Advanced hydrogels for tissue engineering and regenerative medicine: from material design to clinical translation

1 Introduction

Tissue and organ dysfunction is a major healthcare concern in the world, driven by age, trauma, and chronic illnesses. Tissue and organ dysfunction is a major healthcare concern in the world, driven by age, trauma, and chronic illnesses (Liao Y. et al., 2025). Although essential in surgical practice, traditional treatment is characterized by major shortcomings. Autografts are limited by donor-site morbidity and the insufficient availability of tissue, whereas allografts and xenografts carry the risk of immunogenicity, disease transmission, and rejection. These limitations have spurred tissue engineering and regenerative medicine (TERM), an interdisciplinary field that seeks to repair, preserve, or improve tissue functionality by the tactical assembly of cells, signaling molecules, and scaffold materials (Ganesan et al., 2025). This approach aims at reducing the severe lack of organs that can be transplanted to patients, which is always much higher than the supply, and leads to very long queues of patients. This acute imbalance between demand and supply of organs has led to the development of regenerative engineering, an interface of tissue engineering with material science, stem cell biology, and developmental biology to assemble intricate tissues (U.S. Food and Drug Administration, 2016).

Within this regenerative paradigm, hydrogels have emerged as a pivotal class of scaffold materials. These three-dimensional (3D) polymeric networks have a strong affinity for water, which absorbs and retains huge quantities of cellular fluids, while their structure is well-defined. Their primary function is that they are physically and mechanically similar to the native ECM (Pardo et al., 2024). This gives a moist microclimate in which cells are able to perform essential tasks like binding, migration, and various forms of differentiation. The hydrogel technology has now evolved into highly advanced and intelligent systems as opposed to the traditional and inert systems that are weak in terms of mechanical properties and bio-inertia. Such new materials are aimed at dynamically responding to environmental cues like pH, temperature, and enzyme activity to offer spatiotemporal control of the regeneration process (El-Husseiny et al., 2024). The therapeutic importance of hydrogel lies in its capacity to resolve the core areas of tissue engineering challenges, especially by fabricating bio-compatible scaffolds that facilitate cellular differentiation, growth, and tissue implantation. Furthermore, the versatility of hydrogels, which includes both natural and synthetic kinds, enables precise tuning of their mechanical characteristics, degradation rate, and biochemical characteristics to fit a wide range of regenerative engineering applications (Segneanu et al., 2025).

Such a design highlights a shift towards bio-instructive materials that not only offer passive structural support but also actively influence the biological healing process. Rather than acting as passive scaffolding, these advanced hydrogels interact in both directions with encapsulated or invading cells, providing bio-physical and bio-chemical signals that govern tissue formation. This review focuses on the fundamental needs for a regenerative scaffold and subsequently digs into advanced materials (Segneanu et al., 2025). Despite substantial advances, transforming hydrogel technology from lab to clinic remains a difficulty. These include insufficient mechanical characteristics for load-bearing applications, unpredictable degradation rates, batch-by-batch variability in natural polymers, and regulatory challenges associated with combination products. Furthermore, the sector lacks defined characterization techniques, which makes cross-study comparison difficult and hinders the discovery of effective design solutions (Capella-Monsonís et al., 2024).

This review addresses four key scientific and translational questions: (Liao Y. et al., 2025) How have the strategies in hydrogel design changed to act beyond the limitations of traditional scaffolds (Ganesan et al., 2025) ? What are the compared advantages and disadvantages of synthetic and natural polymers for specific tissue uses (U.S. Food and Drug Administration, 2016) ? What can we do for hydrogels that respond to stimuli, heal themselves, and conduct electrical energy to control regeneration in space and time (Pardo et al., 2024) ? What can stop clinical translation, and how can governing research, scalable manufacturing processes, and new technologies like AI-assisted design and 4D bioprinting help? We compile evidence-based design concepts and determine gaps in knowledge that need to be bridged via a systematic literature review approach, including publications published between January 2020 and February 2026, to speed up the clinical adoption of hydrogel-based regenerative therapies.

1.1 Literature search methodology

This systematic literature review follows the PRISMA 2020 framework, which makes sure that the methods are strict and the topic is covered in depth. From 1 January 2020, to 28 February 2026, the search strategy used well-known electronic databases like Scopus, ScienceDirect, PubMed/MEDLINE, Web of Science, and Google Scholar. The search used different combinations of keywords and Boolean operators to look for topics like hydrogel technology in tissue engineering and regenerative medicine. It also looked for specific types of polymers, such as alginate, chitosan, and collagen. Citation chaining was one of the extra search methods used to find relevant publications. The inclusion criteria mandated an emphasis on original data, thereby excluding commentaries, opinion articles, and studies related to non-biomedical hydrogel applications. The PRISMA guidelines were followed for data extraction, and EndNote 21 was used to manage records and get rid of duplicates. Two independent reviewers did the first screening of titles and abstracts, and then they did a full-text article evaluation. A PRISMA 2020 flow diagram summarizing the identification, screening, eligibility assessment, and final study selection process is presented in Figure 1.

2 Fundamental requirements for hydrogels in regenerative medicine

A hydrogel must meet a wide range of mechanical, biological, and physicochemical requirements to function efficiently as a regenerative scaffold and to integrate with the host tissue. The most significant aspect is biocompatibility; the material must not be toxic and should not cause an immunological or inflammatory reaction when it is implanted (Revete et al., 2022). For example, chronic inflammation might cause fibrous encapsulation, which isolates a scaffold from the tissue around it and makes it impossible for the scaffold to work with the surrounding tissue. Biodegradability is also a significant aspect of regenerative medicine because it guarantees that the scaffold breaks down at the same pace as new tissue forms, which ensures replacement of new tissue by host tissue with no residuals. This indicates that the degradation profile must match the rate of tissue regeneration so that the structure doesn’t break down quickly or stay in place for too long, which could slow down tissue maturation. The mutual dependence of porosity along with pores in hydrogels is also very important. It helps nutrients and oxygen get within the cells and eliminates waste, which keeps the cells alive and helps them grow in the scaffold. The structure of the scaffold, especially its porosity, directly affects how efficiently it will transport material. A network of interconnecting pores is necessary for cells to move into and through the construct and eventually become blood vessels. A hierarchical structure of pore sizes is typically useful. For instance, in bone regeneration, pore sizes between 50 and 150 µm may help cells settle in, whereas bigger pores (100–600 µm) are needed for full tissue implantation and blood vascular infiltration (Witherel et al., 2019; Dickenson et al., 2026).

The second key component is the native ECM, which is not just a structural framework but also a functioning repository for biological and mechanical signals. High water content and viscoelastic characteristics of hydrogel enable them to mimic the soft tissue environment, allowing the diffusion of oxygen, nutrients, and metabolic waste (Berdiaki et al., 2024; Carton et al., 2024). Hydrogels also require the right mechanical characteristics, like elastic modulus and tensile strength, to keep their shape while also matching the mechanical properties of the host tissue to avoid stress shielding and encourage mechanotransduction. The mechanical characteristics of hydrogels at the microscopic and macroscopic levels are crucial because it keeps the structure stable and the volume constant while also affecting the way cells function. To keep physiological stability and avoid stress shielding, which is if a too stiff scaffold makes the surrounding bone or soft tissue shrink, mechanical characteristics must be carefully adjusted to fit the target tissue. The crosslink density and molecular weight of the polymers that make up a hydrogel have a major role in determining its mechanical performance (El-Sherbiny and Yacoub, 2013; Hu et al., 2024).

Additionally, the rate at which the scaffold collapses ought to correspond to the rate at which new tissue forms. If a scaffold breaks down too slowly, it may become in the path of growing tissue. If it breaks down too quickly, it doesn’t give adequate interim support for remodeling. It is also important that the by-products of degradation are not harmful and can be readily eliminated by the human body to ensure long-term safety. Recent improvements have addressed these requirements by substituting non-degradable cross-linkers, such as MBAA (N, N’-Methylenebisacrylamide), with hydrolytic or enzymatic degradable analogues to develop resilient adhesives with regulated mass loss (Freedman et al., 2021). These substances can withstand fracture energies of more than 6 kJ m^-2 and stretch over twenty times their initial length while having an abundance of water in them. This shows that degradable architectures are not always required to be structurally strong enough to adhere to wet tissue (Freedman et al., 2021). Liu J. et al. (2026) examined the degrading characteristics of 3D-printed polyurethane/β-tricalcium phosphate (β-TCP) composite scaffolds intended for bone regeneration. By adjusting the amount of β-TCP, the degradation half-lives could be changed from 10.5 to 16.7 weeks in vitro and from 11.2 to 17.7 weeks in vivo. Importantly, scaffolds whose degradation kinetics were in accordance with the rates of new bone formation produced much better regeneration results than those whose degradation was too quick or too slow. This provides direct experimental proof that the timing of degradation is a measurable factor in the success of regeneration (Liu J. et al., 2026).

3 Material design strategies for advanced hydrogels

3.1 Polymeric building blocks

The physicochemical parameters of the hydrogel are mostly determined by selecting polymer building blocks. These blocks are normally classified into three categories: natural, synthetic, or hybrid by people. Natural polymers have inherent advantages since they are of organisms. They can be given an example of being biocompatible and having cell-adhesion patterns that are already established. Widely used polysaccharides include alginate, chitosan, collagen, gelatin, and HA due to an overlap in structure between them and the ECM glycosaminoglycans (Zhao L. et al., 2023; Mehta et al., 2023).

Alginate is a natural anionic polysaccharide extracted from the brown seaweed, which can be used as an important ingredient in the hydrogels with advanced characteristics because of the presence of three-dimensional network formed by the ionic crosslinking, high water retention abilities and biocompatibility and biodegradability (Tomić et al., 2023). Appropriately designed hydrogels can be chemically or mechanically modified, and can be prepared using techniques such as Ca2+-mediated gelation, for use in a variety of applications including wound dressings, controlled drug delivery, and tissue engineering (Ahmad et al., 2021; Abourehab et al., 2022). Although the alginate hydrogels are good, there are some problems in using it in large numbers such as low mechanical strength, lack of natural binding sites, and solubility. In the clinical arena, there are approaches to enhance the efficacy like the use of other polymers, the introduction of RGD peptides for cell adhesion and the design of advanced polymeric networks, such as interpenetrating and stimulus-responsive networks (Feyisa et al., 2023; Rahman et al., 2024). Of interest, dual-crosslinked alginate-carboxymethyl cellulose hydrogels can be self-healing, injectable, and antibacterial; sodium alginate interpenetrating matrices can provide long-term drug release (Zhu et al., 2023). The chitosan-alginate fusion hydrogels have been found to be effective in tissue repair, and chitosan-alginate strontium ion hydrogels are effective in tissue repair by improving angiogenesis (Zou et al., 2020; Toumaj et al., 2024). Algisyl-LVR is a calcium alginate based hydrogel that is injected into the body for advanced heart failure treatment and represents the development of clinical use of alginate based hydrogels (Lu et al., 2020).

Chitosan, derived from chitin, is a natural and biodegradable biopolymer that supports wound healing because of its biocompatibility, biodegradability, non-toxicity, and high antimicrobial properties. This decreases the chance for wound infection and speeds up hemostatic processes. Chitosan is used to manufacture both hydrogels and electrospun fibers that provide a moist, permeable microenvironment for the diffusion of oxygen and nutrients between cells, helping them to thrive and regenerate tissue (Rajinikanth et al., 2024; Singh et al., 2017). Chitosan’s benign nature ensures that it decomposes naturally without causing damage to patients. Unfortunately, chitosan has some limitations, such as low strength and an inability to dissolve at neutral pH, that researchers are working to address through chemical modification and blending with other polymers (Zhao et al., 2018; Chicea and Nicolae-Maranciuc, 2024). Stimuli-responsive chitosan-based hydrogels that incorporate bioactive agents for the purpose of promoting neurogenesis in instances of trauma (e.g., brain injuries) are being used more frequently. The commercially available BST-carGel(R) chitosan scaffold is currently marketed for use in repairing damaged hyaline cartilage, allowing for stem cell migration from the surrounding tissue for the purpose of regenerating cartilage (Stanish et al., 2013).

Collagen, an essential protein of the extracellular matrix, is also used in advanced hydrogels for wound healing and tissue regeneration, and its excellent biocompatibility, biodegradability and natural cell interactive property enables in situ gelling collagen injection (Pires Figueiredo et al., 2025; Jin et al., 2026). Despite these benefits, collagen may have immunogenicity problems, inconsistent mechanical properties, and batch-to-batch inconsistency without reinforcing it via blending or composites. Collagen has been recently used in combination with alginate and nanoparticles to improve mechanical properties and bioactivity (Gao et al., 2025). The development of recombinant human collagen has overcome several limitations associated with animal-derived collagen, namely, batch variability and immunogenicity concerns. Collagen based nanocomposite hydrogels with enhanced biocompatibility and migration and angiogenesis of fibroblasts provide potential applications in wound healing (Li et al., 2023). Hydrogels, which contain silver nanoparticles, are injectable and self-healing, also improving their antibacterial properties and healing capabilities (Gu et al., 2023; Song et al., 2024). The hyaluronic acid/collagen hydrogels have been shown to promote dermal fibroblast proliferation and expression of ECM in vitro and in vivo (Hu and Lo, 2021). Also, recombinant human collagen has solved problems associated with both batch-to-batch variation and immunogenicity, with engineered collagen systems showing promising skin regeneration effects via mechanisms such as angiogenesis and organized collagen deposition, suggesting a clinical translation potential (Tong et al., 2025; Han et al., 2023).

Gelatin is a derivative of collagen that has been hydrolyzed to maintain intrinsic bioactivity because of integrin-binding motifs, including RGD sequences, and is therefore a basic polymer in complex hydrogels, which are used in TERM (Zhao et al., 2025). It has many advantages, such as being biocompatible, biodegradable, having minimal immunogenicity, and being soluble at physiological pH, which makes it possible to encapsulate cells and distribute them (Dehli et al., 2025). GelMA-based hydrogels are becoming useful tools because they can do many things. This is happening because of things like quaternization and combining types of polymers. When we add groups like quaternary ammonium groups to GelMA it becomes GelMAQ, which is really good at fighting off bad bacteria. It is also safe for cells, which is what we saw with the mix of GelMA and GelMAQ. We still have to think about what might happen after a long time and if it is stable and how it works with the good bacteria in our bodies. We need to do tests in living things to be sure (Lu et al., 2025; Azmir et al., 2025).

At the time GelMA is not strong and breaks down quickly so we cannot use it by itself. When we combine GelMA with things, like PEGDA or alginate it becomes stronger and we can control how it works with cells. This is good because it does not hurt cells. With these new discoveries we have to be careful because these materials are getting more complicated and we do not fully understand how cells work with them. This makes it hard to use them to help people. We should try to make these materials simpler and make sure they work well for a time and understand how they work so we can use them to help our bodies heal (Ferchichi et al., 2024) (Abtahi et al., 2025).

Advanced hydrogel systems find wide application because of the inherent bioactivity of HA, including its binding to CD44 receptors, as well as its multiple chemically modifiable sites and enzyme-regulated degradability, which allows it to be designed to be cell-instructive (Dovedytis et al., 2020; Burdick and Prestwich, 2011). Chemical modifications like methacrylated HA (HAMA) and tyramine-functionalized HA and supramolecular guest–host systems enable various crosslinking approaches (covalent, enzymatic, or physical), resulting in a precise control of mechanical properties, porosity, and drug delivery kinetics (Highley et al., 2016). In addition to the known biocompatibility (Misra et al., 2015). High water content and ease of processing, HA hydrogels facilitate cellular signaling by interacting with the CD44 and RHAMM receptors, which regulates cellular proliferation, migration and differentiation. Their drawbacks, however, include their fragility, degradation, absence of intrinsic cell adhesive ligands, and mechanical weakness, putting them off-limits to load-bearing applications unless modified further (Donnelly et al., 2017). These challenges have been overcome in recent times with the addition of secondary networks, nanofillers, or bioactive motifs to create a more mechanically stable and functional structure (Nejati and Mongeau, 2023). For instance, tyramine modified HA (HA-Ty) has tunable mechanical properties for cartilage applications, and double-network systems (e.g., DAHA–HAMA) are shown to be injectable, self-healing, and adhesive. Comprehensive studies emphasize the need for reinforced mechanics and controlled degradation for clinical translation. Remarkably, hydrogels based on HA have already been successfully used clinically as dermal fillers and as a treatment for osteoarthritis, thus demonstrating their translational potential (Rashid et al., 2025).

In addition to natural polymers, synthetic polymers like polyethylene glycol (PEG), poly lactic acid (PLA), polycaprolactone (PCL), polyacrylamides, and polyvinyl alcohol (PVA) are also commonly used to make hydrogels. These polymers provide a higher mechanical tunability, reproducible, and controllable degradation profiles over the natural polymers. They, however, tend to have no natural biological cues to cell adhesion and cell proliferation, which require functionalization with bioactive peptides or extracellular matrix factors (Vasile et al., 2020; Bolívar-Monsalve et al., 2021).

Polyethylene glycol is a synthetic polymer with a broad range of applications as a backbone in hydrogel systems because it is an excellent biocompatible, low immunogenic and FDA approved polymer used in biomedical applications. The tunable molecular weight, functional end groups and “stealth” properties allows the design of well-defined hydrogels through photo-crosslinking, click chemistry, and hybridization with natural polymers. PEG is however non-biodegradable and non-bioactive, and can generate anti-PEG immune responses that are generally mitigated by copolymerization with bio-active peptides or degradable linkages (Alayoubi et al., 2025). PEG-based hydrogels are frequently functionalized with bio-molecules to improve functionality. For instance, peptide reinforced PEG hydrogels are used to provide higher mechanical strength and biomimetic structure while DNA–PEG based systems are used to provide spatiotemporal control of growth factor delivery for bone regeneration (Russell et al., 2026), (Wu et al., 2026). PEG hydrogels with ECM-like properties containing RGD sequences and MMP-degradable crosslinks can be used to create controlled cellular microenvironments and to enable 3D cell culture (Wu et al., 2026). Moreover, the use of PEG-based hybrid bioinks (e.g., GelMA-PGDA) in high-resolution bioprinting for cartilage regeneration is currently under investigation (Zhu et al., 2019). In the clinical arena, PEG-based systems like Jelmyto™/UGN-101 have proven to be effective for localized and sustained drug delivery, further highlighting PEG’s potential in regenerative medicine.

Polylactic acid (PLA) is a biodegradable and renewable synthetic polyester, which is extensively utilized in preparation of advanced hydrogels and composite scaffolds. It has numerous advantages such as FDA approval, tunable crystallinity, high mechanical strength and controllable hydrolytic degradation, which is suitable for load-bearing and 3D-printed applications in bone, cartilage, and vascular tissues (Farjaminejad et al., 2024; Santoro et al., 2016). Its hydrophobic nature restricts cell adhesion and bioactivity however, acidic degradation products could cause local inflammation therefore it requires modification or incorporation with hydrophilic or natural polymers to improve bioactivity. To overcome these drawbacks, bioactives are often added to PLA. An example of this is the PEG-PLA/gelatin hydrogels, which show that the adhesion, proliferation and cartilage regeneration of chondrocytes increases as the gelatin concentration increases. Likewise, multilayered vascular grafts made from PLA/PCL offer superior mechanical properties in addition to good endothelialization efficiency (Chen Y. et al., 2025). The blended PLA/gelatin nanofibers possess better hydrophilicity and promote wound healing; in recent years, biocomposite hydrogels based on PLA combined with collagen and bioactive substances (such as curcumin) have been developed with improved properties in terms of angiogenesis and skin regeneration (Tong et al., 2025; Mukta et al., 2024). In conclusion, PLA-based systems are flexible platforms that would be useful for mechanically demanding and biologically functional tissue engineering applications.

Poly (ε-caprolactone) is a semi-crystalline, FDA-approved synthetic polymer that has a long degradation time, excellent processability into electrospun fibers, 3D-printed constructs, and microspheres for advanced applications such as bone, cartilage, vascular, and neural tissues (Omidian, 2025). It is also viscoelastic, so it is able to resist physiological stress, but it is also intrinsically hydrophilic, which can interfere with the adhesion of living cells and bioactivity, and it has a slow degradation period of 2–3 years that can hinder timely tissue remodeling. Furthermore, low compatibility with hydrophilic hydrogels requires a need to hybridize them with natural polymers or bioactive elements (Navaneethan et al., 2025). For these reasons, PCL is often used in conjunction with other systems. For instance, scaffolds electrospun from PCL and cell-laden hydrogels have been shown to enhance mechanical properties and to promote epithelialization, and PCL based triphasic constructs with GelMA have been reported to provide spatially controlled osteogenic, chondrogenic differentiation and vascular network formation (Navaneethan et al., 2025; Pirosa et al., 2021). Likewise, 3D printed composites from PCL with gelatin, nano-hydroxyapatite and nanoclay exhibit increased wettability, tensile strength and cell proliferation (Nazari et al., 2023). In conclusion, PCL is a versatile structural element for hybrid scaffolds, providing both mechanical strength and biological activity to create functional and supportive tissue engineering structures.

The temperature responsive synthetic polymer Poly(N-isopropylacrylamide) (PNIPAM) is a widely used polymer in tissue engineering smart hydrogel systems. It has a reversible phase transition around its lower critical solution temperature (∼32 °C), allowing for gelation of the injectable at physiological temperature, which allows for minimally invasive delivery (Ortega-García et al., 2022). The tunable transition behavior, copolymerizability and chemical versatility of its materials can be used in drug delivery, cell sheet engineering, wound healing and 3D cell culture, where temperature-controlled cell detachment preserves the integrity of the ECM (Narayana et al., 2025). Although these benefits exist, the mechanical strength is low, the response kinetics are slow, it is not biodegradable and the potential cytotoxicity of residual monomers requires copolymerization with hydrophilic or biodegradable materials (Kobayashi et al., 2025). Recent studies have shown that these modifications can improve the functionalities of the systems, such as the use of injectable PNIPAM-based systems with lignin or graphene oxide, which exhibit improved antibacterial activity, drug delivery capability and wound healing potential, and advanced synthetic PNIPAM hydrogels with tuning mechanics that are capable of regulating stem cell differentiation through mechanotransduction pathways (Bai et al., 2024; Yang et al., 2024; Wang et al., 2026). In summary, PNIPAM is still a decent platform to design stimuli responsive hydrogels, but it should be considered with the limitations mentioned above, which can be overcome with material engineering.

Due to the competing requirements, the design of hydrogel building blocks is not possible to be achieved within a single polymer class. Natural polymers have inherent biocompatibility, cell-instructive motifs (such as RGD sequences), and ECM-mimetic enzymatic degradability, but have drawbacks with respect to batch variability, potential immunogenicity, and poor mechanical properties, which restrict their applications to load-bearing situations (Ribeiro et al., 2025). Synthetic polymers can be tuned to have specific mechanical properties, reproducible degradation characteristics and can be manufactured in a scalable manner, however, they are not bioactive and can elicit undesirable host responses if they do not degrade completely (Kon et al., 2023). Therefore, the choice of polymer should be tissue specific. Superior mechanical properties are required for synthetic or reinforced hybrid systems for bone and cartilage regeneration, while natural or quickly degrading materials are needed for soft tissue, where cell infiltration and minimal chronic inflammation are important (Scopelliti et al., 2026). This compromise has encouraged the development of hybrid systems, such as interpenetrating polymer networks (IPNs), semi-IPNs and nanocomposites, where a natural polymer bioactivity is combined with a synthetic mechanical robustness. Representative GelMA-PEG hybrids allow for independent fine-tuning of stiffness and ligand density for tuning cell-matrix interaction and mechanotransduction. Finally, however, rational, application-specific design is needed rather than the search for a universal ideal polymer. Table 1 gives a comparative guide for selecting materials for biological performance, mechanical behavior, manufacturability and translatability.

TABLE 1. A comparative understanding of natural and synthetic polymers.

Scoring rationale: 5 = excellent/optimal, 1 = poor/limiting. Scores represent consensus from >50 comparative studies analyzed in this review.

3.2 Mechanism of hydrogel formation

Crosslinking of the polymer chains is required in order to form three-dimensional hydrogel networks using hydrophilic polymer solutions. This is critical in the establishment of the end mechanical properties, degradation behavior, and biological functioning of the material. Physical crosslinking, chemical crosslinking, and dynamic covalent systems, which combine characteristics of all of these approaches, are the primary forms of crosslinking (Bhuyan and Jeong, 2025; Yammine et al., 2025).

3.2.1 Physical crosslinking

Physical networks are created by reversible non-covalent interactions through physical crosslinking without adjusting the polymer backbone chemistry. There are several mechanisms by which physical crosslinking may be carried out, including ionic crosslinking, hydrogen bonding, and hydrophobic associations. Guluronate residues in polyelectrolyte polymer chains like alginates can form ionic bridges with divalent cations (e.g., Ca²⁺, Ba²⁺) (Ribeiro et al., 2025; Kon et al., 2023). It offers a low-toxicity and cytocompatible way of gelation, applicable to cell encapsulation and to building injectable formulations, but generally yields mechanically weak hydrogels that exchange ions when in contact with physiological fluids. Polymers with complementary hydrogen-bonding groups (e.g., PVA, gelatin) can create physical networks by freezing and thawing or through the process of annealing. These networks are self-healing thermoreversible, but can be dissolved at high temperatures. Hydrophobic associations: Amphiphilic block copolymers (e.g., Pluronics, PEG - PPG - PEG) are self-assembling micellar aggregates above their critical gelation concentrations, which are physically cross-linked networks due to hydrophobic domain interactions (Scopelliti et al., 2026; Chauhan et al., 2025). PNIPAM-based systems take advantage of hydrophobic associations at and near the lower critical solution temperature (LCST, ∼32 °C) for thermally triggered gelation. Host-guest Interactions Supramolecular hydrogel Host-guest complexation (e.g., cyclodextrin-adamantane, cucurbituril-viologen) is a dynamic, reversible cross-linking method allowing shear-thinning injectability, self-healing, and stimuli-responsive behavior (Jain et al., 2022; Zhao et al., 2019).

3.2.2 Chemical crosslinking

Chemical crosslinking creates permanent covalent bonds among polymer chains, yielding mechanically tough networks with tunable degradation behavior. The major methods include free radical polymerization and click chemistry. Free radical polymerization is a popular method, which is based on the polymerization of vinyl-functionalized macromers like gelatin methacryloyl (GelMA), polyethylene glycol diacrylate (PEGDA), and hyaluronic acid methacrylate (HAMA). Free radicals are quickly formed in the presence of photo-initiators and light irradiation (UV or visible) to cause a covalent network (Deng et al., 2022). Photo-crosslinking provides superior spatiotemporal control of gelation, allowing a high level of precision in patterning and in situ polymerization, and has been utilized with other fabrication technologies, including 3D bioprinting. In addition, other initiator systems, including riboflavin-mediated photoinitiation, have been proven to be more cytocompatible than other widely used initiators, like Irgacure 2959. Click chemistry (Bioorthogonal Reactions) is a very efficient and specific technique, with mild cross-linking intensity during physiological conditions without the production of cytotoxic by-products. The most common reactions are strain-promoted azide alkyne cycloaddition (SPAAC) (Agard et al., 2004), thiol-ene coupling, and Diels–Alder cycloaddition (Nimmo et al., 2011). They are especially beneficial for the encapsulation of cells and gelation in vivo because of their fast kinetics, high selectivity, and biocompatibility. Schiff base formation: Dynamic imine bonds formed between amine and aldehyde groups (e.g., chitosan-aldehyde HA, gelatin-oxidized alginate) that allow self-healing and injection moldable hydrogel formation. The pH-responsive linkages are designed to break down in an acidic environment to allow them to release the drug into the tumour microenvironments or infected wounds in a targeted manner (Devi et al., 2021).

3.2.3 Enzymatic crosslinking

Enzyme-mediated systems, such as horseradish peroxidase (HRP) or transglutaminase-catalyzed reactions, enable gel formation under mild physiological conditions. Cross-linking of tyramine-functionalized polymers (i.e., tyramine-gelatin, tyramine-HA) achieves gelation in a relatively short time, wherein the mechanical properties are regulated by the concentration of H₂O₂. This approach is cytocompatible and has been applied to the clinic as surgical sealants. These systems also allow fine control over gelation kinetics and are especially suitable for cell-laden hydrogels and injectable systems (Basha et al., 2025; Kurisawa et al., 2014).

3.2.4 Systems of dynamic covalent and supramolecular nature

Recent progress has been in the use of hydrogels that synergize both the strength of chemical cross-links and the reversibility of physical interactions. These systems include double-network (DN) hydrogels. DN consists of a tightly crosslinked first network (conferring stiffness) and loosely crosslinked or physically associated second network (dissipating energy via the rupture of sacrificial bonds). DN hydrogels achieve fracture energies >1000 Jm^-2 and high-water content (>90%). These kinds of DN hydrogels can be formed using metal-ligand coordination. For example, catechol-Fe³⁺ complexes have been developed which are inspired by the mussel adhesive proteins, dynamic crosslinking, self - healing, wet adhesion, and stimuli-responsive behavior. A recently reported system of reversibly interlocking polymer networks (RILNs), in which the catechol-ferric ion coordination is combined with imine bonds, has shown tensile strengths of 0.87–3.21 MPa and 75.9%–83.5% self-healing efficiencies, under different pH levels ranging from 4 to 9.14. In another study, the boronate ester chemistry principle was used to develop a DN hydrogel. Phenylboronic acid-diol complexation for glucose-responsive hydrogels for insulin delivery and self-healing materials with tunable dynamics. The reversible nature of boronate esters allows rearrangement of the network and self-repair without loss of mechanical integrity (Xin, 2022; Dutta and Das, 2019; Sun et al., 2020).

4 Smart and multifunctional hydrogel systems

Multifunctional and smart hydrogels are novel biomaterials in the form of smart hydrogels that are expected to dynamically interact with the biological environment and perform a variety of therapeutic tasks (Figure 2). They include stimulus responsiveness, self-healing, mechanical strength and conductivity, which allow them to respond to changes, such as pH, temperature, or biochemical signaling. All these features render them extremely useful in tissue engineering and regenerative medicine, where they can regulate the drug release, facilitate tissue regeneration, and allow real-time monitoring. In general, they are a promising area of more accurate, efficient and individualized medical therapies.

4.1 Stimuli-responsive hydrogels

Stimulus-responsive hydrogel is a superior group of biomaterials designed to experience reversible physicochemical reactions through exposure to certain environmental cues and is therefore useful in spatiotemporal control of therapeutic delivery and real-time monitoring of wounds. Such responsive systems normally use dextran, chitosan, and alginate polysaccharides, which are functionalized with reactive moieties that respond to changes in pH, temperature, reactive oxygen species (ROS), and enzyme activity, which characterize chronic and diabetic wounds (Serpico et al., 2023). The governing system entails reversible cleavage of bonds or conformational motion of the polymer network, driven by pathophysiological microenvironmental signals; this regulates swelling behaviour and kinetics of drug delivery. The benefits of these materials are on-demand administration of therapeutic doses, decreased systemic toxicity, and improved patient adherence, and the disadvantages include complicated synthetic regimens, possible batch-to-batch uncertainty, and difficulties in realizing response kinetics. Recent studies have resulted in a dextran-based redox-sensitive hydrogel, which can deliver antimicrobial agents in diabetic wound milieus, and the release of which is selective in the presence of ROS, thereby accelerating wound healing by regulating infections in a specific manner. Liu et al. designed pH-responsive hydrogel wound dressings patches with flexible sensor arrays that can real-time measure the wound exudate pH with a sensitivity of 0.02 pH units and wireless transmission of the data to smartphone interfaces to provide closed-loop therapeutic feedback (Liu et al., 2017). Sincari et al. engineered giant unilamellar vesicles synthesized in microfluidics devices with pH-sensitive PEO-b-PDPA block copolymer membranes containing Janus gel compartments with specific pH-dependent release profiles (90% drug release at 6.7 vs. <20% drug release at 7.4) targeted to the tumor microenvironment (Sincari et al., 2023). Zhao and co-authors fabricated pH-stimulated dual-responsive PNIPAM-methylcellulose hydrogel, whose thermo-hysteresis windows could be adjusted between 0 °C and 17.6 °C, to allow adaptive memory functions that may be used in the applications of intelligent microvalve and smart window (Zhao et al., 2015).

4.2 Self-healing hydrogels

Dynamic polymer networks that can self-repair after damage similar to natural tissue repair by reversible crosslinking. Most of these systems involve polymers like PVA, cellulose nanocrystals, starch, or urushiol derivatives, which are linked through dynamic covalent bonds (borate esters, imine bonds) and/or non-covalent interactions (hydrogen bonding, dipole interactions, metal–ligand coordination). It has been found that healing can take place by bond exchange and polymer chain diffusion at damaged interfaces, and no external action is needed to achieve healing (Devi et al., 2021). Extended lifespan, cyclic loading resistance, sustained barrier function, and decreased mechanical properties and healing efficiency may be obtained from such hydrogels, which also can result in decreased healing efficiency depending on environmental conditions. For example, the dual-network catechol-functionalized hydrogels have high tensile strength, tunable adhesion, and efficient self-healing under physiological conditions (Guo et al., 2026). Starch-based ionogels exhibit self-healing properties underwater and are suitable for use in electronic skin, whereas Janus hydrogel patches allow for reversible and wet adhesion in sutureless tissue repair. Furthermore, the conductive composite hydrogels with PVA–borax and CNTs possess fast self-healing property, outstanding flexibility, and stable performance in wearable sensing and motion monitoring (Koh et al., 2026; Su et al., 2026; Peng et al., 2025). The effectiveness of self-healing is evaluated by comparing the mechanical properties of the healed specimen with those of the original specimen. Stress healing efficiency (η σ) can be determined using the equation (Ramesh et al., 2022; Luo et al., 2026).

η σ = σ h e a l e d σ o r i g i n a l × 100 %

η σ → Self-healing efficiency (%)

σ h e a l e d → Mechanical strength (e.g., tensile strength or stress) of the healed sample after damage and repair

σ o r i g i n a l → Mechanical strength of the original (undamaged) sample

To be clinically viable, hydrogels must maintain >80% healing effectiveness under physiological conditions (37 °C in aqueous media).

4.3 Tough hydrogels

Tough hydrogels are mechanically robust polymer networks that are designed to resist high stress, strain and fracture energy while preserving their integrity under physiological loading, thereby solving the problem of the load-bearing limitation of conventional hydrogels (Huang et al., 2026). Their designs are mostly based on hybrid structures like interpenetrating polymer networks, double network systems, inorganic nanowire reinforcement, and sacrificial bond structures (such as PVA, polyacrylamide, aramid nanofibers) (Liu Y. et al., 2026). The toughening is the result of concurrent energy dissipation processes such as bond rupture, chain entanglement and nanofiber pull-out that inhibit crack propagation and maintain elasticity (Wang L. et al., 2023). They have improved load-bearing capacity, fatigue resistance, and adaptability to dynamic tissues, but are complicated to produce and may have compromises in terms of the other properties they possess, such as conductivity or transparency. Importantly, the bioinspired conductive PVA/ANF/PEDOT: PSS hydrogels have high tensile strength and electrical conductivity, supporting the accurate monitoring of bioelectronics. Likewise, nanowire–polymer organogels show excellent extensibility and resistance to fracture. The porosity and mechanical strength of PVA/silk fibroin cryogels align well with cartilage regeneration, and multilayered hydrogel vascular grafts offer enhanced mechanical properties and endothelialization, demonstrating their potential in complex tissue engineering applications (Niu et al., 2025).

4.4 Conductive and Janus hydrogels

The conductive and Janus hydrogels are a novel generation of multifunctional biomaterials for bioelectronic interfacing, electrical stimulation, and real-time sensing, which are crucial for wound healing and tissue engineering applications (Cheng et al., 2025; Yan et al., 2025). These systems are generally based on polymer matrices like PVA, gelatin and alginate and are combined with conductive elements like PEDOT:PSS, carbon nanomaterials, metallic nanoparticles, or ionic liquids to transport charges through electronic or ionic channels. In contrast, Janus hydrogels are systems with two different domains, one hydrophilic and one hydrophobic, that allow differential interactions with tissues and fluids (Guo Z. et al., 2025; Wang et al., 2025; Guo W. et al., 2025). The conductive hydrogels are based on connected conductive networks to transmit signals during deformation, and Janus hydrogels are based on phase separated structures that achieve strong adhesion to a wet surface and allow adaptation to surface interactions (Su et al., 2026). While these materials have a number of benefits (including real-time monitoring, electro-responsive drug delivery, and improved tissue integration), they also pose a number of difficulties (such as mechanical instability of conductivity, the cumbersome fabrication process, and concerns about long-term biocompatibility) (Liu Y. et al., 2026). Recent developments are Janus hydrogel patches for sutureless tissue repair, conductive ionogels for electronic skin and aquatic devices, degradable conductive composites for controlled drug release and biosensing, and microfluidic Janus vesicles for targeted cancer therapy, among others, and their wide biomedical applications.

Multifunctional hydrogel systems have advanced significantly, incorporating adaptable parts and nature-inspired structures designed for specific tasks. These new platforms can perform multiple functions simultaneously, regulating stiffness, cell interactions, and drug delivery. Their ability to adjust and adapt enhances their compatibility with the body, unlike older static systems. With dynamic connections that can separate and reconnect, these hydrogels effectively interact with the body’s microscopic environment. Such innovations highlight their crucial role in future medicine, particularly in healing and targeted therapies, paving the way for improved treatments (Mohanty et al., 2026). In the recent investigation, injectable hydrogel platforms are really good for helping the body heal. They have ways of working that let them release medicine over a long time. This is very helpful for fixing damaged tissues without needing to cut the body open. The hydrogel platforms can change shape to fit the damaged area stay there for a time and keep working to help the body heal. This makes them very useful, for different types of tissue repair. The hydrogel platforms are a way to help people heal from injuries or illnesses. They can be used in different ways to help the body fix itself (Tan and Marra, 2010).

5 Tissue-specific applications of hydrogels

Various hydrogel systems exhibit distinct performance characteristics depending on the target tissue (Figure 3). For example, GelMA-based hydrogels have been shown to show a high level of cell adhesion and osteogenic differentiation in the rescuing of bone, and alginate-based hydrogels are more effective in supplying structural stability to cartilage tissue engineering. Hydrogels made of conductive polymers with graphene or polypyrene have demonstrated great potential in neural tissue regeneration and cardiac tissue regeneration because of their capability to conduct electrical impulses (Choi et al., 2024).

5.1 Bone and cartilage tissue engineering

Hydrogels have emerged as a highly promising biomaterial in the engineering of bone and cartilage tissues due to their structural equivalence to the extracellular matrix (ECM), high water content, tunable mechanical properties, and the ability of the hydrogel to encapsulate cells and bioactive molecules to use them as a regenerative therapy (Vieira et al., 2022). They are interrelated porous structures that enable diffusion of the nutrients and osteogenic differentiation and proliferation of the chondrocytes and allow growth factors like BMP-2 and TGF-β to be delivered through them, enhancing tissue regeneration in the areas of injury (Chen C. et al., 2017). Stimuli-responsive and injectable hydrogel scaffolds are specifically beneficial in the case of minimally invasive procedures, as they are able to fit around irregular bone defects and gradually degrade with the creation of new tissues (Maiti et al., 2020). Additionally, this is promoted by nanocomposite and bioactive hydrogel containing hydroxyapatite or bioactive glass to facilitate the mechanical integrity and osteoconductivity to be used as load-bearing materials. As an example, Yue et al. found that compared to non-treated defects, composite hydrogels stimulated osteogenic marker expression and bone regeneration in vivo (Wang et al., 2020). On the same note, new nanoclay-reinforced hydrogels also significantly enhanced the adhesion, growth, and differentiation of bone tissue engineering models (Hwang and Lee, 2024). Engineered hydrogel scaffolds have been shown to have the ability to recapitulate cartilage ECM and promote chondrocyte proliferation in cartilage regeneration in preclinical studies (Ansari et al., 2024). Three-dimensional (3D) bioprinted polysaccharide hydrogels, often incorporating components like alginate, tragacanth, or gelatin, combined with hydroxyapatite (HA) nanoparticles, are effective in promoting the osteogenic differentiation of mesenchymal stem cells (MSCs). The incorporation of HA nanoparticles within these 3D printed scaffolds enhances osteoconductivity, bioactivity, and mechanical properties, providing a superior environment for bone regeneration compared to non-printed, 2D, or non-mineralized controls (Khoshnood et al., 2022).

5.2 Skin wound healing

Hydrogels are highly explored as innovative wound-healing biomaterials because of their high retention of moisture, oxygen permeability, and their capability to recreate a moist microenvironment, which contributes to re-epithelialization and tissue healing (Zehtabi et al., 2017). They can also entrap antimicrobial agents, growth factors, and stem cells in their three-dimensional polymeric networks to facilitate controlled delivery of therapeutics and regeneration of chronic wounds and burns (Zehtabi et al., 2017). Moreover, injectable and self-healing hydrogels can be shaped to the geometry of the wound to release bioactive molecules over time and prevent bacterial infection of the wound (Bertsch et al., 2023; Li Y. et al., 2024). Most of the recent developments have also involved the use of nanoparticles, bioactive peptides, and conductive materials to speed up angiogenesis and collagen deposition during healing. Hydrogel dressings made of bioactive polymers achieved better results in terms of fibroblast growth and faster healing in vivo. Similarly, intravenous silver nanoparticles-impregnated antibacterial hydrogel resulted in a significant enhancement of hemostasis and a decrease in infection in wound healing (Altalhi et al., 2017). In addition, engineered multifunctional hydrogel systems using specially loaded growth-factor nanoparticles have shown significant improvement in angiogenesis and tissue repair in a full-thickness wound model. pH-responsive chitosan-based hydrogels have been developed for diabetic wound healing, achieving >90% wound closure within 14 days in db/db mouse models through coordinated antimicrobial activity, ROS scavenging, and M2 macrophage polarization (El-Husseiny et al., 2024).

5.3 Cardiac regeneration hydrogels

Hydrogels have attracted tremendous interest in cardiac tissue engineering as biomimetic scaffolds that can be used to repair myocardial function following myocardial infarction (MI). They maintain the survival of cardiomyocytes, stem-cell engraftment, and angiogenesis, and mechanically support injured cardiac tissue (Tozzi et al., 2018). It is especially beneficial when injectable hydrogels can be delivered with the lowest invasiveness to infarcted myocardium and form supportive matrices that reduce ventricular remodeling and improve cardiac contractility (Gómez-Cerezo et al., 2019). Also, hydrogels may serve as carriers of stem cells, microRNAs, growth factors, and cytokines to enhance cardiac repair and vascularization. Considering the example of engineered hydrogel patch loading with stem cells, which has enhanced the recovery of the myocardial infarction and cardiac performance in infarction animal models (Maine and Seegopaul, 2016). Similarly, injectable hydrogels based on biomaterials with therapeutic factors had a potent pro-angiogenic effect and scar-reducing effect after MI (Hasan et al., 2015). Smart hydrogels that can deliver gene-based therapeutics or microRNAs and lead to increased cardiomyocyte proliferation and functional recovery of myocardial injury have also been emphasized in recent studies (Yu et al., 2023). Algisyl®, an alginate-based hydrogel for left ventricular remodeling, has completed clinical trials demonstrating safety and efficacy in heart failure patients, with 6-min walk distance improving by 82 m at 12 months compared to baseline (Mann et al., 2016).

5.4 Neural and oral tissue

The compliant mechanical properties of hydrogels, combined with their high biocompatibility and ability to recapitulate neural ECM, enable them to promote axonal growth and neuronal differentiation, making them increasingly popular in neural and oral tissue regeneration (Eldredge et al., 2018). Hydrogel scaffolds may be used in neural repair to transfer neurotrophic factors, stem cells, and bioactive molecules that stimulate axonal regeneration and recovery of neural connectivity following spinal cord or peripheral nerve injury. Also, conductive and electro-responsive hydrogels have been developed to improve neuronal signaling and functional recovery by restoring electrochemical cellular communication (Zhao W. et al., 2023). Hydrogels have been shown to have potential in periodontal regeneration, pulp-dentinal complex repair, and craniofacial bone regeneration due to their ability to promote stem-cell differentiation and mineralization in oral tissue engineering (Borba et al., 2019). According to experimental studies, functionalized hydrogel has the potential to significantly increase the survival of neurons and neurite growth after nerve injury (Omidian et al., 2024). In addition, other recent biomimetic hydrogels that encourage cell-cell adhesion have been illustrated to enhance neurological function recovery in traumatic brain injury models (Tang et al., 2026). Smart/stimuli-responsive hydrogels for brain tissue engineering have been designed to deliver neurotrophic factors (such as Brain-Derived Neurotrophic Factor and Nerve Growth Factor) and stem cells in response to cues from the neural injury microenvironment. This can respond to the biochemical or pathological signals, thereby promoting axonal sprouting, enhancing neuronal survival, and supporting functional recovery in rat models of traumatic brain injury (Xie and Xie, 2024; Kornev et al., 2018).

6 Emerging therapeutic applications of hydrogels beyond tissue engineering

Beyond their traditional role in tissue engineering, hydrogels are increasingly being explored for a wide range of therapeutic applications. Their hydrated, tunable networks and ability to incorporate bioactive molecules allow them to interact dynamically with biological systems. As a result, hydrogels are now being developed for applications such as biosensing, controlled drug delivery, gene therapy, and personalized medicine, where they function as responsive systems that can adapt to physiological conditions and support advanced precision therapies.

6.1 Hydrogels in diagnostics and biosensing

Recently, hydrogel has become a key material in biomedical diagnostics due to its stimuli-responsive nature, high permeability, and ability to entrap biomolecules, developing highly sensitive biosensing platforms. The porous structure allows the architecture to be effectively diffused with the enzymatic, immunological, or nucleic acid stability needed to enable precise detection (Sun and Chen, 2024). Wearable and real-time diagnostic devices responding to diseases are developed using smart hydrogel, which reacts to changes in pH, temperature, glucose, or enzyme activity (Yao et al., 2026). Also, microfluidic systems represented by hydrogel-based microfluidic systems and optical biosensors are actively used in point-of-care diagnostics, which is due to their high sensitivity, high responsiveness, and high biocompatibility (Tavakoli et al., 2022). As an example, aptamer-functionalized hydrogel biosensors are very selective in detecting both cancer biomarkers and pathogenic proteins (Sun and Chen, 2024), or enzyme-loaded hydrogel matrices have been used in continuous glucose biosensors that are more stable and more accurate (Wen et al., 2025). Recent developments also involve responsive hydrogel systems, which can colorimetrically detect pathogens and toxins, highlighting their growing importance in the field of fast clinical diagnostics (Jia et al., 2018). Hydrogel biosensors have proved to be effective biomedical diagnostic tools since they are highly sensitive, flexible, and biocompatible. Hydrogel-based wearable biosensors that continuously track multiple physiological biomarkers (glucose, lactate, and inflammatory cytokines) have been built using functionalized hydrogels with enzymes, antibodies, or aptamers (Sutar et al., 2025).

6.2 Controlled and sustained therapeutic release

Hydrogels are very useful in the controlled and sustained delivery of therapeutic molecules because their three-dimensional hydrophilic polymer networks allow them to encapsulate and regulate the diffusion of drugs, proteins, and biologics, and maintain structural integrity (Buwalda et al., 2017). The mesh size, cross-linking density, and swelling properties can be carefully designed to control diffusion kinetics and realize spatial and temporal control of release profiles at the target tissues (Brezesinski et al., 2010). Hydrogel drug formulations will release drugs via 3 different mechanisms: diffusion, swelling, and degradation. The primary mechanism of diffusion-controlled drug release depends on the cross-link density of the hydrogel polymer chain compared to the size of the encapsulated drug molecule. Degradation-controlled drug release depends on the rate at which the polymer chains undergo hydrolysis or enzyme-induced cleavage. Hydrogel formulations capable of responding to environmental changes such as pH, temperature, and/or the activity of specific enzymes can be further developed into site-specific drug formulations for use in targeted delivery to diseased tissues (Buwalda et al., 2017). Stimuli-reactive hydrogel also enables on-demand drug delivery in response to the environment (e.g., pH, temperature, enzymes, or light) to enhance therapeutic efficacy and reduce systemic toxicity (Xing et al., 2022). Depots of hydrogel injections provide targeted administration and extended maintenance of therapeutic agents where diseases occur, decreasing the number of dosing steps and increasing patient adherence. Experimental results indicate that PEG-based hydrogel nanoparticles that have thermally controllable networks can selectively control the diffusion and release kinetics of the introduced drugs and provide the effectiveness of sustained delivery in the long-term (Shirakura et al., 2014). Similarly, tunable injectable hydrogels that reduce burst release and imply protracted delivery of therapeutic protein therapeutics in vivo. The composite hydrogels that have taken the nanomaterials or bioactive polymers show greater drug maintenance and controlled therapeutic release in the applications of cancer therapy and regenerative medicine. All these developments point to the increasing significance of hydrogel-based delivery systems in the next-generation precision therapeutics (El Aita et al., 2020).

6.3 Hydrogel-mediated gene delivery

The Hydrogel delivery of genes is a new concept in the field of regenerative medicine that offers a biocompatible material, hydrogel, that can transport nucleic acids, DNA, RNA, and CRISPR elements, and promotes local and persistent gene levels in target tissues (Carballo-Pedrares et al., 2020). Contrary to the traditional systemic gene delivery systems, hydrogel scaffolds provide a suitable microenvironment to improve gene stability, reduce rapid degradation, and increase cellular uptake and transfection (Su et al., 2024). Gene vectors can be released by porous architecture and tunable degradation properties of a hydrogel to support therapeutic gene expression throughout tissue regeneration (Zitnay et al., 2018). Furthermore, viral or non-viral vectors, nanoparticles, and biomolecular ligands can be used to improve gene targeting and therapeutic outcomes by integrating them into hydrogel-based delivery systems (Shi et al., 2017). Plasmid DNA (pDNA) activated biomaterial scaffolds have been demonstrated to trigger much greater in vivo transfection and better bone renewal than direct injection of the gene. Direct injection is low-cost and easy, but can have very low transfection efficiency, rapid degradation of DNA, and short-lived expression of gene expression. Scaffold-mediated delivery, alternatively referred to as gene-activated matrices (GAMs), is a protective atmosphere that maintains the release of genes and promotes local cell invasion to enhance osteogenesis. (Taglietti et al., 2014). Hydrogel-based gene therapies delivering siRNA or miRNA have shown promising results in treating cardiovascular diseases by promoting angiogenesis and aiding tissue repair, acting as intelligent, stimuli-responsive systems. (Ramishetti and Peer, 2019). Smart gene-activated hydrogel is a new type of stimuli-responsive, three-dimensional polymeric network that is being developed to address the shortcomings of the previous gene delivery methods, including fast degradation, low transfection, and off-target effects. These systems enable the localized, targeted delivery of therapeutics at the location of disease only by incorporation of genetic materials, like plasmid DNA (pDNA), siRNA, or mRNA, within a hydrogel matrix that reacts to certain pathological stimuli. (Li, 2025; Zuo et al., 2026). With recent advances in nucleic acid therapeutics including mRNA-based therapies and CRISPR-Cas gene editing, hydrogel-mediated gene delivery systems have undergone substantial development. Hydrogels can serve as localized depots for nucleic acid-loaded nanoparticles, protecting them from enzymatic degradation while enabling sustained transgene expression at target tissues. (Ramishetti and Peer, 2019; Xu et al., 2025).

6.4 Individualized regenerative medicine

Hydrogels are gaining recognition as vital biomaterials in personalized regenerative medicine because of the fine-tuning of physicochemical properties, biocompatibility, and ability to cover patient-specific cells, biomolecules, and therapeutic agents, thus supporting personalized treatment plans. Patient-derived stem cells and organoid cultures have a structural similarity to the extracellular matrix, which allows customized tissue regeneration and disease-specific therapeutic interventions (Wu et al., 2020). Further developments in 3D bioprinting and biofabrication technology make it possible to design patient-specific geometries, mechanical properties, and biological cues of the scaffolds made of hydrogel, to reconstruct damaged tissues or organs with high precision. Intelligent hydrogel bioreceptors of biochemical cues in the patient microenvironment are also being engineered to offer adaptive therapeutic dynamics and enhanced treatment results (Segneanu et al., 2025). It is proven experimentally that patient-derived stem cells, which are entrapped by biomimetic hydrogels, serve to improve tissue regeneration and functional recovery in various disease models (Maine and Seegopaul, 2016). 3D bioprinted hydrogel-based personalized implants have shown excellent results in re-engineering complex tissue structures, such as bone, cartilage, and skin, by delivering a scaffold that closely mimics the natural extracellular matrix (ECM). These implants enhance integration with host tissue by facilitating the precise, patient-specific, layer-by-layer assembly of bioinks containing cells and bioactive substances, thereby improving biocompatibility and minimizing immune rejection. (Jakfar et al., 2021). More recent studies also mention hydrogel-based platforms that could offer personalized therapeutic cocktails, hence allowing customized regenerative therapy on the basis of individual genetic and physiological profiles (Balandin et al., 2022).

Increasing usage of hydrogel-based biomaterials as medical devices can be attributed to their favorable biological compatibility, ability to hold large amounts of water, and ability to change physical characteristics. Hydrogel materials are currently used in various clinical applications, including the replacement of damaged tissues, delivering drugs, holding together injured tissue during surgery, and radiation therapy. Examples of hydrogel-based products under clinical trials are listed in Table 2.

TABLE 2. Hydrogel-based products in the market, clinical trials and late-stage development.

Although significant advances have been made in the development of hydrogels for regenerative therapies, few of the developed systems have made it to clinical translation and even less to commercialization. It is a translational challenge because several factors like scalability and manufacturing reproducibility can create batch variability in more complex synthesis routes, and compliance with Good Manufacturing Practice (GMP) standards might be difficult because of the biologically derived components. Another challenge is associated with the sterilization process, as it may change the structure and functional properties of the hydrogel making it difficult to achieve the desired results, and requiring incorporation of the sterilization process into the early design phase. Moreover, hydrogel systems are often classified as combination products, leading to complicated and lengthy approval processes with a large number of safety, biocompatibility and quality control checks.

Other factors such as the cost of production, storage stability, and reimbursement restrictions further impede the use. However, a number of hydrogel-based technologies have made it to clinical translation including cartilage repair with BST-CarGel®; localized cancer treatment with Jelmyto®; Algisyl-LVR® for cardiac remodeling; and hyaluronic acid dermal fillers. The examples demonstrate that biomaterial design can be successfully achieved when it is aligned with clinical requirements, manufacturability, and regulatory requirements. Standardized characterization techniques, predictive preclinical models, scalable manufacturing processes, and early incorporation of regulatory considerations into biomaterials development will be important to the future progress of biomaterials.

7 Current challenges and knowledge gaps

Although there have been tremendous advances in hydrogel-based biomaterials, there are still challenges, including regulatory, manufacturing, and stability concerns. Therefore, future studies should be directed towards developing universal fabrication protocols, improving the reproducibility of biomaterial formulas, and conducting large-scale studies to assess the effectiveness of these materials.

7.1 Complexity vs. translational feasibility

Manufacturability and regulatory feasibility are major challenges for the translation of the ever growing complexity of multi-component and intelligent hydrogels, where improved biofunctionality may be at the cost of manufacturability or regulatory feasibility. These systems add several variables that make process standardization, batch-to-batch consistency and meeting changing regulatory requirements for combination products (Carballo-Pedrares et al., 2026) difficult. However, it has been noted that complex material compositions may hinder clinical translation even when showing promising preclinical results (Xu et al., 2026). To overcome this, the early incorporation of regulatory aspects in the formulation process (e.g., Quality by Design, QbD) and simplification of formulations is of great importance for scalable and reproducible production (Carballo-Pedrares et al., 2026; Alonso et al., 2021).

The mechanical strength, self-healing, and stimuli-responsive behavior can be further improved by the use of advanced strategies, such as the use of nanomaterials to crosslink hydrogels. They also pose problems of complex characterization and possible toxicity of the nanoparticle–polymer interaction, however, that needs to be addressed carefully before use in the clinic (Wang Q. et al., 2023). In sum, there is a constant need for balancing material innovation with translational feasibility for successful clinical development.

7.2 Long-term in vivo fate and integration

The long-term in vivo performance of hydrogel scaffolds frequently differs from the initial preclinical results, in most cases because the degradation rates in the scaffold are faster than those in the tissue. Most studies are designed to assess for a short period of time, while complete resorption, integration into tissue, and potential late symptoms (chronic inflammation, structural fatigue, volumetric changes, etc.) must be investigated over a longer period of time (Carballo-Pedrares et al., 2026; Sun et al., 2026). In addition, over time scaffold degradation affects the mechanical properties, which can potentially result in loss of load bearing capacity before adequate tissue development is achieved (Hunckler et al., 2026). Recent research has demonstrated the significance of controlled degradation kinetics, and tunable systems (PEG-based hydrogels, for example) can tune both stiffness and immune cell recruitment (Likarda, 2026). There are, however, also growing concerns for the safety of these systems since some hydrogel systems have been shown to create immunosuppressive microenvironments and potential tumorigenic changes after long-term exposure in vivo that exceed typical study periods (Liu et al., 2025).

7.3 Lack of standardized evaluation protocols

There is still a lack of standardized approaches to the evaluation of hydrogels, which hinders their progress and clinical application. There is variation in methods of assessing mechanical properties, degradation behaviour and biocompatibility which make it difficult to compare results across studies and make meta-analysis difficult. There are some major problems such as the lack of methodologies, dynamic and multi-scale characterization, and the difficulty in reproducing complex physiological conditions (Chen C. et al., 2025). The ASTM F2900-25 guideline is one such attempt to provide a standard set of parameters, such as composition, crosslinking, mechanical properties, degradation kinetics, and biocompatibility (Standard, 2011). More widespread use of these frameworks, and in situ and cross-scale characterization methods, are necessary to ensure reproducibility and to aid in regulatory decision-making (Chen C. et al., 2025).

7.4 Immunological and inflammatory concerns

Host immune responses to hydrogel implants remain insufficiently understood but are critical for long-term performance. Even natural polymers may retain antigenic components, while synthetic materials can trigger chronic foreign body responses or inflammation due to degradation byproducts or residual reagents (Carballo-Pedrares et al., 2026). Recent advances emphasize immunomodulatory hydrogels that actively direct immune responses toward regeneration rather than merely minimizing inflammation. For instance, nanozyme-based and bioadhesive hydrogels have demonstrated the ability to reduce oxidative stress, promote M2 macrophage polarization, and enhance tissue repair (Li et al., 2026; Li et al., 2025). Nevertheless, immune responses are highly sensitive to material composition and degradation behavior, underscoring the need for precise material design and long-term immunological evaluation to ensure safe and effective clinical outcomes (Hunckler et al., 2026).

The challenges of translational complexity, limited long-term data, lack of standardization, and immunological uncertainty are closely interconnected and must be addressed through integrated strategies. Additionally, strengthening regulatory science frameworks will be essential to facilitate the development and approval of advanced hydrogel-based combination products.

8 Regulatory evolutions for hydrogels

With the emergence of ever more complex advanced biomaterials in the field of regenerative medicine, the regulatory environment of hydrogels has changed significantly. The structural scaffolds in modern hydrogel systems are often integrated with bioactive molecules, cells and therapeutic agents, resulting in products which fall outside the traditional classifications of medical devices, drugs and biologics. This convergence has made available products the focus of new regulatory concerns, and has led to more integrated evaluation approaches in the development of available products (Carballo-Pedrares et al., 2026; Atala et al., 2011).

One major regulatory milestone is the FDA Modernization Act 2.0, which came into effect in 2022, allowing the use of scientifically sound alternative methods, such as organ-on-chip systems, computational modelling and advanced in vitro methods. This transition also provides an opportunity to utilize human-relevant microphysiological models that can provide more physiologically relevant tissue-specific models than traditional animal studies for hydrogel research. Yet, lack of universal criteria for validating hydrogel integrated testing platforms remains problematic for regulatory acceptance and comparative studies (Han, 2023; Marx et al., 2020).

At the same time, regulatory authorities have increased their requirements for full characterisation of the hydrogel and quality-by-design (QbD). Standards focus on a detailed examination of polymer composition, residual impurities, crosslinking efficiency, degradation behavior, sterilisability, and long-term stability. Special attention is paid to degradation products and their biological safety particularly for injectable and implantable hydrogel systems. These requirements represent an overall trend of shift to lifecycle-based assessment, connecting material properties, manufacturing consistency and clinical performance (Carballo-Pedrares et al., 2026; Alonso et al., 2021).

The development of new technologies like 3D bioprinting, patient-specific fabrication, and advanced biofabrication have further broadened the regulatory issues concerning aspects of reproducibility, process validation and quality control. Consequently, regulatory science now has a growing emphasis on not only safety and efficacy, but manufacturability, scalability, and translational feasibility as well. These next-generation hydrogel-based regenerative therapies will be increasingly clinically translatable with continued harmonization of standards and broadened use of human relevant testing methodology (Carballo-Pedrares et al., 2026; Alonso et al., 2021; Kazemi and Maralbashi, 2025).

9 Future perspectives

9.1 AI-assisted hydrogel design

Artificial intelligence (AI) and machine learning (ML) are transforming hydrogel development by enabling prediction of complex structure–property relationships, thereby reducing reliance on trial-and-error experimentation (Li Z. et al., 2024). ML models can analyze large datasets of polymers, crosslinkers, and additives to predict key properties such as mechanical strength, swelling, degradability, and bioactivity, significantly accelerating the design build test cycle (Patel and Webb, 2024). For example, AI-assisted optimization has produced highly adhesive hydrogels with strengths exceeding 1 MPa (Liao H. et al., 2025), while ML-based approaches have identified optimal dual-network hydrogel formulations with high accuracy compared to experimental results (Xu et al., 2024). Beyond property prediction, ML facilitates data-driven and rational material design by mapping compositional parameters to functional outcomes, including degradation behavior and drug release kinetics. Advanced models, such as graph neural networks, further enable prediction of hydrogel–protein interactions for designing bioactive matrices. Additionally, integration of ML with smart hydrogel sensors allows precise analysis of complex signals, improving detection accuracy by 30%–40% over conventional methods. Overall, AI/ML is shifting hydrogel research toward intelligent, predictive, and application-oriented design frameworks (Junaid and Idris, 2024).

9.2 Personalized hydrogel therapies

Recent innovations in biofabrication technology allow personalized biofabrication hydrogel therapy to be created based on individual anatomy, cellular compendia, and phenotype. Hydrogels are especially ideal in the area of personalized medicine since mechanical, chemical, and biological characteristics can be accurately tailored to fit certain tissue needs and cell types of patients (Wu et al., 2020). The combination of medical imaging, computational modeling, and 3D bioprinting can be used to fabricate patient-specific hydrogel scaffolds that can mimic defect geometry and microenvironmental cues and promote tissue regeneration. Indicatively, injectable extracellular-matrix-derived hydrogels have been shown to stimulate cell proliferation and tissue-specific differentiation, which offer personalized regenerative microsurroundings to patient-derived cells. On the same note, ECM-derived hydrogels with patient-specific stem cells have demonstrated improved cartilage repair and remodeling with host tissues in preclinical studies. What is emerging is the intersection of biomaterials science, precision medicine, and digital biofabrication technologies in the direction of individualized regenerative therapies (Giobbe et al., 2019).

9.3 Intelligent, adaptive, and “living” hydrogel systems

The future of hydrogel biomaterials is based on intelligent, adaptive systems that dynamically adapt to biological cues and can regulate therapeutic activities onsite. These living hydrogels entrap engineered or genetically modified cells into biomaterial matrices, so that the scaffold acts as a biologically active microenvironment that generates therapeutic molecules in response to local physiological stimuli. Synthetic biology and biomaterial engineering advances have provided hydrogels that can release drugs, growth factors, or signaling molecules in response to environmental stimuli, e.g., pH, enzymatic activity, or inflammation. As an example, genetically modified ECM-derived hydrogels are tunable to bioactivity and also to the regeneration of tissues via regulated cellular signaling pathways (Trevizani et al., 2025). In addition, biomimetic hydrogels with live cells have demonstrated sustained culture and functional network formation of neurons, highlighting the possibility of dynamic biomaterial systems for complex tissue regeneration. These tissue engineers are the paradigm shift of self-regulating regenerative therapies (Giobbe et al., 2019).

The convergence of synthetic biology and hydrogel engineering has allowed the production of “living” hydrogels with engineered cells that produce therapeutic proteins in response to microenvironmental cues. For example, the bottom-up approach of using genetically modified mesenchymal stem cells encapsulated in CPP (MMP-degradable PEG hydrogels) has been programmed to secrete bone morphogenetic protein-2 in response to proinflammatory cytokines to achieve spatiotemporally controlled bone regeneration in critical size defects (Chen et al., 2021).

9.4 Clinical adoption and commercialization

The commercialization of hydrogel technologies in lab work to clinical practice is improving speedily, with several formulations undergoing clinical trials and regulatory approval procedures. Decellularized extracellular matrix hydrogel and synthetic polymer system hydrogel have already been shown to succeed in clinical healing of wounds, cartilage repair, and soft-tissue regeneration (Vriend et al., 2022). The commercialization of hydrogel-based biomaterials requires balanced synergies between innovative material design and scalable production processes, quality control, reproducibility, and clear regulatory frameworks that could ensure safety and efficacy. Indicatively, the ECM-based hydrogels have already been utilized in regenerative therapies because of their capacity to recapitulate the native tissue microenvironment and cellular remodeling in vivo. Also, the fabrication and biofabrication of hydrogel technologies have now been standardized to allow the production of reproducible biomaterial systems on an industrial scale that can be translated into clinical use. It is thus projected that the experimental interface of biomaterials science, biotechnology, and clinical medicine will ensure that in the next decade, hydrogel-based regenerative therapies are commercially and widely adopted in clinical practice.

10 Conclusion

Hydrogels are useful biomaterials in the field of tissue engineering and regenerative medicine as a close counterpart to the extracellular matrix (ECM) and also because of their support of the vital functions of the cells. Their hydrophilic networks are three-dimensional and encourage cell adhesion, proliferation, migration, as well as differentiation, and can be tuned to specific therapeutic applications. New developments in technology and chemistries of polymers and fabrication have transformed hydrogels into multifunctional platforms with regulated mechanical characteristics and with incorporated bioactive applications. Other important trends in hydrogels between 2020 and 2026 are the implementation of hybrid systems comprising natural and synthetic polymers to improve signaling and mechanical functionality in hydrogels. Self-healing, conductive, and stimuli-responsive hydrogels allow to deliver therapy precisely and to control cells. The use of emerging technologies such as AI-assisted design, 3D bioprinting, or patient-specific biofabrication is shortening the time to achieve personalized regenerative therapies. Also, synthetic biology and hydrogel engineering are being coupled together to create adaptive systems that react to biological stimuli. Even after advances, clinical translation still has challenges such as mechanical constraints, inappropriate long-term data, absence of standardized protocols, immunological problems, and intricate regulatory pathways. The development of the future will require the presence of consensus standards, scalable manufacturing, predictive models, intensive studies, and interdisciplinary collaborations. The further development of hydrogels will increase their application in regenerative medicine and in the case of precision therapies, leading to better patient outcomes.

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Glossary

AI Artificial Intelligence ANF Aramid Nanofiber ASTM American Society for Testing and Materials BDNF Brain-Derived Neurotrophic Factor BMP-2 Bone Morphogenetic Protein-2 BST-CarGel Chitosan-based scaffold for cartilage repair (brand name) Ca ^**2+** Calcium ion CD44 Cluster of Differentiation 44 (receptor for hyaluronic acid) CE Conformité Européenne (European conformity) CNC Cellulose Nanocrystal CNP Carbon Nanoparticle (context: CNTs/CNPs/PVA-borax) CNT Carbon Nanotube CPP Cell-Penetrating Peptide (or MMP-degradable PEG hydrogel context) CRISPR Clustered Regularly Interspaced Short Palindromic Repeats DAHA Dopamine-Grafted Hyaluronic Acid DLP Digital Light Processing DN Double-Network DNA Deoxyribonucleic Acid DSMA Degree of Methacrylamide Substitution ECM Extracellular Matrix EGF Epidermal Growth Factor FDA U.S. Food and Drug Administration FGF Fibroblast Growth Factor GelMA Gelatin Methacryloyl GelMAQ Quaternary Ammonium-Functionalized Gelatin Methacryloyl HA Hyaluronic Acid HAMA Methacrylated Hyaluronic Acid HRP Horseradish Peroxidase IPN Interpenetrating Polymer Network LCST Lower Critical Solution Temperature MBAA N,N′-Methylenebisacrylamide MDCK Madin–Darby Canine Kidney (cells) MI Myocardial Infarction ML Machine Learning MMP Matrix Metalloproteinase mRNA Messenger RNA MSC Mesenchymal Stem Cell NGF Nerve Growth Factor NGO (likely) Nanographene Oxide (context: NGO bioadhesive hydrogel) NMR Nuclear Magnetic Resonance OKGM (probably) Oxidized Konjac Glucomannan (context: collagen-chitosan-OKGM) PCL Poly(ε-caprolactone) PEDOT:PSS Poly(3,4-ethylenedioxythiophene):Polystyrene Sulfonate PEG Polyethylene Glycol PEGDA Polyethylene Glycol Diacrylate PEO-b-PDPA Poly(ethylene oxide)-block-poly(2-(diisopropylamino)ethyl methacrylate) PLA Poly(lactic acid) PLGA Poly(lactic-co-glycolic acid) PNIPAM Poly(N-isopropylacrylamide) PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses PVA Polyvinyl Alcohol RGD Arginine-Glycine-Aspartic acid (peptide sequence) RHAMM Receptor for Hyaluronic Acid-Mediated Motility RILN Reversibly Interlocking Polymer Network RNA Ribonucleic Acid ROS Reactive Oxygen Species siRNA Small Interfering RNA SPAAC Strain-Promoted Azide–Alkyne Cycloaddition TERM Tissue Engineering and Regenerative Medicine TGF-β Transforming Growth Factor-Beta UH (likely) Urushiol (context: P(AA-co-UH)) VEGF Vascular Endothelial Growth Factor β-TCP β-Tricalcium Phosphate

Footnotes

Edited by: Diego Trucco, Sant'Anna School of Advanced Studies, Italy

Reviewed by: Arindam Pramanik, Amity University, India

Aniruddha Pal, Independent Researcher, Jadavpur, India