Hydrogels possess unique structural characteristics that enable them to closely mimic biological tissues, rendering them highly biocompatible and suitable for a myriad of biomedical applications 1. These matrices can encapsulate therapeutic agents and release them in a controlled and sustained manner, thereby addressing various therapeutic needs across disease contexts owing to their ability to retain water while maintaining structural integrity 2. Hydrogels play a pivotal role in modern drug delivery by facilitating targeted delivery and minimizing systemic side effects 3. The ability to incorporate responsive elements within hydrogels, such as pH, temperature, or enzyme sensitivity, further enhances their relevance in precision medicine, where treatments can be tailored to an individual’s unique biological environment (Figure 1). Overall, the flexibility, biocompatibility, and precision with which hydrogels control drug release make them indispensable for advancing therapeutic delivery.

Matrix-based hydrogels have been designed to address several critical challenges that have traditionally hindered effective drug delivery, including stability, bioavailability, and controlled release. Conventional drug delivery methods often suffer from poor bioavailability due to rapid drug clearance or degradation within the body. However, matrix-based hydrogels offer enhanced stability, creating a protective barrier around the encapsulated drug that prevents premature degradation and prolongs its therapeutic effects 4,5. In addition, matrix-based hydrogels provide a high degree of control over drug release profiles. By modifying the crosslinking density and molecular composition of the hydrogel matrix, researchers can design systems that release drugs over an extended period or in response to specific biological triggers. Furthermore, the development of matrix-based hydrogels aligns with the principles of personalized medicine, in which treatment regimens are tailored to individual patient profiles. For instance, pH-sensitive hydrogels with crosslinked networks can release drugs in response to the acidic environment of tumor tissues, thereby maximizing drug delivery efficacy while reducing off-target effects 6,7. Thus, matrix-based hydrogels can significantly improve the precision and efficacy of drug therapies, particularly in the treatment of chronic diseases such as cancer, diabetes, and cardiovascular conditions, where conventional drug delivery methods are often inadequate.

In this narrative review, we systematically present matrix-based hydrogels and their biomedical applications. We conducted a comprehensive database search across ScienceDirect, PubMed, Web of Science (WOS), and Scopus using a strategy that combined keywords with Boolean operators: “Hydrogel,” “matrix-based hydrogel,” “Drug delivery,” and “Biomedical application” (Figure 2). All studies published between 2015 and 2025 were initially screened based on their titles and abstracts to eliminate duplicates and irrelevant literature. Full-text English articles were then assessed for eligibility. The inclusion criteria comprised original research, reviews, books, and clinical trials that focused on matrix-based hydrogel design, crosslinking, properties, and biomedical applications. Editorials, commentaries, and conference proceedings without primary data were excluded. Following screening, the studies deemed eligible for this review were included in the qualitative analysis. A narrative synthesis approach was employed due to the inherent variability in study design and reporting. Data were manually extracted using a standardized framework to document hydrogel composition, fabrication, crosslinking, functional features, and biomedical applications.

The performance of matrix-based hydrogels in biomedical systems fundamentally depends on their internal architecture, which is governed by both the synthesis route and crosslinking mechanism. This section integrates these two core design parameters into a unified framework, detailing how the polymer source, network-forming chemistry, and fabrication methods determine mechanical integrity, degradation, and therapeutic suitability. The translational implications of each approach are emphasized, bridging materials science with regulatory and clinical perspectives. The most commonly used methods for hydrogel preparation are tabulated in Table 1. Methods such as radiation crosslinking and free radical polymerization are preferred for large-scale production because of their efficiency and reliability. Simpler methods, such as physical crosslinking or freeze-thaw cycling, are cost-effective and commonly utilized for low-tech applications.

Hydrogels are increasingly recognized for their versatility across a wide range of biomedical applications, largely due to their high water content, biocompatibility, and adjustable physical and chemical properties. Recent advancements in hydrogel design have facilitated significant progress in various medical fields, including targeted drug delivery, tissue engineering, wound healing, cancer treatment, and biosensing. This section examines these developments, emphasizing how novel materials, synthesis techniques, and functionalization strategies have broadened the potential of hydrogels for medical and therapeutic applications (Figure 3). Hydrogels have undergone substantial evolution in recent years, with enhancements in their design, functionality, and applications (Table 2).

Although matrix-based hydrogels have advanced rapidly in preclinical models, the clinical portfolio remains concentrated in a few application domains: wound management, soft-tissue augmentation, and localized drug depots, while definitive trials for more complex indications (e.g., load-bearing tissue regeneration and intratumoral drug release) are still emerging. Several ongoing clinical studies have demonstrated the translational breadth of matrix-based hydrogels in surgical reconstruction, wound care, orthopedics, and intervertebral disc repair (Figure 5). The role of a self-assembling RADA16 peptide hydrogel (PuraGel) is being assessed in endoscopic skull base surgery to expedite mucosal healing of nasoseptal flap donor sites and reduce sinonasal morbidity following cranial base procedures (interventional; recruiting). This trial evaluated wound healing and postoperative sinonasal outcomes, providing evidence for the regenerative applications of short-peptide hydrogels in soft tissues 94. A randomized study (NCT06978569) comparing an acellular dermal matrix (ADM) hydrogel with conventional alginate dressings is planned to determine whether the ADM hydrogel accelerates wound closure in chronic traumatic wounds and improves the local tissue quality. This study (sponsor: Isfahan University of Medical Sciences) will determine whether biologically derived hydrogel matrices can outperform standard care in chronic wound management and whether they meet clinical endpoints, such as wound area reduction at 12 weeks. In orthopedics (NCT04840147), a multicenter, randomized, controlled trial is comparing JointRep (a matrix scaffold/hydrogel adjunct) plus microfracture with microfracture alone for focal chondral defects, evaluating both functional and structural outcomes (e.g., patient-reported outcomes and imaging endpoints) 95. This study aimed to determine whether hydrogel-augmented cartilage repair confers durable functional benefits compared to established surgical techniques. Collectively, these trials highlight two important translational themes: (1) matrix-based hydrogels are being tested across diverse anatomic sites and indications, often with primary endpoints anchored to local tissue healing, pain relief, or functional restoration rather than long-term survival; and (2) early phase studies prioritize safety, biocompatibility, and surrogate efficacy measures—outcomes that must be bridged to larger randomized trials with clinically meaningful endpoints for definitive regulatory acceptance. To accelerate translation, future trials should harmonize biomaterial characterization (International Organization for Standardization, ISO-10993 testing, and GMP specifications), incorporate standardized clinical endpoints and imaging/biomarker panels to enable cross-study comparisons, and include longer follow-ups to capture durability and late adverse events.

The patent landscape for matrix-based hydrogels has expanded significantly over the past five years, reflecting the growing interest in both biomedical applications and translational potential 101. An analysis of patents filed between 2020 and 2024 revealed a focus on hydrogel design for tissue engineering, drug delivery, and organ-on-chip platforms. Key trends include innovations in crosslinking strategies, stimuli-responsive functionalities, and hybrid natural-synthetic formulations. Major stakeholders include academic institutions, biotech startups, and established medical device companies, highlighting both research-driven and commercially motivated development 102. This patent landscape provides insights into emerging directions, guiding future research and the potential commercialization of matrix-based hydrogel technologies.

Hydrogels hold immense potential for biomedical applications; however, translating laboratory innovations into clinical use requires addressing mechanical limitations, cost-effective production, scalability, and regulatory compliance issues. Regulatory considerations are critical for the successful clinical translation of hydrogel-based biomedical devices. Depending on device classification, the FDA may require either a 510(k) premarket notification or a more rigorous premarket approval (PMA) process. Sterilization compatibility is also essential, as standard methods such as γ-irradiation and ethylene oxide (ETO) can alter the hydrogel structure and functionality, necessitating careful optimization to preserve its mechanical and drug-release properties. Rather than viewing these as insurmountable barriers, ongoing research provides evidence-based solutions that are reshaping the field 103. A significant limitation of hydrogels, particularly in load-bearing applications (bone, cartilage, and skin), is their low mechanical strength and susceptibility to enzymatic degradation under physiological stress 104,105. Recent advances have demonstrated that incorporating nanocellulose, graphene oxide, or silica nanoparticles into nanocomposite matrices markedly enhances their tensile strength and elasticity, while maintaining cytocompatibility 106. For instance, Feng et al. 107 reported a GO-GO-chitosan hybrid hydrogel with 4-fold higher compressive modulus than unreinforced gels, whereas Zhao et al. achieved similar mechanical gains using nanocellulose crosslinkers 108. The apparent variability stems from differences in crosslinking chemistry (hydrogen bonding vs. covalent grafting) and nanoparticle surface functionalization, which govern the load transfer and water retention. There is a consensus that dual-network and hybrid crosslinking (physical + covalent) approaches best balance the injectability, resilience, and degradation rate. However, contradictions remain regarding nanoparticle cytotoxic thresholds and long-term inflammatory responses, especially in cartilage or bone implantation models.

The reliance on specialized synthetic polymers and reactive crosslinkers often inflates production costs and complicates GMP compliance 109. Comparative studies have shown that bio-based hydrogels made from chitosan, alginate, or bacterial cellulose can achieve mechanical and biological properties comparable to those of PEG or PVA systems when processed via enzymatic crosslinking (e.g., transglutaminase or horseradish peroxidase). Enzymatic and radiation-induced crosslinking are now favored for their scalability and reduced chemical residue, supporting both environmental sustainability and regulatory acceptance. Industrial-scale manufacturing strategies, such as freeze–thaw cycling and radiation crosslinking, have been adapted to achieve batch consistency and sterility 110. The regulatory landscape is increasingly aligned with the ISO-10993 standards for biocompatibility, which govern cytotoxicity, genotoxicity, immunogenicity, and degradation byproducts. For instance, researchers developed a gelatin–hyaluronic acid–chondroitin sulfate hydrogel crosslinked using 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and evaluated its safety according to ISO-10993-11 (acute systemic toxicity, implantation, and intracutaneous reactivity), demonstrating regulatory-grade preclinical validation 109. Early integration of ISO-compliant testing accelerates translational timelines and facilitates alignment with FDA and EMA GMP standards, particularly for drug-loaded and implantable systems 111. Despite promising preclinical outcomes, most pH-, enzyme-, and temperature-responsive smart hydrogels remain confined to early-stage trials. Emerging translational approaches couple multi-stimuli responsiveness with patient-specific molecular profiling, enabling personalized drug delivery and the development of regenerative strategies. However, reproducibility and response stability across patient cohorts remain key barriers. Comparing approved and experimental systems highlights the translational gap: ISO-compliant, clinically validated hydrogels (alginate wound dressings, hyaluronic acid fillers) exhibit consistent safety and mechanical predictability, whereas nanocomposite or smart hydrogels, although highly functional, face challenges in regulatory standardization and reproducibility (Table 4).

A critical evaluation of different hydrogel classes reveals inherent trade-offs among mechanical strength, biodegradability, and biological performance, with natural polymers excelling in biocompatibility but lagging in durability 125. In contrast, synthetic polymers offer structural robustness at the expense of bioactivity (Table 5). Beyond materials science, emerging translational solutions include AI-guided hydrogel formulation optimization, organ-on-chip testing for preclinical biocompatibility, and in silico degradation modeling, which reduce animal use and accelerate approval. Collaboration among materials scientists, clinicians, and regulatory agencies is essential to standardize bench-to-bedside evaluation pipelines and ensure that hydrogel innovations achieve clinical and commercial viability 126.

The future of hydrogel research is poised for rapid expansion, with multiple exciting directions on the horizon. One promising avenue is the development of hydrogels that can respond to multiple stimuli simultaneously. Multi-responsive hydrogels, which can respond to combinations of physical, chemical, and biological cues, can provide sophisticated drug delivery systems that adapt to the dynamic environments within the body. For instance, such systems can release drugs in response to temperature and pH changes within a tumor, offering a dual-action approach to cancer treatment. Additionally, integrating biosensors into hydrogels could enable real-time monitoring of drug release and therapeutic efficacy, leading to personalized and adaptive treatments. The integration of bioinformatics and computational design methods is an exciting development. By applying advanced modelling techniques to predict the behavior of hydrogels in biological systems, researchers can optimize hydrogel design before synthesis, accelerating the development of new materials. Machine learning algorithms can also help identify novel polymer structures and fabrication techniques, thereby streamlining the discovery of hydrogels with specific functionalities. As our understanding of hydrogel behavior continues to improve, the potential to create fully autonomous hydrogel-based systems that dynamically respond to the body’s needs is increasing, thereby boosting the overall effectiveness of treatments. The future of hydrogel research is set for rapid growth, although many recent innovations remain preclinical or under regulatory review, with several exciting directions on the horizon that hold great promise.

Matrix-based hydrogels are a highly versatile and promising class of materials for drug delivery and other biomedical applications. Their ability to retain large amounts of water and provide a soft biocompatible matrix for the encapsulation of drugs, cells, or bioactive agents makes them ideal for a range of therapeutic applications. With advances in hydrogel synthesis and functionalization, hydrogels are now being developed to respond to specific environmental triggers, release drugs in a controlled and targeted manner, and adapt to patients changing needs. These innovations promise to revolutionize drug delivery, tissue engineering, wound healing, and other medical fields. Although significant progress has been made, the future of hydrogel technology in medicine depends on overcoming key challenges, such as improving mechanical strength, reducing production costs, and developing hydrogels that can respond more precisely to complex physiological signals. The ongoing development of multi-stimuli-responsive hydrogels, combined with the integration of bioinformatics and personalized medicine strategies, holds promise for these materials. As hydrogels continue to evolve, they are expected to play a central role in advancing therapeutic strategies and improving patient care. Hydrogels are a versatile and rapidly evolving class of biomaterials with significant potential for supporting next-generation therapeutic and diagnostic platforms. Taken together, the literature shows that hydrogel performance arises from interactions between polymer chemistry, network architecture, and additive components (nanoparticles, peptides, and drugs) rather than any single material property. Dual- or multi-stimuli systems outperform single-stimuli systems only when the stimuli operate through complementary, non-redundant mechanisms and when network reversibility and degradation kinetics are harmonized with the intended dosing regimen. Similarly, nanoparticle incorporation enhances functionality but requires careful optimization of size, surface chemistry, and loading to avoid undesirable immunogenicity or cytotoxicity. Therefore, moving hydrogel platforms from bench to bedside requires systematic cross-study comparisons, standardized characterization protocols, and long-term in vivo safety data.

3D: Three-dimensional; ADM: Acellular Dermal Matrix; AI: Artificial Intelligence; Ca²⁺: Calcium ions; CDx: Companion Diagnostic; CFR: Code of Federal Regulations; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; DNA: Deoxyribonucleic acid; ECM: Extracellular Matrix; EDC: 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide; EMA: European Medicines Agency; ETO: Ethylene Oxide; FDA: Food and Drug Administration; GMP: Good Manufacturing Practice; GO: Graphene Oxide; HA: Hyaluronic Acid; IPN: Interpenetrating Polymer Network; ISO: International Organization for Standardization; MDR: Multidrug-resistant; mRNA: Messenger Ribonucleic Acid; PEG: Poly(ethylene glycol); PMA: Premarket Approval; PNIPAAm: Poly(N-isopropylacrylamide); PVA: Poly(vinyl alcohol); RADA16: Arginine-Alanine-Aspartic Acid-Alanine 16-mer peptide; RGD: Arginylglycylaspartic acid; RNA: Ribonucleic acid; UV: Ultraviolet; WOS: Web of Science

We thank BioRender for providing a platform that improved the graphical representation. Figures 1, 3, 4, and 5 were created using BioRender (https://app.biorender.com/) with permission to publish.

RS and RSh conceptualized the study. AR, RS, and RSh conducted analyses, drafted, and revised the manuscript. DS, RB, and AC analyzed and reviewed the manuscript.

None.

Data and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Not applicable.

Not applicable.

The authors declare that they have not used generative AI (a type of artificial intelligence technology that can produce various types of content including text, imagery, audio and synthetic data.

The authors declare that they have no competing interests.