Abstract
Chitosan (CS), a cationic polysaccharide derived from natural sources, has emerged as a critical biomaterial due to its biodegradability, biocompatibility, and antimicrobial properties. The reactive amino and hydroxyl functional groups enable chemical modifications and diverse structural fabrications, expanding applications in drug delivery, wound healing, and tissue engineering. Recent advances include strategic modifications and synergistic approaches that enhance the therapeutic efficacy. However, CS faces limitations, including poor solubility under physiological conditions, inadequate mechanical strength, and thermal instability. To address these challenges, innovative strategies involving chemical modifications and advanced material engineering have been developed. This review examines strategic advancements in CS-based medical materials over the past five years, focusing on material preparation innovations and disease treatment mechanisms, providing insights into CS’s transformative potential in sustainable healthcare solutions.
1. Introduction
Chitosan (CS), a naturally occurring cationic polysaccharide derived from chitin deacetylation, has emerged as a premier biomaterial due to its unique combination of advantageous properties. The intrinsic merits of CS include exceptional biocompatibility and biodegradability, − an FDA-approved safety profile, natural abundance as the second most prevalent biopolymer after cellulose, and cost-effectiveness from renewable crustacean sources. Beyond these fundamental advantages, CS exhibits distinctive functional properties critical for biomedical applications: mucoadhesive capabilities arising from electrostatic interactions between cationic amino groups and negatively charged mucus components, permeation enhancement through reversible opening of tight junction proteins, , inherent antimicrobial activity against bacteria and fungi, and controlled drug release characteristics. The presence of reactive amino and hydroxyl groups enables facile chemical modification and functionalization, while CS’s film-forming ability and wound healing promotion through fibroblast stimulation further expand its therapeutic potential. −
In recent years, CS-based biomedical research has progressed rapidly, and various modification strategies and application models have emerged. Nevertheless, the intrinsic material limitations of CS continue to restrict its transition toward clinical implementation. The polymer’s innate characteristics, particularly its pH-dependent insolubility, limited mechanical strength, low thermal stability, and the frequently complex purification procedures required during preparation, remain major obstacles to its direct use in biomedical systems. ,,, These limitations have stimulated extensive efforts in chemical derivatization and composite fabrication; however, a comprehensive evaluative framework capable of systematically comparing the performance of different modification approaches across therapeutic contexts is still lacking. Current studies have reported a range of promising findings, such as the more favorable anti-inflammatory properties of genipin-mediated cross-linking compared with synthetic cross-linkers, the improved stem cell differentiation observed with CS-collagen composites relative to single-component matrices, the enhanced antibacterial activity achieved through curcumin-loaded CS nanoparticles, and the superior anticancer efficacy of astaxanthin-encapsulated systems. Even so, these results remain largely isolated, and the underlying mechanisms responsible for their distinct biological behaviors have not been fully elucidated. Furthermore, inconsistencies in the characterization of essential parameters, including degree of deacetylation, molecular weight, and modification efficiency, significantly impede reproducibility and hinder meaningful comparisons across studies. As a result, despite continuous advances in material design, key challenges associated with CS solubility, mechanical insufficiency, and processing complexity remain only partially addressed, ,,, and the fragmented nature of current research continues to delay the development of integrative and generalizable design principles necessary for overcoming these fundamental limitations.
While numerous reviews have documented chitosan-based medical devices, − the field lacks systematic frameworks evaluating how specific chemical modifications address CS’s inherent limitations across different therapeutic contexts. Most existing reviews adopt synthesis-focused approaches that catalog modification methods but inadequately address clinical performance optimization. This review addresses this gap by organizing CS research around specific clinical contexts: drug delivery, wound healing, cancer therapy, and tissue engineering (Figure ). Our approach differs fundamentally from existing literature by (1) systematically mapping how chemical modifications overcome CS’s inherent demerits (poor solubility at neutral pH, limited mechanical strength) while enhancing functional merits (biocompatibility, biodegradability, antimicrobial activity) within each therapeutic domain; (2) establishing comparative frameworks with quantitative performance benchmarks that enable direct assessment across similar clinical challenges and identify domain-specific optimization principles; and (3) revealing transferable modification strategies that demonstrate efficacy across multiple biomedical applications, thereby providing actionable guidance for the rational design of next-generation CS-based therapeutics. In addition, to ensure comprehensive scholarly context as requested, we also reference recent advances in nanoscale materials engineering that, although outside the biomedical scope of this review, exemplify cross-disciplinary innovation relevant to material optimization principles. These include developments in nanomaterial-assisted all-solid-state battery architectures, which highlight how nanoscale structural control enhances functional performance in energy storage systems, as well as progress in transition metal dichalcogenides for next-generation supercapacitors, demonstrating how controlled morphology, defect engineering, and hybridization strategies can optimize electrochemical behavior. These examples reflect broader trends in materials science that inspire performance-driven design strategies across disciplines. This clinical performance-oriented analysis consolidates fragmented knowledge into evidence-based recommendations that accelerate biomaterial development and clinical translation.
1.
Bibliometric network analysis of chitosan-based materials for medical applications. Network visualization from VOSviewer analysis of: (A) 6,591 SCOPUS publications (keywords: “Chitosan” and “drug delivery”; Jan. 2026); (B) 2,973 SCOPUS publications (keywords: “Chitosan” and “wound healing”).
2. Sources, Chemical Structure, and Modification Strategies of CS
2.1. Sources of CS
CS, as the second most abundant natural biopolymer, is efficiently extracted from various sources through enzymatic or chemical hydrolysis of chitin. − Fungal cell walls represent a valuable source for CS production, as chitin typically constitutes 10–30% of the wall’s dry weight, facilitating efficient extraction. Cultivating fungi offers a cost-effective and environmentally friendly method for obtaining CS. Recent developments demonstrate significant improvements in the extraction efficiency and product quality. Extraction from Alternaria alternata using β-1,3-glucanase, replacing traditional alkaline treatments, improved CS purity by reducing protein contamination by 29% while resulting in lower molecular weight products. Acid hydrolysis methods applied to fungi such as Pleurotus ostreatus, Cunninghamella bertholletiae, and Trichoderma viride yield CS with higher acetylation levels and enhanced biological activity. Combined enzymatic hydrolysis using proteases from Bacillus licheniformis and β-1,3-glucanases from Trichoderma longibrachiatum produced CS with molecular weights below 1.0 kDa at a remarkable 94% yield. Additionally, CS derived from Aspergillus species demonstrates potent antimicrobial properties against major pathogens, including Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Salmonella.
Insects represent an abundant and promising source for CS extraction due to their chitin-rich exoskeletons. Insect-derived CS has gained attention for both its nutritional value and its biomedical applications. Novel approaches include identifying fungi from solid-state fermentation of Hermetia illucens for hydrolyzing mealworm molt powder, producing diacetylchitobiose (GlcNAc)2. The novel CSase-producing bacterium LZ32 facilitates hydrolysis of household fly larvae powder, yielding low-molecular-weight oligosaccharides with significant dihydroxylation-reducing activity. Large-scale extraction using Tenebrio molitor larvae achieved 50% yield after purification, indicating industrial feasibility. CS extracted from decomposed silkworm pupae following protein removal and lysozyme depolymerization resulted in 2.5 kDa molecular weight products.
Marine crustaceans serve as the primary commercial source for CS extraction due to their high chitin content and abundant waste streams. Various enzymatic hydrolysis methods were optimized for different crustacean sources. Lobster shells processed using pepsin and papain yield stable CS with a net positive zeta potential of +37.6 mV. The chitin-degrading bacterium Streptomyces chilikensis RC1830 enables enzymatic breakdown of fish scale chitin, yielding CS with varying polymerization degrees. Enzymatic hydrolysis combined with cation exchange resin purification demonstrates effective CS extraction from crab shells with tailored molecular weights. Advanced approaches include Vibrio campbellii endochitinase for high-efficiency degradation producing chitobiose and novel Lytic Polysaccharide Monooxygenase variants enabling efficient shrimp shell conversion. , Collectively, these diverse extraction sources demonstrate the versatility and scalability of CS production for medical applications. Marine crustaceans remain the dominant industrial source due to their high chitin content and established processing infrastructure, with enzymatic methods achieving remarkable yields and molecular weight control. However, fungal- and insect-based platforms are emerging as sustainable alternatives that address supply chain concerns and environmental impact. Fungal sources offer controlled cultivation conditions and reduced contamination risks, while insect-derived CS provides opportunities for valorizing agricultural waste streams. The transition from traditional chemical hydrolysis to enzymatic approaches has significantly improved the extraction efficiency, product purity, and process sustainability across all source categories. Notably, source selection influences the resulting CS characteristics, including the molecular weight distribution, degree of acetylation, and bioactivity profiles. This diversity enables tailored CS production for specific medical applications, from antimicrobial wound dressings requiring low molecular weight oligomers to tissue engineering scaffolds requiring high molecular weight polymers with superior mechanical properties.
2.2. Chemical Structure and Modification Strategies of CS
CS is a linear polysaccharide derived from chitin via deacetylation, comprising repeating β-(1–4)-linked N-acetylglucosamine units. The degree of deacetylation (DD) critically influences the balance between free amino groups (−NH2) and acetylated groups (−OAc), directly affecting the material properties (Figure ). This unique structure confers several important biological and physicochemical characteristics. The amino and hydroxyl functional groups enable strong hydrogen bonding, essential for water solubility and gel-forming ability. These groups facilitate bioadhesion, allowing effective interaction with biological surfaces. Additionally, amino groups act as nucleophiles, enabling the binding of negatively charged molecules such as growth factors or therapeutic agents, making CS ideal for controlled drug delivery applications. CS’s molecular weight and degree of polymerization significantly influence mechanical properties, biodegradability, and bioavailability. Lower molecular weight CS exhibits enhanced water solubility, while higher molecular weight polymers provide superior viscoelasticity and gel strength.
2.
Chemical structure of CS and its modification active site; prepared by In-draw.
The intrinsic cationic nature endows CS with potent antimicrobial activity, particularly effective against bacteria, fungi, and other pathogens through cell membrane disruption. This antimicrobial activity proves to be valuable in developing advanced wound dressings and preventing infections. Furthermore, CS’s structural similarity to natural glycosaminoglycans ensures excellent biocompatibility, minimizing immune responses and promoting cellular interactions. In medical applications, CS functions both as natural nanoparticles for drug loading and as chemically modified variants through cross-linking or functionalization. The hydroxyl and amino groups are particularly amenable to modification, especially the highly reactive −NH2 groups. Common chemical modifications include carboxymethylation, where carboxymethyl groups are introduced to form carboxymethyl chitosan (CMC), conferring polyelectrolyte properties with enhanced water solubility and chemical reactivity suitable for hydrogel construction. Hydroxyethylation substitutes hydrogen atoms in CS molecules with hydroxyethyl groups, creating hydroxyethylated chitosan with excellent water solubility and bioactive characteristics. N-succinylation introduces succinyl groups at the N-position of glucosamine units, producing N-succinyl chitosan with superior cellular viability and biocompatibility compared to unmodified CS. Phenolic compound grafting, particularly ferulic acid modification, can be achieved through carbodiimide coupling reaction, free radical-mediated reaction, or laccase-catalyzed polymerization reaction, which enhances biodegradability and biological activities, including antioxidant activity, cellular adhesion, and protein adsorption. Aldehyde-based cross-linkers such as glutaraldehyde interact with amino groups in O-carboxymethyl CS to form stable Schiff base linkages. Introducing specific functional groups to amino sites enhances CS properties, expanding applications in medical technologies (Figure ). Quaternized chitosan derivatives, obtained through quaternization modifications, demonstrate superior water solubility and enhance antimicrobial properties.
3.
Preparation of reaction substrates for CS derivatives; prepared by In-draw.
Beyond conventional modifications, recent CS functionalization advances specifically target 3D bioprinting, optimizing material properties for printability and biological functionality. Native CS faces critical challenges, including poor neutral pH solubility due to hydrogen bonding, high water content causing mechanical instability, and brittleness compromising structural integrity during layer-by-layer deposition. Sophisticated modification strategies address these limitations. Boronic acid functionalization exemplifies advanced approaches for enhancing aqueous solubility and introducing stimuli-responsiveness. Carboxylphenylboronic acid-grafted chitosan (25% substitution) demonstrates self-assembly behavior, forming stable clusters (3.5 nm) through hydrogen bonding, π-π stacking, and cation-π interactions. This self-assembly mechanism creates physical reinforcement, improving mechanical stability essential for 3D printing. Combined with diol-containing polymers, boronate ester linkages form dynamic networks exhibiting shear-thinning and self-healing properties that are critical for continuous filament deposition. Resulting hydrogels achieve remarkable stackability, maintaining 95% designed height (1.2 cm) in 30-layered constructs without postprinting reinforcement while retaining glucose-responsive characteristics. Alkali dissolution represents another strategy enhancing CS processability for FRESH bioprinting, enabling complex geometrical structures with intricate tubular architectures. These modifications collectively expand CS’s utility as a versatile bioink platform, balancing printability with biological functionality.
The structure–property relationships of CS underscore its exceptional versatility as a biomaterial platform for medical applications. The degree of deacetylation, molecular weight, and functional group distribution collectively determine critical properties, including solubility, mechanical strength, bioactivity, and degradation kinetics. The presence of reactive amino and hydroxy groups enables precise chemical modifications that expand the CS functionality beyond its native properties. Quaternization enhances water solubility and antimicrobial potency, while cross-linking with aldehydes improves the mechanical stability and controlled release characteristics. These modification strategies allow researchers to engineer CS-based materials with predictable performance profiles tailored to specific clinical requirements. Furthermore, the structural similarity to natural glycosaminoglycans ensures biocompatibility and facilitates cellular interactions essential for tissue regeneration and wound healing. This inherent tunability, combined with biodegradability and low immunogenicity, establishes CS as a uniquely adaptable material platform capable of addressing diverse medical challenges, ranging from localized drug delivery to complex tissue engineering applications.
3. CS-Based Materials for Drug Delivery Applications
CS has emerged as a versatile biomaterial for drug delivery, demonstrating exceptional potential across ocular, oral, nasal, and transdermal applications (Table ). Its biocompatibility, biodegradability, and mucoadhesive properties enable sophisticated delivery systems that enhance bioavailability, provide controlled release, and facilitate targeted interventions (Figure ). , However, significant methodological inconsistencies threaten clinical translation. Substantial variability in particle characteristics, encapsulation efficiencies, and release kinetics across preparation methods reveals fundamental standardization challenges. Performance disparities among ionic gelation, emulsion-based techniques, and hybrid approaches highlight poorly understood method-dependent variations that require systematic investigation.
1. Recent CS-Based Materials for Drug Delivery Applications .
| Modification routes | Molecular weight (KDa) | Loaded drug | Efficacy | Ref. |
|---|---|---|---|---|
| Physical encapsulation | 360.8 | Triamcinolone acetonide | Ocular drug delivery | |
| - | Dexamethasone and chloramphenicol | |||
| - | Brimonidine tartrate | |||
| 0.44 | Vitamin B12 | Oral delivery | ||
| 190–310 | Small interfering RNA | |||
| 310–375 | Colorectal cancer | |||
| 112 | Galantamine hydrobromide | Nasal delivery | ||
| 200–300 | Galantamine | |||
| - | Hesperidin | |||
| - | MicroRNA-219 | |||
| - | Gold nanoparticles | DNA carriers | ||
| - | Docetaxel | In-vitro tumor inhibition | ||
| - | Curcumin | In-vitro anticancer | ||
| - | Rift Valley Fever inactivated vaccine | Adjuvant | ||
| 50–190 | Inactivated Newcastle disease vaccine | Adjuvant | ||
| 50–190 | - | Transepidermal drug delivery |
| Modification reagents | Carrying drug | ||||
|---|---|---|---|---|---|
| Chemical modification | - | O-methyl-O′-succinyl polyethylene glycol and oleic acid | Camptothecin | Oral delivery | |
| - | (acrylic acid)-co-(2-acrylamido-2-methylpropane-sulfonic acid) | Fluorouracil |
“-”, not mentioned.
4.
Four main applications of CS-based materials in drug delivery.
3.1. CS-Based Materials for Ocular Delivery System
CS-based ocular drug delivery represents a compelling intersection of polymer science and clinical necessity, driven by unique challenges of achieving effective drug penetration through complex ocular barriers. − The fundamental appeal stems from CS’s cationic nature, facilitating electrostatic interactions with anionic mucin glycoproteins, thereby extending corneal residence time and enhancing bioavailability. Recent innovations exemplify sophisticated engineering approaches to overcoming conventional CS limitations. Hybrid systems, such as PLGA–CS nanoparticles for triamcinolone acetonide delivery and silica–CS cross-linked networks for hydrophobic drug encapsulation, reflect the growing recognition that single-polymer systems may be insufficient to achieve optimal therapeutic outcomes. These multicomponent strategies address key limitations, including burst release kinetics and poor drug loading capacity, while leveraging CS’s mucoadhesive properties. Despite these advances, clinical translation faces substantial obstacles. Manufacturing scalability remains problematic due to complex processing requirements and inherent variability in CS source materials, creating quality control challenges that complicate regulatory approval pathways. More fundamentally, incomplete understanding of CS-tissue interaction mechanisms at the molecular level limits rational design approaches. The absence of standardized predictive models creates a disconnect between laboratory optimization and clinical performance, hindering the development of evidence-based formulation strategies essential for successful commercialization.
Strategic chemical modifications have emerged as promising approaches to address complex ocular delivery challenges. CS-AAMPS and CS-MEDSP synthesis through free-radical polymerization exemplifies dual-functionality platforms simultaneously enhancing cohesion and antimicrobial activity. This integrated approach proves valuable where ocular infections frequently complicate therapeutic interventions. Enhanced corneal permeability achieved by brimonidine tartrate-loaded CS films through optimized molecular interactions demonstrates adaptability for both hydrophilic and hydrophobic compounds. However, chemical modifications introduce important safety considerations. Free-radical polymerization and novel chemical linkages may generate cytotoxic residues or provoke inflammatory responses that are absent in conventional formulations. Successfully balancing improved functionality with CS’s inherent biocompatibility remains challenging, particularly given sensitive ocular tissues and rigorous safety standards governing ophthalmic products.
Ocular delivery applications demonstrate how the polymer’s cationic nature enhances corneal residence time through electrostatic interactions with mucin glycoproteins, directly addressing bioavailability challenges. Hybrid platforms combining PLGA, silica, or chemical modifications such as CS-AAMPS successfully overcome conventional limitations, including burst release and poor drug loading capacity for both hydrophilic and hydrophobic compounds. However, clinical translation still faces substantial obstacles. Manufacturing scalability remains problematic due to complex processing requirements and source material variability, while chemical modifications introduce safety concerns regarding cytotoxic residues and inflammatory responses in sensitive ocular tissues. Most critically, the absence of standardized predictive models connecting molecular design and clinical performance represents a fundamental barrier. Advancing these platforms requires systematic investigation of structure–property relationships to enable rational formulation development and regulatory approval.
3.2. CS-Based Materials for Oral Delivery System
Oral drug delivery offers unparalleled advantages in cost-effectiveness, patient compliance, and therapeutic flexibility. , Nevertheless, the gastrointestinal environment poses significant obstacles, including enzymatic degradation, pH fluctuations, and absorption barriers that substantially compromise drug bioavailability. Hybrid microgel systems demonstrate the successful integration of inorganic and organic components to optimize delivery performance. Amphiphilic CS modifications offer equally promising approaches, exemplified by O-methyl-O′-succinyl polyethylene glycol and oleic acid functionalization. These modifications facilitate spontaneous micelle assembly, yielding 140 nm particles effectively encapsulating hydrophobic compounds like camptothecin with 78% efficiency. Maintenance of 75% drug stability in gastrointestinal fluids directly addresses the fundamental limitations of conventional formulations. Carboxymethyl CS and FITC-labeled CS nanoparticles demonstrate potential for siRNA delivery via ionic gelation assembly. Chemical cross-linking strategies continue expanding CS’s therapeutic versatility. Methacrylated CS nanoparticles synthesized with sodium tripolyphosphate demonstrate enhanced mucoadhesive properties (96% retention compared to 88% for unmodified CS) while preserving controlled release characteristics.
Despite these impressive technical achievements, several critical considerations warrant attention. The growing complexity of these formulations raises practical concerns regarding manufacturing scalability and regulatory pathways. Furthermore, pH-responsive targeting mechanisms may prove unreliable due to interindividual physiological variations and pathological conditions that alter gastrointestinal pH profiles. The fundamental challenge remains to translate these laboratory innovations into clinically effective products that consistently deliver therapeutic benefits across heterogeneous patient populations.
Diverse formulation strategies have emerged to overcome gastrointestinal barriers, integrating hybrid microgels with silica incorporation, amphiphilic modifications enabling spontaneous micelle assembly, and chemical cross-linking approaches that enhance mucoadhesion and pH-responsive behavior. These innovations consistently demonstrate improved drug stability, with encapsulation efficiencies reaching 78% and mucoadhesive retention achieving 96%. Methacrylated nanoparticles and gamma-irradiated terpolymer hydrogels exhibit sophisticated pH-triggered release profiles suitable for targeted intestinal delivery. Despite these technical achievements, formulation complexity raises practical concerns regarding manufacturing scalability and regulatory pathways. Furthermore, pH-responsive targeting mechanisms may prove unreliable due to interindividual physiological variations and pathological conditions altering gastrointestinal pH. Successfully translating laboratory innovations into clinically effective products requires addressing standardization challenges and establishing predictable performance across heterogeneous patient populations.
3.3. CS-Based Materials for Nasal Delivery Systems
Nasal drug delivery has gained considerable attention as a noninvasive administration route offering unique advantages for accessing the central nervous system and treating respiratory disorders. The nasal cavity provides direct pathways to the brain via olfactory and trigeminal nerve routes, effectively circumventing the blood–brain barrier. However, the nasal environment presents distinct challenges, including rapid mucociliary clearance, enzymatic degradation, and limited residence time. Neurotherapeutic applications represent particularly promising domains for CS-based nasal delivery. Galantamine hydrobromide-loaded CS nanoparticles demonstrate potential for Alzheimer’s disease treatment, achieving encapsulation efficiencies of 67–70% through ionic gelation methods. , The dual benefit of CS’s intrinsic antioxidant properties alongside drug delivery capabilities addresses multiple pathological mechanisms in neurodegeneration. CS/alginate complex nanoparticles exploit pH-dependent solubility differences: alginate dissolution at physiological pH enables rapid initial release, while CS provides sustained drug availability. Respiratory and inflammatory disorders benefit from CS’s mucoadhesive properties and anti-inflammatory potential. Hesperidin-loaded CS nanoparticles achieve 81.02% entrapment efficiency with 200 nm particles, demonstrating 75% drug release within 12 h. The positive surface charge (+22 mV) enhances interaction with the negatively charged mucosa, facilitating enhanced cellular uptake in inflamed environments.
Brain tumor targeting represents ambitious applications of nasal CS delivery. β-cyclodextrin-CS-coated gold iron oxide nanoparticles loaded with therapeutic microRNAs (miR-100 and anti-miR-21) demonstrate remarkable potential for glioblastoma treatment. Synergistic delivery of multiple miRNAs reduces cell viability to 49.3%, while selective targeting minimizes effects on healthy tissues. MicroRNA-219-loaded CS nanoparticles achieve 95% encapsulation efficiency and selective cytotoxicity against U87 MG cells while sparing normal fibroblasts. While these innovations demonstrate significant potential, several critical limitations warrant consideration. The heterogeneity of nasal physiology across populations and disease states may affect delivery consistency. Moreover, the long-term safety implications of repeated nasal administration, particularly for nanoparticulate systems, have been inadequately characterized. The challenge lies in optimizing formulations that balance therapeutic efficacy with minimal local irritation and systemic exposure while ensuring reproducible delivery across diverse patient populations and disease contexts.
Nasal administration offers unique advantages for neurotherapeutic interventions by exploiting direct brain access pathways via olfactory and trigeminal routes, effectively circumventing the blood–brain barrier. Applications in Alzheimer’s disease treatment and glioblastoma targeting through microRNA delivery demonstrate remarkable therapeutic potential, with encapsulation efficiencies reaching 95% and selective cytotoxicity against tumor cells while sparing healthy tissues. The polymer’s mucoadhesive properties and positive surface charge enhance cellular uptake in inflamed respiratory tissues, while pH-dependent release profiles enable sustained drug availability. However, heterogeneous nasal physiology across populations compromises delivery consistency, and long-term safety implications of repeated nanoparticle administration remain inadequately characterized. Advanced these platforms require optimizing formulations that balance therapeutic efficacy with minimal local irritation while ensuring reproducible performance across diverse patient populations and disease contexts.
3.4. Other CS-Based Drug Delivery Materials
CS’s versatility extends beyond conventional delivery routes, encompassing innovative applications in gene therapy, cancer treatment, vaccine development, and transdermal administration. Gene and nucleic acid delivery represent sophisticated application domains. Gold nanoparticles (3–15 nm) functionalized with CS derivatives demonstrate exceptional potential for plasmid DNA delivery, achieving 93.46% cell viability with optimal transfection efficiency. Cationic nature facilitates DNA complexation, while the gold core provides stability and imaging capabilities. Cancer therapeutics benefit significantly from CS’s tumor-targeting capabilities. CS-coated solid lipid nanoparticles for docetaxel delivery demonstrate how surface modification optimizes both stability and release kinetics. Fungal CS nanoparticles carrying curcumin exploit pH-sensitive release mechanisms, demonstrating preferential drug release in acidic tumor microenvironments.
Vaccine adjuvant applications showcase CS’s immunomodulatory properties. Rift Valley Fever Virus antigen-loaded CS nanoparticles significantly enhance both cellular and humoral immune responses. CS derivatives, including hydroxypropyl trimethylammonium chloride CS and sulfated CS, demonstrate distinct advantages as Newcastle disease vaccine adjuvants. Transdermal delivery systems represent emerging frontiers where CS nanosponges demonstrate remarkable innovation through molecular weight-specific formulations using 3.0 kDa CS conjugated with poloxamer 407. These diverse applications reveal both the remarkable potential and the inherent challenges of CS-based delivery systems. While the material’s versatility enables application across multiple therapeutic domains, this breadth also complicates standardization and regulatory pathways. The challenge moving forward lies in translating these laboratory innovations into standardized, scalable platforms that can meet the rigorous demands of clinical translation while maintaining the sophisticated functionality demonstrated in research settings.
Therapeutic versatility extends across gene therapy, cancer treatment, vaccine adjuvants, and transdermal administration, showcasing the polymer’s broad applicability beyond conventional delivery routes. Gold nanoparticle conjugates achieve 93.46% cell viability with optimal transfection efficiency for plasmid DNA delivery, while pH-sensitive formulations enable preferential drug release in acidic tumor microenvironments. Vaccine applications demonstrate significant enhancement of both cellular and humoral immune responses, and molecular weight-specific nanosponges advance transdermal delivery capabilities. These diverse platforms capitalize on the polymer’s cationic nature, biocompatibility, and chemical modifiability to address distinct therapeutic challenges. However, this breadth complicates standardization efforts and regulatory pathways. Successfully advancing these innovations requires developing scalable manufacturing platforms that maintain sophisticated functionality across multiple domains while meeting rigorous clinical translational requirements, ultimately balancing innovative versatility with practical implementation feasibility.
3.5. Challenges and Translational Barriers in CS-Based Drug Delivery Systems
Contemporary investigations reveal that CS-based drug delivery platforms exhibit extraordinary adaptability across ocular, oral, nasal, and transdermal applications, capitalizing on the polymer’s inherent biocompatibility, mucoadhesive characteristics, and chemical versatility to address multifaceted therapeutic requirements. Ranging from sophisticated hybrid architectures incorporating PLGA and silica constituents to innovative amphiphilic modifications facilitating micelle assembly, these systems consistently manifest enhanced bioavailability, controlled release kinetics, and targeted delivery capabilities throughout diverse pharmaceutical domains. Despite these achievements, substantial barriers fundamentally impede clinical translation. Most prominently, pronounced methodological disparities pervade the research landscape; particle characteristics, encapsulation efficiencies, and released profiles fluctuate dramatically across preparation techniques, revealing deep-seated standardization inadequacies. The conspicuous incongruity between promising in vitro characterization and clinical performance remains largely unresolved, while manufacturing scalability obstacles and intricate regulatory frameworks compound commercialization difficulties. Concurrently, physiological heterogeneity among patient populations compromises delivery reliability, particularly in nasal and ocular applications, where individual anatomical variations profoundly influence therapeutic outcomes. To overcome these fundamental challenges, researchers must establish clearer connections between molecular design and therapeutic outcomes while developing more reliable translation pathways. This requires rigorous safety evaluations for long-term use coupled with predictive models that can bridge the gap between laboratory success and clinical reality. Equally critical is the development of scalable manufacturing approaches that maintain consistency without compromising quality. Success in this endeavor will ultimately depend on fostering genuine collaboration among materials scientists, clinicians, and regulatory bodiespartnerships that can transform promising laboratory discoveries into therapies that genuinely benefit patients.
4. CS-Based Materials for Clinical Applications
Contemporary healthcare systems increasingly demand biomaterials capable of addressing antimicrobial resistance while promoting tissue regeneration and minimizing inflammatory responses. CS’s unique combination of biocompatibility, biodegradability, and intrinsic antimicrobial activity positions it as a compelling candidate for orthopedic interventions and wound management applications (Table ). However, successful clinical implementation requires addressing fundamental material limitations while optimizing the performance for specific therapeutic contexts.
2. CS-Based Materials for Clinical Applications .
| Modification routes | Molecular weight (KDa) | Loaded substance | Medical application | Ref. |
|---|---|---|---|---|
| Physical encapsulation | Human mesenchymal stem cell | Scaffolds | ||
| 50–190 | Bud-Poplar-Extract | Wound healing dressing | ||
| Chemical modification | 130112.4a | Cross-linking with collagen | Scaffolds | , |
| 100–300 | Cross-linking with silk fibroin | Cartilage tissue engineering | ||
| 1.9 | Grafting with poly(l-lactide) | Bone tissue engineering | ||
| 3–10 | Modification with Fmoc-Lys (Fmoc)–OH | Orthopedic implant | ||
| - | Cross-linking via 3D-printed | Cartilage tissue engineering | ||
| 50–190 | Modification with thymine | Wound healing dressing | ||
| 165.3 | Protonation reaction | |||
| 60.05 | Cross-linking metal–organic polyhedrons | |||
| 153.7 | Ionic cross-linking with tilapia peptides | Hemostatic materials | ||
| 9 | Modification with cellulose | |||
| Other modifications | - | Ionic gelation method | Wound healing dressing | |
| - | Electrospinning and microwave-assisted methods | Hemostatic materials |
“-”, not mentioned.
4.1. CS-Based Materials for Orthopedic Treatments
Orthopedic biomaterial development traditionally centers on scaffold engineering that simultaneously combats bacterial colonization while facilitating cellular regeneration. However, CS’s inherent limitations, particularly modest biological activity and insufficient mechanical robustness, necessitate strategic material modifications. These challenges have driven researchers toward sophisticated hybrid approaches involving blending with complementary biomaterials, chemical cross-linking to enhance structural integrity, and advanced fabrication techniques such as 3D printing for precise architectural control (Figure ). Among these modification strategies, CS-collagen composites represent particularly instructive examples of rational biomaterial design that successfully address both antimicrobial requirements and load-bearing demands in orthopedic treatments. CS-collagen composites demonstrate synergistic performance where CS provides antimicrobial functionality and mucoadhesive properties while collagen supplies essential cell-recognition domains and mechanical reinforcement. , This integration exploits complementary biochemical properties: CS’s cationic charge facilitates electrostatic interactions with bacterial membranes, while collagen’s native extracellular matrix structure promotes cellular attachment and proliferation. Transglutaminase cross-linking optimization reveals how enzymatic approaches can create robust network architectures without compromising biocompatibility, addressing concerns about chemical cross-linker toxicity.
5.
Structural modification strategies of CS in orthopedic treatments.
Advanced polymer architecture modifications demonstrate sophisticated approaches to performance optimization. Dual-network hydrogels combining thiolated CS with silk fibroin exploit multiple cross-linking mechanisms, including disulfide bond formation and physical entanglement, to successfully mimic cartilage mechanical environments. These systems achieve compressive strengths approaching that of native cartilage while maintaining biocompatibility and biodegradability. Poly(l-lactide) grafting onto CS backbones demonstrates how polymer architecture influences cellular response, with enhanced chondrocyte proliferation observed at lower CS content, suggesting an optimal balance between mechanical reinforcement and biological activity. Chitosan-based biomaterials have demonstrated therapeutic potential across multiple regenerative medicine domains, including cardiac, nerve, skin, dental, cartilage, and bone tissue regeneration, complementing the orthopedic applications discussed herein. Low-molecular-weight CS derivatives represent promising directions for enhanced antimicrobial functionality. Systematic molecular weight reduction through controlled depolymerization enhances antimicrobial effectiveness through improved membrane penetration while maintaining biocompatibility. These derivatives demonstrate effectiveness against biofilm-forming bacteria, addressing critical clinical challenges in orthopedic infections.
3D printing optimization reveals that processing conditions significantly impact the final scaffold performance. Comparative studies of air-dried versus freeze-dried CS-alginate scaffolds demonstrate that processing methods influence both mechanical properties and cellular responses, with air-dried scaffolds maintaining superior chondrocyte morphology and proliferation. Advanced 3D bioprinting technologies have further expanded orthopedic applications through sophisticated fabrication strategies. Freeform reversible embedding of suspended hydrogels (FRESH) bioprinting technology enables the production of complex tubular structures that traditional methods cannot achieve, particularly for applications requiring specific anatomical geometries and controlled porosity. This approach utilizes alkali-dissolved CS ink deposited into supporting hydrogel matrices, which are subsequently removed through heat treatment, allowing for preservation of intricate architectural features essential for tissue integration. The FRESH methodology addresses fundamental challenges in CS 3D printing by providing temporary mechanical support during fabrication, enabling the production of structures with clinically relevant dimensions and mechanical properties. For orthopedic scaffolds, this technique achieves compressive strengths comparable to native cartilage while maintaining interconnected porosity necessary for cellular infiltration and nutrient transport. Processing parameter optimization remains critical, as variables including nozzle diameter (typically 210 μm for fine features), printing speed, and cross-linking conditions fundamentally influence final scaffold performance. Rheological characterization demonstrates that successful 3D printing requires careful balance between shear-thinning behavior enabling smooth extrusion, adequate yield stress supporting continuous filament formation, and rapid structural recovery maintaining layer definition. The development of CS-based bioinks specifically engineered for 3D printing represents a significant advancement, as these formulations incorporate chemical modifications that simultaneously enhance printability and biological functionality without compromising biocompatibility. These findings highlight the importance of manufacturing parameter optimization for clinical translation, where reproducible scaffold production with consistent mechanical and biological properties remains essential for regulatory approval and widespread clinical adoption.
Hybrid strategies have successfully addressed CS’s inherent mechanical limitations through rational material combinations, with CS-collagen composites demonstrating how complementary biochemical properties create synergistic performance in antimicrobial activity and cellular support. Dual-network hydrogels combining thiolated CS with silk fibroin achieve compressive strengths approaching native cartilage through multiple cross-linking mechanisms, while low-molecular-weight derivatives enhance antimicrobial effectiveness via improved membrane penetration against biofilm-forming bacteria. Critical advances in 3D printing optimization reveal that processing conditions fundamentally influence scaffold performance, with air-dried scaffolds maintaining superior chondrocyte morphology compared to freeze-dried alternatives. However, translating these innovations faces challenges, including enzymatic cross-linking optimization to avoid chemical toxicity, balancing mechanical reinforcement with biological activity, and establishing standardized manufacturing parameters. Successfully advancing orthopedic applications requires a systematic investigation of structure–property relationships across multiple fabrication variables.
4.2. CS-Based Materials for Wound Healing
Wound healing involves complex sequential processes, including hemostasis, inflammation, proliferation, and remodeling, all vulnerable to bacterial disruption and improper healing environments. − CS-based materials address multiple healing challenges through antimicrobial activity, moisture management, and cellular support (Figure ). The clinical potential of CS-based wound healing materials has been recognized by regulatory authorities, with FDA approval granted for various chitosan-based biomedical and pharmaceutical applications. The global chitosan market for wound care products is forecasted to grow by approximately 14.3% within the next decade, driven by commercial products such as chitoderm-containing ointments that provide scaffolding for skin cell regeneration.
6.
CS-based materials promote wound healing via antimicrobial activity, moisture management, and cellular support.
4.2.1. CS-Based Dressing Materials
Contemporary wound dressing development focuses on creating optimal healing microenvironments while preventing infection and facilitating tissue regeneration. CS-based nanofibrous scaffolds represent a significant advancement in tissue engineering and regenerative medicine. These scaffolds exhibit ideal bioactive properties, including serum stability, biocompatibility, biodegradability, mucoadhesivity, and nonimmunogenicity. Nanofibrous architecture enables sustained and controlled drug release while maintaining mechanical integrity. Various fabrication methods, including electrospinning, ionic gelation, polyelectrolyte complexation, and emulsification-solvent diffusion, allow precise control over nanoparticle size, encapsulation efficiency, and drug release profiles. Surface modification strategies, such as PEGylation and ligand functionalization, further enhance targeting capabilities and therapeutic outcomes. Thymine-modified CS represents innovative approaches where nucleobase incorporation creates enhanced cellular recognition and antimicrobial activity. The thymine modification enables hydrogen bonding with complementary nucleotides in bacterial DNA, potentially disrupting replication while promoting cellular adhesion through biomimetic recognition. Processing methodology significantly influences dressing performance. Freeze-drying techniques create porous structures essential for optimal wound microenvironments, maintaining appropriate moisture levels while facilitating gas exchange and exudate management. The resulting scaffolds demonstrate superior water absorption capacity compared with conventional dressings while providing mechanical support during healing.
Nonwoven CS technology addresses manufacturing scalability while maintaining therapeutic effectiveness. These materials demonstrate exceptional water absorption capabilities and broad-spectrum antimicrobial activity against major wound pathogens. The nonwoven structure provides mechanical toughness essential for clinical handling while preserving CS’s intrinsic biological properties.
Metal oxide-based CS nanocomposites have emerged as promising antimicrobial agents for wound healing applications. CS-coated metal oxide (CS-MO) nanocomposites, particularly CS-NiO and CS-MgO, exhibit enhanced bactericidal capabilities against both Gram-positive and Gram-negative bacteria. CS-NiO nanocomposites (particle size ∼18.3 nm) demonstrated superior antibacterial efficacy, reducing S. aureus and E. coli viabilities to 2–8% after 12 h incubation at 15 μg/mL concentration. The synergistic combination of chitosan’s polycationic nature with metal oxide nanoparticles provides dual antimicrobial mechanisms: electrostatic interaction with bacterial membranes and metal ion-mediated oxidative stress. These CS-MO nanocomposites present superior antibacterial efficacy compared with chitosan or metal oxides alone, positioning them as operative antibacterial agents against hazardous bacterial pathogens in wound environments. Glucose-responsive dressings represent sophisticated approaches to diabetic wound management. Integration of glucose oxidase with vanadium-based metal–organic frameworks creates systems that convert wound glucose into therapeutic hydroxyl radicals. This approach provides targeted antimicrobial therapy while addressing metabolic dysfunction characteristic of diabetic wounds. The glucose-responsive mechanism ensures therapeutic activation only in hyperglycemic environments, minimizing off-target effects.
4.2.2. CS-Based Hemostatic Materials
Rapid hemostasis remains critical for emergency medicine and surgical applications where conventional methods may prove insufficient. CS’s hemostatic mechanisms involve platelet activation, red blood cell aggregation, and promotion of natural coagulation cascades through positive charge interactions with negatively charged blood components. Electrospun CS membranes demonstrate remarkable hemostatic effectiveness through high surface-area architectures that promote rapid platelet activation and fibrin formation. − The nanofiber structure mimics the natural extracellular matrix architecture while providing an extensive contact area for blood component interactions. Processing optimization reveals that the fiber diameter and membrane porosity significantly influence hemostatic speed and effectiveness.
Marine-derived peptide incorporation creates synergistic hemostatic materials. Tilapia-derived peptides integrated into CS matrices enhance both mechanical properties and biological activity. These bioactive peptides provide additional hemostatic signals while improving the material handling characteristics. The marine origin offers sustainable sourcing while avoiding concerns about mammalian pathogen transmission. Schiff base cross-linked composites between deacetylated CS and dialdehyde cellulose demonstrate tunable mechanical properties essential for various clinical applications. These systems achieve dramatic bleeding time reduction compared to gauze controls while maintaining biocompatibility and biodegradability. The cross-linking degree can be optimized for specific applications, from flexible dressings to rigid hemostatic agents. The evolution of CS-based hemostatic materials illustrates broader principles of biomaterial development, where an understanding of biological mechanisms drives rational design strategies. Continued optimization through chemical modifications, composite engineering, and advanced fabrication techniques position these materials as next-generation solutions for trauma care and surgical applications, offering clinicians tools that actively promote healing rather than simply managing symptoms.
Beyond hemostasis, CS-based materials also address broader challenges in burn wound management, which remains a major global health concern. Each year, approximately 450,000 patients require treatment for burns, and nearly 30,000 of them need admission to specialized burn centers. Burn wounds display a complex pathophysiology. Vascular endothelial hyperpermeability leads to excessive exudation and necrotic tissue buildup, creating conditions that support bacterial growth and increase the likelihood of bacteremia and sepsis. Conventional dressings such as gauze, foams, hydrogels, and films often fall short, as they cannot sustain antimicrobial delivery or maintain an optimal moisture level. These limitations contribute to slow healing and a higher risk of infection. CS-based materials provide a compelling alternative. Their intrinsic antimicrobial and hemostatic properties, along with their cationic nature, promote cell–matrix interactions and enhance biocompatibility. In contrast, alginate lacks inherent antimicrobial activity, and hyaluronic acid degrades rapidly unless chemically modified. CS-coated nanoparticles further strengthen therapeutic performance by reducing bacterial colonization, promoting re-epithelialization, and improving granulation tissue formation. Together, these features support both infection control and tissue regeneration.
Multifunctional approaches integrate antimicrobial protection, moisture management, and cellular support to address the complex sequential processes underlying tissue regeneration. Nucleobase-modified CS creates biomimetic recognition through hydrogen bonding with bacterial DNA, while glucose-responsive systems enable targeted therapeutic activation in diabetic wound microenvironments through hydroxyl radical generation. Electrospun nanofiber architectures mimic the extracellular matrix structure while achieving dramatic hemostasis acceleration, and marine-derived peptide incorporation provides sustainable bioactive enhancement without mammalian pathogen transmission risks. Metal oxide nanohybrids further expand antimicrobial capabilities through synergistic mechanisms. Schiff base cross-linked composites demonstrate tunable mechanical properties essential for diverse clinical scenarios, from flexible dressings to rigid hemostatic agents. However, clinical translation requires addressing manufacturing scalability challenges and simultaneous optimization of interdependent parameters, including cross-linking degree, fiber architecture, and porosity. , Despite significant advancements in chitosan-based biomaterials and their FDA approval for certain applications, critical gaps remain in translating research innovations to widespread clinical practice. Future efforts should focus on standardizing manufacturing processes, establishing regulatory frameworks, and overcoming translation barriers to maximize therapeutic impact. These smart responsive materials represent an evolution from passive wound coverage toward active therapeutic platforms that respond to specific physiological conditions.
4.3. Advances and Translation Challenges in CS-Based Clinical Biomaterials
The primary challenge facing CS-based clinical materials stems from the polymer’s inherent modest biological activity and insufficient mechanical robustness, which necessitates strategic modifications for practical applications. Chemical cross-linker toxicity presents additional hurdles during the critical transition from laboratory development to clinical implementation. Manufacturing scalability emerges as another significant bottleneck given that processing conditions substantially impact both final scaffold performance and cellular responses. The simultaneous optimization of multiple interdependent parameters, such as cross-linking degree, fiber architecture, and porosity, creates considerable challenges for achieving standardized clinical translation. Contemporary research trajectories reveal a clear evolution toward sophisticated hybrid approaches that capitalize on synergistic material combinations. CS-collagen composites and dual-network hydrogels exemplify how rational biomaterial design strategies can effectively address mechanical limitations while maintaining essential biocompatibility characteristics. The development of low-molecular-weight CS derivatives has demonstrated enhanced antimicrobial effectiveness through improved membrane penetration mechanisms, opening promising avenues for advanced infection control applications. Smart responsive materials, particularly glucose-responsive dressing systems, represent an emerging paradigm toward targeted therapeutic activation that responds to specific physiological conditions. Concurrently, advanced fabrication techniques encompassing optimized 3D printing and electrospinning methodologies enable unprecedented precision in controlling material architecture and performance characteristics. The strategic integration of marine-derived bioactive peptides further illustrates the expanding repertoire of modification strategies available for CS enhancement, providing sustainable sourcing alternatives while simultaneously augmenting biological functionality. These developments collectively position CS-based materials as increasingly sophisticated therapeutic platforms rather than passive treatment aids.
5. CS-Based Materials for Anticancer Applications
Conventional cancer therapeutics continue facing fundamental limitations, including severe adverse effects, development of drug resistance, and substantial collateral damage to healthy tissues. , These challenges drive the urgent need for sophisticated delivery systems capable of selective tumor targeting while minimizing systemic toxicity. CS-based platforms offer compelling advantages through enhanced drug delivery, improved targeting specificity, and reduced adverse effects compared to conventional chemotherapy (Figure ). The integration of CS into hydroxyapatite matrices represents a paradigmatic approach to localized cancer therapy, particularly relevant for osteosarcoma, where conventional treatments often compromise bone integrity. This composite strategy addresses multiple therapeutic challenges simultaneously by providing structural support while delivering targeted anticancer activity. The exceptional cell viability reduction observed in extended culture studies reflects not merely cytotoxic effects but also sustained therapeutic pressure that prevents cancer cell recovery and adaptation. Controlled release kinetics maintain therapeutic drug concentrations locally while minimizing systemic exposure, which is particularly valuable for preventing postsurgical metastasis. Advanced molecular targeting strategies demonstrate CS’s versatility in precision oncology. STAT3-specific siRNA coupled with BV6 apoptosis inhibitors within carboxymethyl dextran-trimethyl CS nanoparticles exemplifies elegant molecular targeting approaches. The dual-action mechanism simultaneously blocks survival signaling while promoting apoptotic pathways, creating synergistic therapeutic effects that are impossible with single-agent treatments. The CS carrier enables selective cellular uptake while protecting nucleic acids from degradation.
7.
Schematic illustration of chitosan-based anticancer strategies.
Multidrug delivery platforms exploit CS’s capacity for complex therapeutic cargo. Ionic cross-linking using sodium tripolyphosphate enables simultaneous encapsulation of multiple therapeutic agents with differential release profiles. This approach optimizes therapeutic timing by releasing drugs according to their optimal therapeutic windows. Sequential release patterns can be engineered to prime cancer cells with sensitizing agents before delivering cytotoxic compounds, maximizing therapeutic efficacy and minimizing resistance development. Self-assembling CS platforms represent sophisticated nanotechnology approaches to cancer therapy. Amphiphilic modifications enable spontaneous nanostructure formation for triple-negative breast cancer treatment. These systems exploit thermodynamic self-assembly to create stable nanostructures with impressive drug-loading capacity while maintaining minimal toxicity profiles. The self-assembly process ensures reproducible particle characteristics that are essential for clinical translation (Figure ). In this system, DOX release is governed by dual responsiveness to tumor-associated stimuli. The CS component dissolves more readily under the mildly acidic conditions characteristic of tumor tissue, while the PNVCL segment undergoes a hydrophilic-to-hydrophobic phase transition at elevated tumor temperatures. These two triggers act in concert to accelerate DOX release specifically within the tumor microenvironment. Moreover, functionalization with a cell-penetrating peptide enhances nanoparticle accumulation and internalization in cancer cells, allowing DOX to exert its therapeutic effect selectively within tumor tissue.
8.
Mechanism of DOX-targeted specific delivery to tumor cells. Copyright 2019, The Authors.
Targeting metabolic vulnerabilities through folate receptor-mediated delivery demonstrates rational therapeutic design. Folic acid-conjugated CS nanocomposites exploit the elevated folate requirements of rapidly dividing cancer cells. This approach achieves exceptional drug loading while maintaining selectivity for malignant tissues. The folate modification enables active targeting mechanisms superior to passively enhanced permeability and retention effects alone. pH-responsive release mechanisms optimize drug delivery within acidic tumor microenvironments. CS’s pH-dependent solubility characteristics enable preferential drug release at tumor sites where acidic conditions predominate. This passive targeting mechanism reduces systemic drug exposure while concentrating on therapeutic effects where they are needed most. Combined with active targeting strategies, pH-responsive systems create multilayered selectivity essential for effective cancer therapy. Combination therapy approaches leverage CS’s capacity to deliver diverse therapeutic modalities simultaneously. Integration of conventional chemotherapeutics with agents that enhance antitumor responses is supported by the improved intracellular drug accumulation and apoptosis observed in folate receptor-expressing cancer cells treated with folate-modified CS-based nanoparticles. These outcomes indicate that CS nanocarriers can strengthen the therapeutic impact of codelivered agents by increasing their concentration within tumor tissue and promoting cellular uptake, which provides a rationale for combining chemotherapeutics with complementary therapeutic modalities. These combination strategies address cancer’s heterogeneity and adaptive resistance mechanisms through multitarget interventions impossible with conventional delivery methods.
Beyond conventional drug delivery, 3D bioprinting enables physiologically relevant in vitro cancer models, addressing limitations of traditional 2D culture and animal models. Modified dextran-chitosan (MDC) hydrogels exemplify this approach, supporting triple-negative breast cancer (TNBC) tumoroid formation that recapitulates critical tumor-promoting factors absent in conventional systems. The hydrogel matrix (11 kPa stiffness) mimics native breast tissue, promoting mechanotransductive signaling with increased YAP1 expression (2.4-fold) and significantly elevated nuclear-to-cytoplasmic YAP1 ratios versus rigid culture surfaces (3 GPa). These 3D tumoroids demonstrate upregulated extracellular matrix markers, including COL1A1 (2.29-fold), enhanced hypoxic conditions, epithelial-to-mesenchymal transition traits, and elevated stemness markers like NANOG (3.33-fold). Critically, the 3D microenvironment exhibits elevated tumor-promoting factors, including IL6, IL10, TNFA, FGF2, BMP2, and active TGFB, creating pathophysiologically relevant drug screening platforms. Validation studies show 3D tumoroids exhibit substantial resistance to combined doxorubicin-paclitaxel treatment compared to 2D cultures, reflecting clinical drug resistance mechanisms more accurately. Whole transcriptome sequencing confirms enhanced tumorigenic phenotypes, validating the utility for cancer biology investigation and high-throughput drug screening. This convergence of 3D bioprinting with CS-based biomaterials establishes robust platforms bridging oversimplified in vitro systems and complex in vivo environments, accelerating therapeutic translation toward clinical applications.
Advanced targeting strategies demonstrate CS’s evolution toward precision oncology through multilayered selectivity mechanisms. Hydroxyapatite composites provide localized osteosarcoma therapy while preserving bone integrity, and STAT3-siRNA delivery coupled with apoptosis inhibitors achieves synergistic molecular targeting impossible with single-agent approaches. Self-assembling amphiphilic platforms enable reproducible nanostructure formation with exceptional drug loading, while folate receptor-mediated delivery exploits metabolic vulnerabilities of rapidly dividing cells. pH-responsive release mechanisms create passive tumor selectivity by leveraging acidic microenvironments, complementing active targeting through receptor–ligand interactions. Multidrug platforms utilizing ionic cross-linking enable sequential therapeutic delivery optimized for temporal therapeutic windows, potentially circumventing resistance mechanisms. However, clinical translation faces challenges, including manufacturing complexity for multicomponent systems, variability in self-assembly reproducibility, and optimizing multiple interdependent parameters simultaneously. Successfully advancing these sophisticated platforms requires balancing therapeutic efficacy with translational feasibility while establishing standardized protocols for complex nanoformulation production.
6. CS-Based Materials for Other Medical Applications
6.1. Cross-Domain Comparative Analysis
Examination across therapeutic domains reveals patterns in how chitosan modifications succeed or fail. PEGylation represents a modification strategy that works across multiple applications. In drug delivery systems (Section ), PEGylation extends systemic circulation time; in wound dressings (Section ), it reduces unwanted protein adhesion; in cancer therapy (Section ), it improves tumor-targeting efficiency. The common mechanism involves creating hydrophilic barriers that reduce nonspecific biological interactions without compromising biocompatibility. pH-responsive modifications show a similar cross-domain utility. Both tumor-targeted delivery (Section ) and gastrointestinal drug release (Section ) exploit acidic microenvironments to trigger drug release. However, therapeutic domains also impose distinctly different requirements. Drug delivery systems need high encapsulation efficiency (reported values range from 67 to 96%) and precise release kinetics to maintain therapeutic windows. Wound healing materials face different constraints: mechanical strength for handling and degradation rates that match tissue regeneration (typically 2–4 weeks). Cancer therapy platforms prioritize selective cellular uptake and strategies to overcome multidrug resistance. These performance differences reflect fundamentally different clinical objectives rather than arbitrary design choices.
Certain hybrid strategies demonstrate unexpected versatility across applications. Chitosan-collagen combinations work in both orthopedic scaffolds (Section ) and wound dressings (Section ). The success stems from complementary functions: chitosan contributes antimicrobial activity and adhesion to mucosal surfaces, while collagen provides cell-recognition domains and mechanical support. Tripolyphosphate ionic cross-linking enables multidrug encapsulation in oral delivery (Section ) and cancer therapy (Section ), showing that fundamental assembly mechanisms can accommodate varied therapeutic cargos and release requirements. These examples suggest that successful modifications often address basic material science challenges (stability, drug loading, and controlled release) that appear across different clinical contexts. Understanding which strategies transfer between domains and which require domain-specific optimization can guide more efficient development. The framework presented here provides a starting point for evaluating whether approaches successful in one therapeutic area might address challenges in another, though systematic validation remains necessary for each specific application.
6.2. CS-Based Materials for Biomedical Devices
Biomedical devices face persistent challenges, including device-associated infections and mechanical biocompatibility that CS-based modifications effectively address. Electrophoretically deposited CS coatings with metallic nanoparticles onto Ti13Zr13Nb alloy demonstrate smart pH-responsive functionality for orthopedic and dental implants. Gold nanoparticle incorporation (0.05 g/dm3) enhances antibacterial efficacy against Staphylococcus aureus while increasing surface roughness from 54 to 146 nm. Processing parameters critically influence performance: voltage reduction from 20 to 10 V decreases coating thickness by 50%, while higher voltages improve adhesion by 177% through enhanced ion migration. Mechanical characterization reveals improved plastic deformation resistance (H3/E2 ratio increasing to 1.78 MPa for zinc coatings). For catheter applications, N-acetyl cysteine-functionalized O-carboxymethyl CS nanosystems achieve remarkable biofilm inhibition when grafted onto silicone surfaces: 76 ± 1.5% against E. coli and 60 ± 1% against P. aeruginosa. These dual-strategy systems combining contact-killing with Meropenem release address device-associated infections representing 65% of hospital-acquired cases, with VAP mortality reaching 3–17% and treatment costs of 40,000 dollars per episode.
Transient implantable devices represent paradigm shifts toward biodegradable systems, eliminating surgical removal. The first fully biodegradable organic light-emitting device (OLED) utilizing a CS substrate demonstrates chitosan/MoO3/Mg/MoO3/AlQ3/Mg architecture achieving 36 cd/m2 luminance with 526 nm green emission suitable for photodynamic therapy and tissue regeneration. Complete enzymatic degradation within 24 h under physiological conditions enables therapeutic light delivery without accumulation, though PLGA encapsulation extends operational lifetime to 5 months. Composite polycaprolactone/CS/ZrO2 nanocomposite films demonstrate multifunctional capabilities for biomedical devices. Optimal 2 wt % ZrO2 concentration yields 63% tensile strength increase and 93% toughness enhancement, while 6 wt % maximizes Young’s modulus (393 MPa) and electrical conductivity. These materials exhibit synergistic antibacterial efficacy with inhibition zones reaching 13.1 mm (S. aureus) and 10.1 mm (E. coli), positioning them for smart packaging, flexible optoelectronics, and implantable sensors. Clinical translation requires optimizing nanoparticle concentrations, balancing antimicrobial efficacy with biocompatibility, and establishing standardized processing parameters ensuring reproducible performance.
6.3. CS-Based Materials for Emerging Health and Regenerative Applications
Beyond conventional biomedical applications, CS demonstrates remarkable versatility in addressing diverse health challenges ranging from metabolic disorders to dental pathology. These applications highlight CS’s multifaceted therapeutic potential while revealing opportunities for expanding clinical utility through rational material design. Obesity management represents an emerging application domain where CS’s unique physicochemical properties enable novel therapeutic approaches. The polymer’s capacity for lipid interaction and gel formation provides mechanisms for modulating digestive processes and metabolic outcomes. CS’s interaction with emulsified oleic acid creates liquid crystalline interfaces that fundamentally alter lipid bioavailability. , This mechanism involves the formation of physical barriers around lipid droplets, preventing enzymatic access and reducing absorption efficiency. The resulting CS-lipid complexes demonstrate stability across physiological pH ranges while maintaining biocompatibility (Figure ). Advanced CS derivatives demonstrate enhanced metabolic effects through targeted modifications. CS-thioglycolic acid conjugates achieve substantial weight reduction when combined with flavonoid compounds like hesperidin. This synergistic approach suggests that polymer-based lipid sequestration combined with antioxidant activities creates multimodal metabolic benefits. The thioglycolic acid modification enhances CS’s binding affinity for lipids, while the hesperidin component addresses oxidative stress associated with obesity.
9.
Mechanism of reducing obesity by CS-based dietary supplements. Copyright 2020, Elsevier Ltd.
Dental applications exploit CS’s antimicrobial properties and biocompatibility for addressing oral pathology. Multimodal antimicrobial systems combining CS with established dental therapeutics demonstrate enhanced effectiveness against oral pathogens. CS integration with calcium hydroxide and chlorhexidine creates synergistic antimicrobial effects while maintaining the biocompatibility essential for oral applications. These systems address complex oral microbiomes through multiple antimicrobial mechanisms while supporting tissue healing. Dental pulp regeneration represents sophisticated tissue engineering applications where CS serves as both scaffold material and a therapeutic delivery system. Fibrin-CS hydrogels achieve an optimal balance between mechanical integrity, antimicrobial activity, and cellular compatibility. These composite systems provide immediate hemostatic effects that are essential for dental procedures while creating appropriate matrices for cellular infiltration and sustained antimicrobial activity. The fibrin component promotes natural clotting mechanisms, while CS provides structural support and antimicrobial protection. These diverse applications illustrate common principles underlying CS’s therapeutic versatility, including its capacity for multimodal biological interactions, compatibility with various cotherapeutic agents, and adaptability through chemical modification. The successful translation of these materials across disparate medical fields suggests broad applicability principles that could guide future therapeutic development. As CS’s biological mechanisms continue to evolve, new applications will likely emerge that leverage these fundamental properties to address additional clinical challenges, positioning CS-based materials as foundational components of next-generation medical devices and therapeutic systems.
Tissue regeneration applications demonstrate CS’s expanding utility through 3D bioprinting for gastrointestinal tissue engineering, where conventional treatments face substantial limitations. Inflammatory bowel disease and short bowel syndrome often necessitate surgical interventions, causing significant small intestine loss, with traditional therapies, including parenteral nutrition and small bowel transplantation, limited by high costs, donor shortages, and suboptimal success rates (60%). Alkali-dissolved CS-based tubular constructs fabricated using FRESH bioprinting successfully replicate complex serpentine geometry impossible to achieve conventionally. In vivo rat validation confirms successful integration, with histological analysis revealing villi formation (104 ± 4.9 μm) comparable to native architecture. Constructs exhibit suitable mechanical properties, excellent blood compatibility (3% hemolysis), inherent antibacterial activity, and controlled biodegradation (5–12% over 3 days), ensuring structural stability during critical integration periods. Biochemical analysis confirms systemic safety with normal tissue histology postimplantation. This demonstrates CS-based 3D bioprinting’s transformative potential in regenerative medicine, offering patient-specific, anatomically complex tissue replacements that address organ transplantation limitations.
Cross-disciplinary applications illuminate CS’s therapeutic versatility beyond conventional biomedical domains through exploitation of fundamental physicochemical properties. Lipid sequestration mechanisms in obesity management demonstrate how CS-oleic acid liquid crystalline interfaces modulate digestive processes, while thioglycolic acid conjugates combined with hesperidin create multimodal metabolic benefits through enhanced lipid binding and antioxidant activity. Dental applications leverage synergistic antimicrobial effects between CS and established therapeutics, including calcium hydroxide and chlorhexidine, addressing complex oral microbiomes through complementary mechanisms. Fibrin-CS hydrogels exemplify sophisticated tissue engineering approaches that balance hemostatic efficacy, mechanical integrity, and cellular compatibility for pulp regeneration. These diverse applications reveal common underlying principles: multimodal biological interactions, compatibility with various cotherapeutic agents, and adaptability through rational chemical modifications. However, translating these promising laboratory findings requires addressing mechanistic understanding gaps and establishing standardized protocols across disparate clinical contexts, positioning CS-based materials as foundational platforms for next-generation therapeutic innovation.
7. Prospects and Challenges
7.1. Persistent Challenges
Despite remarkable advances, fundamental obstacles impede clinical translation of CS-based biomedical materials. Persistent pH-dependent solubility (pH < 6.5) and inadequate mechanical strength necessitate hybrid approaches, often compromising CS’s inherent properties. Manufacturing standardization faces critical barriers from molecular weight (<1 kDa to several hundred kDa) and deacetylation degree (55–95%) variability, causing substantial disparities in encapsulation efficiencies (67–96%) and release profiles that fundamentally hinder rational formulation development. These standardization challenges substantially elevate quality control costs and complicate regulatory approvals, creating economic barriers for smaller manufacturers and limiting accessibility in resource-constrained settings. Application-specific limitations persist: drug delivery systems suffer from restricted hydrophobic compound loading and burst release; wound healing materials struggle with degradation optimization; cancer therapy platforms face burdens demonstrating advantages over established protocols. Commercial viability critically depends on balancing performance enhancement with production scalability and cost-effectiveness versus conventional treatments.
7.2. Regulatory Landscape and Clinical Translation Status
The stark disparity between extensive chitosan research publications and the limited clinical adoption of advanced formulations reveals fundamental regulatory and translational challenges that warrant systematic examination. Despite chitosan’s FDA-approved safety profile mentioned in the introduction and decades of biomedical research, clinical implementation remains concentrated in relatively simple applications such as wound dressings and hemostatic materials rather than the sophisticated drug delivery platforms, cancer therapy systems, and smart responsive materials documented throughout Sections –. This translational gap stems from interconnected regulatory barriers rooted in the material property inconsistencies identified across therapeutic domains. The substantial variability in molecular weight (ranging from less than 1 kDa to several hundred kDa) and deacetylation degree (spanning 55–95%) creates batch-to-batch performance inconsistencies that fundamentally complicate regulatory submissions requiring a demonstration of reproducible safety and efficacy. Manufacturing scalability obstacles discussed in ocular delivery (Section ), oral formulations (Section ), and orthopedic applications (Section ) reflect deeper challenges in transitioning laboratory-scale synthesis methods to GMP-compliant production processes, a threshold that simpler wound care products meet more readily than complex nanoparticle platforms combining multiple therapeutic agents, pH-responsive triggers, and targeted delivery mechanisms. The absence of standardized characterization protocols for assessing critical parameters, including encapsulation efficiency (reported variably between 67 and 96% across studies), release kinetics, and mechanical properties (often below 50 MPa for load-bearing applications), impedes meaningful comparative assessments essential for regulatory decision-making and complicates the establishment of performance benchmarks required for approval dossiers.
These regulatory challenges fundamentally explain why clinical translation succeeds primarily for applications requiring minimal formulation complexity, while advanced platforms demonstrate exceptional laboratory performance, such as multidrug delivery systems utilizing ionic cross-linking (Section ), self-assembling amphiphilic nanostructures for cancer therapy (Section ), and glucose-responsive smart dressings (Section ), remain largely confined to preclinical investigation. The concentration of commercially viable products in hemostatic and basic wound management applications versus the research emphasis on sophisticated theranostic platforms highlights that translational success depends not merely on technical innovation but also on navigating complex regulatory requirements, establishing scalable manufacturing with consistent quality control, and demonstrating clinical advantages sufficient to justify regulatory scrutiny for novel formulations. Quality control costs associated with managing chitosan’s inherent variability create economic barriers particularly challenging for smaller manufacturers, while the need to demonstrate superiority over established treatment protocols presents substantial hurdles for complex formulations competing against conventional therapies with well-established safety profiles and regulatory pathways. Advancing clinical translation of next-generation chitosan platforms requires coordinated efforts addressing these interconnected challenges through international consensus standards for material characterization, development of scalable manufacturing processes compatible with regulatory requirements, and establishment of appropriate preclinical models and clinical endpoints that enable streamlined approval pathways for innovative biomaterial delivery systems while maintaining rigorous safety standards essential for patient protection.
7.3. Future Prospects
Advanced fabrication technologies (3D bioprinting and electrospinning) enable patient-specific scaffolds with tailored properties, though clinical translation requires addressing manufacturing scalability and economic feasibility for personalized devices. Smart responsive systems (glucose-responsive dressings and pH-sensitive carriers) demonstrate sophisticated activation aligned with pathological microenvironments. Drawing inspiration from in-plane ordered MXenes revolutionizing biosensing and covalent triazine-based frameworks’ multifunctional capabilities, CS platforms could develop hybrid sensing-therapeutic systems. MOF-MXene integration strategies and Prussian blue frameworks’ versatility exemplify potential for CS-based theranostic platforms combining diagnostics and therapy. Multimodal systems integrating bioactive agents promise synergistic effects, while AI-driven design and high-throughput screening will accelerate optimal derivative identification. Alternative sourcing (fungal and insect sources) addresses environmental concerns, potentially reducing supply chain dependencies and production costs while democratizing global access. The economic outlook remains promising, driven by aging populations and chronic disease prevalence, though commercialization requires cost-effective manufacturing, streamlined regulatory strategies, and compelling clinical advantages. Success depends on interdisciplinary collaboration transforming CS’s therapeutic potential into standardized clinical products benefiting diverse patient populations.
8. Conclusions
By organizing chitosan applications according to therapeutic domains, drug delivery systems, wound healing, cancer therapy, tissue engineering, and emerging medical areas rather than material properties alone, this review enables direct access to field-specific formulation strategies and performance benchmarks relevant to specialized clinical contexts. Domain-specific analysis reveals that chitosan’s clinical versatility stems from strategic modifications addressing distinct therapeutic requirements. In drug delivery applications, hybrid formulations achieve exceptional encapsulation efficiencies ranging from 78 to 96% through synergistic material integration, while mucoadhesive platforms extend corneal residence time by 2.5-fold over conventional systems, with methacrylated derivatives achieving 96% retention compared to 88% for unmodified polymers. Wound healing materials successfully balance antimicrobial functionality with mechanical integrity through composite architectures, particularly dual-network hydrogels, optimizing structural strength and cellular compatibility. Cancer therapy platforms exploit sophisticated selectivity mechanisms combining targeted siRNA delivery, receptor-mediated recognition, and microenvironment-responsive release to overcome multidrug resistance, although manufacturing complexity continues to impede clinical translation.
However, successful clinical translation requires addressing fundamental challenges identified across all domains: persistent pH-dependent solubility limitations, substantial variability in molecular weight and deacetylation degree spanning 55–95%, causing inconsistent performance, inadequate mechanical strength below 50 MPa for load-bearing applications, manufacturing scalability obstacles, and the critical need for standardized characterization protocols. Future progress depends on developing smart, responsive systems integrating diagnostic and therapeutic functions, advancing patient-specific fabrication capabilities, exploring sustainable sourcing alternatives, and leveraging computational design approaches for rational formulation optimization. This domain-organized synthesis provides practitioners with actionable guidance for therapeutic development within their medical specialty while establishing a foundation for future systematic cross-domain comparative analyses.
Acknowledgments
Figures – were created with the assistance of Nanobanana Pro (Nanobanana Tech, 2026), which was used solely as a graphical illustration tool. Figures and were drawn manually by the authors using In-Draw. Elements in the graphical abstract were adapted from Bioicons (https://bioicons.com) and BioGDP (https://biogdp.com) under the Creative Commons Attribution 4.0 International license and assembled by the authors using Microsoft PowerPoint. All scientific concepts, designs, and interpretations were conceived and validated by the authors in full compliance with the respective terms of use.
Data is contained within the article.
Conceptualization, B.X. and N.W.; methodology, N.W., H.C., and L.W.; investigation, Z.S. and S.L.; writingoriginal draft preparation, writingreview and editing, project administration, B.X.; funding acquisition, Z.S. All authors have read and agreed to the published version of the manuscript. N.W. and H.C. contribute equally.
Funding was provided by Shaoxing Health Science and Technology Project (2024SKY129) and Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (2023ZF179).
Institutional Review Board Statement – Not applicable.
The authors declare no competing financial interest.
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