority, and the remaining third demonstrated superiority of ANG procedures.
All studies assessed morphometric and histological parameters, yielding more homogeneous results. These analyses showed an increase in fiber number, axonal diameters, and the proportion of myelinated fibers in chitosan polymer interventions compared to other study arms. Histological improvement was the most frequently evaluated outcome, combining measurements of myelinated fiber number and size, myelin sheath thickness, and axon count and diameter. Most studies showed comparable results among animals treated with chitosan conduits (with or without saline solution) and those receiving ANG or control interventions (Dietzmeyer et al., 2020; Haastert-Talini et al., 2013; Ilkhanizadeh et al., 2017; Shapira et al., 2016). Chitosan conduits enhanced with substances like PQQ and vitamin E demonstrated better performance compared to standard chitosan nerve conduits (CNCs) (Azizi et al., 2014; Ilkhanizadeh et al., 2017; Li et al., 2018).
Overall, chitosan conduits show significant potential as carriers for pharmacological substances that enhance nerve regeneration, presenting a promising field for developing new therapeutic techniques. However, three experiments demonstrated better histological outcomes for ANG despite variations in CNC formulations (Carvalho et al., 2018; Duda et al., 2014; Zhang et al., 2008). This discrepancy was also observed in electromyographic parameters. A consistent indicator of histological improvement across studies was the number of regenerated axons and fibers in chitosan-only nerve grafts. Generally, there appears to be a correlation between this parameter, walking track analysis, and electromyographic improvement.
The initial phase of nerve regeneration involves the migration of local cells, which gradually synthesize a new extracellular matrix and form the bands of Büngner. These structures guide growing axons from the proximal to the distal nerve stump. All these cellular and molecular processes are essential for complete nerve regeneration. A single histological method is insufficient to measure the degree of regeneration; therefore, a combination of different histological techniques, along with electromyographic assessment and Walking Track Analysis (WTA), may be necessary (Carriel et al., 2014). Currently, one of the most reliable techniques for evaluating nerve regeneration is electrophysiological assessment of distal muscles innervated by the injured nerve, which can determine the level of muscle denervation or reinnervation (Carriel et al., 2014). These assessments offer an integrated approach using sensory and motor nerve transmission studies, electromyography, spinal reflex tests, and motor and sensory evoked potentials. The low invasiveness of some electrophysiological methods allows for serial evaluation of sensory and motor reinnervation distal to the injury site without interrupting the regeneration process (Raimondo et al., 2009).
Recent studies from 2023 and 2024 have further expanded our understanding of chitosan-based interventions for peripheral nerve repair. These studies (Sun et al., 2024; Zhang et al., 2024; Jafarisavari et al., 2024; Xue et al., 2024; Al-Haideri and Al-Timmemi, 2024; Li et al., 2024; Zhang et al., 2023; Qi et al., 2023; Wang et al., 2023; Li et al., 2023) consistently demonstrated improvements in various outcome measures, including myelin sheath thickness, axon diameter, nerve conduction velocity (NCV), and Sciatic Functional Index (SFI). Notably, these recent studies showed a trend towards more rigorous methodological approaches, as evidenced by their SYRCLE risk of bias assessments.
The SYRCLE tool analysis revealed significant improvements in study design and reporting in the 2023-2024 studies compared to earlier research. For instance, studies by Zhang et al. (2024), Li et al. (2024), Qi et al. (2023), Wang et al. (2023), and Li et al. (2023) demonstrated low risk of bias across all or most domains, including adequate allocation sequence generation, baseline similarity, allocation concealment, random housing, blinding, and addressing incomplete outcome data. This marks a substantial improvement over earlier studies, where many of these aspects were unclear or at high risk of bias.
However, some recent studies still showed limitations. For example, Jafarisavari et al. (2024) and Xue et al. (2024) had high risk of bias in blinding procedures and random selection for outcome assessment. These areas remain critical for future research to address. The improved methodological rigor in recent studies enhances the reliability of their findings, providing stronger evidence for the efficacy of chitosan-based interventions in peripheral nerve repair. Future research should continue this trend of improved study design and reporting, particularly focusing on areas where bias risk remains high, such as blinding procedures and randomization techniques.
4.2. Overall completeness and applicability of evidence
All studies included in this review evaluated peripheral nerve repair in animals, specifically the sciatic nerve in rats. Electrophysiological outcomes were mixed and varied in analyzed parameters. The number of studies directly comparing primary repair with chitosan scaffolds was limited. Most studies were published before 2016. Newer polymers, such as laminin and self-assembling peptides, are now available for peripheral nerve repair (Yang et al., 2020). Additionally, techniques like 3D Bioprinting show promise and should be evaluated in future studies involving chitosan (Soman and Vijayavenkataraman, 2020).
4.3. Certainty of the evidence
None of the included studies had a negligible risk of bias across all domains of the SYRCLE tool. One trial demonstrated low risk in all domains except allocation (Raisi et al., 2012). Considerable heterogeneity was observed among study results, given the variety of treatment groups evaluated. Three trials reported imprecise results with wide confidence intervals across all evaluated outcomes (Haastert-Talini et al., 2013; Liu et al., 2019; Shapira et al., 2016). The identified risks of bias, particularly in sequence generation and blinding, suggest that the findings should be interpreted cautiously. These potential biases could affect the reliability of reported outcomes, such as the Sciatic Functional Index (SFI) and histological improvements. Future studies should employ rigorous randomization and blinding procedures to minimize bias. Detailed reporting of these procedures is necessary for accurate assessment of study quality.
4.4. Potential biases in the review process
The authors chose to focus on sciatic nerve injuries due to clinical and academic experience with this nerve, which limited the inclusion of studies evaluating other nerves (e.g., intercostal nerves). The search for studies in the gray literature did not yield results meeting the inclusion and exclusion criteria.
Axon count and degree of myelination assessment alone, obtained from histological analysis, are insufficient to predict whether axons reach the correct target organ. The Walking Track Analysis (WTA) evaluates functional recovery of injured nerves, which is not estimated by histomorphometry. WTA assesses gait and the temporal and spatial relationships of footprints during normal walking (Sarikcioglu et al., 2009).
This study had several limitations. First, a meta-analysis could not be performed due to the heterogeneity of materials used in experimental groups and the varied or unavailable numeric parameters used to quantify outcomes. The use of various substances linked to chitosan supports may have influenced the standardized analysis of chitosan's effectiveness relative to primary sutures and nerve grafts, yielding different results across intervention groups. The use of chitosan scaffolds as adjuncts in nerve repair after peripheral nerve trauma is recent, which may explain the limited availability of studies, particularly involving humans. The authors used the SYRCLE tool to reduce bias. The primary contribution of this review is to demonstrate the potential effectiveness of chitosan as a more accessible and reproducible alternative to nerve grafts.
5. Conclusion
In this systematic review of rat studies with sciatic nerve gaps of at least 10 mm, chitosan conduits demonstrated promising results compared to primary repair, autologous nerve grafts, or control interventions. Improvements were observed in walking track analysis, electromyography, and histological parameters. While functional and histological outcomes generally favored chitosan-based interventions, electrophysiological results were mixed. Recent studies (2023-2024) showed enhanced methodological rigor, strengthening the evidence base. Despite limitations in study heterogeneity and potential biases, the current evidence supports the potential of chitosan conduits as a viable alternative to conventional peripheral nerve repair methods in rat models, warranting further research for potential clinical translation
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Publication Dates
-
Publication in this collection
04 Apr 2025 -
Date of issue
2024
History
-
Received
08 Nov 2023 -
Accepted
07 Nov 2024
