High-performance hydrogels in orthopedics: Structural design, performance tuning, and clinical potential.

High-performance hydrogels in orthopedics: Structural design, performance tuning, and clinical potential - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Mater Today Bio . 2026 Apr 3;38:103101. doi: 10.1016/j.mtbio.2026.103101 Search in PMC Search in PubMed View in NLM Catalog Add to search High-performance hydrogels in orthopedics: Structural design, performance tuning, and clinical potential Xuan Sun Xuan Sun a Department of Orthopedic Surgery, Jiujiang University Affiliated Hospital, Jiujiang, 332006, China c First Clinical Medical College of Yangtze University, Jingzhou, 434000, China Find articles by Xuan Sun a, c, 1 , Weiliang Wu Weiliang Wu b Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China Find articles by Weiliang Wu b, 1 , Guoliang Chen Guoliang Chen b Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China Find articles by Guoliang Chen b, ⁎⁎⁎ , Bo Huang Bo Huang a Department of Orthopedic Surgery, Jiujiang University Affiliated Hospital, Jiujiang, 332006, China d Jiujiang Orthopedic Medical Quality Control Center, Jiujiang, 332006, China Find articles by Bo Huang a, d, ⁎⁎ , Kai Sun Kai Sun a Department of Orthopedic Surgery, Jiujiang University Affiliated Hospital, Jiujiang, 332006, China d Jiujiang Orthopedic Medical Quality Control Center, Jiujiang, 332006, China Find articles by Kai Sun a, d, ⁎ Author information Article notes Copyright and License information a Department of Orthopedic Surgery, Jiujiang University Affiliated Hospital, Jiujiang, 332006, China b Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China c First Clinical Medical College of Yangtze University, Jingzhou, 434000, China d Jiujiang Orthopedic Medical Quality Control Center, Jiujiang, 332006, China ⁎ Corresponding author. Department of Orthopedic Surgery, Jiujiang University Affiliated Hospital, Jiujiang, 332006, China. [email protected] ⁎⁎ Corresponding author. Department of Orthopedic Surgery, Jiujiang University Affiliated Hospital, Jiujiang, 332006, China. [email protected] ⁎⁎⁎ Corresponding author. Department of Orthopedic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China. [email protected] 1 These authors contributed equally to this study. Received 2026 Jan 25; Revised 2026 Mar 21; Accepted 2026 Apr 3; Collection date 2026 Jun. © 2026 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). PMC Copyright notice PMCID: PMC13090724  PMID: 42006711 Abstract Orthopedic diseases ( e.g. , bone defects, degenerative spinal conditions, fracture non-unions, and bone infections) pose significant challenges to traditional clinical treatment strategies. Since hydrogels are polymeric materials characterized by three-dimensional hydrophilic network structures, they have broad application prospects for orthopedic treatment due to their excellent biocompatibility, tunable mechanical properties, efficient drug loading and controlled release capabilities, and structural characteristics closely resembling bone tissue microenvironments. A systematic review of the design principles for hydrogels in orthopedics is presented in this paper, covering material selection, structural regulation strategies, cross-linking mechanisms and functional modifications. Hydrogel applications in the orthopedic field include bone defect repair, spinal fusion, fracture healing promotion, infection control, and cartilage regeneration. In addition, the paper examines key challenges in hydrogel clinical translation for orthopedic applications. These challenges include insufficient mechanical strength and mismatched degradation rates in bone regeneration. Finally, this paper explores future development directions for integrating hydrogels with cutting-edge technologies such as 3D printing, smart responsive systems, and gene therapy, providing a theoretical basis for translating fundamental research on orthopedic hydrogels into clinical applications. Keywords: Hydrogel, Orthopedic diseases, Material design, Challenge, Clinical translation Graphical abstract Using orthopedic hydrogels as a design strategy (material selection, structural regulation, cross-linking methods, and functionalization), this review examines their application for treating bone defects, spinal diseases, fracture healing, infection prevention, and regeneration of articular cartilage. Along with mechanical properties, degradation kinetics, and clinical translation, the article also discusses future developments integrating 3D printing, stimulus-response systems, and gene therapy, providing a theoretical basis for basic research and clinical translation. Open in a new tab 1. Introduction In recent years, accelerated global population aging and the widespread prevalence of unhealthy lifestyles and dietary habits have led to a marked increase in the incidence of skeletal disorders and injuries. Pathological bone defects caused by osteoporosis, infection, diabetes, and nonunion, along with conditions such as spinal degenerative disease, delayed fracture healing, orthopedic implant infections, and articular cartilage damage, have become significant challenges in clinical orthopedics. [ [1] , [2] , [3] ]. Such orthopedic conditions not only cause severe pain but also significantly elevate disability and mortality rates, imposing a substantial burden on healthcare systems worldwide [ 4 ]. Although bone possesses an intrinsic regenerative capacity, this innate ability is often compromised when confronting complex and severe musculoskeletal pathologies. Consequently, its self-repair mechanisms frequently prove insufficient to achieve effective healing [ [5] , [6] , [7] ]. Therefore, there is an urgent need for highly effective therapeutic interventions and novel biomaterials to overcome the limitations of traditional treatments. Currently, traditional orthopedic treatment methods employed for various orthopedic conditions in clinical practice primarily include autografts [ 8 ], allografts [ 9 ], bone cement [ 10 ], and metallic implants ( Fig. 1 ) [ 19 ]. Autologous transplantation is a typical therapeutic approach involving the removal of healthy cells, tissues, or organs from a patient's body. These are then processed outside the body before being reimplanted to repair or replace diseased or deficient tissues. Autologous bone grafting is regarded as the "gold standard" for bone defect repair due to its trifecta of osteoinductive, osteogenic, and osteoconductive properties [ 20 ]. However, this technique is hampered by several significant limitations, including not only a high recurrence rate of donor-site fracture, and prolonged recovery but also an increased risk of postoperative pain and infection due to the requirement for multiple surgical procedures [ [21] , [22] , [23] ]. Allogeneic transplantation refers to the implantation of biological tissues or organs derived from another individual of the same species and carrying homologous antigens into the recipient's body. These grafts exhibit diverse morphological forms ( e.g ., cancellous bone blocks and cortical bone plates) and owing to their relatively broad sources, are more readily amenable to standardized processing and storage [ 24 ]. Compared to autografts (using the patient's own bone), allografts avoid donor site surgery and related complications while offering potential to promote bone healing and remodeling. However, they still face core challenges including immune rejection, poor osseointegration, disease transmission, and ethical controversies [ 25 , 26 ]. Bone cement (BCs) has emerged as an efficient biomimetic material for bone repair due to its self-setting properties at physiological temperatures and superior osteogenic capacity [ 27 ]. However, its synthetic components may induce immune stimulation, leading to adverse reactions such as poor degradation and inflammation. Furthermore, it may trigger serious complications including delayed bone healing, implant subsidence, and even nonunion, thereby prolonging patients' bed rest duration [ 28 , 29 ]. Metal implants ( e.g. , stainless steel, Nickel-titanium alloy, Cobalt-chromium alloy and titanium alloys) are widely used in bone defect repair due to their excellent mechanical properties, biocompatibility, and manufacturing processes. Compared to BCs, certain metals also avoid local high-temperature issues through their injectability and low melting points. However, the inability of metals to undergo in-situ shaping within the body remains a primary limitation to their clinical applicability. Although traditional methods such as autogenous bone grafting, allogeneic grafts, artificial bone cement, and metal implants are widely used in orthopedic reconstruction, their inherent limitations constrain further clinical adoption [ [30] , [31] , [32] , [33] ]. Key challenges include donor shortage, immune rejection, risk of infection, and poor biocompatibility. These factors collectively compromise therapeutic outcomes and patient prognosis. Therefore, there is an urgent need to develop novel multifunctional biodegradable materials and related therapeutic strategies to effectively repair various orthopedic defects and treat related diseases, thereby advancing progress in this field [ [34] , [35] , [36] ]. Fig. 1. Open in a new tab A comparative schematic of conventional treatments (autograft, allograft, bone cement, and metal prosthesis) versus hydrogel-based therapy for bone repair [ [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] ]. Given the limitations of traditional implants, such as immune reactivity, poor host-tissue integration, and the necessity for secondary surgical extraction, the research paradigm in bone regenerative biomaterials has been redirected toward degradable bioactive materials [ 37 ]. These materials not only interact with living tissue to promote osseointegration, and their degradation rates can also be precisely engineered to initiate breakdown after the repair process is complete. This enables synchronization between the degradation rate and the rate of bone regeneration. Tissue engineering has garnered significant attention due to its immense potential in bone tissue reconstruction, prompting extensive research to focus on key biomaterials for constructing engineered bone tissue, particularly various natural and synthetic polymers [ [38] , [39] , [40] ]. However, traditional scaffold materials prepared through tissue engineering often fail to effectively promote cell adhesion, proliferation, and differentiation due to their inherent lack of biological activity. They also suffer from inadequate biological properties and issues of non-degradability or uncontrolled degradation rates [ 41 ]. Therefore, developing biomimetic hydrogels that can highly mimic the complexity of natural bone tissue is regarded as a key breakthrough direction for replacing traditional bone engineering materials [ 42 , 43 ]. Hydrogels are three-dimensional network materials formed by hydrophilic polymer chains through physical or chemical cross-linking [ [44] , [45] , [46] ]. Their most distinctive feature is the ability to absorb and retain water far exceeding their own weight. When swollen, they remain rich in water yet insoluble in it. The essence of this property stems from its chemical structure: hydrophilic groups on the polymer backbone confer strong water absorption capabilities, while crosslinks between the network chains ensure the material's structural integrity, preventing dissolution in water [ 47 ]. These unique characteristics demonstrate immense application potential in the biomedical field, particularly in tissue engineering. Additionally, hydrogels have garnered significant attention due to their three-dimensional tissue-like structure, high water content, excellent biocompatibility, tunable physicochemical properties, and capacity to serve as therapeutic molecular carriers [ [48] , [49] , [50] ]. First, hydrogels' outstanding biocompatibility enables them to effectively avoid significant side effects such as cytotoxicity and immune reactions after implantation, providing a safe biological interface for tissue repair. Second, their in vivo sustained-release degradation characteristics and swelling behavior effectively prolong drug retention time at the lesion site [ 51 ]. Through flexible modification strategies, hydrogels can also be endowed with enhanced mechanical properties, superior cell adsorption capabilities, controllable drug release characteristics, and favorable osteoconductivity. They exhibit a range of ideal physicochemical properties and demonstrate multi-modal stimulus responsiveness, responding to various biological microenvironments or external physical signals such as pH changes, near-infrared light irradiation, reactive oxygen species levels, and ultrasound [ [52] , [53] , [54] ]. These unique advantages make hydrogels highly promising materials for bone tissue engineering, with widespread applications in bone scaffolds [ 55 ], defect fillers [ 56 ] and multifunctional drug delivery systems [ 57 ]. Early research focused on developing hydrogel matrices from natural polymers ( e.g ., hyaluronic acid (HA) [ 58 ] and sodium alginate [ 59 ]) and synthetic polymers ( e.g. , polyethylene glycol [ 60 ] and polylactic acid [ 61 ]). For instance, HA is utilized for joint lubrication due to its biocompatibility and viscoelasticity, while alginates form injectable hydrogels through calcium ion cross-linking for bone defect filling. With the advancement of tissue engineering and regenerative medicine concepts, research has shifted toward constructing multifunctional composite hydrogels designed to provide mechanical support, bioactive signaling guidance, and synergistic therapies like antimicrobial and anti-inflammatory effects simultaneously. Currently, this field is rapidly evolving toward intelligent, precise, and personalized approaches. Current research is primarily focused on the following key directions: In terms of multi-drug synergy, anti-inflammatory drugs and growth factors are co-loaded to enable more precise modulation of the local pathological microenvironment. In the area of intelligent drug release, pH/enzyme-responsive hydrogels are designed to respond to specific signals in the diseased region, such as pH and reactive oxygen species (ROS) levels, achieving on-demand and precise drug release. For personalized treatment, patient-specific medical imaging data are utilized to fabricate personalized implants that highly match the anatomical structures via 3D printing technology [ [62] , [63] , [64] , [65] ]. Based on this, this paper systematically reviews recent research advances in functional hydrogels for bone engineering, focusing on material design and preparation strategies. It details their specific applications in bone defect repair [ 66 ], spinal disease treatment [ 67 ], fracture healing [ 11 ], prevention and treatment of orthopedic infections [ 68 ] and joint cartilage repair [ 69 ]. Additionally, it summarizes key challenges facing hydrogel applications in orthopedics and outlines future prospects for hydrogel materials through material innovation, technological integration, and clinical translation. 2. Design principles of hydrogels for orthopedic applications The design of hydrogels for orthopedic applications mimics the extracellular matrix of the body. A "microenvironment" is created that promotes cellular behavior, material transport, and dynamic interactions with bone tissue, playing a key role in orthopedics [ 70 ]. Biocompatibility is the cornerstone of its design. Upon contact with biological tissues or bodily fluids, the designed hydrogel material and its degradation products must not cause adverse reactions such as inflammation, immune rejection, or toxicity in the host ( e.g. , the human body), while maintaining its inherent functional stability [ 71 ]. With biological functionality as the core objective, hydrogels must simultaneously fulfill multiple requirements: actively supporting cell adhesion, facilitating cell growth, proliferation, and migration, and inducing osteogenic differentiation, while achieving a gradual degradation synchronized with the regeneration process [ 72 ]. The use of biomedical hydrogels in the repair of bones and tissues is essential. The mechanical properties of the implanted materials ( e.g. , strength, elastic modulus, toughness, extensibility, and fatigue resistance) must be compatible with the mechanical properties of the host bone tissue ( e.g. , cortical and cancellous bone regions) [ 73 ]. Such compatibility ensures effective transmission of physiological mechanical signals in vivo to guide bone regeneration, while avoiding stress-shielding effects caused by mechanical mismatch, thereby safeguarding both repair outcomes and long-term stability of the bone tissue [ 74 ]. To realize these principles, key technologies span the entire hydrogel development process, from material screening to functional design to molding and processing. Through a combination of chemical and physical cross-linking strategies, robust, tunable three-dimensional networking structures are constructed. Hydrogels can be modified to have bioactive properties such as antimicrobial, osteoconductive, and smart-response capabilities. Additionally, advanced fabrication techniques, such as 3D printing, allow the precise production of personalized bone repair scaffolds with complex macrostructures and optimal pore distributions [ 75 ]. 2.1. Material selection: properties and applications of natural polymers and synthetic polymers Hydrogel functional systems are built on certain materials, with their selection directly determining their biological properties ( e.g. , immunogenicity, cell compatibility, and biodegradability) and mechanical properties ( e.g. , strength, modulus, and toughness) [ 76 ]. Natural polymers and synthetic polymers are the most commonly used materials in orthopedic repair. Utilizing their unique advantages, these materials provide a variety of solutions for constructing an optimal microenvironment for bone regeneration. The substrates of natural polymer hydrogels are mainly obtained from biological organisms or natural sources ( e.g. , collagen, alginates, etc. ). In addition to their exceptional biocompatibility and low risk of triggering immune rejection or inflammation when they come in contact with cells or bodily fluids, they also possess active functional groups ( e.g. , hydroxyl, amino groups) that facilitate cell adhesion and growth. By naturally endowing the material with biological activity, it supports physiological functions. The molecular structure, degree of polymerization, and cross-linking methods of synthetic polymer hydrogels are precisely controlled artificially to achieve exceptional property controllability. This enables on-demand design of both fundamental physicochemical properties such as mechanical strength, degradation rate, and hydrophilicity-hydrophobicity balance, as well as customized functionalities such as intelligent responsiveness to temperature or pH and targeted delivery through functional group grafting. These hydrogels possess high degrees of chemical modifiability and performance stability, making them suitable for a wide variety of applications [ 77 , 78 ]. In order to meet the demanding requirements of diverse application scenarios, it is essential to gain a deeper understanding of the core properties and complementary advantages of these two material types, and to enhance those properties through the implementation of composite strategies. In the following sections, we will systematically review three major systems (natural polymers, synthetic polymers, and composite hydrogels) by integrating specific case studies and application scenarios ( Fig. 2 ). Furthermore, Table 1 systematically outlines the representative materials, primary application areas, core advantages, and limitations of natural polymer hydrogels, synthetic polymer hydrogels, and composite hydrogels. Fig. 2. Open in a new tab Types of different hydrogels (natural polymer hydrogels, synthetic polymer hydrogels and composite hydrogels) and their applications in orthopedics [ 16 , 62 , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] , [89] , [90] , [91] , [92] , [93] ]. Table 1. Representative materials, applications, and performance comparisons of different types of hydrogels. Types of hydrogels Representative materials Application Scenarios Core Strengths Limitations Natural polymer hydrogels Collagen, gelatin, alginates, chitosan, hyaluronic acid, fibronectin Cartilage repair, Excellent biocompatibility, Biodegradability, Ability to promote cell adhesion and proliferation, Abundant sources Low mechanical strength, Difficulty in precisely controlling the degradation rate, Significant batch-to-batch variability Bone defect Filling, Drug delivery, Joint lubrication Synthetic polymer hydrogels PEG, PLA, PLGA, PVA, PNIPAM Repair of weight-bearing bones, Bone tissue engineering scaffolds, Controlled-release drug delivery systems Adjustable mechanical properties, Controllable structure, Insufficient biological activity, Lack of cell recognition sites, Degradation products that may trigger inflammation Tunable degradation rate, Good batch-to-batch consistency Composite hydrogels Natural-synthetic polymer composites, polymer-inorganic composites ( e.g. , HAp, β-TCP, BG, nanoclay, carbon nanotubes) Repair of weight-bearing bone defects, Combines the advantages of both natural and synthetic materials, Synergistically enhances mechanical properties and bioactivity, Enables functionalized design Preparation process is complex, Interfacial compatibility between components needs to be optimized Repair of the osteochondral interface, Treatment of infectious bone defects Open in a new tab 2.1.1. Natural polymer hydrogels Natural polymeric materials are considered ideal for the preparation of hydrogels due to their excellent biocompatibility, biodegradability, non-toxicity, abundance of resources, and low cost [ 79 , 94 ]. Polysaccharides and proteins can be broadly categorized as these materials. The former includes HA [ 80 ], chitosan [ 81 ], sodium alginate [ 82 ] and others; the latter encompasses collagen [ 95 ], gelatin [ 96 ], silk protein [ 83 ] and others. In addition to their fundamental roles in human tissues ( e.g. , collagen in connective tissue and HA in joint cartilage), they also possess unique biological functions, such as chitosan's antibacterial properties and collagen's ability to adhere to cells. Moreover, its molecular structure is readily modified by physical or chemical methods, enabling more effective regulation and enhancement of hydrogel properties for diverse biomedical applications. It is worth noting that certain inherent properties of natural hydrogels also impose application limitations. Their mechanical properties ( e.g. , elastic modulus and compressive strength) are typically poor, causing them to fail to meet rigid requirements for mechanical support in bone tissue engineering. Furthermore, their self-healing efficiency is relatively low, with prolonged healing cycles that may disrupt repair functions and trigger inflammatory reactions. Additionally, the performance of natural polymer materials varies from batch to batch. As a consequence of this inherent variability, it is challenging to precisely control the final properties of products during processing, which makes it difficult to achieve standardized, large-scale industrial production [ 84 ]. Yang et al. employed a novel preformed dual-effect post-enhancement method (PFDEPE) to prepare preformed hydrogels with predetermined mechanical strength through a controlled "heating-mixing-cooling" process [ 97 ]. The specific process involves dissolving insoluble chitosan (CTS) and CaCO 3 powder in a high-viscosity neutral agar solution at elevated temperatures, introducing sodium alginate (SA) polymer chains, and subsequently forming a crosslinked network through cooling ( Fig. 3 A). This method employs SA and CTS to synergistically enhance hydrogel toughness by leveraging their dissociable ionic crosslinks and stable electrostatic interactions. This strategy successfully constructs post-enhanced multi-network hydrogels, effectively addressing the dual challenges of uncontrollable preparation processes and low mechanical strength inherent in traditional natural hydrogels. This work establishes a novel hydrogel design framework whose outstanding performance demonstrates significant potential for addressing the challenge of interface integration in osteochondral defect repair, opening new avenues for research in this field ( Fig. 3 B). The introduction of SA serves as an effective strategy to prevent phase separation of chitosan; another commonly employed approach involves enhancing the water solubility of CTS itself through acetylation modification. Yu et al. successfully constructed a hydrogel with an interpenetrating network (IPN) structure by combining β-sheet blocks of silk fibroin (SF) with a photopolymerized chitosan methacrylate (CSMA) network ( Fig. 3 C) [ 98 ]. As a linear macromolecule, SF not only effectively compensates for the shortcomings in mechanical properties of CSMA but also preserves the system's inherent biocompatibility and biodegradability. Moreover, this design leverages multiple interactions between proteins and polysaccharide chains to confer exceptional mechanical properties to the hydrogel. Building upon this, the researchers further fabricated CSMA/SF hydrogels into bone fixation screws. By enhancing osteoblast activity, they demonstrated the hydrogels' outstanding biocompatibility and mechanical performance, showcasing promising potential for clinical translation. Fig. 3. Open in a new tab PEMN hydrogel constructed by the PFDEPE method based on sustainable natural polymers. (A) Scheme of the PFDEPE method; (B) Scheme of the PFDEPE method [ 97 ]. Copyright 2023, The Royal Society of Chemistry. (C) Gelation mechanism of CSMA/SF hydrogels [ 98 ]. Copyright 2024, Elsevier. (D) An injectable IPN hydrogel system encapsulating ZnBCP and HABP was developed via bio-orthogonal reaction (Tz and Nb) and effective electrostatic coordination (HABP and ZnBCP); (E) Treatment of bone defects under RA with injectable IPN hydrogel; (F) Schematic presentation depicting the effect of RA condition on the bone regeneration [ 99 ]. Copyright 2024, Wiley-VCH GmbH. HA is a natural polymer found in the extracellular matrix. Due to its excellent biocompatibility, it effectively promotes cell migration, proliferation, and collagen deposition. However, its inherent lack of mechanical strength and poor tissue adhesion limit its direct application in regenerative medicine. A novel IPN hydrogel has been constructed by Liu et al. [ 99 ] using a click chemistry reaction between camphene-modified collagen and azetidine-modified hyaluronic acid and electrostatic interactions between bisphosphonate (BP)-functionalized HA macromers (HABP) and zinc (Zn)-doped biphasic calcium phosphate (ZnBCP) ( Fig. 3 D). In a rabbit model of collagen-induced arthritis, this bioactive IPN hydrogel successfully remodeled the bone immune microenvironment by synergistically regulating pro-inflammatory resolution, promoting osteogenesis, and inhibiting bone destruction, demonstrating exceptional bone healing capacity ( Fig. 3 E and F). For the construction of hydrogels, biomacromolecules such as polysaccharides and peptides have become preferred materials due to their excellent biocompatibility and degradability. The degradation products produced by these natural polymers, derived from a wide variety of sources, are not only non-toxic and harmless to humans, but can also be absorbed and utilized by them. Due to their inherent advantages as carriers for drugs or nutrients, they have a wide range of potential applications in fields such as bone regeneration. Hydrogels have been prepared using natural polymers such as gelatin, chitosan, alginate, and hyaluronic acid. It is important to note that these materials often suffer from insufficient mechanical strength and difficulty in precisely controlling their degradation processes and rates. Synthetic polymers and composite hydrogels can be developed using methods such as cross-linking or functionalization modifications, thereby enhancing their performance and enabling widespread application in a wide range of fields. 2.1.2. Synthetic polymer hydrogels Synthetic polymer hydrogels have gained significant attention due to their superior stability, high mechanical strength, and excellent adaptability. Currently, most synthetic hydrogels are formed by chemical cross-linking of polymers such as polyethylene glycol (PEG) [ 86 ], methyl acrylate copolymer, polycaprolactone, and polylactic acid (PLA). These hydrogels typically exhibit high mechanical strength, and their chemical properties can be precisely controlled by adjusting the ratio of monomers and cross-linking agents. They are therefore widely used in fields such as tissue engineering scaffolds, controlled drug delivery systems, and orthopedics. In addition to their excellent biocompatibility and degradability, polymers such as PLA, polyhydroxyacetic acid (PGA), and their copolymers (PLGA) [ 100 ] are widely used across a wide range of fields. Particularly, PLGA with tunable degradation rates can be obtained by adjusting the ratio of PLLA to PGA monomers. PLGA is primarily used for implantable devices such as bone plates, fixation screws and pins, and sutures. PEG and PLGA together with lactic and glycolic acid were copolymerized by Zhu et al. [ 101 ]. In order to construct HA-PELGA composite scaffolds containing 25% HA, these copolymers were combined with HA particles ( Fig. 4 A). It has been demonstrated that the PLA/PGA ratio (L/G ratio) in PLGA can be adjusted to regulate its degradation rate and mechanical properties, allowing its use in cranial defects requiring slow healing. With the help of poly(N-isopropylacrylamide) (PNIPAM), precise controlled drug release can be achieved. By triggering drug release at specific temperatures, this system enhances therapeutic efficacy while minimizing unwanted side effects. By copolymerizing PNIPAM with acrylamide (AAm), Zhang et al. were able to increase the application adaptability across a variety of temperature scenarios by effectively regulating their low critical solution temperature (LCST) [ 102 ]. As an artificial muscle for soft robotics, thermoresponsive PNIPAM hydrogel was used to form an epidermis-dermis-muscle architecture ( Fig. 4 B and C). Moreover, it can be combined with various nanomaterials to form multimodal soft robots with diverse functionalities. This system achieves skin-like multifunctional localized sensing capabilities due to its high level of integration ( Fig. 4 D–H), which is significant for the advancement of soft robotics. Fig. 4. Open in a new tab (A) Overview of scaffold development and evaluation process [ 101 ]. Copyright 2024, Elsevier. (B) Schematic illustration of epidermis-dermis-muscle structure of skin. (C) Bioinspired structure of soft robot from skin. (D) Conceptual illustration of the integrated multi-modal sensory soft robot. (E) Schematic illustration of a starfish-inspired multi-modal sensory soft robot. (F) Optical image of the flexible e-skin with six nanocomposite sensors. Optical image showing conformal attachment of the soft sensory robot onto human skin (G) and porcine tissue (H) with high mechanical compliance [ 102 ]. Copyright 2024, Springer Nature. (I) Preparation process of RPO hydrogel; (J) Schematic representation of RPO hydrogel responsive release of rutin to promote osteogenic differentiation through immunomodulation [ 103 ]. Copyright 2024, Elsevier. (K) A high-strength gelatin hydrogel designed for 3D printing to fabricate drug-loaded scaffolds. (M) The drug-loaded gelatin scaffold remodels the inflammatory microenvironment by activating the HIF-1α pathway, thereby repairing osteoporotic bone defects [ 62 ]. Copyright 2025, Wiley-VCH GmbH. PEG is a hydrophilic polymer with excellent biocompatibility, non-immunogenicity, tunable physicochemical properties, and high stability, making it widely used in biomedical and tissue engineering applications. PEG can be combined with other substances to form hydrogels through radical polymerization or functional group reactions [ 104 ]. Besides having good controlled drug release properties, these PEG-based hydrogels can also be biofunctionalized to impart biological activities, such as antimicrobial activity and bone regeneration promotion. Based on aminated gelatin, PEG, and oxidized starch, Xing et al. constructed a stable and biocompatible three-dimensional network hydrogel containing rutin, a molecule with antioxidant and anti-inflammatory properties ( Fig. 4 I) [ 103 ]. Using its unique structural design, the bio-responsive bone-adhesive hydrogel (RPO) intelligently responds to changes in ROS levels within diabetic fracture microenvironments, releasing rutin precisely to inhibit excessive NLRP3 inflammasome activity ( Fig. 4 J). In treating diabetic fractures, this strategy breaks through the limitations of traditional approaches. Furthermore, osteoporosis is a common problem in daily life. Due to the inflammatory microenvironment it creates, conventional treatments are not only less effective but also severely compromise the ability to repair bone defects as well. A high-strength gelatin hydrogel scaffold loaded with roxadustat was developed by Liao et al. [ 62 ] to simultaneously remodel the inflammatory microenvironment and promote osteoporotic bone regeneration. Hyaluronic acid methacrylate (HAMA) was incorporated into nitrobenzene-functionalized gelatin (GelNB) matrix to construct a three-dimensional network structure with tensile strength of 10 MPa ( Fig. 4 K). By using Digital Light Processing (DLP) 3D printing technology, it not only enhances the structural stability of the material, but also allows precise control of the scaffold structure. By effectively overcoming the limitations imposed by the inflammatory microenvironment on the repair process, this drug-loaded scaffold significantly increases the regenerative capacity of bone defect areas, providing an innovative method for improving the effectiveness of osteoporotic bone repair. In general, synthetic polymer hydrogels such as PEG and polyacrylamide effectively compensate for the shortcomings of natural materials in terms of mechanical strength and self-healing capacity. Their tunable properties make them widely used in tissue engineering. However, they often suffer from poor biocompatibility and degradation. Thus, combining synthetic and natural polymers to create composite hydrogels with excellent mechanical properties and favorable biological functions has become a key strategy for advancing the field [ 105 ]. 2.1.3. Composite hydrogels Natural or synthetic polymer hydrogels, their application in orthopedics remains challenging due to inherent limitations. In weight-bearing areas, natural hydrogels are limited by inadequate mechanical properties and difficult-to-control degradation behavior. In contrast, synthetic hydrogels pose potential risks relating to biocompatibility, cell recognition signals, and degradation products. Single-component systems are unable to simultaneously meet the complex demands of bone regeneration, which include mechanical support, bioactivity, and controlled degradation. The aim of researchers is to overcome this bottleneck by developing composite hydrogel strategies by integrating them with inorganic components such as hydroxyapatite (HAp) [ 106 ], bioactive glass (BG) [ 107 ] and calcium phosphate salts [ 108 ]. By biomimetically constructing an organic-inorganic composite microstructure analogous to that of natural bone, this material effectively integrates mechanical support with biological functions, enabling the regulation of the bone regeneration microenvironment. This structural and functional synergy offers a highly promising new strategy for the efficient clinical repair of bone defects. The physicochemical structure of synthetic calcium phosphate ceramics closely resembles the structure of natural bone tissue, which makes them a promising candidate for bone repair. Combined with their unique porous micro-nano structure and surface enrichment of bioactive ions, they exhibit excellent osteoconductivity and osteoinductivity, effectively promoting bone regeneration[ 109 , 110 ]. Based on their calcium-to-phosphorus ratios, calcium phosphate ceramics can be classified as hydroxyapatite, tricalcium phosphate, and biphasic calcium phosphate. Using engineered proteins and oxidized SA, Jin et al. successfully developed a dual-crosslinked hydrogel [ 87 ]. A hydrogel similar to the extracellular matrix supports cell adhesion, angiogenesis, and osteogenic differentiation ( Fig. 5 A). As a result of the embedded zinc/calcium phosphorene nanoparticles, the initial burst of Ca 2+ activated M1 macrophages, eliminating pathogens, while the sustained release of Zn 2+ polarized macrophages toward M2 phenotypes, promoting osteogenesis. Furthermore, the system exhibits both antioxidant and antibacterial properties, promoting bone regeneration in a rat model of infectious cranial defects. Tricalcium phosphate (TCP) has excellent biocompatibility and degradability, but its degradation kinetics remain difficult to synchronize with bone growth. Moreover, its inherent mechanical weakness makes it difficult to achieve optimal results when it comes to bone regeneration. The most significant advantages of HAp over TCP are its high stability and low solubility. Because of these properties, it decays slowly within the body, making it an ideal scaffold for long-term bone conduction [ 112 ]. The HAp material also possesses excellent mechanical strength and cell adhesion capabilities, making it a superior option for bone repair applications requiring stable structural support. Xu et al. developed magnetic magnesium-doped hydroxyapatite particles with magnetically induced double bonds within polyethylene glycol diacrylate/sodium alginate hydrogels [ 111 ]. Subsequently, a counter-gradient system of Mn 2+ /magnetically doped magnesium hydroxyapatite was constructed using diffusion-based post-modification ( Fig. 5 B). By regulating Mn 2+ distribution within magnetically doped magnesium hydroxyapatite, this hydrogel simultaneously stimulates chondrogenic differentiation as well as osteogenic differentiation of mesenchymal stem cells derived from bone marrow. Using this design, osteochondral defects in rats can be efficiently regenerated, a novel approach to addressing the challenge of gradient tissue regeneration. BG is an inorganic component that is highly regarded along with tricalcium phosphate and HAp. In contrast to traditional calcium phosphate ceramics, which provide primarily bone conductivity, bioactive glass continuously releases active ions such as silicon, calcium, and phosphorus during degradation. In addition to conferring exceptional osteogenic activity, these materials also induce vascular and neural regeneration effectively, opening new avenues for the development of functional bone repair materials. Jiao et al. successfully developed an injectable, self-healing pH/ROS dual-responsive polycationic hydrogel system (OSPPB) ( Fig. 5 C) [ 107 ]. There are multiple mechanisms used to treat osteoarthritis in this system, including aldehyde-modified sodium alginate/grafted protocatechuic acid poly(ethyleneimine) (OSAP/PPCA) and bevacizumab-loaded bioactive glass nanoparticles (BGN@Be). It exerts direct effects through sodium alginate's lubricating action and BGN@Be's sustained drug release and osteogenic potential. In addition, it leverages the cationic properties of PPCA to passively target the osteochondral interface. The core advantages of this OSPPB hydrogel are: (1) its polycationic nature effectively removes excess extracellular RNA under pathological conditions; (2) dual pH/ROS responsiveness ensures precise, on-demand release of active components; (3) sequential delivery of multiple active ingredients enables significant structural repair of the temporomandibular joint in rats. Fig. 5. Open in a new tab (A) Schematic illustration of the preparation of the TIH [ 87 ]. Copyright 2025, Wiley-VCH GmbH. (B) Schematic showing the fabrication and components of continuous magneticmechanical gradient hydrogel CGGel [ 111 ]. Copyright 2025, Elsevier. (C) A facile fabrication route of the OSPPB hydrogel [ 107 ]. Copyright 2025, Springer Nature. To optimize the overall performance of hydrogel materials, composite hydrogels are another key research direction for optimizing their mechanical and biological properties beyond combining with inorganic components such as tricalcium phosphate, HAp, and BG. Composite hydrogels are formed by integrating natural polymer hydrogels with synthetic polymer hydrogels [ 113 ]. By utilizing natural components to provide cell recognition sites and biodegradability, and synthetic components to impart stable mechanical frameworks and controllable responsive properties, these composites create biomaterials with more comprehensive performance for applications in orthopedics and other fields. Using a PEG-gelatin bioadhesive based on polyethylene glycol active ester (Bi-PEG-SG) and gelatin, Liu et al. [ 114 ] demonstrated self-healing properties incorporating micro-scale bovine bone particles ( Fig. 6 A). Antioxidant properties, injectability, shape adaptability, strong adhesion, and high compressive strength are all features of this hydrogel system. As well as delivering and immobilizing microscale bovine bone particles, it significantly accelerates the structural and functional repair of bone defects by enhancing their bone-inducing activity and optimizing the osteogenic microenvironment. Also, it has demonstrated highly effective sealing and hemostatic performance in severe arterial and bone wound hemorrhage models. A hyaluronic acid-phenylboronic acid hydrogel containing dual nanooliposomes (DLNPs@HA) was developed by Zhou et al. ( Fig. 6 B) [ 115 ]. Hyaluronic acid phenylboronic acid (HA-PBA) was combined with PVA to construct a synergistic therapeutic platform ( Fig. 6 C) by co-loading anti-CD105 antibody-modified nanoliposomes with anti-CD105 antibody-modified nanoliposomes. With this method, drugs can be released continuously, ROS levels are effectively modulated, oxidative stress is reduced, bone marrow macrophages (BMDMs) are inhibited from polarizing toward the pro-inflammatory M1 phenotype, and bone marrow mesenchymal stem cells (BMSCs) differentiate osteogenically. It offers an innovative therapeutic strategy for treating this challenging fracture under diabetic conditions, as these synergistic effects significantly promote bone repair. A biocompatible PHE-Gel hydrogel was developed by Ma et al. using poly(N-hydroxyethylacrylamide-N-hydroxysuccinimide) [P(HEAA-NHS)] and gelatin as raw materials ( Fig. 6 D) [ 14 ]. The results of research demonstrate that adjusting the composition ratio can achieve exceptional bioadhesive properties, effectively addressing the clinical challenge of inadequate integration between osteochondral grafts and host tissues ( Fig. 6 E). Thus, this composite hydrogel offers a novel and effective strategy for overcoming clinical cartilage repair challenges by structurally and functionally mimicking natural osteochondral tissue [ 117 ]. Using vinyl-functionalized iron oxide nanoparticles (MPS-Fe 2 O 3 ) crosslinked with methacryloyl-modified gelatin (GelMA), Wu et al. developed a functional composite hydrogel system ( Fig. 6 F) [ 116 ]. Using covalent cross-linking between MPS-Fe 2 O 3 and GelMA, this design strategy overcomes the limitations of conventional physical blending or chemical cross-linking, including nanoparticle aggregation, sedimentation, and inadequate mechanical properties. Thus, the hydrogel becomes significantly more stable and mechanically strong. The single-component, multi-functional composition of this material design strategy not only overcomes the inherent limitations of traditional materials but also incorporates the advanced material design concept of "single-component and multi-functional". By repairing maxillofacial bone defects safely and efficiently, it significantly advances the development of bone tissue engineering materials and their clinical translation. By combining natural and synthetic polymers, the composite hydrogel achieves an effective balance between biocompatibility, mechanical properties, and functional tunability. It requires more than mere component composites to achieve precise application in complex biological environments. From a microscopic to a macroscopic level, hydrogel structure is regulated. A new generation of functional hydrogel materials capable of meeting diverse application demands will be developed by modifying structural regulation, cross-linking strategies, and functionalization. Fig. 6. Open in a new tab (A) Schematic showing the preparation of PG/Van/B/CB hydrogel system [ 114 ]. Copyright 2025, Elsevier. Schematic illustration of the synthesis of DLNPs@HA hydrogel. (B) CD105-LNPs and PS-LNPs in DLNPs@HA hydrogel deliver α-lipoic acid to BMSCs and BMDMs; (C) Schematic illustration of the structure and synthesis process of CD105-LNPs and PSLNPs [ 115 ]. Copyright 2025, Wiley-VCH GmbH. (D-E) The design and fabrication process of DMOG liposome-loaded P(HEAA-NHS)/Gelatin (PHE-Gel@DMOG-Lip) hydrogel adhesive for the integration of osteochondral grafting [ 14 ]. Copyright 2025, Elsevier. (F) Schematic diagram of the design and preparation of Fe 2 O 3 /GelMA hybrid hydrogel [ 116 ]. Copyright 2025, Wiley-VCH GmbH. 2.2. Structural regulation: performance optimization from macro to micro Chemical composition and microstructure determine the properties of hydrogels. To achieve precise performance customization, current research focuses on three design principles: structural regulation, cross-linking strategies, and functionalization modifications. In structural regulation, hydrogels are endowed with superior mechanical properties and mass transport capabilities by creating intricate structures like multilevel channels, heterogeneous networks, or anisotropic topologies [ 118 ]. Different cross-linking methods such as dynamic covalent bonds, host-guest interactions, or ionic coordination determine hydrogel stability, responsiveness, and self-healing behavior [ 119 ]. Hydrogels can be functionalized by incorporating specific molecules or nanoscale units, resulting in advanced properties such as conductivity, antimicrobial properties, or tissue regeneration [ 120 ]. Structure regulation is the basis for functional hydrogels in the aforementioned strategies. Building a three-dimensional network hydrogel that meets mechanical requirements and adapts to biological needs is the core objective. We will discuss three key structural design dimensions below in order to achieve this objective: First, porous structure design governs material transport and cellular behavior; second, mechanical property regulation ensures mechanical compatibility between the material and tissues; third, injectable and in-situ molding designs have a direct impact on clinical operability and repair precision ( Fig. 7 ). Fig. 7. Open in a new tab Schematic diagram of a hydrogel with advantages such as good biocompatibility, tunable mechanical properties, and precise drug release capability, achieved through structural control, cross-linking strategies, and functionalization design [ [121] , [122] , [123] , [124] ]. 2.2.1. Porous structure design The final morphology and functionality of hydrogels are largely determined by their preparation and fabrication techniques. These techniques can be broadly classified into two main categories: (i) injectable in-situ forming technologies designed to meet the requirements of minimally invasive procedures, and (ii) scaffold fabrication technologies, such as freeze-drying and 3D printing, employed to construct biomimetic microstructures. A hydrogel precursor solution is mixed with a loaded substance ( e.g. , drugs or cells), injected into the target site, and then triggered by spontaneous or external stimuli ( e.g. , temperature, pH or light). Clinical translation of this method is promising due to its simplicity, minimally invasive nature, and potential for minimally invasive treatment. For preparing porous hydrogel scaffolds, freeze-drying remains a classic technique. The material's porosity, swelling behavior, and mechanical properties can be precisely controlled by adjusting parameters such as freezing temperature and duration. This method is widely used in tissue engineering because of its relatively straightforward process and ease of long-term storage. GelMA hydrogel microspheres with controlled sizes and pore sizes were prepared using microfluidics and gradient freeze-drying technology by Xu et al. [ 125 ]. A multi-cell co-assembled delivery system was established by combining an optimized co-culture system of BMSCs and human umbilical vein endothelial cells (HUVECs). A gradient freeze-drying process requires two critical steps: first, initial cooling at −20 °C promotes ice crystal growth and creates an interconnected porous network. The duration of this stage directly determines ice crystal size, thereby regulating the final pore size of the polyacrylamide gel microspheres (PGMS). The sample is then rapidly frozen at −80 °C to prevent further ice crystal growth and fix the porous structure ( Fig. 8 A). According to the results of the initial cooling phase at −20 °C, the materials were designated as PGMS-0, PGMS-10, PGMS-20, and PGMS-30. Following this, microsphere structures with different pore sizes were observed via SEM and statistically analyzed. PGMS-10 exhibited uniform pore distribution and was selected as the best cell delivery carrier ( Fig. 8 B and C). Hydrogel microspheres possess a porous structure that provides not only space for cells but also influences nutrient transport and metabolic exchange. Therefore, the development of a multicellular co-assembly system with a controllable pore size that enhances paracrine interactions between cells represents a highly promising strategy for bone resorption. By optimizing the cellular microenvironment, this system can synergistically accelerate vascularized bone regeneration. Moreover, Xue et al. formed continuous porous templates from dextran by liquid-liquid phase separation [ 126 ]. The template structure was further reinforced by rigid protein fibers self-assembling at the pore wall interfaces. As a result of this approach, a hydrogel with a rigid coating layer and a porous structure was fabricated ( Fig. 8 D). Shell-free porous hydrogels (NP) and shell-free porous hydrogels (SP) were observed to have nanodrops in their precursors, and both NP and SP hydrogels appeared translucent, indicating micrometer-sized structures ( Fig. 8 E). A further analysis using field emission scanning electron microscopy (FESEM) revealed macropores in both NP and SP hydrogels, which enhance cross-linking density. For stem cell-assisted tissue regeneration, this achievement represents a significant advancement in tailored regulation of hydrogel mechanical properties. In addition to conventional methods such as freeze-drying, which is based on solvent crystallization, and soft templating, which uses sacrificial templates, bubble-based foaming can also be used to fabricate porous hydrogels. Due to its operational simplicity and excellent pore interconnectivity, this technique is particularly suitable for hydrogel systems requiring rapid channel construction due to gas being used directly as a pore template. As a pore-forming template, Jin et al. used PVA foam with microbubbles, which was then gel-fixed through repeated freeze-thaw cycles [ 127 ]. Microbubble templates can be controlled in size to produce porous gel materials with varying porosities ( Fig. 8 F). With acoustic bubble fabrication for focused surface acoustic waves, the size of microbubbles can be controlled within microseconds within a range of 10 μm to several hundred micrometers ( Fig. 8 G and H). In fields such as tissue engineering and functional material manufacturing, this approach offers broad application prospects. Fig. 8. Open in a new tab (A) Schematic diagram of PGMS preparation; (B) SEM images of PGMS with different pore sizes; (C) Particle size distribution of PGMS-0 [ 125 ]. Copyright 2025, Wiley-VCH GmbH. (D) Schematic depicting the fabrication and structure of shell-hardened macroporous hydrogels; (E) Micrographs (left) and fluorescent micrographs (right) for the precursors of NN, NP and SP hydrogels. Optical image and FESEM images of NN, NP and SP hydrogels [ 126 ]. Copyright 2025, Springer Nature. (F)Schematic of polyvinyl alcohol foam prepared via freeze-thaw and freeze-drying processes; (G-H) Schematics of fabrication by surface acoustic wave and live video capturing the process of micro-pore formation [ 127 ]. Copyright 2020, American Chemical Society. (I) Hydrogel scaffolds loaded with SSC-Exos were prepared using 3D printing technology and applied to cartilage-bone defect sites [ 128 ]. Copyright 2025, Elsevier. (J) Experimental schematic; (K) Schematic of bioprinting; (L) Cryo-SEM (scanning electron microscopy) images [ 129 ]. Copyright 2024, Wiley-VCH GmbH. The conventional methods of freeze-drying, soft templating, and gas foaming can produce porous hydrogels, but they lack precise control over pore size, morphology, and spatial distribution. Thus, directed regulation of cellular activities and biomimetic construction of complex tissue architectures are limited by this limitation. To address these challenges, 3D printing technology has emerged as a breakthrough solution. Using its high accuracy and capability for structural customization, hydrogel porous networks can be digitally fabricated and accurately fabricated. With the help of single-cell RNA sequencing and flow cytometry, Lou et al. identified and isolated a novel population of skeletal stem cells (SSCs) from the infrapatellar fat pad (IFP) of mice, and subsequently isolated exosomes secreted by these cells (SSC-Exos) [ 128 ]. Using 3D printing technology, SSC-Exos was combined with bioink to construct a hydrogel scaffold precisely matching the defect morphology, which was successfully transplanted into the osteochondral defect model region ( Fig. 8 I). Meanwhile, novel bioinks composed of GelMA, methacrylamidated sodium alginate (AlgMA), and hydroxyapatite have been extensively studied. In addition to replicating the complex composition of natural bone matrix, these materials also promote directed cell differentiation and self-mineralization. It is possible to print hydrogel scaffolds with porous structures using this bioink. Using GelMA, AlgMA, and HAp, Wang et al. developed a new bioink [ 129 ]. This material exhibits remarkable osteogenic activity due to the synergistic interaction between its components ( Fig. 8 K). HAp, as a key inorganic component of bone tissue, is crucial to the formation and maintenance of bone mineralization structures. This biomimetic structure can be achieved using DLP bioprinting technology ( Fig. 8 J), which provides a powerful tool for creating matrix structures containing cells arranged in a manner that closely resembles natural bone tissue. Through the development of tools and strategies, this study provides not only a potentially effective new therapeutic approach for bone defect repair, but also crucial technical support and novel research directions for basic research in bone tissue engineering and clinical translation ( Fig. 8 L). Porous structure design optimizes material transport and cell behavior guidance by controlling pore size, porosity, and connectivity, laying a crucial structural foundation for tissue regeneration. The stability and durability of hydrogels under complex in vivo mechanical environments are equally important as an implantable material. Therefore, subsequent research has focused on precisely controlling their mechanical properties. To meet the clinical needs of load-bearing tissue repair, hydrogel systems must combine ideal pore structures with superior mechanical performance. The biological functionality of porous hydrogels is intrinsically linked to their structural parameters and must be tailored to the mechanical microenvironment of the target orthopedic tissue. Pore size serves as a critical design parameter that dictates the balance between cellular behavior and mechanical performance. Specifically, micropores (<10 μm) primarily support nutrient diffusion but are insufficient to mediate cell ingrowth. In contrast, macropores (100-300 μm), which are suitable for bone ingrowth, facilitate cell migration, angiogenesis, and bone matrix deposition, yet they inevitably compromise the mechanical strength of the scaffold. Therefore, in load-bearing applications such as cancellous bone repair, a delicate balance must be achieved between high porosity (70-90%) and adequate mechanical support. Furthermore, pore interconnectivity is equally critical. A highly interconnected pore network not only ensures uniform cell seeding, efficient deep-tissue nutrient delivery, and metabolic waste removal but also mitigates the risk of localized stress concentration and premature material failure caused by isolated pores. In summary, the design of porous hydrogels should be approached as a multi-dimensional optimization process, wherein pore architecture and mechanical properties are custom-tailored according to the specific application scenario, specifically the prioritization of rapid vascularization versus immediate mechanical support. 2.2.2. Mechanical property regulation As water-swollen polymer networks, hydrogels possess unique properties such as mechanical flexibility, deformability, and tunable properties. Due to their broad application prospects, they are applicable to a variety of fields, including soft robotics, flexible electronics, sensors, adhesives, and biomedical engineering. Under conditions of large deformation or repeated loading, such materials exhibit low fracture toughness and poor mechanical durability, which has become the primary limitation of their application in scenarios requiring higher mechanical strength. Multiple design strategies have been developed for high-toughness hydrogels to overcome these challenges. Structures include dual-network architectures, highly chain-entangled single networks, nanoreinforcing phases (carbon nanotubes, graphene), and dual cross-linking. Introducing thermosensitive bonds can be used to regulate mechanical properties in dynamic chemistry. In contrast to conventional hydrogels, dual-network hydrogels consist of two interwoven polymer networks: a rigid short-chain network provides support as a brittle skeleton, while a flexible long-chain network dissipates energy through elongation. This synergistic effect endows them with exceptional mechanical toughness, enabling them to withstand high-intensity deformation without sustaining permanent damage or fracture [ 130 ]. To produce a dual-network injectable hydrogel (PVA-DN), Cai et al. used methacrylated polyglutamic acid grafted with phenylboronic acid (PBA-m-PGA) and GelMA to form a rigid network (PBA-m-PGA/GelMA) and PVA-borate to form a flexible network (PVA-borate) by introducing borate bonds through PVA ( Fig. 9 A) [ 131 ]. Its structure not only provides outstanding self-healing capabilities and tunable viscoelastic properties, but it also effectively mimics the mechanical microenvironment of extracellular matrix. In addition, its multiscale mechanical adaptability across macroscopic, microscopic, and nanoscale dimensions promotes NP tissues’ ability to repair. To achieve this, the ratio of GelMA to PBA-m-PGA and PVA was adjusted to ensure that the elastic modulus and stress relaxation time of the dual-network hydrogel closely matched those of native NP tissue. Fresh NP tissue was most closely approximated by the fast-relaxing hydrogel. The hydrogels all exhibited reliable self-recovery during cyclic compression tests, with the fast stress relaxation hydrogel exhibiting particularly exceptional energy absorption capabilities ( Fig. 9 B–D). Thus, this hydrogel has demonstrated significant potential as a repair material for NP tissue across multiple scales. Yang et al. utilized oxidized hyaluronic acid (OHA) as a matrix for cross-linking Yoda 1-loaded PLGA-collagen fiber fragments, while simultaneously introducing catechol-Fe 3+ coordination bonds to increase their stability. The result was a robust, self-healing three-dimensional network ( Fig. 9 E) [ 132 ]. To verify the gel state of the hydrogel, an inverted bottle test can be performed ( Fig. 9 F). As shown in Fig. 9 I, within the frequency range of 10-100 rad s −1 , the storage modulus (G′) of both a dual-network hydrogel system (OHADN) and OHADN fiber hydrogel consistently exceeded the loss modulus (G″), confirming that both formed stable gel networks. OHADN fibrous hydrogel exhibits a significantly higher storage G′, which indicates superior deformation resistance. Under dynamic physiological conditions, this enhanced mechanical property is crucial for maintaining structural integrity. As the shear rate increases, the viscosity of the OHADN fiber hydrogel decreases, directly confirming its excellent injectability ( Fig. 9 J). Therefore, this hydrogel demonstrated potent osteogenic effects in a rat alveolar bone defect model, significantly increasing the bone volume fraction of newly formed bone and improving its quality. Fig. 9. Open in a new tab (A) A multiscale mechanical-adapted hydrogel for the repair of IVDD; (B) Macro-mechanical adaptation; (C) Statistical results of the elastic modulus at the macroscale; (D) Statistical results of the relaxation times at the macro-scale [ 131 ]. Copyright 2025, Elsevier. (E) Schematic representation for fabricating the OHADN fiber@Yoda1 hydrogel; (F) Vial inversion tests; (G) The G′ and Gʺ; (H)The viscosity-shear rate curves [ 132 ]. Copyright 2025, Springer Nature. (I) Electrical stimulation promotes skull repair and schematic diagram of the preparation of G-A-CNTs/G-A-GO hydrogel [ 133 ]. Copyright 2025, Elsevier. (J) Schematic diagram of the formation of dECM-MA via functionalization reactions; (K) Statistical analysis was performed using one-way ANOVA [ 134 ]. Copyright 2025, Wiley-VCH GmbH. Dual-network architecture provides a robust design framework for regulating hydrogel mechanical properties. In modern cutting-edge applications, materials must not only achieve superior mechanical performance, but also integrate electrical, thermal, and other functions. To achieve this goal, nano-reinforcing phases ( e.g. , carbon nanotubes and graphene) can be introduced into polymer networks. To create a composite system that offers excellent mechanical properties as well as electrical conductivity, Geng et al. integrated carbon nanotubes and graphene oxide into a gelatin/polyacrylamide double-network hydrogel [ 133 ]. Carbon nanotube-based composite hydrogel demonstrated outstanding biocompatibility and significantly accelerated bone tissue regeneration when implanted into a calvarial defect model under electrical stimulation ( Fig. 9 I). Clinical challenges in bone repair, such as scarcity of donor materials and postoperative infections, can be addressed through this innovative strategy. Through filling and interfacial interactions, nano-reinforcing phases enhance the mechanical properties of hydrogels at the micro- and nanoscales. Modifying the cross-linking density of polymer chains is the key to fundamentally regulating the load-bearing capacity of the polymer network. Dekker et al. successfully developed a light-crosslinked porcine bone-derived decellularized extracellular matrix (dECM) hydrogel (dECM-MA) ( Fig. 9 J) [ 134 ]. Following 10% EDTA demineralization and 3.4 M NaCl osmotic shock treatment, 94% of DNA is removed while key bone extracellular matrix (ECM) proteins are preserved. A functionalization degree of 87-98% is achieved after pepsin digestion and methacrylation modification. The Young's modulus of the hydrogel can also be precisely controlled within a broad range of 0.5-120 kPa by systematically adjusting the dECM-MA concentration (0.25-2% w/v) and photopolymerization time (8-120 s) ( Fig. 9 K). A wide range of mechanical properties enables it to match varying mechanical requirements from soft tissue to mature bone, demonstrating excellent reproducibility across multiple batches. As a result of precise composition and cross-linking parameters, we were able to regulate soft tissue to hard bone hydrogel mechanical properties. For many minimally invasive surgical scenarios, the material's operability during implantation is equally important to its final mechanical properties. Consequently, subsequent research will focus on improving the injectability and in-situ shaping capabilities of hydrogels, thereby ensuring precise implantation and rapid establishment of stable mechanical support. 2.2.3. Injection molding and in-situ molding design To achieve minimally invasive implantation and precisely match irregular tissue defects, it has become increasingly important to develop hydrogels that combine excellent injectability with rapid in-situ shaping capabilities. Moreover, traditional scaffolds have inherent limitations when it comes to encapsulating cells, regulating components, and conforming to complex defect shapes. Thus, the design of smart hydrogels capable of responding to physiological environments or external stimuli, self-assembling or solidifying at the implantation site has become a current research focus. Hydrogels with injectability and in-situ formation abilities can currently be designed primarily through temperature-responsive, pH-responsive, ion-cross-linking, and photo-cross-linking mechanisms. Using a two-component hydrogel composed of hyaluronic acid modified with dopamine (Dop-HA) and pluronic F127 ( Fig. 10 A), Zeng et al. synthesized magnesium-proanthocyanidin coordination nanoparticles (Mg-PC) by self-assembly [ 13 ]. By cross-linking catechol with Mg-PC, the sudden release of Mg 2+ was effectively suppressed, extending the release cycle to 56 days. The resulting hydrogel (Mg-PC@Dop-HA/F127) is injectable, thermosensitive, and shape-adaptable, which allows it to conform well to the irregular implantation site of the supraorbital muscle. Accordingly, the composite hydrogel developed in this study represents a novel drug delivery system that seamlessly integrates material properties with biotherapeutic functions [ 138 ]. Photo-responsive imine crosslinked (PIC) hydrogel scaffolds based on hyaluronic acid have been developed by Lv et al. [ 135 ]. Scaffolds such as these achieve in situ curing under 365 nm light exposure, precisely conforming to defect morphology while serving as sustained-release carriers that significantly extend the duration of local retention of exosomes, thus enhancing therapeutic efficacy ( Fig. 10 B). Fig. 10. Open in a new tab (A) Schematic representation of the design of an injectable composite hydrogel [ 13 ]. Copyright 2024, Elsevier. (B) Raw materials and preparation process for ExoshEZH 2 @HG synthesis [ 135 ]. Copyright 2025, Wiley-VCH GmbH. (C) Design and gel formation mechanism of the dualnetwork of CA-Mg/BSA-GP (CMBG) gel [ 136 ]. Copyright 2025, Elsevier. (D) The amino group of BST and gelatin, as well as the aldehyde group of oxidized chondroitin sulfate, were utilized for cross-linking via Schiff base bonds to prepare a BST/Gelatin/OCS nanocomposite injectable hydrogel (BGO hydrogel) [ 137 ]. Copyright 2024, Elsevier. To construct an antibacterial dual-network hydrogel, Yu et al. used a synergistic approach: on the one hand, employing CA-Mg 2+ coordination and genipin-bovine serum albumin (GP-BSA) covalent reactions to create a robust dual-network structure; on the other hand, incorporating peptide antibiotics ( e.g. , vancomycin) into the network, increasing its antibacterial efficacy significantly ( Fig. 10 C) [ 136 ]. Using compression testing and rheological analysis systems, this study evaluated the mechanical properties of hydrogels. To ensure suitability for minimally invasive implantation, syringe extrusion experiments were conducted to verify their injectability. Additionally, their ability to gel in situ under physiological conditions was investigated. To achieve both injectability and in situ gelation, ionic cross-linking relies on the coordination reaction between ions and polymers. Bi/SrTiO 3 (BST) nanoheterostructures were incorporated into in situ synthesized injectable polymer hydrogels by Xiao et al. ( Fig. 10 D) [ 137 ]. Injectable hydrogels are ideal platforms for delivering nanomedicines since they integrate and protect nanomedicines while enabling precise targeting. This significantly enhances therapeutic efficacy and promotes tissue repair. Hydrogels’ injectability and in-situ shaping represent core design strategies. During injection, these materials achieve fluidity, shear thinning during injection, and rapid solidification and shaping post-injection through mechanisms such as thermosensitivity, pH responsiveness, and ionic cross-linking. Minimally invasive therapies become more effective as a result of precise filling of irregular defects, effective encapsulation of cells and bioactive factors, and mechanically stable microenvironments for tissue regeneration. To provide a schematic overview of how distinct fabrication strategies dictate the microstructural characteristics and macroscopic properties of hydrogels, Fig. 11 delineates a logical framework that correlates the preparation methodology with the resulting hydrogel type and its structural features. The realization of macro-level structural control strategies such as porous architecture, mechanical properties, and injection molding is fundamentally dependent on a molecular cross-linking network after systematically exploring macro-level structural control strategies. The cross-linking strategy determines the network topology, dynamic properties, and functional integration capabilities of hydrogels. In the following sections, we will discuss how cross-linking strategies enable precise control over hydrogel structural stability, environmental responsiveness, and biological function. Fig. 11. Open in a new tab Schematic illustration of preparation strategies, hydrogel types, and corresponding structural characteristics for orthopedic hydrogels. 2.3. Cross-linking strategy A hydrogel can be classified into two types based on the nature of the cross-linking forces in the polymer network: physically crosslinked and chemically crosslinked. By linking polymer chains through covalent bonds, chemically crosslinked hydrogels form stable and robust three-dimensional networks, thereby exhibiting superior mechanical properties and structural stability. Cross-linking typically involves toxic chemical cross-linking agents ( e.g. , glutaraldehyde) and harsh reaction conditions, which may compromise the activity of encapsulated biological components, limiting their use in sensitive fields such as biomedicine and wearable electronics. By contrast, physically crosslinked hydrogels are formed by reversible non-covalent interactions such as ionic bonds, hydrogen bonds, and hydrophobic forces. Even though their mechanical strength is generally lower, their excellent biocompatibility, stimulus responsiveness, and reversible remodeling properties make them more suitable for in vivo environments and flexible device applications [ 139 ]. Hydrogels often exhibit a trade-off between mechanical strength and self-healing properties. By combining physical cross-linking with chemical cross-linking strategies, researchers have developed composite hydrogels with excellent mechanical properties and rapid self-healing. Despite their structural stability, these materials exhibit dynamically reversible healing properties, which greatly expands their application potential in fields such as flexible electronics and tissue engineering. This research represents a cutting-edge approach to functional hydrogels. 2.3.1. Physical cross-linking Through noncovalent interactions such as hydrogen bonds and ionic bonds, physically crosslinked hydrogels form dynamic networks. These hydrogels exhibit excellent reversibility and swelling properties, but also suffer from inadequate stability due to the bond energies of the interactions being significantly lower than those of covalent bonds (approximately 1%-10%). Its dynamic responsiveness makes it particularly suitable for scenarios such as smart textiles and drug delivery systems that require dynamic responsiveness. By optimizing the physical cross-linking process of sodium alginate, Ma et al. successfully developed the “LipoGel” material, which effectively reduced gel shrinkage and incorporates liposomes to enhance lubrication ( Fig. 12 A) [ 140 ]. High mechanical strength, high water content, and outstanding lubrication properties are all characteristics of this material. This study systematically regulated key parameters, such as sodium alginate concentration, calcium ion concentration, cross-linking time, and cross-linking agent addition method, to effectively suppress shrinkage in calcium ion-crosslinked alginate hydrogels. The results indicate that calcium ion concentration is critical to inhibiting gel shrinkage and promoting uniformity. These optimization strategies resulted in alginate hydrogel films with a smooth macroscopic morphology, uniform structure, and high transparency ( Fig. 12 B and C). In addition to its simplicity of preparation, excellent biocompatibility, and reversible gelation, the physically crosslinked hydrogel offers several advantages. In spite of this, its mechanical properties are typically weak, which limits its application to some extent. Due to their reversible dynamic bonding mechanism, physically crosslinked hydrogels exhibit excellent self-healing properties and biocompatibility. However, their weak bond strength results in poor mechanical properties and structural stability. As a result, they are not suitable for use in load-bearing environments or in long-term implant situations. By forming stable covalent bond networks, chemical cross-linking strategies provide hydrogels with increased mechanical strength, structural rigidity, and long-term durability. Biomedical applications requiring high mechanical performance and stability, such as tissue engineering scaffolds and sustained-release drug delivery systems, can benefit from this approach. Fig. 12. Open in a new tab (A) The flow chart of the LipoGel preparation method; (B) Photographic images of opaque shrinking (top) and transparent nonshrinking (bottom) alginate hydrogels; (C) Schematic of alginate gelation at low and high cross-linking densities and the "Egg-Box" cross-linking model [ 140 ]. Copyright 2024, Wiley-VCH GmbH. (D) Schematic diagram showing the design principle of click-crosslinked in-situ hydrogel [ 141 ]. Copyright 2023, Elsevier. (E) Schematic representation of the design of dynamic CGDE hydrogel [ 142 ]. Copyright 2025, Wiley-VCH GmbH. (F) Schematic illustration of the preparation of biomimetic sandwich-layered hydrogel [ 143 ]. Copyright 2025, Elsevier. 2.3.2. Chemical cross-linking The cross-linking process creates a permanent three-dimensional network within hydrogels through the formation of covalent bonds, which plays a significant role in the development of high mechanical strength and structural stability in materials. The design of this material depends on the selection of cross-linking agents and the control of reaction conditions, which directly influence the final properties of the hydrogel, as well as the cross-linking process itself. It is possible to categorize chemical cross-linking strategies based on the mechanism by which covalent bonds are formed and the reaction pathways involved. These include Michael addition, condensation reactions, and enzyme-mediated cross-linking; aldehyde-based Schiff base reactions and disulfide bond exchange; and photo- or thermally initiated radical polymerization. By using Michael addition and Schiff base reactions in “click” chemistry, Lei et al. crosslinked modified maleimide-functionalized sodium alginate (AM) and thiocarboxymethyl chitosan (CS) [ 141 ]. These were mixed in equal volumes or different mass percentages to form A x C y (x, y = 3, 4, 5, 6, 7; x + y = 10) in situ hydrogels via Michael addition and Schiff base reactions in click chemistry ( Fig. 12 D). Multiple bioactivities of the hydrogel prepared in this study have been demonstrated both in vitro and in vivo, including excellent antibacterial and antioxidant properties, stimulation of macrophage M2 polarization, and enhancement of angiogenesis. With the ability of this hydrogel to demonstrate favorable wound-healing properties, it shows broad translational potential in the treatment of diabetic wounds, treatment of infected wounds, and postoperative care. I believe that it holds potential as a novel intervention strategy for the repair of clinically difficult-to-heal wounds. There are many limitations associated with single chemical cross-linking processes, including irreversible cross-linking processes and the inability to regulate these processes dynamically. To overcome the limitations of single cross-linking modes, physicochemical dual-crosslinked hydrogel systems have emerged as a cutting-edge approach for optimizing material properties by combining dynamically reversible physical cross-linking with stable, durable chemical cross-linking. Utilizing two distinct cross-linking mechanisms, this strategy enhances the hydrogel's self-healing, stimuli-responsive, and fatigue recovery properties while maintaining its structural stability. 2.3.3. Physicochemical dual cross-linking A common strategy for improving the mechanical properties of hydrogels is to construct dual-network structures that incorporate both chemical and physical cross-linking. There are, however, significant challenges associated with this approach: when chemical cross-linking is performed, residual unreacted cross-linking agents may induce cytotoxicity and limit biocompatibility; at the same time, covalent networks are typically irreversible, making it challenging to precisely control the gel formation process. The question of how to achieve high mechanical strength and controllable shaping in natural polymer-based hydrogels while maintaining their biological activity remains an urgent issue in this field that requires urgent attention. As of now, chemically crosslinked hydrogels such as GelMA are widely used for bone organoid culture, but their networks usually lack the dynamic viscoelasticity required for bone growth. Due to their tunable viscoelasticity and self-assembly properties, hydrogen-bond crosslinked DNA hydrogels are capable of supporting 3D cell and organoid culture, but their mechanical strength is insufficient for use as an individual matrix for bone organoids. A GelMA/DNA dual-network hydrogel (CGDE) was developed by Zhu et al. to combine the advantages of both materials [ 142 ]. By integrating the dynamic hydrogen bonds of the DNA network with the stable chemical crosslinks of GelMA, it achieves ideal viscoelastic properties while maintaining sufficient mechanical strength, providing bone organoids with a more biomimetic microenvironment ( Fig. 12 E). CGDE hydrogels exhibit excellent biocompatibility, significantly promoting osteogenic differentiation and mineralized nodule formation of BMSCs, as well as exhibiting anti-inflammatory and proangiogenic properties. A biomimetic bone matrix material closely mimics the composition and function of a natural bone microenvironment. Bone tissue engineering research and the development of therapeutic strategies for bone regeneration can benefit from this versatile organoid culture substrate. In addition, Shan et al. have prepared PACG-CS@Mn(III) hydrogels with a biomimetic sandwich structure by cross-linking poly (acryloyl 2-glycine)-chitosan (PACG-CS) composite hydrogels through end-to-end immersion in Mn 3+ ( Fig. 12 F) [ 143 ]. Through the synergistic effects of chain entanglement, hydrogen bonding, and metal coordination, this strategy utilizes multiple physicochemical cross-linking mechanisms to control hydrogel structure in an efficient manner. To mimic the gradient structure and anisotropic mechanical properties of natural cortical and cancellous bone, the manganese concentration and immersion time are precisely controlled. This SL hydrogel offers a novel approach for the construction of bone tissue engineering materials by overcoming limitations in structural biomimicry and functional integration inherent in conventional methods. By combining covalent and noncovalent bonds, the dual cross-linking strategy in physicochemistry effectively balances the mechanical strength and dynamic properties of hydrogels, providing an ideal approach for the development of high-performance biomaterials. In this context, "high performance" refers to the exceptional and synergistic multidimensional properties exhibited by hydrogels in orthopedic applications, including robust mechanical properties suitable for weight-bearing orthopedic sites, excellent biocompatibility and bioactivity, as well as tunable biodegradability that matches the rate of new bone formation. This sentence should be translated into English in accordance with the technical terminology requirements of high-impact journals. Having achieved ideal structural regulation, the key challenge now is to expand their biological capabilities. The selection of a cross-linking strategy represents a core design consideration in orthopedic applications, as it directly dictates the trade-off between structural stability and dynamic functionality. Physically crosslinked hydrogels, characterized by excellent biocompatibility, injectability, and self-healing properties, are well-suited for scenarios requiring flexibility and fatigue resistance, such as articular cartilage repair. However, their relatively weak bond strength limits their capacity to maintain long-term structural stability in high-load-bearing environments. In contrast, chemically crosslinked hydrogels provide robust and tunable mechanical strength through permanent covalent bonds, making them the preferred choice for load-bearing applications like cortical bone defect repair, albeit often at the expense of toughness and injectability. To overcome the limitations of single-network systems, physicochemical dual cross-linking strategies have been developed. By integrating a stable covalent network with a dynamic reversible network, these hydrogels achieve a synergy between high strength and self-healing or fatigue-resistant properties; for instance, in intervertebral disc repair, they can withstand spinal loads while effectively dissipating cyclic stress. Consequently, the selection of an appropriate cross-linking strategy must be grounded in a precise understanding of the mechanical microenvironment at the target implantation site to achieve an optimal match between material properties and clinical requirements. The subsequent discussion will focus on functionalization strategies, such as modification with active molecules, to endow hydrogels with osteogenic, antimicrobial, and smart responsive capabilities, thus meeting the complex demands of tissue engineering and regenerative medicine. 2.4. Functional modification The conventional single-function hydrogels do not meet the comprehensive clinical demands for bone regeneration efficiency, infection control, and long-term stability that have become increasingly demanding to achieve effective integration of orthopedic implant materials with the complex physiological microenvironment. Research is increasingly focused on developing multifunctional integrated systems. It is extremely important that the next generation of biomaterials not only promote osteogenic differentiation precisely, but also synergistically confer multiple biological effects, such as anti-inflammatory properties, antibacterial properties, and delayed cellular senescence properties, to the cells. Additionally, smart materials with external stimulus-responsive capabilities are opening up new avenues for enhancing bone regeneration by sensing microenvironmental changes and regulating osteogenic behavior in real-time to maximize bone regeneration. On the basis of this rationale, this section aims to systematically present the actual research progress in functionalization strategies that endow hydrogels with three core properties: enhanced osteogenesis, antibacterial protection, and intelligent response. 2.4.1. Osteogenic function modification Osteogenic modification is a key element in functional design for osteogenic induction in hydrogels for bone defect repair. Three strategies are currently being employed to enhance osteogenic properties: loading osteomorphogens and vascular endothelial growth factor to promote bone formation and vascularization; incorporating bioactive ions such as strontium, magnesium, and silicon to regulate bone metabolic balance; and modifying surfaces with collagen-mimetic peptides and RGD peptides to promote cell adhesion and osteogenic differentiation. By combining these strategies, osteoinductive properties of materials are enhanced on a molecular, ionic, and interfacial level. Among them, Bone Morphogenetic Proteins (BMPs) are acidic proteins present in the bone matrix, structurally composed of various amino acids and belong to the Transforming Growth Factor-beta (TGF-β) superfamily. Many bone metabolism and regeneration processes are controlled by BMPs, which are key regulators of skeletal development and bone formation. In embryonic angioblast development and angiogenesis, Vascular Endothelial Growth Factor (VEGF), also known as Vascular Permeability Factor (VPF) or VEGFA, acts as a central regulator. According to Ren et al. [ 92 ], calcium ion-recruiting peptide (FVDVT, abbreviated as CP) and vascular endothelial growth factor-related proprotein-1 derivative peptide (DRVQRQTTTVVA, abbreviated as BP) have significant synergistic effects in a GelMA hydrogel system modified with methyl acrylate (GM@BCP). In combination, they promote angiogenesis and the establishment of an osteogenic microenvironment ( Fig. 13 A and B). In addition to its excellent cell compatibility, non-toxicity, and bioabsorbability, the GM@BCP hydrogel has also been shown to effectively fill irregular bone defects. A model evaluation further confirms that the hydrogel has significant potential for fracture repair through a dual mechanism involving calcium ion binding and VEGF recruitment. In bone tissue engineering and related regenerative medicine fields ( Fig. 13 C), this strategy holds broad scientific value and application prospects. Fig. 13. Open in a new tab An overview of the bone regeneration by the GM@BCP hydrogels. (A) The preparation of BP and CP. (B) The preparation of PLA/G@CP short ffbers and GM@BCP hydrogels. (C) The healing process of GM@BCP hydrogels during bone repair [ 92 ]. Copyright 2025, Elsevier. (D) Schematic diagram of the preparation of CA-Cur@Cu hydrogels and the mechanism of CA-Cur@Cu hydrogels for repairing bone defects [ 144 ]. Copyright 2025, Elsevier. (E) Schematic Diagram of CA-Cur@Cu Hydrogels Preparation [ 145 ]. Copyright 2024, Oxford University Press. (F) Preparation process of L-Gln@GMs@QCSFP [ 146 ]. Copyright 2025, Elsevier. 2.4.2. Antimicrobial functional modification Antimicrobial functionalization has emerged as a key direction in hydrogel design to combat postoperative infections in orthopedic implants. The current antimicrobial strategies use three approaches: first, loading antibiotics such as vancomycin and gentamicin into sustained-release systems, which enable continuous prevention and treatment of implant-associated infections. The second step is to incorporate natural antimicrobial agents such as chitosan, curcumin, and silver nanoparticles into the formulation to reduce the risk of bacterial resistance through a variety of antimicrobial mechanisms. The third approach involves using photothermal/photodynamic materials such as black phosphorus nanosheets and MXene to trigger localized, precise antimicrobial action using near-infrared light, thereby avoiding systemic side effects associated with oral medications. Through multiple mechanisms, including chemical sustained release, bioactivity, and physical response, these antimicrobial strategies establish a multilayered infection defense system for orthopedic implants [ 147 ]. An ideal antimicrobial property should be temporal regulated: rapidly exerting powerful bactericidal effects during the initial implantation phase to eliminate pathogens introduced during surgery; maintaining sustained antimicrobial activity throughout long-term implantation for effective inhibition of bacterial adhesion, colonization, and biofilm formation, thereby achieving comprehensive control throughout the entire infection cycle. A hydrogel injectable CMPMg-VCM for the treatment of osteomyelitis was successfully developed and systematically evaluated by Zhang et al. [ 144 ]. MgO nanoparticles were coordinated with phosphocreatine-modified chitosan and vancomycin (VCM) was loaded onto this material. According to the results of our experiments, the loading of VCM did not affect the injectability of the hydrogel, and the incorporation of MgO improved the anti-swelling properties of the hydrogel ( Fig. 13 D). In a rat osteomyelitis model, the CMPMg-VCM hydrogel demonstrated significant therapeutic efficacy: in addition to disrupting bacterial biofilms through the rapid release of VCM, it also continuously inhibited bacterial growth by generating Mg 2+ and -OH ions from MgO degradation, thereby preventing bone loss caused by infection. The characteristics outlined above indicate that this hydrogel has significant translational potential in the treatment of microbial bone infections. In addition, Lu et al. prepared curcumin-PLGA microspheres via a double emulsion method and incorporated them into a carboxymethyl chitosan/SA hydrogel network that was cross-linked with copper ions, resulting in the CA-Cur@Cu composite hydrogel ( Fig. 13 E) [ 145 ]. In addition to its antioxidant and anti-inflammatory properties, the composite system enhances the bone immune microenvironment by inducing macrophage polarization toward the M2 phenotype. Meanwhile, the sustained-release Cu 2+ within the hydrogel promotes angiogenesis and osteogenic differentiation in a synergistic manner. Copper ions accelerate bone defect repair through their immunomodulatory effects when combined with curcumin. Moreover, the CA-Cur@Cu hydrogel exhibits significant inhibitory activity against clinically prevalent pathogens, offering a novel approach to the treatment of infected bone defects. 2.4.3. Intelligent response modification The term "smart hydrogel" refers to a class of three-dimensional polymer networks that are capable of responding spatiotemporally to internal and external stimuli, such as pH, temperature, enzymes, or light. Nanoparticles and functional biomolecules are efficiently loaded into their hydrophilic matrix, allowing for precise controlled drug release and targeted cell encapsulation. In the fields of bone tissue engineering and regenerative medicine, these properties have significant application value. Smart hydrogels offer outstanding biocompatibility, dynamically tunable mechanical properties, and precise drug release compared to conventional hydrogels. Through spatiotemporal regulation, they modulate osteoblast behavior and local factor distribution within the bone repair microenvironment. In the field of bone defect repair, smart hydrogels are a highly promising preferred strategy because of their ability to promote bone tissue regeneration. In orthopedic applications, smart hydrogels have evolved multiple response types, primarily including systems sensitive to endogenous biochemical signals such as enzymes, temperature, ROS, redox states, and pH, as well as those capable of responding to exogenous electromagnetic radiation such as ultraviolet and infrared light. By sensing and responding to specific stimuli, these materials are able to dynamically regulate their structure and function, providing precise and controllable therapeutic strategies for bone repair. Wang et al. successfully constructed a composite hydrogel (L-Gln@GMs@QCSFP) responsive to inflammatory microenvironments by encapsulating L-glutamine in gelatin microspheres (L-Gln@GMs) and combining them with quaternized chitosan-polyvinyl alcohol self-assembled hydrogel ( Fig. 13 F) [ 146 ]. With this material, excellent mechanical properties are combined with injection properties, resulting in stable adsorption onto articular cartilage surfaces and controlled release of L-Gln under ROS-induced conditions. It thus provides a novel functional material for regulating the inflammatory microenvironment. A rat model of osteoarthritis showed that this hydrogel effectively delayed cartilage tissue degradation and reduced synovial inflammatory responses. This study demonstrated that the functionalized hydrogel developed in this study is capable of delaying osteoarthritis progression and cartilage degeneration using a multi-mechanism synergistic approach. Building upon this foundation, researchers have further explored smart hydrogel systems capable of responding to multi-stage pathological processes. The HTF@HA injectable multifunctional hydrogel, collaboratively developed by Fan Zhen and Xu Chun, leverages a dynamic boronate ester crosslinked network to achieve temporally controlled and environmentally responsive delivery of bioactive factors [ 148 ]. The intelligent regulatory mechanism of this hydrogel is primarily manifested in three aspects. First, a rapid release effect triggered by the inflammatory microenvironment. The dynamic boronate ester bonds within HTF@HA undergo accelerated hydrolysis under the acidic pH and high reactive oxygen species levels characteristic of inflamed regions. This facilitates the preferential release of antioxidant and anti-inflammatory components, which rapidly alleviate local inflammation by scavenging excess reactive oxygen species, suppressing pro-inflammatory cytokine expression, and inducing macrophage polarization toward the M2 phenotype. Second, a sustained release function oriented toward the repair phase. As inflammation subsides, the hydrolysis rate of the boronate ester bonds decreases. Concurrently, the hydrogel mediates the long term, stable release of concentrated growth factors and low dose bone morphogenetic protein-2 through calcium-phosphate interactions, thereby promoting osteogenic differentiation and angiogenesis. Third, a dose optimization strategy enhancing clinical translation potential. Leveraging its on-demand release capability, this system achieves precise spatiotemporal control over growth factor delivery. Remarkably, at a bone morphogenetic protein-2 concentration of only 50 μg L-1, its bone regeneration efficacy is comparable to that of the traditional high dose of 500 μg L-1, fully embodying the therapeutic concept of reduced dosage with enhanced efficacy. In summary, the evolution from single-stimulus reactive oxygen species responsive systems to the multi-stage, temporally sequenced responsive hydrogel represented by HTF@HA illustrates the continuous advancement of smart materials toward precise adaptation to the dynamic progression of pathological microenvironments. Through phased intervention, achieving rapid immunomodulation during the inflammatory phase and providing sustained osteogenic support during the repair phase, this approach offers a precisely controllable, synergistically enhanced therapeutic strategy for bone defect repair. Developing hydrogel technology into multifunctional integrated intelligent systems is the future direction of hydrogel technology: promoting bone regeneration through osteogenic modification; creating multi-level infection defense mechanisms through antimicrobial functionalization; and achieving adaptive regulation of pathological microenvironments through smart response modules. By combining these three functions, hydrogels provide innovative solutions for clinical translation of orthopedic regenerative medicine by simultaneously guiding biological activity, eliminating pathogens, and delivering dynamic precision therapy during complex bone defect repair. 3. Primary applications of hydrogels in orthopedics Due to their unique physicochemical properties and biological functions, hydrogels have a wide range of potential applications in orthopedics. This type of technology can be used to repair bone defects, deliver drugs, lubricate joints, treat spinal diseases, promote fracture healing, repair articular cartilage, and prevent infections. Since hydrogels mimic the extracellular matrix microenvironment, they have become a key direction in the advancement of orthopedic materials technology because they provide critical support for bone tissue repair ( Fig. 14 ). Fig. 14. Open in a new tab Schematic of hydrogel applications in orthopedics [ 142 , [149] , [150] , [151] , [152] , [153] , [154] , [155] , [156] , [157] , [158] , [159] , [160] , [161] ]. 3.1. Bone defect repair There are various causes of bone defects in orthopedics, including infection, trauma, tumor resection, and congenital disorders. The etiology of bone defects can be divided into three categories: traumatic, pathological, and infectious. In most cases, bone grafting surgery is necessary due to the limited self-healing capacity of bone tissue. As the global population ages at an accelerated rate, bone has become the second most commonly transplanted biological tissue after blood. Currently, autologous bone grafting and allogeneic bone grafting commonly used in clinical practice face issues such as limited donor sources, immune rejection reactions, and disease transmission risks. Despite excellent mechanical properties, inorganic biomaterials ( e.g. , metal implants and bioceramics) are severely lacking in biocompatibility, intraoperative conformability, and bioadhesion to the host bone. As a result of these limitations, they are unable to meet the demands of modern orthopedics for minimally invasive and precision-guided treatments. Furthermore, the rapid advancement of minimally invasive surgical techniques has led to a new demand for bone repair materials. Efforts are underway to develop injectable bone regeneration materials that can be precisely adapted to minimally invasive procedures and enable in-situ filling and osteogenesis. 3.1.1. Traumatic bone defect Bone defects caused by trauma are generally characterized by disruptions in the continuity of bone tissue and volumetric loss due to high-energy injuries, severe fractures, or surgical debridement of the bone. The local microenvironment is often disrupted and blood supply compromised, resulting in extremely limited self-repair ability. Without effective intervention, they rapidly progress to nonunion, which presents a highly challenging clinical problem in orthopedics. Among bone regeneration materials, hydrogels have received significant attention because of their biocompatibility, ability to immobilize bioactive substances, and capacity to promote cell proliferation, migration, and differentiation. According to Wang et al. [ 162 ], a photothermal-triggered smart bone repair bandage has been successfully developed with a dual-layer thermoresponsive structure consisting of a shape-adaptive PAG-PDA inert hydrogel substrate and a photothermal-responsive PNG-PDA active scaffold ( Fig. 15 A). By combining body temperature and near-infrared light stimulation, this system achieves dual functionality: the underlying substrate softens and deforms in response to body heat to precisely conform to irregular bone defect contours, while the upper scaffold undergoes controlled contraction upon NIR irradiation, providing dynamic mechanical stimulation to surrounding bone tissue. Using this intelligent platform, a new paradigm is established for the minimally invasive and dynamic repair of irregular bone defects, particularly in elderly patients and in complex anatomical locations, representing a technological leap from static filling to dynamic regulation. Fig. 15. Open in a new tab (A) Schematic illustration of the design and function of the 4D scaffold [ 162 ]. Copyright 2025, Wiley-VCH GmbH. (B) Synthesis of Qu@ZIF-8 nanoparticles and preparation of cryogel precursor solution; In vivo evaluation of bone regeneration in the diabetic rat critical-size calvarial defect model. (C) Schematic diagram illustrating the time frame of the in vivo study [ 163 ]. Copyright 2025, American Chemical Society. (D) Synthesis of PDA@CeO 2 -Mg composite nanoparticle; In vivo new bone formation evaluation. (E) Schematic diagram of osteoporosis modeling and in vivo osteogenesis of nanocomposite hydrogel [ 164 ]. Copyright 2025, Wiley-VCH GmbH. (F) Schematic illustration of preparation and cross-linking of novel MgO 2 -potentiated multifunctional hydrogel; In vivo antitumor studies. (G) Scheme of the postoperative antitumor effects by implanting hydrogel after surgical removal of the primary tumor [ 165 ]. Copyright 2025, Elsevier. 3.1.2. Pathological bone defect On the basis of their underlying mechanisms, pathological bone defects can be divided into three groups: osteoporotic bone defects resulting from imbalance in bone metabolism, diabetic bone defects resulting from impaired glucose metabolism and microvascular lesions, and postsurgical bone defects resulting from tumor erosion or surgical removal. In diabetic patients, however, excessive reactive oxygen species create a vicious cycle with chronic inflammatory responses, severely inhibiting the processes of osteogenic differentiation and angiogenesis. Due to their disordered pore structures, traditional bone repair scaffolds cannot support cell migration and functional expression, making them ineffective at reversing this complex pathological process. A composite hydrogel with radially aligned microchannels was constructed using a combination of directional freezing and photo-cross-linking by Wang et al. [ 163 ]. Nano-hydroxyapatite (nHA) is incorporated to enhance mechanical properties in this system, which uses GelMA and sericin methacrylate (SilMA) as polymer matrices. By embedding Qu-loaded ZIF-8 nanoparticles (Qu@ZIF-8) within the matrix, a controlled release of quercetin (Qu) was achieved ( Fig. 15 B and C). Through a synergistic combination of "radial structure-guided directional repair" and "active microenvironment regulation", this hydrogel regenerates diabetic bone defects efficiently. A "structure-function" design strategy provides a new paradigm for tissue engineering treatments of other degenerative bone diseases, including osteoporosis. Additionally, ROS and persistent inflammatory responses can lead to osteoclast dysfunction within the pathological microenvironment of osteoporosis, thereby disrupting the dynamic equilibrium between bone formation and resorption. This severely impedes the repair and regeneration processes of bone tissue. Traditional therapeutic strategies are largely confined to drug interventions such as bisphosphonates and estrogens. Despite their direct targeting of the local microenvironment at the lesion site, these approaches have a limited clinical efficacy. Consequently, Wang et al. successfully developed a photocrosslinkable hydrogel (GCPM) based on GelMA matrix, constructed by integrating poly(dopamine)-modified cerium oxide nanoparticles (CeO 2 NPs) with Mg 2+ ( Fig. 15 D) [ 164 ]. Further, in vitro experiments confirmed that this hydrogel effectively enhances osteogenesis-related gene expression and mineral nodule formation under conditions of oxidative stress. Furthermore, the GCPM hydrogel demonstrated significant bone regeneration-promoting properties in osteoporotic bone defect models, speeding up new bone growth while improving the mechanical properties of the repaired bone ( Fig. 15 E). The findings of this study fully explain the dual mechanisms by which GCPM hydrogel promotes bone regeneration by remodeling the pathological microenvironment, thereby providing robust evidence for its clinical application as a repair material for osteoporotic bone defects. In children, adolescents, and young adults, osteosarcoma is the most common primary malignant bone tumor, and it is typically treated with surgical resection and neoadjuvant chemotherapy. However, this strategy faces dual challenges: on one hand, complete tumor clearance is difficult to achieve surgically, and local residual disease frequently leads to postoperative recurrence; on the other hand, extensive tumor resection results in large bone defects, which create significant challenges for subsequent functional bone reconstruction. Zhang et al. successfully developed a composite hydrogel system (MOG) that combines injectability with in situ shaping capability by incorporating magnesium peroxide (MgO 2 ) and horseradish peroxidase (HRP) into GelMA ( Fig. 15 F) [ 165 ]. It is believed that this hydrogel achieves synergistic treatment by sequentially releasing H 2 O 2 and Mg 2+ : in the initial release of H 2 O 2 synergizes with photothermal therapy to eliminate residual tumor cells post-surgery, significantly reducing the risk of local recurrence. A sustained release of Mg 2+ stimulates osteoblast differentiation and angiogenesis, thereby accelerating the structural and functional reconstruction of bone defects. Through its dual-timing function, the material is capable of exerting synergistic effects in the postoperative treatment of tumors, simultaneously suppressing tumor recurrence and stimulating bone regeneration ( Fig. 15 G). Hydrogel technology has evolved from simple “filling and supporting” to a precision-controlled system that integrates structure and function. As future advancements continue, clinical imaging and 3D printing may be integrated to ensure precise structural matching between hydrogels and defect morphology. Develop smart hydrogels that respond to multiple signals ( e.g. , enzyme, pH, mechanical) for dynamic intervention throughout the repair process; validate long-term safety through large animal models; and investigate the potential application of hydrogels in frontier fields such as gene therapy and immune regulation. 3.2. Treatment of spinal disorders The degeneration of intervertebral discs is often closely associated with spinal disorders. Various poor lifestyle habits, such as prolonged excessive weight-bearing on the lower back, abnormal posture and positioning, prolonged sitting at a desk, prolonged exposure to bumpy environments, and women's long-term use of high heels, can all trigger biomechanical imbalances in the spine. Chronic repetitive external stress accelerates the degenerative process of intervertebral discs and vertebral bodies. There are three main types of spinal disorders: intervertebral disc degeneration, spinal cord injuries, and dural tears that cause cerebrospinal fluid leaks. With their excellent mechanical properties, excellent plasticity, biocompatibility, biodegradability, high safety profile, and significant therapeutic efficacy, hydrogels can address clinical treatment needs involving nerve compression risks. Thus, they can be used for the sealing and repair of spinal wounds, as well as for the repair of dural and meningeal defects. 3.2.1. Repair of degenerative intervertebral disc disease As a highly prevalent degenerative disease, intervertebral disc degeneration (IDD) may cause low back pain (LBP), neurogenic complications, and motor dysfunction. In addition to reducing the quality of life of patients, it also increases the burden on public health. Currently, conventional treatment strategies, including conservative management and surgical intervention, demonstrate limited efficacy in delaying IDD progression and restoring IDD physiological function. Due to their diverse compositions and polymerization methods, hydrogels have opened up a wide range of applications in the field of tissue engineering and medicine. The loading of growth factors and therapeutic drugs onto different types of hydrogel carriers provides novel strategies and research directions for the repair and regenerative treatment of IDD. Meng et al. designed high-strength composite microneedles (MN) based on polydopamine (PDA) and methacrylamide-modified GelMA [ 93 ]. It is possible to puncture the annulus fibrosus (AF) with these needles and achieve accelerated drug release in synergy with synergistic hyperthermia through the use of remote near-infrared light control ( Fig. 16 A). This microneedle system loaded with diclofenac sodium exhibits dual functionality: it actively modulates the inflammatory microenvironment in the extracellular space to mitigate tissue damage, while simultaneously upregulating the expression of protective heat shock proteins within cells to enhance cellular defense capabilities under pathological conditions. The result is a precise synergistic treatment for intervertebral disc degeneration. The DPG + N treatment group demonstrated significant reparative effects eight weeks after surgery in a caudal intervertebral disc defect model in rats (21G needle puncture): MRI data revealed a 50% increase in disc height index compared to the defect group, but only an 8% decrease in nucleus pulposus water content ( vs. 35% reduction in the defect group, n = 3, p < 0.05) ( Fig. 16 B and C). Both in vivo and in vitro experiments demonstrated that this treatment effectively suppressed inflammatory responses and apoptosis while promoting the synthesis of extracellular matrix, restoring the biomechanical function of the intervertebral disc [ 168 ]. Fig. 16. Open in a new tab (A) The preparation of the composite MNs. (B) Schematic illustration of experimental process; (C) X-ray images of rat caudal vertebra at week 8, Quantitative analysis of DHI, MRI images of rat caudal vertebra at week 8, Quantitative analysis of the relative water content of IVD [ 93 ]. Copyright 2023, Wiley-VCH GmbH. (D) Schematic illustration of the preparation and fabrication of G, GH, and GHP hydrogel; (E) Illustration of HAVDI and RGI peptides function in GHP@NSC 3D bioprinted constructs; (F) Schematic illustration of animal experiment grouping and evaluation timeline in vivo; (G) Representative walking gaits (D1, D3, D5) and the detailed footprints (D2, D4, D6) of rats recorded by Catwalk system [ 166 ]. Copyright 2025, KeAi Publishing Communications. (H,I) Preparation process of the SFMA-SIS; (J) Application of Janus SIS in a Rat Spinal Cord Dural Defect Model; (K) Macroscopic photographs of spinal tissues at 8 weeks after operation [ 167 ]. Copyright 2025, Springer Nature. 3.2.2. Spinal cord injury repair The spinal cord injury (SCI) is a central nervous system disorder that causes severe impairment of motor and sensory functions, presenting a major challenge in neural repair. A detailed understanding of its pathophysiological progression and inhibitory microenvironment characteristics is crucial for elucidating functional recovery mechanisms and developing effective therapeutic methods. There are many challenges associated with managing SCI in the clinical setting, including the uncontrollable nature of graft-versus-host disease, the high risk of serious infections that result from delayed immune reconstitution after transplantation, and the poor prognosis for recurrent and refractory cases. Despite some relief from symptoms, existing treatments cannot reverse the structural damage to tissues and permanent loss of neural function caused by injury. Patients‘ functional recovery has been hindered by this bottleneck. To restore the structural and functional integrity of the spinal cord, emerging therapeutic approaches like adult immature spinal cord tissue transplantation, tissue-engineered artificial spinal cord-like constructs, and 3D-printed bionic scaffolds are pioneering these approaches. Hydrogels have been extensively utilized in preclinical SCI research for their ability to promote tissue repair and serve as therapeutic delivery vehicles (loading cells, drugs, or bioactive molecules). A high-performance drug delivery system can enhance the therapeutic efficacy of stem cells, therapeutic drugs, and various bioactive molecules. Despite these limitations, traditional hydrogels have inherent limitations, such as limited capacity for loading stem cells, low loading efficiency for bioactive molecules, and insufficient capacity for functional conversion. Due to these constraints, it is difficult to achieve optimal stem cell loading and the synergistic delivery of diverse drugs/bioactive factors with varying properties. Therefore, Yang et al. successfully constructed a dynamic bioactive hydrogel system (GHP@NSC) containing neural stem cells (NSCs) using GelMA/OHA ( Fig. 16 D and E) [ 166 ]. Through Schiff base dynamic covalent bonds, this system forms a reversible cross-linked network that enhances mechanical sensing and interactions within a cell, while also releasing N-calmin mimetic peptide (HAVDI) and brain-derived neurotrophic factor mimetic peptide (RGI) simultaneously. This promotes the proliferation of neural stem cells (NSCs) and their differentiation into neurons, speeding up the reconstruction of functional neural networks. This strategy significantly enhances neurological recovery following spinal cord injury ( Fig. 16 F and G), offering a novel approach with clinical translation potential for regenerative medicine. A highly effective treatment for spinal cord injuries requires the integration of cutting-edge diagnostic and therapeutic technologies with bioactive hydrogels. As part of an integrated therapeutic platform that integrates repair capabilities with real-time monitoring, these technologies should be organically combined with biosensing, molecular imaging, and physical diagnostic methods such as magnetic resonance imaging and computed tomography. 3.2.3. Dural seal The dura mater, a dense connective tissue membrane covering the brain and spinal cord, plays a crucial role in protecting and supporting the nervous system. A failure to achieve effective repair following dura mater incision can result in cerebrospinal fluid leakage, leading to headaches, nausea, vomiting, and impaired consciousness. Clinical practice currently relies primarily on suturing for dural closure. This technique, however, has significant limitations: it takes a considerable amount of time and is highly dependent on the surgeon's skill level, making it difficult to achieve rapid and reliable seals in anatomically narrow areas. Suturing itself may cause secondary tissue damage, and residual needle holes can leak. Recently, tissue adhesives and biological sealants have gained significant attention as cutting-edge approaches for achieving minimally invasive dural closure. The advantages of these devices include ease of use, the elimination of suturing, and the prevention of iatrogenic injuries. Therefore, developing a hydrogel material with high adhesion, low swelling rate, and excellent sealing properties as a patch can effectively block cerebrospinal fluid leakage, speed up tissue repair, and reduce the occurrence of postoperative adhesions. A novel Janus-like small intestinal submucosa (SIS) membrane was successfully developed by Bi et al. [ 167 ]. The silk-based hydrogel coating on the SIS substrate surface provides dual core functions: dura mater repair and epidural adhesion prevention. There is a microgroove coating (SFMA) comprised of a composite of SF and SilMA, which induces directed cell migration and proliferation, accelerating regeneration and repair of dura mater tissue. An outer layer of methacrylated HAMA and SilMA prevents non-specific protein adsorption and abnormal cell adhesion, thereby inhibiting epidural fibrotic adhesions ( Fig. 16 H–J). To assess the in vivo therapeutic efficacy of the Janus SIS membrane, a dural defect animal model was constructed by laminectomy. A macroscopic examination of spinal cord tissue revealed that the material in the Janus-coated group exhibited a morphology that was very similar to that of natural dura mater. Additionally, hematoxylin and eosin (H&E) staining and Masson's trichrome staining results confirmed that Janus SIS membrane formed continuous new collagen fiber tissue in the dura mater defect area, displaying morphological structures highly consistent with normal dura mater tissue ( Fig. 16 K). Due to their excellent biocompatibility, biodegradability, and functional loading capability, hydrogels demonstrate significant value in the treatment of spinal disorders. In the case of intervertebral disc degeneration, it can deliver bioactive factors and drugs to regulate the microenvironment precisely, thereby facilitating tissue regeneration and repair. As a carrier for therapeutic molecules, it promotes the repair of damaged tissue in spinal cord injury applications. In dural sealing, it effectively blocks cerebrospinal fluid leakage and inhibits postoperative adhesions. Spinal disorders can be treated with this novel, highly effective material. 3.3. Promoting fracture healing Fractures are pathological conditions in which bones break or crack as a result of external force. Traumatic factors make up the majority of its causative factors. Traumatic factors: The most common cause, encompassing accidents, falls, sports injuries, and violent impacts. Osteoporosis-related factors: Osteoporosis increases bone fragility and reduces resistance to injury, increasing the risk of fractures. Individuals with osteoporosis, those undergoing long-term glucocorticoid therapy, and malnourished populations are most likely to experience this condition. Pathological factors: There are certain diseases or pathological conditions associated with fracture risk, including bone tumors, bone infections, and congenital skeletal defects. There is no doubt that fractures result in restricted mobility, severe pain, and localized swelling, regardless of the cause. Severe cases may result in the delay of the healing process and may result in serious complications such as osteomyelitis or sepsis, which will negatively impact treatment outcomes and other typical clinical manifestations. The application potential of hydrogels in fracture healing is demonstrated primarily by two forms: First, fracture-end injectable hydrogels precisely fill bone defects, conforming to the injury interface with excellent biocompatibility. In addition, they may also load active components such as growth factors and anti-inflammatory drugs in order to regulate the local microenvironment and accelerate the formation of calluses. Furthermore, the hydrogel coating for fracture fixation scaffolds enhances the biocompatibility of internal fixation devices and reduces the inflammatory response at the interface by modifying their surface. Additionally, it promotes osseointegration between the scaffold and the bone by enabling the sustained release of active substances. Zha et al. successfully prepared a bioactive hydrogel by directly blending 4-octyl itaconic acid ester (4-OI) with a copper-based covalent organic framework (Cu COF) into a gelatin/acetyl-β-cyclodextrin (Gelatin/Ac-β-CD) solution system ( Fig. 17 A) [ 169 ]. Researchers developed a mouse femoral fracture model to test the efficacy of 4-OI@Cu@Gel hydrogel in promoting fracture healing and tissue regeneration in vivo. The fracture sites were treated with Cu@Gel hydrogel, 4-OI@Cu@Gel hydrogel, and PBS, respectively. In all three groups, radiographic examination revealed distinct fracture gaps 7 days after surgery. By 21 days postoperatively, the fracture lines in the Cu@Gel and 4-OI@Cu@Gel groups had become blurred and faint, whereas the fracture lines in the PBS control group remained clearly discernible ( Fig. 17 B). Quantitative CT analysis revealed that tissue volume (TV), bone volume (BV), and bone volume/tissue volume ratio (BV/TV) were significantly higher in both experimental groups compared to the control group, with the 4-OI@Cu@Gel group showing the most favorable outcomes for these metrics ( Fig. 17 C–E). Research has confirmed that the 4-OI@Cu@Gel hydrogel accelerates fracture healing by promoting vascular regeneration. Fig. 17. Open in a new tab (A) Schematic illustration of preparation of the 4-OI@Cu@Gel; (B-D) X-ray images of the femurs and Micro-CT construction images; (E) Statistical analysis of the micro-CT results [ 169 ]. Copyright 2024, Elsevier. (F) Schematic illustration of Ti-AQ coating were prepared through polyphenol-amine-mediated covalent modification; (G) Representative images of H&E staining of the tissues around the Ti and Ti-AQ implants; (H) The qualification and quantification of newly formed bone tissues around the Ti and Ti-AQ implants [ 170 ]. Copyright 2025, Wiley-VCH GmbH. (I) Schematic Illustration of Synthesis, Antibacterial, and Osteogenic Performance of a Composite GelBA/PVA/MgO 2 Hydrogel; (J,K) Bone volume/total volume (BV/TV) and bone surface (BS) in the femurs defect area based on micro CT [ 171 ]. Copyright 2025, American Chemical Society. (L) Schematic of injectable PHE-Gel and PHE-Gel@DMOG-Lip hydrogel formation process; (M) Schematic representation of the in situ osteochondral healing process in the control, 10% PHE-Gel, and 10% PHE-Gel@DMOG-Lip groups [ 14 ]. Copyright 2025, KeAi Communications. 3.4. Prevention and treatment of orthopedic infections In orthopedics, postoperative infection can have catastrophic consequences. In addition to causing surgical failure, it causes a cascade of adverse events: local infection can lead to chronic osteomyelitis, form difficult to eradicate biofilms, and ultimately result in implant loosening, nonunion, joint stiffness, or even functional loss, resulting in disability of the limb. When the infection is severe, it may lead to sepsis or multiple organ failure, posing a direct threat to the patient's life. A majority of orthopedic infections are associated with implant-associated infections and infected bone defects. Surgical failures, chronic pain, and even limb dysfunction are linked to the former, which is characterized by the formation of persistent biofilms on implant surfaces. There is a dilemma between bone regeneration and infection control in the case of the latter, which involves persistent infection in conjunction with localized bone necrosis and defects. These issues together represent the most challenging aspects of orthopedic postoperative care. 3.4.1. Implant-related infection In orthopedic surgery, implant-associated infections are a serious and still unresolved clinical problem. Implant failure is often caused by such infections, requiring multiple surgeries to remove or replace the implant. Moreover, infections can easily become chronic or recurrent, thus reducing patients' quality of life and significantly increasing their morbidity and mortality rates. Treatments involving systemic antibiotics and surgical debridement are not only expensive and time-consuming, but may also lead to the development of bacterial resistance and iatrogenic bone defects. The multiple limitations of existing treatment strategies call for the development of novel and highly effective treatment approaches. With their unique three-dimensional porous structure and functionalizability, hydrogels effectively reduce bacterial adhesion, inhibit biofilm formation, and demonstrate outstanding antimicrobial properties by locally releasing antimicrobial agents or creating microenvironments that are detrimental to bacterial growth. Consequently, they have become a key biomaterial for implant-associated infections. Sun et al. proposed a surface modification strategy aimed at enhancing the affinity of dental implants toward mammalian cells during the early stages of implantation, thereby gaining an advantage in cell-bacteria competition [ 170 ]. By using polyphenol-amine chemistry, a spatially ordered bifunctional coating can be formed on titanium surfaces. The quaternary ammonium groups provide contact bactericidal activity, while the phosphate groups recruit and activate osteoblasts to promote osseointegration ( Fig. 17 F). In vivo evaluation in an implant-associated infection model further validated the efficacy of this strategy ( Fig. 17 G and H). Functionalized surfaces significantly suppressed bacterial infection while simultaneously improving osseointegration, demonstrating their potential for treating infected bone defects and preventing implant failure. Furthermore, Peng et al. developed a GelBA/PVA/MgO 2 hydrogel with Gel, BA, PVA and MgO 2 ( Fig. 17 I) [ 171 ]. A dynamic borate ester bond is formed between PVA and BA in this hydrogel, resulting in outstanding self-healing capabilities and pH responsiveness. As pH changes, these bonds reversibly form and dissociate, conferring both core properties to the material. In addition, the incorporation of MgO 2 nanoparticles not only optimizes the hydrogel's network structure, but also enables sustained release of H 2 O 2 and Mg 2+ , laying the foundation for future biomedical applications ( Fig. 17 J and K). 3.4.2. Infected bone defect A significant challenge in orthopedics is the treatment of infected bone defects, primarily involving the presence of pathogens, disruption of the immune microenvironment, and impaired bone regeneration to name a few. Traditional therapies have limitations when it comes to infection control, such as incomplete debridement and antibiotic resistance, at the same time as achieving effective bone repair during regeneration is proving to be challenging. There is a synergistic dilemma between infection control and tissue regeneration as a result of this. Infection-related bone defects require five critical stages for repair: antimicrobial action, immune modulation, angiogenesis, osteogenic differentiation, and biomineralization. The problem is that existing bone repair materials are often limited in their functionality and are unable to provide comprehensive, synergistic support throughout this entire process. In contrast, allogeneic or autologous transplantation is restricted by donor availability, immune rejection, and the possibility of infection. For precise regulation of the repair process, it is essential to design and construct novel multifunctional biomaterials. 3.5. Joint cartilage repair Located on the articular surfaces of adjacent bones, articular cartilage is an important component of joint structure. When absorbing vibrations and impact loads generated by walking, jumping, and other movements, this material possesses excellent elasticity and cushioning properties. The term cartilage damage refers to the thinning, tearing, or even wear and tear of joint cartilage caused by factors such as sports injuries or improper weight-bearing [ 172 ]. The inherent repair potential of cartilage tissue is extremely limited due to the absence of blood vessels and nerves. Damaged joints are difficult to restore functionally, leading to fibrocartilaginous scar tissue or degenerative joint diseases, which severely impact the quality of life of patients. According to clinical data, 63% of patients undergoing knee arthroscopy procedures also present with cartilage damage. Despite the fact that current mainstream treatment approaches such as microfracture and osteochondral autograft transplantation system (OATS) achieve some clinical results, they have significant limitations. A number of factors contribute to this process, including unstable adhesion at the repair interface, persistent interference from the local inflammatory microenvironment, and disruption of hypoxic homeostasis within the cartilage repair zone. An injectable biocompatible N-hydroxyethylacrylamide-N-hydroxysuccinimide copolymer/gelatin hydrogel (PHE-Gel) was reported by Ma et al. [ 14 ]. This material exhibits the core characteristics of instant gelation and the formation of a robust biological interface, allowing strong adhesion to osteochondral grafts ( Fig. 17 L). Among the many uses of hydrogels in orthopedics are scaffolds and carriers used to repair bone defects; intervertebral disc replacement; anti-adhesion therapy; delivering sustained-release medications locally to promote fracture healing; preventing and treating orthopedic infections; and providing a three-dimensional environment for cells to repair joint cartilage ( Fig. 17 M). By developing hydrogels that are responsive ( e.g. , thermosensitive, pH-responsive) and self-healing, we will be able to better adapt to complex physiological conditions in the future. In parallel, multifunctional composite scaffolds capable of carrying cells and growth factors will be developed. By combining these advancements with 3D printing technology, orthopedic regenerative medicine is on the verge of achieving precise bone-cartilage repair. 4. Challenges faced by hydrogels in orthopedics The use of hydrogel technology has become a core research frontier in the field of orthopedic regenerative medicine and disease treatment due to its unique three-dimensional network structure, excellent biocompatibility, and customizable physicochemical properties. It displays irreplaceable application potential in the repair of bone defects, the regeneration of joint cartilage, the control of drug release, and the targeted delivery of bioactive factors. Although numerous breakthroughs have been achieved at the laboratory level, the development of hydrogel systems for clinical translation and large-scale application still faces a number of complex scientific challenges and technical obstacles. The challenges arise from three fundamental contradictions: the inherent limitations of materials, the complex physiological microenvironment of the human body, and stringent regulatory requirements. A systematic examination of these core issues at the level of fundamental materials, clinical application, and clinical translation is essential for advancing this field from basic research to clinical practice as well as guiding the design of next-generation high-performance, intelligent orthopedic hydrogel materials. 4.1. Material-level challenges Through the use of synthetic methods and raw materials, it is possible to precisely control the physical and chemical properties of hydrogels, which allows them to be adapted to a variety of application requirements. In spite of their immense potential, their practical implementation still faces a number of challenges. First, traditional hydrogels are unable to meet the mechanical demands of high-stress environments due to their insufficient mechanical properties. Second, the uncontrollable degradation behavior presents another critical bottleneck: excessive degradation leads to premature loss of mechanical support, whereas inadequate degradation physically impedes the ingrowth and integration of new tissue, thereby compromising repair outcomes. In addition, biocompatibility issues are also quite complex: synthetic hydrogels generally lack biological activity, with surfaces that are not conducive to effective cell adhesion and function, and they are more prone to causing chronic foreign body reactions. Although hydrogels derived from natural sources exhibit high cell affinity, residual animal-derived components may cause immunogenic reactions. Therefore, development of novel high-performance hydrogel materials capable of precisely controlling degradation rates while exhibiting excellent mechanical properties and good biocompatibility has become crucial in order to overcome current bottlenecks and expand their applications. As a promising functional material, the future development of hydrogels depends largely on the systematic resolution of these core challenges. 4.1.1. Matching of mechanical properties and load-bearing requirements Clinical applications of metal bone implants are limited by their inability to replicate the complex structure, mechanical strength, and elastic modulus of natural bone tissue. Mismatches in elastic modulus are particularly prevalent among these factors, and they can result in stress shielding effects that prevent effective integration of the implant with the surrounding cells and tissues. Research in the field of orthopedics has focused on developing bone implant materials with tunable mechanical properties, appropriate porosities, and elastic moduli that are similar to those of natural bone. In this context, the use of biodegradable bioactive scaffolds to guide bone regeneration is considered a highly promising therapeutic approach. Existing scaffold materials, however, remain limited by a critical bottleneck: achieving precise conformability with irregular bone defect morphologies while maintaining mechanical properties similar to native bone tissues. To achieve bone regeneration, these two aspects must be considered to provide stable mechanical support at the defect site. In addition, they must transmit appropriate biomechanical signals. Liao et al. successfully prepared a high-strength gelatin hydrogel by combining methacrylated HAMA with o-nitrobenzyl-functionalized GelNB [ 62 ]. There are tensile strengths of up to 10 MPa in this hydrogel, along with excellent structural stability and controllable degradation ( Fig. 18 A–D). Based on this material system, precise scaffold fabrication was achieved using DLP 3D printing technology. Loading roxadustat onto these scaffolds further demonstrated its ability to effectively remodel the local inflammatory microenvironment by activating the hypoxia-inducible factor-1α (HIF-1α) signaling pathway, thereby significantly promoting bone defect repair and regeneration in osteoporosis models. Evaluation of the results demonstrated that the GelNB gel exhibits outstanding elasticity and shape recovery capability. After over 1000 cycles of repeated stretching, its initial shape remains stable with no significant decrease in mechanical strength ( Fig. 18 E and F). Additionally, GelNB gel exhibits outstanding tensile and compressive strengths across various solid contents ( Fig. 18 G and H). Degradation behavior and biocompatibility assessments demonstrate that GelNB gel achieves exceptional mechanical properties without compromising its excellent cell compatibility, and it can be integrated with advanced 3D printing technologies such as DLP ( Fig. 18 I and J). This study utilized 3D printing technology to fabricate hollow tubular scaffolds suitable for osteoporotic bone repair ( Fig. 18 K). Compared to conventional hydrogels, the structurally robust GelNB gel exhibits significantly enhanced self-supporting capability and macroscopic structural integrity, providing key advantages for its application in bearing-type bone defect repair. Fig. 18. Open in a new tab (A-H) Comprehensive Strength and Toughness of GelNB gels supplemented with HAMA; (I) Viability of L929 cells after 24 h exposure to leach liquors from the GelNB gel and the GelMA gel; (J) Rheology analysis of the GelNB gel; (K) The 3D-printed hollow tubular scaffold and locally magnified features are fabricated with the GelNB gel [ 62 ]. Copyright 2025, Wiley-VCH GmbH. (L) Schematic depicting the surgical procedure for creating bone defects and filling them with hydrogel in New Zealand white rabbits; (M) Bone regeneration assessed through micro-CT analysis for different groups at 12 weeks post-implantation; (N) Quantitative micro-CT analysis for different groups [ 126 ]. Copyright 2025, Springer Nature. (O,P) Immunofluorescence staining images and quantitative analysis of iNOS in RAW 264.7 cells [ 173 ]. Copyright 2025, KeAi Communications. 4.1.2. The issue of synchronizing degradation rates with bone regeneration rates Material degradation must be precisely matched to tissue repair cycles. The degradation period of bone repair materials should be controlled between three and six months in order to ensure sustained mechanical support for the slow bone regeneration process. For cartilage repair materials, the degradation period should be shortened to one to three months to align with its faster regeneration rate. It is intended to prevent issues like structural failure caused by premature degradation, foreign body reactions, and poor tissue integration caused by excessive degradation. Therefore, it is essential to design and prepare hydrogels with tunable degradation rates. The hydrogels can provide stable mechanical support during the initial repair phase by precisely controlling their degradation behavior to match the slow rate of bone tissue regeneration. As new bone grows, they gradually degrade, ultimately undergoing harmless metabolism and complete absorption. In this manner, bone can be regenerated and structurally reconstructed in a perfect manner. A shell-hardened macroporous hydrogel with unique mechanical properties and tunable degradation properties was developed by Wang et al. [ 126 ]. As part of the preparation strategy, a soft template is constructed based on the liquid-liquid phase separation behavior between PEG and dextran. To effectively control the size of discontinuous droplets generated during phase separation, it is necessary to precisely control the concentrations of both components. The system is then introduced with pre-assembled lysozyme nanofibers. To solidify the macroporous structure, they use their self-assembly process at the droplet interface to form a stable protein fiber shell. Furthermore, the degradation rate of the hydrogels was effectively tailored by modulating the relative proportion of degradable ester-bonded crosslinkers within the system. The NN, NP, and SP hydrogels encapsulating rat bone marrow-derived mesenchymal stem cells (rBMSCs) were implanted into fresh bone defects created in the femoral condyles of New Zealand white rabbits, and their in vivo bone regeneration performance was systematically evaluated ( Fig. 18 L). The experimental results demonstrate that the degradation behavior of the aforementioned hydrogel is highly tuneable, with its degradation process showing excellent dynamic matching with the new bone formation process ( Fig. 18 M and N). Further validation in rabbit and pig bone defect models demonstrated that this material system exhibits significant bone regeneration-promoting capabilities. A new pathway for stem cell-mediated bone tissue regeneration has been developed using this cell encapsulation strategy that overcomes the limitations of traditional hydrogel scaffolds in terms of sustained mechanical support and degradation synchrony. 4.1.3. Insufficient biological activity and host immune response Due to their excellent biocompatibility and low immunogenicity, hydrogels display significant advantages in bone tissue engineering and drug delivery. Generally speaking, polymers used in the construction of hydrogels can be categorized into three types: natural polymers, synthetic polymers, and materials derived from decellularized tissues. The differences in their sources directly affect the biological properties and application potential of hydrogels. In regenerative medicine and immunotherapy, the focus is shifting from passive biocompatibility of traditional hydrogels to active immune modulation. Hydrogels that are capable of precisely guiding specific host immune responses to promote the recruitment of beneficial immune cells and direct their participation in tissue repair processes have emerged as a promising research strategy. Using polyphenols, peptides, and clay nanoplates (CNSs), Chen et al. have successfully constructed a self-healing hydrogel system that is capable of combining strong bioadhesion, superior mechanical properties, and immunomodulatory functions for the treatment of irregular bone defects [ 173 ]. In addition to forming a robust bond with bone tissue, this hydrogel exhibits significant antibacterial and immunomodulatory properties. Furthermore, the CNSs enhance the hydrogel's mechanical strength by acting as nano-reinforcing phases, while promoting osteogenic differentiation of bone marrow-derived mesenchymal stem cells through the sustained release of bioactive ions. The in vivo experiments have demonstrated that this hydrogel, which combines mechanical reinforcement, bioadhesion, and immunomodulatory properties, is capable of firmly adhering to and anchoring itself within irregular bone defects. Through active regulation of the local inflammatory microenvironment, it ultimately results in significant acceleration of bone tissue regeneration and repair ( Fig. 18 O and P). Regenerative therapy for bone and other tissue injuries using this approach offers a versatile and promising approach. In addition, Yu et al. designed a multifunctional photocurable GelMA hydrogel (GelMA-ZC-Yoda1) that synergistically regulates host immune responses and osteo-/angiogenesis to achieve efficient bone regeneration [ 174 ]. This hydrogel integrates two key functional components: ZnCe-layered double oxide (ZnCe-LDO) nanozymes with catalase-like activity, and Yoda1, a Piezo1 channel agonist. The ZnCe-LDO nanozymes effectively scavenge excess ROS locally at the bone defect site, alleviating oxidative stress damage. By reprogramming inflammatory macrophages toward the M2 phenotype, they downregulate pro-inflammatory factors and upregulate the secretion of pro-regenerative factors, thereby establishing a favorable immune microenvironment for tissue regeneration. Concurrently, the sustained release of Zn2+ and Ce3+ from the nanozymes directly promotes angiogenesis and osteogenic differentiation. Furthermore, Yoda1 activates the Piezo1 channel and its downstream Piezo1/YAP1 signaling pathway through chemo-mechanical stimulation, regulating the osteogenic differentiation of BMSCs at the molecular level. These two mechanisms act synergistically to construct an immune-osteogenic-angiogenic regulatory network. In vivo studies demonstrated that the GelMA-ZC-Yoda1 hydrogel effectively ameliorated the inflammatory microenvironment in a rat calvarial defect model, significantly enhancing both bone and vascular regeneration. This study provides a novel strategy for the development of multifunctional hydrogels that integrate inflammatory microenvironment modulation with osteogenic and angiogenic activities. Despite the tremendous potential of hydrogel materials for bone tissue engineering, widespread adoption poses a significant challenge. The achievement of synergistic effects among mechanical strength, degradation controllability, and bioactivity remains elusive, failing to meet the complex and dynamically changing biological demands of bone regeneration. It is due to this fundamental limitation that existing hydrogels cannot be used in critical scenarios such as the repair of load-bearing bone defects, the provision of long-term mechanical support, or the regulation of biological signaling. 4.2. Challenges at the application level In spite of the excellent biocompatibility and functional plasticity of hydrogel materials, several critical technical bottlenecks remain in their clinical application, limiting their ultimate therapeutic efficacy. Specifically, at the operational level, the primary challenge affecting the subsequent functionality of hydrogels after minimally invasive injection lies in maintaining their predetermined morphology and precise anatomical positioning within the wet, dynamic physiological environment. When it comes to determining the effectiveness of tissue regeneration, the key challenge is guiding rapid neovascularization into the core region of large bone defects within hydrogels. To ensure nutrient delivery and metabolic waste removal, this is essential. Additionally, the long-term safety and reliability of treatment depends directly on the structural stability of hydrogels in complex in vivo environments, the biological safety of their degradation products, and whether they induce chronic foreign body reactions. In the following sections, we will discuss these three aspects of the challenges hydrogels face at the application level. 4.2.1. Shape and position control following minimally invasive injection Hydrogel materials must possess injectability and rapid in-situ fabrication capabilities to achieve minimally invasive implantation and precisely match the morphology of irregular bone defects. It is currently not possible for large (supercritical) bone defects to heal spontaneously. Clinically, bone grafts are used primarily to treat this condition. There are, however, a number of challenges associated with this approach, such as the limited availability of donor sources, secondary damage to the donor site, and immune rejection. Due to their minimally invasive implantation and exceptional adaptability to complex defect geometries, injectable hydrogels are highly promising candidates for bone regeneration. A conventional injectable hydrogel, however, typically exhibits a dense nanoporous structure that severely inhibits the migration of cells and the establishment of vascular networks. Zhou et al. successfully developed an injectable hydrogel system based on SA and β-tricalcium phosphate (β-TCP) ( Fig. 19 A) [ 175 ]. They have successfully overcome the limitations of traditional alginate gels by regulating the ionic cross-linking process with glucono-delta-lactone (GDL), which have accelerated cross-linking and reduced injectability when divalent metal ions (such as Ca 2+ , Sr 2+ ) are added directly. To further enhance the mechanical properties and osteogenic activity of the material, coaxial electrospun microfibers containing poly(3-hydroxybutyrate-co-4-hydroxybutyrate)/magnesium oxide and polyethylene glycol were incorporated to achieve controlled magnesium oxide release (P34HB/MgO + PEG, abbreviated as PMP). Experimental results demonstrate that the SA/β-TCP@2%PMP composite hydrogel containing 2% PMP microfibers not only successfully passes through a 22G injection needle, exhibiting excellent injectability, but can also be precisely molded into various complex three-dimensional structures such as stars, cubes, and cylinders. Fig. 19 B illustrates its outstanding advantages in terms of minimally invasive implantation and shape adaptation. The PMP microfiber-reinforced composite hydrogel system provides a novel material with significant potential for the minimally invasive repair of irregular bone defects, such as avascular necrosis of the femoral head (ANFH). Additionally, Lai et al. successfully developed a novel injectable MgO 2 -reinforced multifunctional hydrogel (MOG hydrogel) ( Fig. 19 C) [ 165 ]. By using a sequential regulation mechanism, this material suppresses tumor recurrence in the early postoperative period while simultaneously promoting bone tissue regeneration in the later stages. Using this innovation, osteosarcoma can be prevented and treated using a phased, precision-based approach. MOG multifunctional hydrogel shows excellent tissue adhesion, injectability, and rapid hemostatic properties, as well as repeatable adhesion and detachment properties ( Fig. 19 D–F). Following tumor resection, this enhances its ability to precisely fill irregular bone defects. Fig. 19. Open in a new tab (A) Gross appearance and gelation of SA/β-TCP@PMP composite hydrogels; (B) Injectability and in-situ molding capability of hydrogel (SA/β-TCP@2%PMP) [ 175 ]. Copyright 2025, Wiley-VCH GmbH. (C) Schematic showing the preparation of novel MgO 2 -potentiated multifunctional hydrogel; (D) Schematic diagram of the principle of hydrogel self-healing and tissue adhesion; (E) Inverted container proving hydrogel F) Schematic Diagram of Hydrogel Injectability [ 165 ]. Copyright 2025, Elsevier. (G) Overall view of the biomimetic cortical bone scaffold and enlarged details of different cross-sections; (H) The PH scaffold has better tensile and compression properties; (I) Shear stress distribution across the scaffold wall during perfusion; (J) Flow velocity distribution within the scaffold during perfusion. (K) Volcano map of differentially genes. (L) Heat map of partial differentially genes [ 176 ]. Copyright 2025, Elsevier. (M) Representative images of H&E staining of major organs including heart, liver, spleen, lung, and kidney [ 164 ]. Copyright 2025, Wiley-VCH GmbH. 4.2.2. The challenge of vascularization in large bone defects A large bone defect presents significant challenges for clinical repair, with the main bottleneck being the severe hypoxic microenvironment formed in the defect area. Hypoxia not only inhibits the migration and functional differentiation of endogenous host cells, but also induces significant oxidative stress damage in local cells, impairing repair efforts severely. To induce bone regeneration, it is essential to efficiently restore local blood supply during the early stages of repair and establish a fully vascularized network. In addition to providing oxygen and nutrients to damaged areas, the neovascular system eliminates metabolic waste. Providing the structural and functional foundation for bone regeneration and maturation. For the repair of large bone defects, traditional hydrogels face a number of challenges. First, although conventional piezoelectric ceramics (such as barium titanate) are highly piezoelectric, their inherent brittleness makes them prone to fracture, making it difficult to maintain structural integrity in the complex mechanical environment of the body. Second, successful bone regeneration requires the synergistic interaction of innervation, vascular supply, and osteogenesis. This critical aspect is often overlooked by traditional materials, limiting the further development and application of hydrogel repair materials. Using a two-layer “rigid shell-flexible core” structure, Wang et al. constructed a bionic bone scaffold. It was constructed using motor-assisted microinjection (MAM) technology using zeolite imidazolidine framework-8/polycaprolactone (ZIF-8/PCL) composite material and successfully mimicked the mechanical properties of cortical bone [ 176 ]. An inner flexible core (PH scaffold) is composed of a tetramolecular polyethylene glycol/hyaluronic acid (PEGNB/HAMA) hydrogel system that is photo-crosslinked. By using DLP technology, it is precisely fabricated to mimic the biological microenvironment of cancellous bone. Hydrogel formulation (10 wt% PEGNB + 2 wt% HAMA) exhibits outstanding performance: its compressive modulus exceeds conventional GelMA hydrogels by 399.79 kPa. In addition, this material permits the printing of interconnected vascular channels with a diameter of 400 mm, thereby providing a critical structural foundation for achieving “pre-vascularization”. Mechanical testing indicates that DLP printing achieves a precision of 20 μm, accurately reproducing the characteristic 400-600 μm pore structure of cancellous bone. The system meets all physiological requirements for cell migration and nutrient transport ( Fig. 19 G–I). A RNA sequencing analysis of the effects of perfusion culture on endothelial cell gene expression revealed that the glycolysis-hypoxia-inducible factor 1 (HIF-1) signaling pathway was significantly activated. Furthermore, the angiogenesis genes ADM, NDRG1, and PGK1 were also upregulated, providing molecular evidence that this structure has a significant pre-vascularization-promoting effect ( Fig. 19 J and K). Currently, the technology requires further optimization, including improving the precision of FDM printing processes so that microstructures such as Haversian channels can be replicated in detail. The integration of synergistic regulation strategies involving stem cells and growth factors may, in the future, significantly enhance the efficacy of bone tissue regeneration, thus advancing this technology from basic research to clinical applications. 4.2.3. Long-term in vivo stability and safety While most hydrogels demonstrate ideal biological properties and functional advantages in vitro, their stability and safety remain critical bottlenecks when applied to long-term in vivo scenarios. Hydrogel structural integrity can be compromised and premature functional decline may result from the complex physiological microenvironment within the body, including body fluid composition, enzymatic degradation systems, oxidative stress, and dynamic mechanical loads. Hydrogels cannot sustain the mechanical support and active substance delivery efficacy required for long-term tissue repair as a result of this. Further, the degradation processes of certain synthetic hydrogels lack precise regulation, potentially releasing cytotoxic small-molecule degradation products. Besides interfering with proliferation, differentiation, and functional remodeling of newly formed tissues, these factors may also lead to local inflammatory reactions, immune rejection, or other ectopic complications, adversely affecting treatment outcomes and biological safety. Based on the embedding of functionalized nanocomposites (CeO 2 @PDA-Mg 2+ ) into GelMA, Zhou et al. were able to construct a photocrosslinkable multifunctional composite scaffold [ 164 ]. Multiple core functions are synergistically possessed by this scaffold, including antioxidant, anti-inflammatory, osteogenic, and angiogenic properties. An osteoporotic rat cranial defect model was further validated after in vitro experiments established excellent cell compatibility, low cytotoxicity, and superior biological activity. The composite scaffold demonstrated stable biocompatibility and safety in vivo while accelerating bone regeneration significantly. It provides a novel multifunctional material strategy for the clinical repair of osteoporosis-related bone defects. 4.3. Challenges in the clinical translation domain Clinical translation of hydrogels remains challenging. The first bottleneck is the large-scale production and quality control. Generally, laboratory preparation processes are difficult to directly scale up to stable mass production in compliance with Good Manufacturing Practices (GMP) standards for medical devices, and batch-to-batch variations may compromise product performance consistency. Secondly, there is a significant gap between animal research and clinical applications, primarily due to systemic differences between experimental models and human physiological environments. The use of small animal models ( e.g. , rats, rabbits) offers advantages such as low cost and rapid reproduction. Nevertheless, their bone regeneration microenvironment, immune responses, and healing mechanisms differ fundamentally from those of humans. The results of experiments often do not accurately predict the behavior of humans. Since sheep and pigs have a similar bone structure and mechanical environment to humans, these models have become critical components in preclinical research. Experimental costs, long growth cycles, and complex ethical approval procedures restrict widespread adoption and rapid iteration of such studies. When transitioning from laboratory to clinical use, bone repair materials like hydrogels must overcome this multi-level, cross-species validation gap. It must also comply with stringent regulatory requirements for medical devices, particularly by undergoing comprehensive biosafety evaluations in accordance with ISO 10993. Systemic risk assessments include cytotoxicity, sensitization potential, and local reactions following implantation. However, its clinical validation process is lengthy and expensive, requiring multiple phases of clinical trials in order to verify its safety in humans and efficacy in repair. Furthermore, the lengthy and costly clinical validation process, coupled with these dual regulatory and clinical challenges, significantly hamper the industrialization of hydrogel materials. The following sections will focus on the challenges and solutions for clinical translation of hydrogels across three dimensions: standardized preparation and quality control, the gap between animal studies and clinical applications, and regulatory policies versus clinical validation. For both human safety and therapeutic efficacy to be thoroughly validated, multiple clinical trials are required. 4.3.1. Standardized preparation and quality control Standardized manufacturing and quality control of hydrogels present significant challenges due to the fact that laboratory-developed synthesis protocols are difficult to transfer into stable and homogeneous industrial production. The majority of current manufacturing methods for hydrogels rely on manual operations or highly sensitive chemical processes, resulting in significant batch-to-batch variations in critical parameters such as pore size distribution, mechanical properties, degradation rate, and bioactive component loading efficiency. It is important to note that this batch inconsistency not only compromises the reliability and reproducibility of experimental results, but also directly translates into uncertainty in clinical efficacy, thereby posing a major obstacle to their translation into medical devices. Efforts must be coordinated from both the materials science and engineering perspectives in order to address this issue. Chemical systems with well-defined synthesis pathways, stable raw material sources, and low sensitivity to environmental fluctuations should be given priority at the material design level. To ensure the stability of polymerization processes, advanced online monitoring and feedback systems are essential for real-time tracking and closed-loop control of critical polymerization parameters. 4.3.2. The gap between animal studies and clinical application The preclinical validation of hydrogels is currently heavily reliant on animal models, but this approach has significant limitations. It is important to note that the most commonly used small animal models ( e.g. , rats and rabbits) exhibit fundamental differences from humans regarding their bone regeneration microenvironment, immune responses, skeletal dimensions, and self-healing capabilities. It may be the animal's inherent regenerative capacity rather than the material's intrinsic properties that are responsible for the superior osteogenic effects observed in small animals using a certain hydrogel. Overestimation of data and inaccurate clinical predictions result from this. On the other hand, while large animal models ( e.g. , sheep and pigs) which closely resemble human physiology provide more reliable experimental data, their high costs, lengthy experimental cycles, and complex ethical and regulatory requirements hinder widespread research and reproducible validation, thus slowing down the R&D process. To effectively bridge this gap and ensure hydrogel technology is beneficial to patients, future R&D strategies must concentrate on several key directions: developing human-derived cell-based in vitro models, including 3D organoids and organ-on-a-chip systems, and standardizing large animal experiments. By using artificial intelligence and computational modeling, existing animal studies can be analyzed and hydrogel behavior can be simulated in vivo, thereby reducing the need for animal testing excessively. 4.3.3. Regulatory policies and clinical validation As an implant material, hydrogels must adhere to the most stringent biosafety assessment standards (such as the ISO 10993 series), undergoing comprehensive testing for cytotoxicity, sensitization potential, as well as local post-implantation reactions. It should be noted, however, that many innovative hydrogels possess dynamic properties, such as their ability to degrade and to load drugs or cells. Traditional evaluation standards, which are designed for inert implants, may not be suitable for use in this application. This may lead to uncertainty in regulatory submissions and approvals. It should also be noted that the clinical validation cycle for orthopedic implants is exceptionally long and costly. To overcome regulatory and clinical challenges, it is not only important that technology be mature, but it is also important to have efficient interaction with the regulatory system in order to overcome these challenges. As a result of effective communication, optimization of trial strategies, and the establishment of new evaluation standards, it will be possible to construct a more efficient and certain translational pathway in the future. It is my hope that this will lead to a broader and faster application of safe and effective hydrogel products in a variety of fields in the future. 5. Future development direction and outlook In the field of orthopedic regenerative medicine, hydrogels face multiple obstacles, including limited predictive efficacy of animal models and complex regulatory approval processes. Despite this, continuous breakthroughs in cutting-edge research have laid a crucial foundation for future advancement. Three key directions will contribute to the core competitiveness of this field: iterative development of intelligent functionalities within the materials themselves, platform-based integration with frontier biotechnologies, and optimization of translational efficacy for clinical applications. In line with this trend, next-generation hydrogels will no longer be limited to serving as passive structural fillers. It is anticipated that these systems will evolve into intelligent repair systems capable of dynamically sensing changes in the skeletal microenvironment, precisely responding by releasing bioactive factors (for example, gene carriers or osteogenic drugs), and achieving “personalized customization” according to each patient's unique anatomical structure and physiological characteristics. The paradigm shift holds the potential to fundamentally resolve core bottlenecks in existing bone regeneration technologies, such as inefficient repair and significant variations in the outcomes of individuals. Ultimately, it ushers orthopedic treatment concepts from the traditional “mechanical fixation” model into a new era centered on “biological functional reconstruction” as an alternative to nonunion and large segment defects. 5.1. Material innovation: advancing multifunctional composites and smart responsiveness Hydrogel materials for orthopedics have progressed beyond optimizing physicochemical properties to offer highly integrated functionality and dynamic intelligent responsiveness. Hydrogels will need to be transformed from relatively static passive scaffolds to “bioactive command systems” capable of actively intervening and precisely regulating the bone regeneration microenvironment. The realization of this vision hinges on two fundamental breakthroughs: multi-component synergistic design and dynamic response enhancement. In multi-component synergistic design, future research will go beyond simple physical blending, focusing instead on achieving spatiotemporal ordered integration and programmed synergistic release. This strategy utilizes precision structural designs such as modular peptides, sequence-controlled polymers, or multi-chamber microspheres to integrate multiple bioactive factors with antibacterial, anti-inflammatory, pro-angiogenic, and osteogenic differentiation functionalities within a single hydrogel network. To prevent infection, a multicomponent integrated mechanism ensures that the hydrogel releases antibacterial agents rapidly upon implantation. In the peak inflammatory phase, it releases anti-inflammatory factors in response to specific enzymatic activity or reactive oxygen species levels. As the process enters the cell proliferation and differentiation stage, osteoinductive factors are released in a sustained, steady-state manner. By constructing a temporally precise multicomponent environment, this strategy intends to overcome the core bottleneck of low regeneration efficiency under complex pathological conditions. Dynamic responsiveness research will shift from single-stimulus responses to complex multi-stimulus logic-gate response systems. At the lesion site, smart hydrogels will be able to simultaneously sense and integrate multiple key biological signals ( e.g. , pH values, enzyme concentrations, ROS levels, mechanical stimulation). By doing so, more targeted and temporally controlled precision drug release can be achieved, as well as dynamically adaptive performance regulation that aligns with the microenvironment throughout bone repair process. In osteoblast differentiation, the hydrogel's mechanical properties can dynamically stiffen in response to alkaline phosphatase activity, while its degradation rate can be linked to matrix deposition. The goal of material innovation is to develop systems that are capable of adapting to the complex biological language of the human body. Next-generation hydrogels will overcome numerous limitations in bone regeneration through multi-component synergistic regulation and multi-stimulus precision response, transforming orthopedic repair from structural replacement to functional reconstruction through core strategies of multi-component synergistic regulation and multi-stimulus precision response. 5.2. Technology convergence: the integration of 3D printing, gene therapy, and hydrogels It is anticipated that hydrogels will transcend the limitations of single materials and be integrated with 3D-printed customized molding techniques in orthopedic regeneration as well as targeted biological regulation methods for gene therapy in the future. By integrating structural adaptation, signal regulation, and efficient regeneration, this will establish a new generation of intelligent bone regeneration systems. Hydrogels play a pivotal role as increasingly versatile bioinks. There will be two parallel trajectories for their advancement: personalization and activation. A precise control over macrostructure ( e.g. , shape) and microstructure ( e.g. , porosity, pore size, connectivity) will optimize cell ingrowth, angiogenesis, and metabolic nutrient exchange. The cutting-edge technology of bioprinting aims to overcome the inert limitations of traditional scaffolds by printing living cells ( e.g. , mesenchymal stem cells), growth factors, and hydrogels simultaneously. By constructing biologically active, pre-vascularized tissue-like constructs in vitro, it is possible to quickly initiate regeneration after implantation, significantly reducing healing time. Next-generation smart bioinks that combine excellent printability, mechanical strength, and cell viability are the challenges and opportunities of the future. Hydrogels can safely, efficiently, and persistently deliver genetic tools to bone defect sites during gene therapy. They reprogram cellular biological behavior by precisely regulating key genes ( e.g. , transcription factors promoting osteogenesis). For treating hereditary or metabolic bone disorders such as osteoporosis, this strategy pioneers new localized therapeutic approaches. To achieve enhanced transfection efficiency, future research will focus on developing smart gene delivery hydrogels with cellular targeting capabilities, microenvironment-responsive release mechanisms, and enhanced transfection efficiency. 5.3. Clinical translation: key breakthroughs from lab to bedside In the future, clinical translation will not be a simple technology push, but rather a systematic engineering endeavor involving manufacturing processes, validation systems, and clinical needs. Its core objective is to transform prototype materials with exceptional potential into medical devices that are safe, effective, stable, and have clear market value. The cornerstone of industrialization is the establishment of standardized and scalable production processes. Clinical-grade products require batch-to-batch consistency and quality control that can't be met by laboratory-scale preparation methods relying on beakers and stirrers. A key component of future breakthroughs will be the integration of advanced manufacturing technologies, such as using microfluidics to control the size and monodispersity of hydrogel microspheres, or employing continuous production lines to ensure process stability from raw materials to finished products. In addition to fulfilling GMP regulatory requirements, this method significantly reduces production costs, guarantees reproducible results, and enables the deployment of large-scale clinical trials. To reduce the risk of clinical failure, it is essential to establish a more clinically predictive preclinical validation system. As part of future research, preliminary validation in small animal models must be extended to systematic evaluation of large animal models, such as minipig femoral critical-size defect models and goat spinal fusion models, which closely mimic human skeletal physiology and regenerative characteristics. Hydrogel long-term degradation behavior, biocompatibility, and biomechanical properties related to host bone integration should be evaluated in such studies. Using these data, we will be able to accurately predict the outcomes of human clinical trials. Therefore, we will be able to support the IND application with robust supporting evidence. To ensure successful commercialization, a physician-driven, disease-specific segmentation philosophy must be implemented. Hydrogel product development must involve close collaboration with clinicians, starting with addressing specific clinical needs. It involves developing specialized product forms and functions for a variety of scenarios, such as spinal fusion, post-arthroplasty bone resorption, and irregularly shaped traumatic bone defects. Intervertebral fusion hydrogels, high-wear-resistant joint cavity coating hydrogels, or trauma repair hydrogels that rapidly form in situ while providing mechanical reinforcement are examples of such products. 6. Conclusion The use of hydrogel materials in orthopedics has become a leading research focus to address complex clinical challenges such as bone defects, spinal disorders, and orthopedic infections. The advantages of these materials include their unique hydrophilic three-dimensional network structure, excellent biocompatibility, and tunable physicochemical properties. In bone regeneration, controlled drug delivery, and minimally invasive surgical applications, hydrogels demonstrate remarkable potential through meticulous material selection ( e.g. , natural-synthetic polymer composites), multiscale structural engineering ( e.g. , dual networks, nanocomposites), and precise functionalization ( e.g. , incorporation of specific peptides or growth factors). They have evolved from passive orthopedic fillers into active biomaterials capable of actively participating in and regulating the regenerative microenvironment. This field still faces critical bottlenecks in the journey from fundamental research to widespread clinical application. In the first place, their inadequate mechanical properties and mismatched degradation rates continue to be major obstacles to their use as weight-bearing materials. In many cases, hydrogels are unable to match the mechanical strength of cortical bone, and their degradation rates within the body frequently fail to sync with the growth rate of newly formed bone tissue, which may lead to the premature failure of the repaired structure. Secondly, clinical translation remains a challenge. In particular, there are several factors contributing to this, including the lack of standardized, scalable production processes, the limited predictive value of preclinical small animal models, and the complex, lengthy approval processes for innovative implants. In this paper, we present a systematic overview of the future trajectory of hydrogels in orthopedics across three dimensions: material systems, technological convergence, and clinical translation. To close the loop by addressing practical clinical needs and facilitating efficient translation of laboratory discoveries into clinical applications, their development path will evolve from functional intelligence within the materials themselves towards deep integration with cutting-edge biotechnologies ( Fig. 20 ). Fig. 20. Open in a new tab Schematic diagram of challenges and prospects for hydrogels [ 15 , 62 ]. Further, at the level of material innovation, future research will transcend single-function stacking and shift toward deepening multifunctional synergy and intelligent responsiveness. On the one hand, the multi-component synergistic design enables the temporal integration of diverse bioactive cues including antibacterial, anti-inflammatory, pro-angiogenic, and osteogenic properties into a single system, thereby simulating the biological process of natural bone healing. Smart hydrogels, on the other hand, will provide precise, on-demand release of therapeutic drugs depending on timing, spatial distribution, and dosage in response to pathological microenvironments ( e.g. , pH, enzymes, reactive oxygen species). This approach maximizes therapeutic efficacy while minimizing side effects. Hydrogels will serve as an ideal platform for combining cutting-edge technologies like 3D printing, gene therapy, and flexible electronics at the technological convergence level. With 3D bioprinting, patient imaging data can be used to create living scaffolds with customized macroscopic shapes and finely tuned microscopic pores. Gene-delivery hydrogels may also be able to regulate key gene expression at defective sites, thereby reprogramming cellular fate and offering hope for treating hereditary bone diseases. Furthermore, integrating hydrogels with flexible sensing electronics enables the development of “smart dressings” capable of real-time monitoring of physiological parameters like strain and pH during bone healing, which can serve as a basis for assessing treatment effectiveness and guiding rehabilitation. Clinical translation requires a tightly coordinated ecosystem involving industry, academia, research, and medical practice. Our future efforts should focus on developing scalable GMP production processes, establishing standardized large-animal model validation systems, and adhering to a clinical-needs-driven design philosophy. Specialist products for spinal, joint, and trauma applications should be developed in collaboration with clinicians. To advance functional hydrogels as reliable therapeutic solutions for clinical bone repair and bone organoid construction, it is imperative to address core challenges in material performance, technology integration, and clinical translation pathways. Funding This work was supported by Science and Technology Program of Health Commission of Jiangxi Province (No. 202311519), National Natural Science Foundation of China (82402846), Science and Technology Projects in Guangzhou (2025A03J4170), Youth S&T Talent Support Programme of Guangdong Provincial Association for Science and Technology (SKXRC2025224). CRediT authorship contribution statement Xuan Sun: Data curation, Software, Writing – original draft. Weiliang Wu: Resources, Software, Writing – original draft. Guoliang Chen: Funding acquisition, Investigation, Writing – review & editing. 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