Novel Hydrogels for Drug Delivery and Regenerative Medicine: Advances, Engineering Strategies, and Clinical Translation

1. Introduction

Hydrogels have emerged as versatile biomaterials for biomedical applications owing to their high-water content, biocompatibility, tunable physicochemical properties, and structural similarity to the extracellular matrix [1,2,3]. Recent advances in hydrogel engineering have enabled the development of multifunctional systems for controlled drug delivery and tissue regeneration, attracting significant interest in translational medicine and regenerative therapeutics [4,5,6,7,8,9,10]. Conventional therapeutic approaches often suffer from poor bioavailability, rapid drug degradation, limited tissue targeting, and undesirable systemic side effects [4,5,6]. Similarly, traditional tissue engineering scaffolds frequently lack appropriate biological and mechanical properties necessary for effective tissue repair [11,12,13,14]. Hydrogels offer promising solutions by providing localized delivery, sustained release profiles, and supportive microenvironments for cellular growth and tissue regeneration [11,12,13,14,15,16].

Recent developments in polymer chemistry, nanotechnology, and biofabrication have significantly expanded the functional capabilities of hydrogel systems [17,18,19,20]. Advanced hydrogels can respond to physiological stimuli such as pH, temperature, enzymes, and reactive oxygen species, enabling site-specific therapeutic delivery. These intelligent systems are increasingly being explored for precision medicine, minimally invasive therapies, and personalized biomedical applications [15,17,18,19,20]. In addition to drug delivery, hydrogels play a crucial role in regenerative medicine through their ability to mimic native extracellular matrices and support cell adhesion, proliferation, and differentiation [7,8,9,10,11,12,13,14]. Injectable and self-healing hydrogels have gained particular attention due to their minimally invasive administration and adaptability to irregular tissue defects [15,16,17,18,19,20]. Such systems have demonstrated potential in wound healing, bone regeneration, cartilage repair, and neural tissue engineering [7,8,9,10,11,12,13,14,15,16,17,18,19,20].

Nanocomposite and bioactive hydrogels have further enhanced the therapeutic performance of hydrogel-based platforms. The incorporation of nanoparticles, peptides, growth factors, and bioactive molecules allows simultaneous improvement of mechanical strength, biological activity, and controlled therapeutic release [9,10]. These multifunctional platforms have opened new opportunities for theranostics, immunomodulation, and synergistic therapeutic strategies in complex disease treatment [10]. Despite remarkable progress, several challenges continue to limit the clinical translation of hydrogel technologies. Issues related to large-scale manufacturing, sterilization, long-term stability, reproducibility, regulatory approval, and potential immunogenicity remain major concerns. Addressing these limitations requires interdisciplinary collaboration among material scientists, clinicians, engineers, and pharmaceutical researchers to ensure safe and effective clinical implementation.

Several excellent reviews have focused on individual aspects of hydrogel research, including stimuli-responsive materials, injectable hydrogels, nanocomposite systems, drug delivery, tissue engineering, or bioprinting [4,5,6,7,8,9,10,11,12,13,14]. However, a comprehensive review that integrates recent advances in hydrogel engineering with their applications in drug delivery, tissue-specific regenerative medicine, and the critical challenges associated with clinical translation remains limited. Moreover, the rapid emergence of smart biomaterials, advanced biofabrication techniques, and multifunctional hydrogel platforms over the past decade warrants an updated and integrated perspective on the field.

In this review, we comprehensively summarize the recent (last decade) progress in hydrogel research by first discussing the fundamental properties and classification of hydrogels, followed by advanced engineering strategies, including stimuli-responsive, injectable, self-healing, nanocomposite, bioactive, biomimetic, and three-dimensional bioprintable hydrogels. We then critically discuss their emerging applications in drug delivery, including cancer therapy, antimicrobial therapy, gene and protein delivery, as well as regenerative medicine covering bone, cartilage, skin, neural, cardiac, ocular, and vascular regeneration. Finally, we highlight the major challenges associated with manufacturing, regulatory approval, and clinical translation, together with future opportunities involving artificial intelligence-assisted material design, advanced biofabrication, and precision medicine. By integrating material design, biomedical applications, and translational perspectives within a single review, we aim to provide researchers and clinicians with a comprehensive overview of the current landscape and future directions of hydrogel-based technologies for drug delivery and regenerative medicine.

2. Fundamentals of the Hydrogels

Hydrogels are three-dimensional polymeric networks capable of absorbing and retaining substantial amounts of water while maintaining structural integrity [21,22,23]. Their unique physicochemical characteristics arise from hydrophilic functional groups and crosslinked architectures [Figure 1]. Due to their soft and hydrated nature, hydrogels closely resemble natural extracellular matrices, making them highly suitable for various biomedical and tissue engineering applications [25,26,27].

Hydrogels can be broadly classified into natural, synthetic, and hybrid systems depending on the source of polymeric materials [25,26,27]. Natural hydrogels such as alginate, gelatin, collagen, and hyaluronic acid exhibit excellent biocompatibility and biodegradability. In contrast, synthetic hydrogels including polyethylene glycol and polyvinyl alcohol provide superior mechanical strength, tunable properties, and enhanced structural stability.

Crosslinking mechanisms play a critical role in determining the physicochemical and biological properties of hydrogel systems [21,22]. Physical crosslinking involves non-covalent interactions such as hydrogen bonding, ionic interactions, and hydrophobic associations, whereas chemical crosslinking relies on covalent bond formation. Chemically crosslinked hydrogels generally exhibit improved mechanical stability and prolonged degradation profiles compared to physically crosslinked systems.

The swelling behavior of hydrogels significantly influences their drug loading capacity, diffusion kinetics, and biological performance [21,22]. Water absorption occurs through osmotic forces generated by hydrophilic polymer networks, enabling efficient encapsulation and controlled release of therapeutic agents. Parameters including polymer composition, crosslinking density, pH, and temperature greatly affect swelling properties and therapeutic efficacy [21,22,23].

Biodegradability is another important characteristic governing hydrogel performance in biomedical applications. Biodegradable hydrogels gradually degrade into non-toxic byproducts through hydrolytic or enzymatic processes, eliminating the need for surgical removal after therapy. Controlled degradation kinetics are particularly important in regenerative medicine, where scaffold persistence must align with tissue healing and regeneration processes [11,13,14].

Mechanical properties strongly influence the functionality and clinical applicability of hydrogel systems. Parameters such as elasticity, stiffness, compressive strength, and viscoelasticity determine the suitability of hydrogels for different tissues and therapeutic environments. Engineering hydrogels with tissue-specific mechanical characteristics remains a major focus for improving cellular interactions and long-term therapeutic performance [23,24].

Injectable hydrogels have emerged as minimally invasive biomaterials capable of conforming to irregular tissue defects following administration. These systems undergo sol-gel transition under physiological conditions, enabling localized therapeutic delivery and enhanced patient compliance. Injectable hydrogels are particularly promising for applications involving wound healing, cancer therapy, cartilage repair, and stem cell transplantation [15,16,17,19,28].

Smart or stimuli-responsive hydrogels possess the ability to alter their physicochemical behavior in response to environmental triggers such as pH, temperature, light, enzymes, or redox conditions. These advanced systems enable site-specific and controlled therapeutic release while minimizing systemic toxicity. Stimuli-responsive hydrogels have gained substantial attention for precision medicine and targeted biomedical interventions [15,17,19,28]. Those advanced engineering strategies are discussed below (section 3).

3. Advanced Hydrogel Engineering Strategies

3.1. Stimuli-Responsive Hydrogels

Stimuli-responsive hydrogels, also known as smart hydrogels, constitute one of the most significant advances in hydrogel engineering over the past decade. Unlike conventional hydrogels, these materials dynamically alter their physicochemical properties in response to specific internal or external stimuli, including pH, temperature, light, electric and magnetic fields, enzymatic activity, reactive oxygen species (ROS), and redox environments. Such adaptive behavior enables precise spatial and temporal control over hydrogel swelling, degradation, mechanical properties, and biomolecule release, making them attractive platforms for regenerative medicine and controlled therapeutic delivery [Figure 2] [27,28,31].

One of the major breakthroughs in this field has been the rational design of polymer networks capable of reversible structural transitions under physiological conditions. By tailoring the molecular architecture and crosslinking chemistry, researchers have developed hydrogels that undergo predictable changes in network structure and functionality in response to disease-specific or tissue-specific microenvironments. This responsiveness allows hydrogels to mimic the dynamic nature of the native extracellular matrix (ECM), thereby improving cell-material interactions and tissue remodelling [28].

Mechanical adaptability has also become a defining characteristic of next-generation stimuli-responsive hydrogels. The introduction of highly stretchable and mechanically resilient hydrogel networks demonstrated that responsiveness could be achieved without sacrificing structural integrity. These mechanically robust materials exhibit reversible deformation under repeated loading, making them particularly suitable for dynamic tissues such as cartilage, muscle, and skin [29].

Beyond bulk mechanical properties, the integration of hydrogel networks with elastomeric materials has expanded the functional capabilities of stimuli-responsive systems. Skin-inspired hydrogel-elastomer hybrids exhibit robust interfacial adhesion while maintaining flexibility, durability, and responsiveness to environmental changes. Such multifunctional platforms have attracted considerable interest for wearable biosensors, soft bioelectronics, and implantable biomedical devices that require continuous adaptation to physiological motion [26,29].

Recent advances have further extended stimuli-responsive hydrogel design toward cell-instructive biomaterials. For example, microfluidic fabrication of photocrosslinkable hydrogel microspheres enables precise control over hydrogel architecture and light-triggered polymerization, providing engineered microenvironments that support stem cell encapsulation and tissue formation with high spatial resolution [27].

Overall, stimuli-responsive hydrogels represent a versatile class of intelligent biomaterials capable of adapting to complex biological environments through programmable physicochemical changes. Their ability to respond to physiological cues has established the foundation for numerous advanced hydrogel platforms, including injectable systems, nanocomposite formulations, bioactive matrices, and 3D bioprintable bioinks, which are discussed in the following sections.

3.2. Injectable and Self-Healing Hydrogels

Injectable hydrogels have emerged as an attractive platform for regenerative medicine by enabling minimally invasive administration while conforming to irregular tissue defects. Unlike preformed scaffolds, injectable systems can be delivered through syringes or catheters and subsequently recover their structural integrity at the target site, thereby reducing surgical trauma, improving patient compliance, and facilitating localized therapeutic delivery. Recent advances in polymer chemistry and dynamic crosslinking strategies have significantly improved the injectability, mechanical stability, and biological performance of these hydrogel systems [Figure 3] [32,33,34,35].

A key design principle underlying injectable hydrogels is shear-thinning behavior, whereby the hydrogel temporarily decreases in viscosity under applied shear stress during injection and rapidly recovers its original network architecture once the stress is removed. This reversible rheological property allows efficient syringe-based administration while maintaining structural fidelity after implantation. Gaharwar et al. highlighted that incorporating nanosilicates into polymer networks can produce shear-thinning nanocomposite hydrogels with enhanced mechanical properties, rapid structural recovery, and excellent cytocompatibility, making them highly promising for minimally invasive tissue engineering applications [33].

Building upon these concepts, Appel et al. comprehensively reviewed supramolecular polymeric hydrogels formed through reversible non-covalent interactions, highlighting their ability to self-assemble into injectable networks with rapid stress relaxation, efficient structural recovery, and tunable mechanical properties. These physically crosslinked hydrogels have emerged as versatile platforms for the sustained delivery of therapeutic molecules and cells owing to their excellent injectability, cargo encapsulation capability, and dynamic responsiveness [32].

Rodell et al. developed shear-thinning supramolecular hydrogels with secondary autonomous covalent crosslinking, demonstrating that dynamically crosslinked injectable networks can achieve rapid recovery after shear, tunable mechanical properties, and prolonged in vivo retention. This work established an important design strategy for mechanically robust injectable hydrogels suitable for diverse biomedical applications [34].

In addition to injectability, autonomous self-healing has become an increasingly desirable characteristic for hydrogel-based regenerative scaffolds. Self-healing hydrogels possess the ability to restore their structural integrity after mechanical damage through reversible dynamic interactions, thereby extending scaffold longevity and maintaining functional performance in vivo. Various dynamic chemistries, including metal-ligand coordination, reversible covalent bonding, hydrogen bonding, host-guest interactions, and supramolecular assembly, have been successfully employed to construct hydrogel networks capable of repeated damage-repair cycles [32,36,37].

Among these approaches, metal-coordination chemistry has attracted considerable attention owing to its rapid bond exchange kinetics and excellent mechanical adaptability. Gao et al. developed an injectable hyaluronic acid hydrogel crosslinked through reversible iron coordination, which exhibited rapid self-healing, injectability, and matrix metalloproteinase (MMP)-inhibitory activity. The dynamic coordination network enabled repeated structural recovery after mechanical deformation while simultaneously suppressing MMP activity, highlighting the potential of multifunctional injectable hydrogels for tissue repair and regenerative medicine [36].

More recently, natural biopolymers have become increasingly important building blocks for injectable self-healing hydrogels due to their inherent biocompatibility, biodegradability, and extracellular matrix-mimicking properties. Hydrogels derived from hyaluronic acid, gelatin, chitosan, alginate, collagen, and other naturally occurring polymers have demonstrated excellent injectability while supporting cell survival, proliferation, and tissue regeneration. Kong et al. comprehensively highlighted how integrating dynamic crosslinking strategies with natural biopolymers enables injectable hydrogels possessing enhanced mechanical resilience, repeated self-healing capability, and favorable biological performance across a wide range of regenerative medicine applications [37].

The versatility of injectable hydrogels has also expanded beyond tissue engineering into localized drug delivery. Wang et al. developed injectable hydrogel composites capable of sustained local release of chemotherapeutic agents while simultaneously enhancing antitumor immune responses. By combining injectable delivery with drug retention and controlled release, these systems effectively increase therapeutic efficacy while minimizing systemic toxicity, illustrating the growing role of injectable hydrogels as multifunctional therapeutic platforms [35].

Collectively, recent advances in injectable and self-healing hydrogels have transformed conventional hydrogel scaffolds into adaptive biomaterials capable of minimally invasive administration, rapid structural recovery, prolonged functionality, and localized therapeutic delivery. Future developments are expected to further integrate injectable formulations with bioactive cues, nanomaterials, and advanced manufacturing technologies to create next-generation regenerative platforms with improved clinical translatability.

3.3. Nanocomposite Hydrogels

Nanocomposite hydrogels have emerged as one of the most transformative developments in hydrogel engineering over the past decade. By incorporating functional nanomaterials within hydrated polymeric networks, these hybrid systems overcome many of the limitations associated with conventional hydrogels, including poor mechanical strength, limited bioactivity, and inadequate responsiveness to external stimuli [Figure 4]. The synergistic integration of nanoscale components with hydrogel matrices enables precise modulation of mechanical properties, degradation behavior, electrical conductivity, therapeutic loading, and biological interactions, thereby expanding their applications in regenerative medicine and tissue engineering [38].

The incorporation of nanoparticles into hydrogel networks provides multiple reinforcement mechanisms through physical interactions, covalent bonding, or supramolecular assembly. Depending on their composition, nanomaterials such as nanosilicates, carbon-based nanomaterials, metallic nanoparticles, hydroxyapatite, polymeric nanoparticles, and bioactive nanocarriers can significantly enhance hydrogel stiffness, toughness, swelling behavior, and structural stability while preserving the hydrated microenvironment required for cellular functions. Gaharwar et al. demonstrated that nanocomposite hydrogels exhibit improved mechanical robustness and tunable physicochemical properties, establishing them as versatile platforms for biomedical applications [38].

Among conductive nanomaterials, carbon nanotubes (CNTs) have attracted considerable attention owing to their exceptional mechanical strength, electrical conductivity, and high aspect ratio. Shin et al. developed carbon nanotube-reinforced hybrid microgels that supported efficient cell encapsulation while simultaneously improving scaffold mechanical integrity and electrical properties. Such conductive nanocomposite hydrogels are particularly attractive for engineering electrically active tissues, including cardiac, skeletal muscle, and neural tissues, where electrical signal transmission plays a critical role in cellular function and tissue maturation [39].

Beyond mechanical reinforcement, nanotechnology has enabled the incorporation of bioinstructive functionalities within hydrogel matrices. Biomimetic nanoparticles engineered to mimic biological membranes or cellular components can actively interact with the host microenvironment, facilitating immune modulation and targeted biological responses. Mo et al. reviewed recent advances in biomimetic nanoparticles, highlighting how biologically inspired nanostructures can interact with the host microenvironment and immune system to enable targeted therapeutic delivery and improved biological responses. These concepts provide valuable design principles for integrating biomimetic nanoparticles into hydrogel platforms for localized tissue regeneration [40].

Nanocomposite hydrogels have also played an increasingly important role in advanced biofabrication. The incorporation of nanomaterials into bioinks enhances rheological properties, print fidelity, structural stability, and post-printing mechanical performance, thereby facilitating the fabrication of complex tissue constructs with improved cellular support. Zhang et al. reviewed recent advances in three-dimensional bioprinting, highlighting the importance of bioink design, structural fidelity, and material properties for fabricating functional tissue constructs. The incorporation of nanomaterials into bioinks has further enhanced rheological performance, print fidelity, and mechanical stability, thereby facilitating the fabrication of increasingly complex engineered tissues [41].

Recent advances have further expanded the functional capabilities of nanocomposite hydrogels through the incorporation of stimulus-responsive nanomaterials. Ultrasound-responsive nanoparticles embedded within hydrogel matrices enable non-invasive, spatiotemporally controlled activation of therapeutic release and hydrogel function. Sun et al. reviewed recent advances in ultrasound-responsive smart implantable hydrogels, highlighting their ability to enable non-invasive, spatiotemporally controlled therapeutic delivery through externally applied ultrasound. Such systems illustrate how physical stimuli can be harnessed to improve treatment precision while minimizing off-target effects [42].

Polymeric nanoparticles have also become valuable functional components of nanocomposite hydrogels due to their high drug-loading capacity, controlled degradation, and excellent biocompatibility. Dartora et al. developed thermosensitive polymeric nanoparticles capable of co-delivering multiple therapeutic agents while responding to temperature-dependent physiological changes. The integration of such smart nanoparticles into hydrogel matrices offers opportunities to engineer multifunctional scaffolds with programmable therapeutic release, enhanced stability, and improved treatment efficacy [43].

Nanocomposite hydrogels integrate the favorable biological characteristics of hydrated polymer networks with the unique physicochemical properties of nanomaterials, resulting in multifunctional biomaterials with superior mechanical performance, biological activity, and environmental responsiveness. These advances have established nanocomposite hydrogels as a versatile platform for regenerative medicine, while also providing the foundation for subsequent developments in bioactive scaffolds, advanced biofabrication, and controlled therapeutic delivery, which are discussed in the following sections [38,39,40,41,42,43].

3.4. Bioactive and Biomimetic Hydrogels

The evolution of hydrogel engineering has progressively shifted from developing passive structural scaffolds to designing bioactive and biomimetic matrices that actively regulate cellular behavior. Native extracellular matrix (ECM) is a highly dynamic and heterogeneous microenvironment that provides not only structural support but also biochemical and biomechanical cues governing cell adhesion, migration, proliferation, differentiation, and tissue remodeling [Figure 5]. Consequently, considerable efforts have been devoted to engineering hydrogels capable of recapitulating these ECM functions to promote functional tissue regeneration [44,45,46,47,48,49].

One of the earliest demonstrations of the importance of cell–matrix interactions was provided by Huebsch et al., who showed that stem-cell fate is regulated by traction-mediated interactions between cells and their surrounding matrix rather than solely by matrix stiffness. Their findings established that cells actively sense and remodel their microenvironment through mechanical feedback, fundamentally changing the design principles of regenerative biomaterials from static supports to dynamic, cell-responsive matrices [44].

Building upon these concepts, hydrogels with precisely tunable physicochemical properties have enabled more accurate control over cellular behavior. Caliari and Burdick provided a practical framework for designing hydrogel-based cell culture systems with independently tunable biochemical and mechanical properties, highlighting how matrix composition, stiffness, and biochemical cues can be systematically engineered to regulate cell adhesion, spreading, proliferation, and differentiation [45].

In addition to matrix stiffness, recent studies have highlighted the critical role of viscoelasticity in directing cellular responses. Unlike conventional elastic substrates, native tissues exhibit time-dependent mechanical relaxation that influences mechanotransduction and cellular remodeling. Chaudhuri et al. demonstrated that hydrogels with tunable stress-relaxation behavior significantly enhance cell spreading, proliferation, and osteogenic differentiation, revealing that stress relaxation represents an independent mechanical regulator of stem-cell fate. These findings emphasized that mimicking the viscoelastic nature of native tissues is essential for designing biomimetic hydrogels capable of supporting long-term tissue regeneration [46] .

The dynamic reciprocity between cells and the surrounding matrix has further expanded the understanding of biomimetic scaffold design. Loebel et al. demonstrated that mesenchymal stromal cells actively deposit and remodel nascent extracellular proteins within hydrogel matrices, thereby generating local microenvironments that subsequently regulate mechanosensing and cell function. This study highlighted that successful biomimetic hydrogels should not only mimic native ECM at implantation but also support continuous matrix remodeling and reciprocal cell–matrix interactions during tissue regeneration [47].

Natural ECM-derived polymers remain among the most widely investigated materials for constructing bioactive hydrogels because of their inherent biological recognition motifs and favorable interactions with cells. Among these, collagen and hyaluronic acid have received particular attention owing to their structural and biological relevance in connective tissues. Xu et al. comprehensively summarized the development of collagen- and hyaluronic acid-based biomimetic hydrogels, emphasizing their ability to reproduce native extracellular matrix architecture, facilitate cell adhesion, promote tissue-specific differentiation, and enhance regenerative outcomes across multiple tissue types [48].

More recently, advances in collagen engineering have enabled the development of hydrogels with highly tunable biochemical and mechanical properties that more closely resemble native tissue microenvironments. More recently, Liu et al. developed tunable blended collagen I/II and collagen I/III hydrogels that closely mimic native tissue microenvironments by allowing precise control over matrix composition, stiffness, and microstructure. These collagen-based tissue mimics provide physiologically relevant platforms for investigating cell–matrix interactions and advancing regenerative medicine applications [49].

Collectively, bioactive and biomimetic hydrogels have transformed hydrogel design from passive structural materials into dynamic, cell-instructive microenvironments that closely emulate the biochemical, structural, and mechanical characteristics of native extracellular matrix. By integrating biologically relevant signaling cues with tunable mechanical properties and supporting continuous cell-mediated matrix remodeling, these advanced hydrogel systems provide an important foundation for the development of next-generation regenerative therapies.

3.5. 3d Bio-Printable Hydrogels

Three-dimensional (3D) bioprinting has emerged as one of the most transformative technologies in regenerative medicine by enabling the precise spatial deposition of cells, biomaterials, and bioactive molecules to fabricate patient-specific tissue constructs. Central to this technology are hydrogel-based bioinks, which provide a hydrated and biomimetic microenvironment that supports cell viability while maintaining the structural integrity of printed constructs. Over the past decade, significant advances in hydrogel engineering have enabled the development of bioinks with tunable rheological, mechanical, and biological properties, substantially improving the fidelity and functionality of bioprinted tissues [50,51,52,53,54,55].

Hydrogels intended for bioprinting must satisfy a unique combination of physicochemical requirements. Ideal bioinks should exhibit appropriate viscosity, shear-thinning behavior, rapid gelation, shape fidelity, and sufficient mechanical stability while simultaneously preserving high cell viability during the printing process [Figure 6]. Furthermore, bioinks should provide a biomimetic extracellular matrix (ECM)-like environment that promotes cell adhesion, proliferation, differentiation, and tissue maturation following fabrication [52].

Early developments in 3D bioprinting established the feasibility of fabricating living tissues using hydrogel-based bioinks. Murphy and Atala highlighted the potential of combining additive manufacturing with cell-laden hydrogels to produce anatomically relevant tissue constructs with controlled architecture and cellular organization, establishing the conceptual framework for modern bioprinting technologies [55].

A major breakthrough in hydrogel bioprinting was achieved through the development of Freeform Reversible Embedding of Suspended Hydrogels (FRESH), which enabled the printing of soft and mechanically weak hydrogel bioinks within a temporary support bath. Hinton et al. demonstrated that this strategy dramatically improved printing resolution and structural complexity while preserving the viability of encapsulated cells, thereby overcoming one of the principal limitations associated with conventional hydrogel bioprinting [50].

One of the greatest challenges in engineering clinically relevant tissues is the fabrication of functional vascular networks capable of supporting nutrient transport and waste removal. Kolesky et al. addressed this challenge by developing bioprinted vascularized tissue constructs containing interconnected perfusable channels, demonstrating that precise spatial patterning of multiple bioinks can recreate complex vascular architectures required for tissue survival and maturation [51].

Subsequent advances further expanded the complexity of engineered vascular systems. Grigoryan et al. fabricated multivascular networks with highly sophisticated intravascular topologies embedded within biocompatible hydrogel matrices, enabling improved fluid transport and tissue perfusion. Similarly, Skylar-Scott et al. developed organ-specific tissue constructs containing embedded vascular channels through advanced biomanufacturing strategies, highlighting the growing capability of hydrogel-based bioprinting to generate increasingly complex and physiologically relevant tissue architectures [53,54].

Alongside advances in printing technologies, substantial progress has been made in the development of next-generation bioinks. Chimene et al. comprehensively described the evolution of advanced hydrogel bioinks incorporating dynamic crosslinking chemistries, nanomaterials, growth factors, and extracellular matrix-derived components to improve printability, mechanical performance, and biological functionality. These multifunctional bioinks enable precise control over cellular organization while providing favorable biochemical and mechanical cues that promote tissue maturation after printing [52].

Despite remarkable progress, several challenges continue to limit the widespread clinical translation of hydrogel-based bioprinting. Achieving the optimal balance between printability, mechanical strength, degradation kinetics, and long-term biological functionality remains a significant obstacle. In addition, the fabrication of large-scale vascularized tissues, integration with host vasculature, and standardization of bioink formulations continue to be active areas of investigation [52].

Overall, the convergence of advanced hydrogel engineering with three-dimensional bioprinting technologies has revolutionized the fabrication of biomimetic tissue constructs. Continuous innovations in bioink design, printing strategies, and vascularization technologies are bringing the field closer to the realization of functional tissue substitutes for regenerative medicine, disease modeling, and personalized therapeutic applications.

4. Hydrogels in Drug Delivery

4.1. Cancer Therapy

Cancer remains one of the leading causes of mortality worldwide, and the efficacy of conventional chemotherapy is often limited by poor drug bioavailability, rapid systemic clearance, off-target toxicity, and the heterogeneous nature of the tumor microenvironment. Hydrogel-based drug delivery systems have emerged as promising platforms for overcoming these challenges by providing localized, sustained, and stimuli-responsive release of therapeutic agents directly at the tumor site. The high water content, tunable network architecture, and excellent biocompatibility of hydrogels enable efficient encapsulation of chemotherapeutics, proteins, antibodies, nucleic acids, and nanomedicines while minimizing systemic exposure and associated adverse effects [Figure 7] [66,67,68].

One of the principal advantages of hydrogel-based cancer therapy is localized drug retention. Following implantation or injection, hydrogels form drug depots that maintain high local concentrations of therapeutics over extended periods while reducing systemic toxicity. Xu et al. developed an injectable nanoparticle generator capable of producing drug-loaded nanoparticles in situ following hydrogel administration. This strategy significantly enhanced intratumoral drug retention and penetration, resulting in improved therapeutic efficacy compared with conventional systemic administration [56].

The unique biochemical characteristics of the tumor microenvironment have further enabled the development of stimuli-responsive hydrogel delivery systems. Tumors typically exhibit elevated levels of reactive oxygen species (ROS), acidic pH, hypoxia, and overexpressed enzymes, all of which can be exploited to achieve site-specific drug release. Wang et al. designed an in situ-forming ROS-responsive hydrogel scaffold incorporating gemcitabine together with an immune checkpoint inhibitor. The scaffold selectively released therapeutic agents within the oxidative tumor microenvironment while simultaneously inducing immunogenic cell death and enhancing antitumor immune responses, demonstrating the therapeutic potential of combining chemotherapy with immunotherapy through hydrogel-based delivery [57].

Recent advances have also focused on combination therapies that simultaneously modulate multiple aspects of tumor progression. Recent advances have increasingly focused on multifunctional hydrogel platforms capable of integrating chemotherapy, immunotherapy, gene therapy, and stimuli-responsive drug release. Tian et al. comprehensively reviewed recent progress in hydrogel-based drug delivery systems for enhanced tumor therapy, highlighting how localized and controlled therapeutic delivery can improve antitumor efficacy while minimizing systemic toxicity through combination treatment strategies [58]. By maintaining prolonged local release and reducing systemic immune-related toxicity, hydrogel-mediated co-delivery significantly enhanced antitumor efficacy, highlighting the growing importance of biomaterial-assisted cancer immunotherapy [58,59].

Hydrogels have also been successfully integrated with externally activated therapeutic modalities. Chen et al. developed an injectable hydrogel platform for synergistic photothermal-immunotherapy in which localized photothermal treatment not only induced direct tumor ablation but also promoted the release of tumor-associated antigens that enhanced immune activation. The sustained release of immunomodulatory agents from the hydrogel further amplified systemic antitumor immunity, illustrating the potential of multifunctional hydrogel systems for combination cancer therapies [60].

Although primarily developed for diabetes management, the work of Yu et al. demonstrated the remarkable versatility of hydrogel-based controlled drug delivery by engineering microneedle-array patches containing hypoxia-sensitive vesicles for rapid, glucose-responsive insulin release. This study established the feasibility of integrating environmental sensing with programmable therapeutic release, providing important design principles that have subsequently influenced the development of responsive hydrogel platforms for localized cancer therapy and other precision medicine applications [59].

Despite substantial progress, several challenges remain before hydrogel-based cancer therapeutics achieve widespread clinical adoption. These include achieving precise control over drug-release kinetics, improving penetration within dense tumor tissues, overcoming patient-to-patient variability in the tumor microenvironment, and ensuring scalable manufacturing and regulatory compliance. Continued advances in smart biomaterials, immunomodulatory strategies, and combination therapies are expected to further enhance the therapeutic potential of hydrogel-based drug delivery systems.

Overall, hydrogel-based platforms have transformed localized cancer therapy by enabling sustained and stimuli-responsive drug release, improving intratumoral drug retention, and facilitating multimodal therapeutic strategies. The integration of chemotherapy, immunotherapy, and externally triggered treatments within multifunctional hydrogel systems offers considerable promise for the development of safer and more effective cancer therapeutics.

4.2. Antimicrobial Delivery

Microbial infection remains a major obstacle in wound management and regenerative therapies, often leading to delayed healing, chronic inflammation, and increased risk of systemic complications. Conventional administration of antibiotics is frequently associated with poor drug penetration, rapid clearance, repeated dosing, and the emergence of antimicrobial resistance. Hydrogel-based antimicrobial delivery systems have attracted considerable attention as localized therapeutic platforms capable of maintaining high concentrations of antimicrobial agents directly at the wound site while minimizing systemic toxicity. Their hydrated three-dimensional network, high loading capacity, and tunable release characteristics enable sustained delivery of antibiotics, antimicrobial peptides, metal nanoparticles, and bioactive molecules while simultaneously providing a moist microenvironment conducive to wound repair [Figure 8] [61,62,63,64].

Recent advances in hydrogel engineering have enabled the development of multifunctional antimicrobial dressings that combine infection control with additional therapeutic functions, including hemostasis, inflammation modulation, oxygen permeability, and moisture retention. Zhu et al. comprehensively reviewed antibacterial hydrogels designed for wound dressing applications, highlighting strategies such as the incorporation of antibiotics, silver nanoparticles, antimicrobial peptides, chitosan derivatives, and stimuli-responsive antimicrobial agents to achieve effective eradication of pathogenic microorganisms while reducing bacterial resistance [61].

Injectable antimicrobial hydrogels further expand the therapeutic potential of localized drug delivery by allowing minimally invasive administration to irregular wound sites. Liang et al. developed an injectable antimicrobial conductive hydrogel that combined antibacterial activity, electrical conductivity, and favorable mechanical properties. The hydrogel effectively inhibited bacterial growth while providing a supportive microenvironment for tissue repair, demonstrating the advantages of multifunctional injectable hydrogels for complex wound management [62].

In addition to antimicrobial activity, effective wound dressings must maintain stable contact with dynamic biological tissues. Bioinspired adhesive hydrogels have therefore emerged as an important class of wound-care materials capable of conforming to irregular tissue surfaces while ensuring prolonged therapeutic retention. Blacklow et al. developed mechanically active adhesive dressings inspired by biological systems that actively promoted wound closure through controlled mechanical contraction. This innovative strategy demonstrated that hydrogel dressings can provide not only localized drug delivery but also mechanical stimulation that accelerates tissue repair [63].

Building upon bioinspired adhesive designs, Qu et al. developed an injectable antibacterial adhesive hydrogel with rapid self-healing, extensibility, and strong wet-tissue adhesion. The hydrogel effectively prevented bacterial colonization while maintaining intimate contact with the wound surface, thereby improving therapeutic efficacy and promoting wound healing. Such multifunctional adhesive hydrogels represent a promising strategy for enhancing localized antimicrobial delivery in challenging wound environments [65].

Beyond infection control, hydrogel-based wound dressings increasingly incorporate bioactive functionalities that regulate multiple stages of the healing process. Liang et al. summarized the development of functional hydrogels capable of simultaneously delivering antimicrobial agents, anti-inflammatory molecules, growth factors, and antioxidants to modulate the wound microenvironment. By integrating controlled therapeutic release with favorable physicochemical properties such as moisture retention, gas permeability, and biodegradability, these multifunctional hydrogel systems provide comprehensive support for wound management while reducing the likelihood of chronic infection [61,62].

Despite significant progress, several challenges remain before antimicrobial hydrogel delivery systems achieve widespread clinical implementation. Long-term antimicrobial efficacy, prevention of bacterial biofilm formation, controlled degradation, large-scale manufacturing, and minimizing the emergence of antimicrobial resistance continue to be important considerations in material design. Future hydrogel platforms are expected to integrate smart responsive release mechanisms, broad-spectrum antimicrobial agents, and real-time monitoring capabilities to enable more effective and personalized infection management.

Overall, hydrogel-based antimicrobial delivery systems have evolved from passive wound dressings into multifunctional therapeutic platforms capable of localized antimicrobial release, infection control, and modulation of the wound microenvironment. Continued advances in bioactive hydrogel design are expected to further improve clinical outcomes while addressing the growing global challenge of antimicrobial resistance.

4.3. Gene and Nucleic Acid Delivery

Hydrogels have emerged as versatile platforms for the localized and sustained delivery of nucleic acids, addressing key limitations of systemic administration such as rapid clearance, off-target effects, and poor tissue penetration. Their tunable porosity, biodegradability, and capacity for stimuli-responsive release make them particularly suited to protecting labile cargos like mRNA, siRNA, and CRISPR/Cas9 components while enabling controlled, site-specific expression [Figure 9][66,67,68,69,70].

A prominent application is cancer immunotherapy, Zheng et al. synthesized a bioactive vitamin E-based ionizable lipid to formulate lipid nanoparticles co-loaded with IL-12 mRNA and the IDO1 inhibitor NLG919 (N@VEBLNP), which were subsequently embedded into polyether F127-diacrylate hydrogel (NVF Gel). This hydrogel enables thermosensitive gelation for intratumoral injection and photocrosslinkable curing for postoperative site retention in the treatment of triple-negative breast cancer (TNBC) [66]. Beyond immunomodulation, hydrogels have also been engineered as delivery platforms for genome-editing and gene-silencing therapeutics. Chen et al. developed liposome-templated hydrogel nanoparticles for targeted CRISPR/Cas9-mediated cancer gene therapy, demonstrating localized delivery of genome-editing components [67]. Likewise, Wang et al. reported sustained hydrogel-mediated delivery of siRNA nanoparticles that accelerated bone fracture healing through prolonged gene silencing, illustrating the versatility of hydrogel platforms for localized nucleic acid therapeutics [68].

Tissue regeneration represents another important application area. Wang et al. demonstrated that sustained hydrogel-mediated delivery of siRNA nanoparticles enhanced bone regeneration by prolonging local gene silencing during fracture healing [68]. Complementing this strategy, Fu et al. developed a pH-responsive DNA nanohydrogel for mRNA delivery that protected labile mRNA cargo while enabling controlled intracellular release, highlighting the expanding role of hydrogels in regenerative nucleic acid therapy [69].

Emerging directions include integrating stimuli-responsive release mechanisms with nanomaterial-assisted CRISPR delivery strategies and multifunctional hydrogel platforms for precision gene therapy applications [70].

Collectively, these studies highlight a shared design principle: hydrogels serve as protective, localized reservoirs that convert transient nucleic acid cargos into sustained, spatially confined therapeutic signals. This is particularly valuable for nucleic acid therapeutics, which are otherwise vulnerable to nuclease degradation and rapid diffusion away from the target site. Emerging directions in this area include combining stimuli-responsiveness (e.g., enzymatic, pH-, or thermally triggered release) with cell-specific targeting ligands, as well as integrating multiple nucleic acid types (e.g., mRNA and siRNA) within a single hydrogel matrix to enable combinatorial gene therapy and editing strategies.

4.4. Protein and Growth Factor Delivery

Growth factors are among the most extensively studied hydrogel-delivered therapeutics, owing to their central role in regeneration, angiogenesis, and wound repair. However, their clinical translation is often hampered by short biological half-lives, rapid diffusion from the site of injury, and the need for precise, dose-controlled exposure. Hydrogels address these challenges by acting as protective reservoirs that sequester proteins from proteolytic degradation and release them in a sustained, spatially confined manner that mimics native signaling kinetics [Figure 10][71,72,73,74,75].

In bone tissue engineering, Chen et al. developed a composite hydrogel enabling spatiotemporal and controlled delivery of genetically engineered BMP-2, resulting in enhanced bone regeneration while reducing the limitations associated with conventional growth factor administration [71]. In parallel, strategies to promote vascularization have employed injectable nanocomposite hydrogels for the localized delivery of pro-angiogenic cues. Ono et al. demonstrated that the combined delivery of deferoxamine (DFO) and vascular endothelial cells from biodegradable nanocomposite hydrogels significantly enhanced angiogenesis, thereby addressing a critical challenge in tissue regeneration [72].

Recognizing that many regenerative processes require the coordinated action of multiple signaling cues, He et al. developed a gene-activated matrix incorporating peptide-modified nanoparticles for the spatiotemporal delivery of pBMP2 and pVEGF, enabling coordinated osteogenesis and angiogenesis during bone defect repair [73]. In the context of wound healing, Xiao et al. reported a zwitterionic hydrogel capable of sustained growth factor release to enhance tissue repair, while Zhang et al. engineered a wound microenvironment-responsive protein hydrogel that combined controlled therapeutic delivery with antibacterial activity to accelerate healing [74,75].

Together, these studies establish hydrogels as a robust platform for growth factor delivery, capable of extending therapeutic half-life, enabling localized bioactivity, and supporting multi-factor release schemes that better recapitulate the complex signaling environments of native tissue repair. Future work in this space is likely to focus on precisely tuning release kinetics to match the temporal dynamics of specific regenerative processes, as well as integrating growth factor delivery with cell-laden or bioprinted hydrogel constructs for more complex tissue-engineering applications.

5. Hydrogels in Regenerative Medicine

5.1. Bone Regeneration

Bone possesses an intrinsic capacity for self-repair; however, large bone defects resulting from trauma, tumor resection, congenital abnormalities, or degenerative diseases often exceed its natural regenerative potential. Although autografts remain the clinical gold standard for bone reconstruction, their application is limited by donor-site morbidity, restricted availability, and prolonged surgical procedures. Consequently, hydrogel-based biomaterials have emerged as promising alternatives capable of providing a biomimetic extracellular matrix (ECM), supporting cellular activities, and promoting new bone formation through the controlled presentation of biochemical and mechanical cues [Figure 11][76,77,78,79].

An ideal hydrogel for bone regeneration should not only provide structural support but also actively regulate osteogenesis by facilitating cell adhesion, proliferation, migration, and differentiation while gradually degrading in concert with new tissue formation. Recent advances in regenerative engineering have enabled the development of multifunctional hydrogel platforms that integrate bioactive molecules, stem cells, and inorganic nanomaterials to better replicate the native bone microenvironment. Gaharwar et al. highlighted how nanocomposite hydrogels combine the favorable biological properties of hydrated polymer networks with mechanically reinforcing nanomaterials to generate osteoconductive and osteoinductive scaffolds capable of enhancing bone regeneration [76].

The incorporation of bioactive nanomaterials has further expanded the regenerative capacity of hydrogel scaffolds. Nanoparticles such as hydroxyapatite, bioactive glass, nanosilicates, and calcium phosphate closely mimic the mineral phase of native bone, providing structural reinforcement while simultaneously stimulating osteogenic differentiation. Bose et al. comprehensively reviewed the integration of hydrogels with nanomaterials for bone tissue engineering, emphasizing that these hybrid systems improve mechanical performance, facilitate mineral deposition, and create favorable microenvironments for bone regeneration [79].

Recent advances in hydrogel engineering have enabled the development of biomimetic hydrogel scaffolds with tunable mechanical properties, bioactive functionalities, and enhanced cellular interactions. Zhang and Khademhosseini reviewed engineering strategies for advanced hydrogels, highlighting how rationally designed hydrogel systems can provide spatial control over tissue architecture while promoting osteogenic differentiation and extracellular matrix formation for bone regeneration [78].

Controlled delivery of osteogenic cues remains one of the most effective strategies for enhancing bone repair. Zhou et al. developed injectable biomimetic porous hydrogels that combined shape-adaptable scaffolds with controllable magnesium ion (Mg²⁺) release to stimulate osteogenic differentiation and accelerate bone regeneration. The multifunctional hydrogel provided prolonged local bioactivity while improving defect healing, demonstrating the importance of hydrogel-mediated therapeutic delivery in regenerative bone engineering [80].

Hydrogels have also become valuable platforms for stem cell-based bone regeneration by providing a supportive three-dimensional microenvironment that preserves cell viability and regulates lineage-specific differentiation. Zhang et al. developed an injectable stem-cell-laden hydrogel for craniofacial bone regeneration that promoted efficient cell survival, osteogenic differentiation, and bone defect repair. The hydrogel served as both a protective carrier and an instructive matrix, facilitating localized stem cell delivery while supporting tissue remodeling within the defect site [77].

Despite remarkable progress, several challenges continue to hinder the clinical translation of hydrogel-based bone regenerative therapies. Achieving sufficient mechanical strength for load-bearing applications, ensuring controlled degradation synchronized with new bone formation, promoting rapid vascularization, and standardizing scalable manufacturing remain important areas of ongoing investigation. Future hydrogel systems are expected to integrate advanced biomaterials, intelligent therapeutic delivery, and patient-specific biofabrication strategies to further improve functional bone regeneration.

Overall, hydrogel-based scaffolds have evolved from passive structural matrices into multifunctional regenerative platforms capable of directing osteogenesis through the coordinated presentation of biochemical, mechanical, and cellular cues. Their ability to support stem cells, deliver osteogenic factors, and recreate biomimetic bone microenvironments positions hydrogels as a key technology for next-generation bone tissue engineering and regenerative medicine.

5.2. Cartilage Regeneration

Articular cartilage is a highly specialized connective tissue that provides a smooth, lubricated surface for joint movement while distributing mechanical loads across articulating bones. Owing to its avascular, aneural, and alymphatic nature, cartilage possesses an extremely limited intrinsic capacity for self-repair following injury or degeneration [Figure 12]. Consequently, cartilage defects often progress to osteoarthritis, resulting in chronic pain and impaired joint function. Conventional clinical treatments, including microfracture, autologous chondrocyte implantation, and osteochondral grafting, frequently produce fibrocartilage rather than native hyaline cartilage and are associated with inconsistent long-term outcomes. Hydrogel-based scaffolds have therefore emerged as promising biomaterials for cartilage regeneration by recreating the native extracellular matrix (ECM) environment and supporting chondrogenic tissue formation [81,82,83].

Hydrogels are particularly well suited for cartilage tissue engineering because of their high water content, viscoelastic properties, and structural similarity to the cartilage ECM, which is rich in collagen and glycosaminoglycans. These characteristics enable hydrogels to provide a three-dimensional microenvironment that supports chondrocyte survival, extracellular matrix deposition, and stem cell chondrogenesis while maintaining the mechanical integrity required for joint function. Levett et al. highlighted the versatility of hydrogel-based scaffolds for cartilage tissue engineering, emphasizing the importance of biomaterial composition, mechanical properties, and degradation behavior in promoting functional cartilage repair [82].

Recent advances in regenerative engineering have focused on developing hydrogels that actively regulate the cartilage repair process rather than serving solely as passive structural matrices. Huey et al. comprehensively reviewed emerging strategies in cartilage tissue engineering, demonstrating that successful regeneration requires the integration of biomimetic scaffolds with appropriate cellular components, biochemical signaling molecules, and biomechanical stimulation to recapitulate the complex native cartilage microenvironment [81].

Localized delivery of cells within hydrogel matrices has shown considerable promise for improving cartilage regeneration.

Inflammation within the joint microenvironment represents another major obstacle to successful cartilage repair, particularly in degenerative diseases such as osteoarthritis. Biomaterials capable of modulating inflammatory responses while supporting tissue regeneration are therefore receiving increasing attention. Nguyen et al. reported chondroitin sulfate–hyaluronic acid hydrogels that not only mimic key biochemical components of native cartilage ECM but also suppress inflammatory responses, creating a more favorable environment for cartilage regeneration. The incorporation of naturally occurring glycosaminoglycans further enhanced the biological functionality of the hydrogel by promoting cartilage-specific cellular activities [83].

Liu et al. developed an injectable self-healing hydrogel capable of conforming to irregular cartilage defects while providing a supportive microenvironment for cell survival and matrix formation. In preclinical models, the hydrogel promoted chondrogenic differentiation and enhanced defect repair, demonstrating the therapeutic potential of adaptable hydrogel scaffolds for minimally invasive cartilage regeneration [84].

Advances in hydrogel-based biofabrication have further improved the ability to engineer anatomically relevant cartilage constructs. Daly et al. developed developmentally inspired hydrogel templates for three-dimensional bioprinting that reproduce the spatial organization and structural complexity of native cartilage tissue. By combining biomimetic hydrogel bioinks with precise architectural control, these engineered constructs provide enhanced support for chondrogenesis and the formation of functional cartilage-like tissue [85].

Despite significant progress, several challenges continue to limit the clinical translation of hydrogel-based cartilage regeneration. Achieving long-term mechanical durability, reproducing the zonal organization of native cartilage, ensuring seamless integration with surrounding tissues, and maintaining stable hyaline cartilage formation remain important research priorities. Future strategies are expected to integrate advanced biomaterials, stem cell engineering, immunomodulatory approaches, and biofabrication technologies to generate more durable and functional cartilage replacements.

Overall, hydrogel-based scaffolds have become indispensable platforms for cartilage tissue engineering by providing biomimetic microenvironments that support chondrogenesis, regulate inflammation, and promote extracellular matrix formation. Continued advances in hydrogel design and regenerative engineering are expected to accelerate the development of clinically effective therapies for cartilage repair and the treatment of degenerative joint diseases.

5.3. Skin and Wound Regeneration

Skin and wound regeneration presents a uniquely demanding set of requirements for hydrogel design, as an ideal dressing must simultaneously provide a moist healing environment, mechanical conformability to irregular wound geometries, protection against infection, and active biochemical cues to accelerate tissue closure [Figure 13]. Multifunctional hydrogels engineered to meet these combined demands have shown promise, especially for chronic and complicated wounds such as those associated with diabetes [86].

Liang et al. (2019) developed a mussel-inspired, antibacterial, conductive, antioxidant, injectable composite hydrogel wound dressing that simultaneously combated infection while promoting skin regeneration through electrical and antioxidant cues that enhance cell migration, proliferation, and tissue repair [87].

Complementing this, Qu et al. (2018) developed injectable antibacterial conductive hydrogels capable of localized smart drug release in response to electrical stimulation and pH while simultaneously promoting skin wound repair, illustrating how conductive hydrogel matrices can enhance regenerative signaling and therapeutic efficacy [88].

Adhesion and ease of application are also critical for clinical usability. Dong and Guo comprehensively reviewed smart wound dressings incorporating bioinspired adhesive hydrogels, stimuli-responsive materials, and multifunctional therapeutic systems, highlighting their ability to maintain intimate contact with dynamic wound surfaces while providing localized therapeutic delivery and promoting tissue regeneration [89]. Building on the need for user-friendly application, Zhang et al. (2023) developed sprayable alginate hydrogel dressings incorporating oxygen-generating components and therapeutic exosomes for diabetic wound treatment. The sprayable formulation enabled rapid, conformal coverage of irregular wound beds while simultaneously enhancing angiogenesis and tissue regeneration [90].

Diabetic wounds, characterized by excessive oxidative stress and impaired angiogenesis, have prompted the development of redox-modulating hydrogels. Li et al. engineered a nanozyme-immobilized hydrogel with endogenous ROS-scavenging and oxygen-generation capabilities that significantly promoted diabetic wound healing by reducing oxidative damage while simultaneously improving tissue oxygenation and regeneration [91].

Collectively, these studies illustrate a shift toward hydrogels that integrate multiple functionalities, antibacterial activity, adhesion, conductivity, and stimuli-responsiveness, within a single platform to address the multifactorial challenges of wound healing. This convergence is especially impactful for diabetic and chronic wounds, where impaired vascularization and susceptibility to infection often render conventional therapies insufficient. Future directions in this area are likely to emphasize smart, environment-sensing hydrogels capable of real-time monitoring and on-demand therapeutic release throughout the phases of wound healing.

5.4. Neural Regeneration

Neural tissue poses one of the most formidable challenges for regenerative engineering, given the limited intrinsic regenerative capacity of the central nervous system, the complex electrophysiological signaling that underlies neuronal function, and the inhibitory microenvironment that forms following injury, particularly in spinal cord damage. Hydrogel platforms designed for neural regeneration have therefore increasingly focused on recapitulating the native bioelectric and biomechanical properties of neural tissue while providing a supportive scaffold for cell survival and axonal growth [Figure 14].

Electrical conductivity has emerged as a central design feature, given the intrinsically electroactive nature of neuronal communication. Liu et al. (2024) developed a microenvironment-responsive injectable conductive hydrogel for spinal cord injury repair. By responding to the post-injury microenvironment while providing electrical conductivity, the hydrogel promoted neural tissue repair and functional recovery, demonstrating the therapeutic value of intelligent conductive biomaterials for spinal cord regeneration [92].

Recent reviews have further emphasized the importance of electroconductive hydrogels for neural regeneration. Ndzi et al. comprehensively summarized advances in conductive hydrogel design for spinal cord injury repair, highlighting how electrically conductive biomaterials provide permissive microenvironments that support neuronal survival, axonal extension, and functional recovery while discussing current challenges for clinical translation [93]. Xuan et al. (2023) engineered a bioinspired self-healing conductive hydrogel that combined electrical conductivity with excellent mechanical resilience, effectively supporting peripheral nerve regeneration under dynamic physiological conditions [94]. Gao et al. (2024) further enhanced peripheral nerve regeneration by developing a biomimetic silk fibroin hydrogel incorporating graphene oxide and fibroblast-derived exosomes. The synergistic combination of conductive nanomaterials and biologically active exosomes significantly improved the regenerative microenvironment and promoted functional nerve repair [95].

Beyond conductive signaling, extracellular matrix-inspired hydrogels have further improved spinal cord repair. Yao et al. (2022) developed an injectable, self-healing, electroconductive extracellular matrix-based hydrogel that enhanced tissue repair following traumatic spinal cord injury by providing both structural support and bioelectrical cues favorable for neural regeneration [96].

Collectively, these studies underscore the importance of electroconductive and self-healing properties in hydrogels designed for neural applications, reflecting a broader strategy of engineering biomaterials that not only provide structural support but also actively participate in the electrophysiological signaling essential to neural repair. The convergence of conductivity, biomimicry, and stem-cell compatibility observed across spinal cord and peripheral nerve studies points toward future hydrogel systems that integrate multimodal cues, electrical, topographical, and biochemical, to more effectively guide axonal regeneration and functional recovery in both central and peripheral nervous system injuries.

5.5. Cardiac Regeneration

Cardiac tissue engineering demands biomaterials capable of matching the unique mechanical and electrophysiological properties of the myocardium, as the heart's continuous contractile activity and reliance on synchronized electrical conduction impose stringent requirements beyond those of most other regenerative applications. Following myocardial infarction, the loss of functional cardiomyocytes and subsequent fibrotic remodelling further necessitate biomaterials that can be delivered with minimal invasiveness while actively supporting tissue repair and electrical integration [Figure 15].

Minimally invasive delivery strategies have been foundational to this field. Rodell et al. developed injectable shear-thinning hydrogels capable of being delivered via catheter to infarcted myocardium, establishing an important precedent for minimally invasive hydrogel therapies that avoid the need for open-chest surgical implantation [97]. Building on this therapeutic foundation, Traverse et al. (2019) demonstrated in a translational study that hydrogel therapy for myocardial infarction could improve ventricular remodeling, providing clinically meaningful evidence that hydrogel-based interventions can mitigate the adverse structural changes that follow cardiac injury [98].

Given the heart's dependence on coordinated electrical signaling, conductive hydrogel systems have emerged as a particularly promising strategy for restoring functional connectivity within damaged myocardium. Kong et al. (2023) developed an extracellular matrix/glycopeptide hybrid hydrogel that created an immunomodulatory niche capable of promoting endogenous cardiac repair following myocardial infarction. By regulating inflammatory responses while providing a biomimetic extracellular matrix, the hydrogel significantly enhanced myocardial regeneration [99]. Conductive hydrogel systems continue to play an important role in restoring electrical integration within damaged myocardium. Zhang et al. (2024) developed an injectable conductive hydrogel capable of dual-responsive release of rosmarinic acid, which improved cardiac function after myocardial infarction by simultaneously providing electrical conductivity, controlled therapeutic release, and anti-inflammatory activity [100].

Beyond mechanical support, hydrogels have also been engineered to actively regulate the oxidative microenvironment after myocardial infarction. Wang et al. demonstrated that a myocardial extracellular matrix hydrogel functions as a reactive oxygen species scavenger while simultaneously supporting a proliferative microenvironment for cardiomyocytes, thereby enhancing endogenous cardiac repair following ischemic injury [101].

Collectively, these studies trace an evolution in cardiac hydrogel design, from early minimally invasive delivery platforms toward increasingly sophisticated systems that incorporate electrical conductivity and cellular therapeutics to more comprehensively address the structural, electrical, and functional deficits following myocardial infarction. The consistent emphasis on conductivity and injectability across these works underscores the field's recognition that effective cardiac repair requires materials that do more than passively fill tissue defects, but must actively participate in restoring the heart's mechanical and bioelectric function. Future research is likely to focus on further integrating conductive properties with cell and growth factor delivery, as well as improving long-term vascularization and electromechanical coupling between engineered and native cardiac tissue.

5.6. Ocular Regeneration

Ocular tissues present a distinct set of engineering constraints for hydrogel design, demanding optical transparency, precise mechanical compliance, and biocompatibility with highly specialized and sensitive cell populations. Whether targeting the cornea, retina, or ocular surface, hydrogel platforms in this domain must balance structural support with minimal interference in visual function, making transparency and controlled degradation particularly critical design parameters [Figure 16].

Corneal regeneration has been a major focus owing to the cornea's avascular structure and the need to preserve optical clarity. Yazdanpanah et al. (2022) developed a light-curable, tunable extracellular matrix hydrogel that enabled in situ suture-free corneal repair while supporting tissue regeneration and maintaining the optical properties required for normal vision [102]. Complementing this extracellular matrix strategy, Zhou et al. (2021) developed hydrogels derived from acellular porcine corneal stroma that enhanced corneal wound healing by providing a biomimetic microenvironment conducive to epithelial regeneration and stromal repair [103]. Extending hydrogel functionality beyond structural support, Na et al. (2024) engineered a hyaluronic acid hydrogel for the sustained delivery of epidermal growth factor and keratinocyte growth factor. The controlled release of these regenerative cytokines significantly enhanced corneal wound healing while reducing the need for repeated topical administration [104].

Beyond the cornea, hydrogels have also been applied to posterior ocular tissues. Kim et al. (2023) developed an inflammation-responsive hydrogel that protected photoreceptors by attenuating outer retinal degeneration, demonstrating the potential of smart biomaterials to regulate inflammatory processes while preserving retinal function [105].

For ocular surface reconstruction, Liu et al. (2022) developed a semi-interpenetrating polymer network bioadhesive that enabled sutureless transplantation for ocular surface repair. This bioadhesive hydrogel provided strong tissue adhesion while minimizing surgical trauma and improving the efficiency of ocular surface reconstruction [106].

Overall, these studies highlight how hydrogel design for ocular regeneration must simultaneously satisfy optical, mechanical, and biological requirements that are far more stringent than in many other tissue types. The recurring emphasis on transparency, injectability, and sustained localized delivery reflects the unique clinical needs of ocular therapies, where minimally invasive administration and preservation of visual function are paramount. Future directions in this field are likely to focus on multifunctional hydrogels that combine regenerative scaffolding with sustained drug or growth factor delivery, as well as the development of tissue-specific hydrogels tailored to the distinct biomechanical and optical demands of corneal, retinal, and ocular surface regeneration.

5.7. Vascular Regeneration

Vascular regeneration requires biomaterials capable of withstanding hemodynamic mechanical stresses while simultaneously promoting endothelialization, preventing thrombogenesis, and supporting long-term functional remodeling into native-like vessel architecture. Hydrogels engineered for vascular applications have thus evolved toward combining structural reinforcement, biomimetic microarchitecture, and biochemical or mechanobiological cues to address the multifaceted demands of vascular tissue engineering [Figure 17].

Structural and architectural biomimicry has been a key strategy for constructing functional vascular conduits. Tan et al. (2024) developed 3D-printed hydrogels with engineered nanocrystalline domains, achieving mechanically reinforced vascular constructs that maintained excellent perfusion capability and long-term functional stability, thereby addressing the persistent challenge of matching hydrogel mechanics to the burst pressures of native vasculature [107]. Building on architectural design, Ding et al. (2024) engineered biomimetic vascular grafts featuring circumferentially and axially oriented microporous structures that closely replicated native vessel wall organization, promoting endothelialization and supporting long-term vascular remodeling in vivo [108]. Similarly, Geng et al. (2021) introduced hydrogel-integrated electrospun scaffolds that combined the mechanical robustness of electrospun fibers with the bioactivity of hydrogels, enhancing mechanical performance while supporting vascular regeneration in situ [109].

Mechanobiological and growth factor-driven approaches have also enabled more biologically active vascular constructs. Keshavarz et al. (2024) demonstrated that gelatin-based hydrogels could drive endothelial self-assembly and de novo vasculogenesis through a YAP–MMP mechanosignaling axis, revealing how substrate mechanics and matrix remodeling can be harnessed to guide vascular morphogenesis directly, rather than relying solely on exogenous cues [110]. Complementing this mechanobiological strategy, Xu et al. (2023) engineered PEG hydrogels for the sustained release of hepatocyte growth factor (HGF), significantly enhancing endothelial regeneration and neovascularization through prolonged, localized growth factor signaling [111].

Translational graft and patch technologies have further advanced clinical applicability. Sun et al. (2022) developed chitosan–heparin polyelectrolyte multilayer-modified PVA vascular patches built on a decellularized scaffold, achieving improved endothelialization and hemocompatibility, both essential properties for reducing thrombotic risk in vascular repair [112].

Collectively, these studies reflect a convergence of mechanical reinforcement, biomimetic microstructure, and biochemical or mechanosignaling cues in the design of vascular hydrogels, moving beyond passive scaffolding toward materials that actively instruct endothelial behavior and vascular remodeling. Future work in this area is likely to focus on integrating multiscale vascular architecture, from capillary-level porosity to macrovascular mechanical performance, alongside strategies to improve long-term hemocompatibility and anti-thrombogenicity for translation into clinically viable vascular grafts and patches.

6. Clinical Translation and Challenges

Over the past decade, hydrogel-based biomaterials have undergone remarkable evolution, progressing from simple hydrated polymeric networks to multifunctional platforms capable of controlled drug delivery, tissue regeneration, immunomodulation, and advanced biofabrication. Despite these significant scientific advances, the successful translation of hydrogel technologies from laboratory research to routine clinical practice remains limited. Bridging this gap requires not only continued innovation in material design but also the development of robust manufacturing processes, standardized characterization methods, scalable production strategies, and well-defined regulatory pathways [6,83].

One of the primary challenges in clinical translation is the inherent complexity of advanced hydrogel systems. Modern hydrogels frequently incorporate multiple functional components, including nanoparticles, therapeutic agents, growth factors, living cells, and dynamic crosslinking chemistries. While these multifunctional designs substantially improve biological performance, they also increase manufacturing complexity, batch-to-batch variability, and quality-control requirements. Therefore, balancing material sophistication with manufacturing reproducibility remains a critical consideration for successful commercialization [83].

Scalable manufacturing represents another major barrier to clinical implementation. Laboratory-scale fabrication methods often rely on carefully controlled synthesis conditions that are difficult to reproduce during industrial production. Parameters such as polymer molecular weight, crosslinking density, gelation kinetics, mechanical properties, degradation rate, and therapeutic loading must be consistently maintained to ensure product quality and clinical reliability. Establishing standardized manufacturing protocols and Good Manufacturing Practice (GMP)-compliant production processes is therefore essential for regulatory approval and large-scale commercialization [6].

Sterilization and long-term storage further complicate hydrogel manufacturing. Conventional sterilization techniques, including autoclaving, gamma irradiation, and ethylene oxide treatment, may alter hydrogel structure, mechanical properties, or biological activity depending on the polymer composition and crosslinking chemistry. Likewise, maintaining hydrogel stability during storage without compromising functionality remains challenging, particularly for injectable formulations, cell-laden constructs, and bioactive hydrogels containing proteins or growth factors. Consequently, the development of sterilization-compatible materials and shelf-stable formulations continues to be an important area of translational research [6,39].

Injectable hydrogel systems illustrate many of the opportunities and challenges associated with clinical translation. Their minimally invasive administration, localized therapeutic delivery, and ability to conform to irregular tissue defects make them attractive candidates for regenerative medicine. However, successful clinical implementation requires reproducible gelation kinetics, predictable degradation behavior, mechanical stability under physiological conditions, and compatibility with standard clinical delivery devices. Rodell et al. highlighted these translational considerations in the development of injectable hydrogels for cardiac repair, emphasizing that engineering solutions must be accompanied by practical considerations for clinical deployment [41].

The emergence of three-dimensional bioprinting introduces additional manufacturing challenges. Although advanced hydrogel bioinks enable the fabrication of highly complex tissue constructs, widespread clinical adoption requires standardized bioink formulations, reproducible printing workflows, scalable biomanufacturing processes, and rigorous quality assurance. Chimene et al. emphasized that successful translation of hydrogel-based biofabrication will depend not only on improvements in bioink performance but also on the establishment of manufacturing standards capable of producing reproducible, clinically relevant tissue constructs [59]

Regulatory approval presents another important consideration for hydrogel-based therapeutics. Depending on their intended application, hydrogels may be regulated as medical devices, drug products, biologics, or combination products, each requiring distinct preclinical evaluation and clinical validation. Comprehensive assessment of biocompatibility, biodegradation, immunogenicity, toxicity, mechanical performance, and long-term safety is essential before clinical implementation. Early integration of regulatory considerations into hydrogel design and manufacturing workflows may substantially accelerate the translation of promising laboratory discoveries into approved medical products [6,83].

Looking forward, future progress in hydrogel translation will require interdisciplinary collaboration among materials scientists, engineers, clinicians, regulatory agencies, and industrial partners. Advances in scalable polymer synthesis, automated manufacturing, quality-by-design principles, artificial intelligence-assisted process optimization, and standardized characterization methods are expected to improve manufacturing consistency while reducing production costs. Furthermore, the development of modular hydrogel platforms with simplified compositions and reproducible performance may facilitate regulatory approval and accelerate commercialization.

Overall, hydrogel technologies have demonstrated enormous potential across drug delivery, regenerative medicine, and biofabrication; however, successful clinical translation will depend on overcoming manufacturing, regulatory, and commercialization challenges. Continued efforts toward scalable production, standardized quality control, and clinically relevant design strategies will be essential to realize the full therapeutic potential of hydrogels in modern medicine.

7. Future Perspectives

Over the past decade, hydrogel research has progressed from the development of polymeric networks to multifunctional biomaterials capable of controlled drug delivery, tissue regeneration, and advanced biofabrication. Continued advances in material chemistry, biomolecular engineering, and manufacturing technologies are expected to further expand the clinical potential of hydrogels. Future research should focus not only on improving the biological performance of hydrogels but also on overcoming the challenges associated with large-scale manufacturing, reproducibility, long-term stability, and regulatory approval.

One of the most promising directions is the development of intelligent hydrogel systems that can dynamically respond to changes in the physiological microenvironment. Hydrogels capable of sensing biochemical or mechanical cues and subsequently modulating therapeutic release, degradation, or mechanical properties could significantly improve treatment precision while reducing off-target effects. The integration of multiple responsive mechanisms within a single hydrogel platform is also expected to enhance therapeutic efficacy across a wide range of biomedical applications.

The convergence of hydrogel engineering with emerging technologies will further accelerate innovation in regenerative medicine. Artificial intelligence (AI) and machine learning (ML) offer powerful tools for predicting hydrogel composition, optimizing crosslinking strategies, and accelerating biomaterial discovery through data-driven design. Similarly, advances in three-dimensional (3D) and four-dimensional (4D) bioprinting are enabling the fabrication of increasingly complex tissue constructs with precise spatial organization, vascular architectures, and patient-specific geometries. Combining these technologies with biomimetic and bioactive hydrogels may significantly improve the structural and functional outcomes of engineered tissues.

Future hydrogel platforms are also expected to serve as versatile carriers for next-generation therapeutics, including nucleic acids (mRNA, siRNA, and CRISPR-based systems), extracellular vesicles, exosomes, peptides, and engineered proteins where needed. The integration of these emerging therapeutic modalities with stimuli-responsive hydrogels could provide precise spatiotemporal control over therapeutic delivery while supporting tissue regeneration and immune modulation.

Despite remarkable scientific progress, successful clinical translation will depend on addressing several practical challenges, including scalable manufacturing, standardized material characterization, sterilization, quality control, and cost-effective production. Establishing harmonized regulatory guidelines and validating hydrogel performance through well-designed preclinical and clinical studies will be essential for accelerating commercialization.

Overall, the future of hydrogel research lies in the development of multifunctional, clinically translatable biomaterials that integrate smart responsiveness, bioactivity, advanced manufacturing, and precision therapeutic delivery. Continued interdisciplinary collaboration among materials scientists, engineers, clinicians, and industry partners will be crucial for translating laboratory innovations into safe and effective biomedical products that improve patient care.