Advanced multifunctional thermo- and electro-stimulative hydrogels for bone regeneration

Abstract

Bone defects caused by trauma, infection, tumors, osteoporosis, and diabetes disrupt skeletal integrity and impair regeneration. The healing process involves inflammatory hematoma formation, callus development, and remodeling, coordinated by diverse cells and signaling pathways. Conventional grafts and inorganic implants are limited by donor scarcity, immune rejection, and low bioactivity, necessitating more effective repair strategies. Recently, multifunctional smart hydrogels have emerged as a frontier in bone regeneration due to their biocompatibility, tunable structure, and ability to integrate diverse functionalities. This review systematically summarizes recent advances in thermotherapy- and electrotherapy-stimulative hydrogels for bone defect repair. Photothermal and magnetothermal hydrogels provide controlled thermal stimulation to activate Wnt/β-catenin, HIF-1α, and heat shock protein pathways, thereby promoting osteogenesis, angiogenesis, and immune modulation while exhibiting antibacterial and antitumor effects. Conductive and piezoelectric hydrogels reconstruct the native bioelectric microenvironment of bone, enhancing cellular activity and matrix mineralization through electrical or mechanoelectrical coupling. Finally, the review discusses the current challenges, design considerations, and future perspectives of advanced hydrogel systems in bone regeneration.

Graphical abstract

Highlights

• •Thermo- and electro-stimulative hydrogels provide controllable microenvironmental modulation for bone regeneration.
• •Photothermal and magnetothermal cues enhance osteogenesis, angiogenesis, and immune regulation.
• •Thermotherapy-integrated hydrogels offer antibacterial and antitumor benefits for complex bone defects.
• •Conductive and piezoelectric hydrogels restore bioelectric signals and promote matrix mineralization.
• •Key challenges include parameter standardization, long-term biosafety, and deep-tissue stimulation capacity.

1. Bone defects

Bone defects represent a significant clinical challenge in orthopedics, and their incidence continues to increase annually. A U.S. survey indicates that patients with segmental bone defects caused by fractures, osteomyelitis, or non-union have an average hospital stay of 11.7 days. The postoperative infection rate within two years ranges from 33.1% to 58.5%, and mean hospital expenditures reach approximately US$156,818 within the first 12 months following surgery [1]. In addition, the global bone graft substitute market exceeded US$3 billion in 2023 and is projected to grow at a compound annual growth rate (CAGR) of 6.6% from 2024 to 2032, reaching approximately US$6.67 billion by 2032 [2]. These data highlight that severe bone defects not only compromise patients’ quality of life but also impose substantial physical, psychological, and economic burdens on individuals, families, and public healthcare systems.

In clinical practice, bone defects commonly arise from diverse diseases or their surgical treatments. Frequent causes include trauma, infection, tumors, osteoporosis, and diabetes mellitus. These conditions disrupt bone tissue integrity through distinct pathological mechanisms, resulting in bone mass loss and exhibiting specific pathophysiological characteristics. This heterogeneity necessitates multifaceted, complex, and individualised therapeutic strategies. Therefore, a comprehensive understanding of the etiology of bone defects and their associated pathophysiological mechanisms is essential for developing precise and effective repair approaches(Fig. 1).

Fig. 1.

Etiology-driven pathological microenvironments in bone defects.

1.1. Trauma

Trauma is one of the most common causes of bone defects and typically results from high-energy injuries, such as road traffic accidents or gunshot wounds, that lead to substantial loss of bone and its supporting tissues. Comminuted fractures are particularly prevalent and frequently produce extensive, irregular bone defects. Concurrent periosteal stripping and muscle laceration are often observed, thereby impeding the regenerative process. Traumatic bone defects are commonly accompanied by vascular and neural disruption, endothelial cell injury, and reduced expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). These alterations inhibit vascular regeneration, reduce oxygen availability at the fracture site and in surrounding tissues, impair nutrient exchange, and limit cellular recruitment to the injured region [3].

Moreover, the compromised local environment becomes highly susceptible to bacterial invasion and infection. Significant neutrophil infiltration is typically observed, with infiltrating cells secreting cytokines and chemokines (e.g., CXCL1) to recruit additional immune cells and releasing reactive oxygen species (ROS) and proteases to eliminate pathogens and necrotic tissue. Subsequently, macrophages and other inflammatory cells are recruited, further aggravating bone resorption through the secretion of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ) [4,5]. In parallel, inflammatory stimulation induces excessive activation of matrix metalloproteinase-9 (MMP-9), which accelerates the degradation of local collagen and other extracellular matrix components. The destruction of extracellular matrix components and disruption of the bone matrix structure further impedes repair and causes local functional impairment [6].

1.2. Inflammation and infection

Inflammation and infection represent another major cause of bone defects and are particularly prevalent in chronic osteomyelitis, infected fractures, and postoperative infections. Most bone infections are caused by bacteria such as Staphylococcus aureus and Streptococcus spp., which disseminate through the bloodstream to bone tissue and induce acute suppurative inflammation [7]. Following infection, extensive inflammatory cell infiltration occurs at the lesion site, accompanied by the release of pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6. These factors promote local vasodilation and exudate accumulation. In addition, stimulation of osteoblasts or activated T cells drives the release of RANKL, which strongly induces osteoclastogenesis. RANKL binds to the receptor activator of nuclear factor kappa-B (RANK) on osteoclast precursors, leading to osteoclast activation and generating an imbalance between bone resorption and formation that disrupts normal remodeling [8,9]. Concurrently, hydrogen ions released by activated osteoclasts reduce the local pH, creating an acidic microenvironment that amplifies inflammatory responses, accelerates bone destruction, and inhibits osteoblast differentiation and function, collectively impairing new bone formation [10,11].Moreover, inflammatory infiltration resulting from bacterial overgrowth substantially elevates reactive oxygen species (ROS) levels, directly damaging bone tissue. Bacterial biofilms forming on bone surfaces continuously release components such as lipopolysaccharide (LPS), which activate tumor necrosis factor receptor-associated factor 6 (TRAF6) and subsequently trigger the nuclear factor kappa-B (NF-κB) pathway, thereby perpetuating inflammation [12]. As the disease progresses, fibroblasts and myofibroblasts are continuously recruited under the influence of inflammatory mediators and secrete large amounts of type I and type III collagen, forming chronic granulation tissue. This tissue exhibits poor vascularization and contains abundant inflammatory cells, making it unlikely to mature into functional bone. Within this tissue, purulent sinus tracts and fibrotic or necrotic bone fragments may also develop, resulting in prolonged impairment of the repair process [13].

In addition, specific infections such as Mycobacterium tuberculosis frequently involve the spine and hip joints, producing persistent bone defects and predisposing patients to sinus tract formation. Mycobacterium tuberculosis evades immune surveillance by residing within macrophages and disrupts bone metabolism through multiple immune-evasion mechanisms. Studies indicate that this pathogen modulates macrophage behavior through the interferon-γ (IFN-γ) and Wnt/β-catenin signaling pathways, inducing M1-type polarization, amplifying local inflammatory responses, and promoting bone resorption and defect formation while simultaneously suppressing M2-type polarization, thus weakening anti-inflammatory capacity and impairing bone repair capacity [14,15]. In addition, toxins and lipid components secreted by Mycobacterium tuberculosis dysregulate macrophage function, alter normal immune responses, and activate several signaling pathways—including NF-κB and MAPK—further exacerbating bone resorption and tissue damage [16].

1.3. Tumors

Tumors constitute another significant cause of bone defects and are particularly common in primary or metastatic malignant bone tumors. Although the incidence of primary bone cancer remains relatively low—accounting for less than 0.2% of all cancers—its incidence has been rising at an average rate of approximately 0.3% per year over the past decade. Tumors such as primary osteosarcoma, chondrosarcoma, Ewing's sarcoma, and multiple myeloma frequently induce irreversible local bone destruction through direct infiltration and osteolytic activity. The RANKL/RANK/osteoprotegerin (OPG) pathway plays a central role in this process, enabling tumor cells to activate osteoclastogenesis while suppressing OPG expression, ultimately resulting in excessive bone resorption and structural defects [17]. In addition, reduced signaling through the BMP/SMAD pathway, together with tumor-secreted DKK1 and sclerostin-mediated inhibition of the Wnt/β-catenin pathway, further suppresses osteoblastic differentiation and bone reconstruction [18,19].

Metastatic bone tumors—such as those arising from breast, prostate, and lung cancers—also produce bone defects through systemic pathological bone resorption. These defects are frequently accompanied by pathological fractures and lesion progression, severely compromising limb function and quality of life. Surveys indicate that approximately 70% of patients with advanced breast or prostate cancer develop bone metastases with destructive lesions, and 30–40% require surgical bone reconstruction. The tumor-associated immune microenvironment exhibits substantial macrophage infiltration, with M2-polarised macrophages suppressing CD8⁺ T cell activity through the release of anti-inflammatory mediators such as IL-10 and transforming growth factor-β (TGF-β). This response promotes immune tolerance and tumor immune escape during metastatic progression and, in certain circumstances, inhibits bone repair [20,21].

1.4. Osteoporosis and diabetes

Osteoporosis (OP) is a common degenerative disease. Osteoporotic bone defects are characterised by trabecular thinning, reduced bone density, and increased bone fragility, resulting in a significantly elevated risk of fractures and bone defects [22]. Approximately 200 million people are affected worldwide, and prevalence increases markedly with age. In developed countries, the prevalence ranges from 9% to 38% in women and from 2% to 8% in men [23]. Diabetes mellitus, which is closely associated with OP, is another major systemic disorder characterised by impaired bone metabolism. Its characteristic hyperglycaemia can directly or indirectly disrupt bone tissue structure and repair.

Compared with typical bone defects, OP- and diabetes-related defects are more difficult to treat, primarily due to abnormal inflammatory responses arising from a compromised bone microenvironment, elevated oxidative stress, impaired osteogenic differentiation, and disrupted bone immune homeostasis. Excessive accumulation of reactive oxygen species (ROS) increases hydrogen peroxide (H₂O₂) levels within the bone marrow microenvironment. Downregulation of the key mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) reduces ROS-scavenging capacity, thereby exacerbating oxidative stress [24]. Elevated ROS activates the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, promoting the maturation and release of IL-1β and IL-18 and intensifying bone resorption [25,26]. Concurrently, ROS inhibits nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), reducing the expression of antioxidant genes and further promoting osteoclastogenesis [27]. Increased H₂O₂ and glucose levels suppress the osteogenic and paracrine functions of bone marrow mesenchymal stem cells (BMSCs) and damage bone marrow endothelial cells through activation of the RhoA/ROCK pathway, ultimately impairing early-stage repair processes [28]. In addition, elevated blood glucose induces pathological deposition of advanced glycation end-products (AGEs) within the bone matrix, resulting in abnormal collagen cross-linking and a decrease in bone elasticity and mechanical strength. Ultimately, defect margins fail to generate robust callus, leading to delayed healing or even non-union [29].

Despite the diverse aetiologies of bone defects, traditional treatment options remain limited, hindering precision and targeted optimization. Currently, bone grafting remains the primary clinical approach for extensive bone defects. However, autogenous bone grafts are restricted by limited donor bone volume and donor site morbidity [30], whereas allogeneic grafts are challenged by immune rejection, risks of disease transmission, and reduced osteoinductive and osteoconductive properties relative to autogenous bone [31]. Among synthetic materials, metallic implants exhibit excellent mechanical strength but limited bioactivity, making them ineffective for promoting bone regeneration and prone to causing stress shielding; long-term implantation may also necessitate secondary removal due to fatigue fractures [32]. Ceramic materials provide good bioactivity and osteoconductivity, yet their high brittleness and fabrication limitations impair their ability to conform to complex bone defects [33,34].

Against this backdrop, advanced multifunctional hydrogels have emerged as highly promising candidates for bone defect repair. Owing to their excellent biocompatibility, tunable mechanical properties, and versatile functional characteristics, these materials show substantial potential for precise and personalized treatment of bone defects arising from diverse aetiologies [35]. They enable controlled release of growth factors and therapeutic agents, promote cellular proliferation and differentiation, regulate cellular behavior, and provide a repair platform that closely mimics the native bone tissue microenvironment [[36], [37], [38]]. Hydrogels equipped with advanced functionalities offer unique advantages in the treatment of bone defects and hold considerable promise for overcoming the inherent limitations of traditional therapies. As a result, they present superior therapeutic options for patients and have become a major research focus and developmental trend in this field [39,40].

2. Bone defect healing process and mechanism

Repair of natural bone tissue is a complex, dynamic, and highly organized process that involves the synergistic regulation of multiple mechanical and biochemical factors as well as interactions among various cell types. This process is broadly divided into three phases: the inflammatory hematoma phase, the callus formation phase, and the bone remodeling phase. Each phase is dynamically coordinated and regulated by cellular populations, signaling pathways, biomaterials, and the mechanical environment(Fig. 2).

Fig. 2.

A spatiotemporal cascade of multiple endogenous factors controls normal bone regeneration during fracture repair in four stages. PDGF = platelet-derived growth factor; VEGF = vascular endothelial growth factor; FGF = fibroblast growth factor; TNF = tumor necrosis factor; SDF = stromal cell-derived factor; IGF = insulin-like growth factor; BMP = bone morphogenetic protein; OPG = osteoprotegerin; IL = interleukin; TGF = transforming growth factor; Ang = angiopoietin; M-CSF = macrophage colony-stimulating factor; RANK = receptor activator of nuclear factor kB; RANKL = RANK-ligand. Reproduced with permission [41]. Copyright 2016, Publisher Elsevier B.V.

2.1. Inflammatory hematoma phase (0–7 days): local clearance and regeneration Initiation

Following fracture or bone defect occurrence, a hematoma is formed due to local vascular rupture. This temporary structure functions not only in hemostasis but also as a "temporary organ" rich in various growth factors and chemokines, thereby establishing the foundation for subsequent tissue repair [42]. Platelet-derived growth factor (PDGF) and transforming growth factor-β1 (TGF-β1) released by platelets promote the proliferation of mesenchymal stem cells (MSCs), fibroblasts, osteoblasts, and endothelial cells, while also recruiting MSCs to the injury site [43]. The ischemic and hypoxic environment induces macrophage polarization toward the M1 phenotype, resulting in the secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). These factors attract migration of repair-associated cells—including fibroblasts, MSCs, and osteoblast precursors—and simultaneously promote the release of angiogenic factors to initiate neovascularization [44].

The hypoxic state further induces the expression of hypoxia-inducible factor-1α (HIF-1α), which promotes the release of angiogenic factors such as angiopoietin-1 and vascular endothelial growth factor (VEGF), thereby enhancing vascular regeneration [45]. As neovascularization progresses, various cellular components respond to chemotactic signals and infiltrate the bone defect region along with invading blood vessels. The primitive fibrin matrix is gradually replaced by granulation tissue, and the extracellular hypoxia is alleviated with vascular regeneration and cell recruitment [46]. Subsequently, macrophages shift from the M1 to the M2 phenotype, secreting anti-inflammatory cytokines including interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β). This transition leads to the resolution of inflammation and a metabolic shift from catabolism to anabolism [44].

2.2. Callus formation (7–21 days): formation and mineralization of temporary reparative tissue

After the inflammatory response subsides, the repair process progresses into the callus formation phase, which can be further divided into the soft callus formation phase (cartilaginous callus) and the hard callus formation phase (woven bone). During the early stage, periosteal and bone marrow-derived mesenchymal stem cells (MSCs) differentiate into chondrocytes and osteoblasts under the regulation of signaling pathways such as Wnt/β-catenin, Runx2, and Indian Hedgehog (IHH), forming the initial cartilage and bone tissue structures [47]. Wnt/β-catenin signaling upregulates the expression of Runx2 and Sox9, which are key transcription factors that regulate the chondrocyte and osteogenic processes. Activation of these factors promotes cartilage maturation and the formation of preliminary bone tissue [48].

As cartilage tissue undergoes progressive mineralization, revascularization occurs simultaneously with cartilage resorption, and the cartilage is ultimately replaced by primary bone (woven bone) formed by osteoblasts. This process is particularly crucial for neovascularization: the release of the second wave of vascular endothelial growth factor (VEGF) along with matrix metalloproteinases (MMP-9/MMP-13) not only supplies oxygen and nutrients to the mineralized area but also enhances osteoblast activity [49]. Additionally, bone morphogenetic protein 2 (BMP2) promotes the differentiation of mesenchymal stem cells (MSCs) into chondrocytes by activating p38 mitogen-activated protein kinase (MAPK) signaling and inhibiting SOX9 degradation, thereby accelerating the cartilage-to-bone transformation process [50].

Notably, the Piezo1 channel plays a key regulatory role as a core mechanoreceptor during bone repair. It is strongly activated during the differentiation of periosteal stem cells (PSCs) into osteoblasts and chondrocytes and accelerates the cartilage-to-bone transformation by enhancing the nuclear localization of YAP and β-catenin. This process synergistically upregulates the expression of key osteogenic factors such as bone morphogenetic protein 2 (BMP2) and Runx2 [51]. Additionally, Piezo1 channels promote PSC secretion of vascular endothelial growth factor A (VEGFA), significantly enhancing vascular neogenesis. This coupling of osteogenesis and angiogenesis is crucial for the maturation of bone scab tissue.

2.3. Bone remodeling period (3 weeks to months): structural optimization and functional recovery

After the formation of the bone scab, the repair process transitions into the bone remodeling phase, which lasts from weeks to months. The initially formed woven bone is gradually resorbed and replaced by structurally ordered lamellar bone with superior mechanical properties. This process is coordinately regulated by osteoclasts and osteoblasts and primarily depends on signaling molecules such as transforming growth factor-β (TGF-β), bone morphogenetic proteins (BMPs), and the receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB/osteoprotegerin (RANKL/RANK/OPG) pathway to maintain the dynamic balance of bone metabolism. TGF-β regulates a variety of transcription factors through activation of the SMAD pathway, which, in turn, modulates the functions of osteoblasts and osteoclasts [52]. It is activated and released by osteoclasts during bone matrix resorption, further promoting the recruitment and proliferation of osteogenic precursor cells and facilitating the coupled regulation of bone resorption and new bone deposition.

The RANKL/RANK/OPG signaling axis plays a crucial role in the regulation of bone metabolism. RANKL is produced by osteoblasts, osteoclasts, and bone marrow-derived mesenchymal stem cells (BMSCs), while RANK is expressed on the surfaces of osteoclast precursors and mature osteoclasts. The binding of RANKL to RANK activates osteoclasts through the TRAF6-mediated mitogen-activated protein kinase (MAPK), nuclear factor κB (NF-κB), and phosphoinositide 3-kinase (PI3K) pathways, thereby enhancing osteoclast differentiation and function. Osteoprotegerin (OPG), a soluble decoy receptor for RANKL, blocks its binding to RANK, thus inhibiting osteoclast formation and bone resorption [53].

In addition, bidirectional communication between osteoblasts and osteoclasts is mediated through the Ephrin B2 (EFNB2)-EPHB4 signaling axis. EFNB2 is expressed on the surface of osteoclasts, while EPHB4 is located on the surface of osteoblasts. The interaction between these two molecules not only inhibits osteoclast differentiation but also promotes osteoclast maturation, thereby effectively maintaining the homeostasis of bone metabolism [54].

3. Strategies for bone repair

In recent years, functional hydrogel materials have advanced rapidly, with increasingly refined, targeted, and personalized designs establishing them as a highly promising therapeutic strategy for bone repair. Despite variations in material composition, fabrication methods, and levels of functional sophistication, these hydrogels are guided by shared fundamental design principles. These principles are intended to achieve efficient and precise repair of bone defects arising from diverse etiologies by modulating pathophysiological mechanisms and regulating the local microenvironment.

3.1. Thermotherapy

Heat is an essential stimulating factor in the repair process of living organisms. By precisely regulating the temperature at the site of injury, various beneficial effects can be achieved, including the promotion of cell metabolism, enhancement of blood circulation, and modulation of the immune response. Currently, thermal therapies are widely applied in the treatment of tumors, chronic pain management, and inflammation control. In the context of bone repair, thermal stimulation has been shown to promote osteogenesis and mineralization. Previous studies have reported that applying thermotherapy, using 915 MHz microwave heating on rabbit femurs, significantly enhanced the formation of new trabeculae and increased cortical bone density, thereby accelerating the process of bone reconstruction [3]. Additionally, two other studies also demonstrated that thermal stimulation enhances both longitudinal and radial growth of long bones in experimental animals [55,56]

With the deeper application of thermal therapy in bone defect repair, it has been observed that different temperature intervals elicit varied biological effects, depending on the pathological characteristics of the bone defects. Mild thermal stimulation (40-45 °C) promotes cell viability, self-repair, and regeneration of skin, blood vessels, and bone tissue. This effect is attributed to the activation of the heat shock response in osteogenesis-related cells, which leads to the up-regulation of heat shock proteins (HSPs). In turn, this activation stimulates the ERK-Wnt/β-catenin signaling pathway, promoting cellular biomineralization and endogenous bone repair [[57], [58], [59]] Moderate thermal stimulation (45-55 °C) causes minimal damage to normal tissue cells in a short period, while effectively inducing cell membrane collapse and protein inactivation to kill tumor cells and bacteria [60]. On the other hand, excessive heat exposure (>55 °C) can cause tissue burns [61].More importantly, photothermal therapy (PTT), which combines bioactive components (e.g., drugs, cytokines, small molecules, extracellular vesicles, growth factors, and metal ions) with photothermal converting agents, can significantly enhance biomaterials-mediated immunomodulation and tissue regeneration. This provides an innovative therapeutic strategy to promote bone healing [62].

Based on the unique advantages of thermotherapy in bone defect repair and the customizable, multifunctional properties of hydrogels, novel therapeutic approaches combining thermotherapy with injectable hydrogels have emerged. Currently, photothermal therapy (PTT) and magnetothermal therapy (MTT), owing to their ability to precisely and easily adjust thermal localization, when combined with specific drugs or nanoparticles, show broad applications and significant research potential(Fig. 3) [63].

Fig. 3.

Thermotherapy mechanisms and photo-/magnetothermal hydrogel systems for bone defect repair. a) Temperature-dependent mechanisms of thermotherapy in bone defect repair. b) Photothermal hydrogels incorporating metal-based, black phosphorus, carbon nanomaterial, and organic polymer photothermal agents for bone regeneration. c) Magnetothermal hydrogel systems and mechanisms of magnetic hyperthermia-mediated bone repair.

3.1.1. Photothermal hydrogels

Light, as a controlled means of exogenous stimulation, has shown great promise in promoting bone defect repair and tissue regeneration, spanning ultraviolet (UV), visible, and near-infrared (NIR) light bands. Compared to UV and visible light, NIR light has become the preferred choice for deep tissue irradiation due to its lower absorption and scattering properties in tissues, as well as reduced damage to surrounding normal tissues [62]. In recent years, near-infrared laser-based photothermal therapy (PTT) has demonstrated significant potential in various applications, including bone repair, tumor ablation, and antimicrobial therapy, owing to its minimally invasive nature, photostability, high effectiveness, and ease of administration [62]. Various photothermal agents, including gold nanoparticles, carbon nanomaterials, and organic nanoparticles, have been widely developed and applied [64,65] Based on the material source of the photothermal agents, they are generally classified into two categories: inorganic and organic(Table 1).

Table 1.

Advanced hydrogel strategies for photothermal in bone repair.

Hydrogel Scaffold Structure	Photothermal Agent	Mechanical properties	Thermal Treatment Conditions			Functional agents	Animal Models	applicable diseases	Reference
			Thermal Treatment Parameters	Radiation Time	Maximum Temperature
Dexp/CuS/PEG/PCL	Cus	Elastic modulus:40.80 Mpa	1064 nm; 1.0W cm−2	10min	42 ± 0.5 °C	CuS NPs equip PCL scaffolds with photothermal, drug-carrying, Cu2+ antibacterial; Dexp drives BMSC osteogenesis.	SD rat, tibia	bone defects	[59]
Gel-MA/NAGA/MoS2/Gd3+ −TCPP(GMNG)	MoS2	/	808 nm; 1.0W cm−2	10min	about 48 °C	MoS2 endows hydrogel with photothermal efficacy; Gd-TCPP serves as an MRI contrast agent for real-time tracking of hydrogel position and degradation; Gd3+ release accelerates de novo bone formation.	Osteogenesis in bone defect: SD rats, near the tibial plateau of the left leg; anti-tumor test: 6-week-old female Kunming mice, leg region.	Osteosarcoma and bone defects	[66]
OSA/HA-EDA/Ce/MnHAp	Ce/MnHAp	/	808 nm00.5 W cm−2	10 min	42 °C	Ce/MnHAp functions as a nanoenzyme to scavenge ROS, induce M2 macrophage polarization, provide photothermal effects, release Ca2+, PO43−, Ce3+, Mn2+, and promote osteogenesis; OSA cross-links with HA-EDA and chelates metal ions for uniform dispersion.	New Zealand white rabbits, trochlear groove	Osteochondral defects caused by sports injuries and aging	[67]
GelMA/Alg-DA/MC	Cu-decorated 2D Ti3C2Tx MXene nanosheets (MC)	Elastic modulus2.5 Mpa	808 nm; 1.5W cm−2	5min	about 42 °C	MC nanosheets serve as multifunctional crosslinkers and fillers, enhancing mechanics and injectability, and confer photothermal, anti-swelling, and pH/NIR dual-responsive release.	Diabetic rat, skull	Diabetic fracture	[68]
nHAP/Mxene/GelMA/HAMA/LAP	Ti3C2Tx MXene nanosheets	/	808 nm,0.5W cm−2	10min	40–41 °C	Ti3C2Tx MXene nanosheets impart NIR photothermal activity, enhance mechanical strength, and exhibit antioxidant and antibacterial effects; nHAP releases osteogenic ions, boosting compressive strength and promoting cell adhesion, proliferation, and osteogenesis.	db/db diabetic mice, tibia	Diabetic fracture	[69]
MPA(PDA-coated Ti3C2Tx Mxene)@aFGF/HPCS/Gel/GP	MP	Tensile strength≈24.1 kPa	808 nm,1 W cm−2	3 min	42 ± 1 °C	MPA provides catechol-amine-reducing groups to enhance cell adhesion; aFGF serves as an angiogenic agent; NIR irradiation triggers rapid release and timely neovascularization.	BALB/c mice, dorsal subcutaneous	Bone defects	[70]
LCgel-L/gel-LDOX	LDH	/	1064 nm; 1.5W cm−2	10min	about 50 °C	Mg-Fe LDH: high-efficiency photothermal agent; ions released upon degradation boost mineralization and osteogenesis. LDOX: tumor-targeted DOX release under PTT enhances uptake, inhibits DNA replication and induces DNA damage.	Subcutaneous/osteogenesis test: mouse calvarial defect model, skull; anti-tumor test: MG-63 tumor-bearing mouse model.	Osteosarcoma	[58]
GNRs/nHA/GelMA/CSMA	GNRs	Elastic modulus:0.67 Mpa; fracture toughness:62 % compression	808 nm; 0.99W cm−2	5min	about 53.8 °C	GNRs act as photothermal agents to eradicate residual tumor cells; nHA supplies minerals for bone repair.	Female BALB/c mice, left hind tibia.	Osteosarcoma	[71]
SA/PEG/CuBGM	CuBGM	/	808 nm; 0.75W cm−2	10min	56.4 °C	CuBGM photothermally suppresses tumor growth early, releasing ions that upregulate osteogenic genes to enhance mBMSC differentiation.	Osteogenesis: SD rats, femoral site; tumor experiment: BALB/c mice, right dorsal subcutaneous area.	Osteosarcoma and tumor-related bone defects	[72]
β-TCP/SrCuSi4O10/HPMC/Sodium alginate@Gelatin/DOX	SrCuSi4O10	/	1064 nm,1.5 W cm−2	5 min	≈52 °C	SrCuSi4O10 serves as a NIR-II photothermal agent releasing Sr/Cu/Si ions to promote osteogenesis and angiogenesis; DOX synergizes with phototherapy to eliminate residual MG-63 tumor cells.	Osteogenesis: SD rats, calvaria; tumor experiment: BALB/c mice, back	Osteosarcoma	[73]
fGelMA-BP	BP	Elastic modulus:about 9.8 kPa	808 nm; 0.83W cm−2	10min	45 °C	fGelMA scaffold: Made of decellularized fish scales and fGelMA, it boosts MSC proliferation and osteogenesis without immune rejection; BP: Adds NIR photothermal conversion to hydrogel for MSC osteogenesis support.	SD rats, calvarial bone	Bone defects	[74]
GelMA/Alg-MA(GA)/BP@PDA@DFO(BPPD)	BP	Elastic modulus:45.1 ± 3.1 MPa	808 nm; 1 W cm−2	5min	41 ± 1 °C	BP: Photothermal agent; PO43− promotes bone regeneration. PDA coating stabilizes BP. DFO activates HIF-1α/VEGF for angiogenesis and osteogenesis.	SD rats, calvarial bone.	Bone defects	[75]
LCgel/LDH@BP	BP	/	808 nm; 1.5 W cm−2	5min	40–42 °C	BP serves as a photothermal agent with good conversion efficiency, and its degradation releases PO43− promoting bone regeneration; PDA coating improves BP biocompatibility/stability; DFO activates HIF-1α/VEGF for angiogenesis and osteogenesis.	SD rats, bilateral hindlimb muscle pouches.	/	[57]
CS/PCL/BP/PDA@Ag	BP	Elastic modulus:1.61 ± 0.15 Mpa	808 nm; 0.75 W cm−2	5.5min	42.1 °C	BP nanosheets offer strong photothermal conversion and promote cellular biomineralization. PDA protects BP and anchors Ag nanoparticles, providing antibacterial function.	SD rats, femoral defects	Infected bone defects	[76]
CS/HA/GP/CPs	CPs	/	808 nm; 0.52 W cm−2	10min	50 °C	CPs serve as photothermal agents inducing local tumor-site heating, promoting apatite-like deposition, enhancing alkaline phosphatase activity, and accelerating new bone formation.	Osteogenesis: SD rats, parietal bone; tumor experiment: BALB/c mice, back	Osteosarcoma	[77]
GelMA/PNIPAM/PAAM/GO-PL@BBR	GO-PL	Elastic modulus:17.3 kPa	808 nm,2.2 W cm−2	5min	40–43 °C	GO-PL enables mild photothermal therapy under NIR irradiation; heat-induced hydrogel contraction triggers pulsed drug release, where high BBR concentration provides antimicrobial effects and low concentration promotes osteogenesis and calcium nodule formation.	Osteogenesis: SD rats, calvaria; tumor experiment: BALB/c mice, back	Infected bone defects	[78]
CS/rGO/H2O2@Teriparatide	rGO	/	808 nm,0.5 W cm−2	10 min	≈45 °C	rGO imparts NIR photothermal activity to hydrogels and enhances drug loading for controlled release; teriparatide promotes osteogenesis and angiogenesis in osteoporotic cranial defects through localized pulsed delivery.	SD rats osteoporosis model, calvaria	Osteoporosis	[79]
GelMA/PMMA/PDA	PDA	Elastic modulus:0.78 Mpa; Fracture toughness:78 %	808 nm,0.99 W cm−2	5 min	about 42 °C	PDA generates a mild photothermal effect under light irradiation, promoting bone regeneration.	SD rats, calvaria	Bone defects	[80]
MDA-NPs/CMP @PAM	MDA-NPs	Elastic modulus:0.28 ± 0.11 Mpa	808 nm; 1 W cm−2	5min	55 °C	MDA-NPs: Offer photothermal therapy via NIR irradiation to kill tumor cells and release Mg2+ for osteogenesis	In vivo tumor model: Balb/c nude mice, right inguinal subcutaneous; Bone defect model: 6-week-old male SD rats, cranial bone	Osteosarcoma	[81]
Ser-ADH/OCS/Se/Mg-HAp/CaO2-PDA(SOH1(CP)1)	CaO2-PDA	/	808 nm; 1 W cm−2	10min	41–45 °C	Se/Mg co-doped HAp nanorods release ions to promote hBMSCs osteogenic differentiation and mineralization; CaO2-PDA NSs provide mild photothermal therapy and release oxygen, enhancing hydrogel anti-tumor effects.	BALB/c nude mouse axillary tumor model, axillary site; New Zealand white rabbit, femur	Osteosarcoma	[82]
Pht@ZIF-8@PDA/OHA-CMCS	PDA	/	808 nm; 1.0 W cm−2	10min	42.5 ± 1.2 °C	Pht: Anti-inflammatory, antibacterial, antioxidant flavonoid; promotes osteogenic factors. ZIF-8: Releases Pht/Zn2+ for antibacterial and osteogenic effects. PDA: Enhances stability via photothermal conversion.	SD rats, calvaria	Bone defects	[83]
GelMA/CMCS/ZIF-8@PDA/PCL	ZIF-8@PDA	/	808 nm; 1 W cm−2	75s	42 ± 1 °C	CMCS chelates Zn2+ to form a secondary ion network for ROS scavenging, while ZIF-8@PDA1 enables photothermal conversion, releases antimicrobial Zn2+, and regulates immune responses.	Diabetic male SD rats, calvaria	Diabetic bone defect	[84]
GelMA/HA-CHO/PDA-Zn2+-D-Cys	PDA NPs	Fracture toughness:about 35%	980 nm,1.0 W cm−2	6min	45.0 °C	PDA serves as a photothermal agent for sterilization; Zn2+ provides antibacterial and osteogenic effects; D-Cys targets bacteria via peptidoglycan metabolism, enriching nanoparticles around bacteria while minimizing effects on normal cells.	SD rats, femoral condyle	Diabetic fracture	[85]
F127/nHA/PDA/ZnO/HMW-HA	PDA	/	808 nm; 1.5 W cm−2	5 min	≈42 °C	nHA-PDA serves as the primary osteoinductive phase promoting bone formation; the PDA shell provides NIR photothermal activity to remove ROS and reduce cytotoxicity, while ZnO NPs offer broad antibacterial activity and release Zn2+ to support bone regeneration.	SD rats, calvaria	Methicillin-resistant Staphylococcus aureus (MRSA)-related bone defects	[86]
NO-NPs@ICG/mPEG-PA-PP	ICG	/	808 nm; 1 W cm−2	2min	40 °C	NO-NPs: NO donors that release NO under near-infrared light to promote angiogenesis and osteogenesis. ICG: A photothermal material that enhances the photothermal effect of NO-NPs, accelerating NO release.	SD rats, bilateral parietal bones	Bone defects	[87]

3.1.1.1. Metals and their derivatives

Metals and their derivatives within inorganic materials have attracted significant attention for photothermal-assisted bone repair due to their exceptional photothermal conversion efficiency. For example, Xue et al. constructed a three-dimensional composite scaffold (D-CuS-PEG-PCL) featuring a “soft–hard hybrid” architecture by integrating a flexible CuS-PEG hydrogel loaded with dexamethasone sodium phosphate (Dexp) into a rigid PCL scaffold. The CuS-PEG hydrogel conferred superior photothermal properties and stable soft elasticity to the PCL scaffold, while the PCL component provided excellent mechanical performance. Under near-infrared (NIR) irradiation, CuS generated mild thermal stimulation, promoting type I collagen synthesis and cellular heat tolerance through upregulation of heat shock proteins (HSPs), including HSP47 and HSP70. Simultaneously, in synergy with the controlled release of Dexp, this system significantly enhanced the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) [59]. As a representative two-dimensional transition metal dichalcogenide, molybdenum disulfide (MoS₂) exhibits advantages including facile preparation and high photothermal conversion efficiency [88]. Huang et al. employed inexpensive metal salts as precursors to synthesize MoS₂ “nano roses” via a wet chemical method, producing particles with uniform size distribution, high yield, excellent dispersibility, and rich chemical functionality. These particles were co-doped with gadolinium (Gd) complexes to generate multifunctional hydrogels (GMNG) (Fig. 4a). GMNG enabled localized tumor hyperthermia through photothermal effects, thereby suppressing tumor recurrence and bacterial infection. Concurrently, sustained release of Gd³⁺ promoted the expression of osteogenesis-related signaling factors, including BMP-2, Runx2, and OPN, accelerating new bone formation. Furthermore, the magnetic resonance imaging (MRI) properties of the Gd complex allowed real-time monitoring of hydrogel localization and degradation [66]. Effective reconstruction of osteochondral defects requires the establishment of an immunomodulatory microenvironment that facilitates osteogenesis [[89], [90], [91]] A major challenge during this process arises from the initial inflammatory response, which drives polarization of pro-inflammatory M1 macrophages and delays the transition to anti-inflammatory M2 macrophages [92,93] Heng et al. fabricated HESH hydrogels by crosslinking oxidized sodium alginate (OSA) with ethylenediamine-modified hyaluronic acid (HA-EDA) via a Schiff base reaction, incorporating Ce/Mn-doped hydroxyapatite nanoparticles (Ce/MnHAp) as functional enhancement components. Mn²⁺ doping in Ce/MnHAp endowed the material with strong photothermal activity, maintaining temperatures of approximately 40 °C under near-infrared (NIR) laser irradiation to promote osteogenic activity. Additionally, Ce³⁺/Ce⁴⁺ and Mn²⁺ conferred biomimetic superoxide dismutase (SOD) and catalase (CAT) activity, scavenging reactive oxygen species (ROS) and alleviating oxidative stress. This redox modulation subsequently induced phenotypic conversion of macrophages from CD86⁺ (M1) to CD206⁺ (M2), thereby mitigating inflammatory responses [67].

Fig. 4.

a) Schematic illustration of the preparation and multifunctionality of the GMNG hydrogel. Reproduced with permission [66]. Copyright 2023, Publisher Wiley-VCH GmbH. b) A photoactivated MXene-based hybrid hydrogel system (HG/MPa) with mild photothermal therapeutic activity and controlled drug delivery ability was designed to spatiotemporally modulate revascularization and osteogenic differentiation for augmented bone repair and schematic illustration of the synthesis of MPa. Reproduced with permission [70]. Copyright 2024, Publisher Wiley-VCH GmbH. c) Schematic illustration of the construction of core/shell hydrogel of LCgel-L/gel-LDOX for achieving early antitumor and antibacterial and late osteogenic effects. The core/shell hydrogel using LCgel-L as the inner core and gel-LDOX as the outer shell enabled “temporal regulation” for the treatment of osteosarcoma-associated bone defects. Reproduced with permission [58]. Copyright 2024, Publisher Wiley-VCH GmbH. d) Schematic illustration of 3D printed gelatin/bioceramics core/shell composite scaffolds for bone tumor chemo-photothermal therapy with triggered drug release, and enhanced bone regeneration. Reproduced with permission [73]. Copyright 2023, Publisher Elsevier B.V.

Two-dimensional (2D) nanomaterials have attracted extensive attention owing to their unique structures and exceptional photothermal properties [94]. Among these, two-dimensional transition metal carbides and nitrides (MXenes) exhibit excellent biocompatibility, degradability, and photothermal conversion efficiency, demonstrating significant potential in biomedical applications, including drug delivery, tumor therapy, and tissue regeneration [95]. Zhu et al. developed a copper-containing Ti₃C₂T_x MXene nanosheet (MC) hydrogel platform (GAD/MC), in which copper-modified MXene nanosheets participate in the construction of an interpenetrating polymer network via covalent and non-covalent interactions. This design endowed the hydrogel with favorable mechanical properties, injectability, bone tissue adhesion, and self-healing capability, as well as outstanding resistance to swelling and efficient near-infrared (NIR) photothermal conversion. Mild photothermal effects alleviated local inflammation in diabetic bone defects, while controlled release of Cu²⁺ scavenged excess reactive oxygen species (ROS) and induced macrophage polarization toward the pro-healing M2 phenotype, demonstrating pronounced antibacterial and antioxidant functions. Additionally, MC activated the Wnt/β-catenin signaling pathway, promoting osteoblast proliferation and bone tissue mineralization [68]. Similarly, Xue et al. fabricated an injectable, NIR-triggered bone cement (nHAP-MXene-GelMA/HAMA) for diabetic bone defects, based on a GelMA/HAMA double-network hydrogel incorporating two functional additives: MXene, which provided superior photothermal conversion, antioxidant capacity, and antimicrobial activity; and nHAP derived from natural oyster shell powder, capable of releasing multiple ions, including Mg²⁺, Sr²⁺, Ca²⁺, and Si⁴⁺ ions to enhance osteogenesis and angiogenesis. The combination of these components strengthened the hydrogel's mechanical properties. Within the 40–43 °C temperature range, NIR-triggered photothermal therapy, coupled with nHAP-mediated ion release, stimulated proliferation of bone marrow mesenchymal stem cells (BMSCs) and bone matrix synthesis for osteogenesis, while simultaneously promoting migration and lumen formation of human umbilical vein endothelial cells (HUVECs) to enhance angiogenesis and vascularization [69]. Wu et al. developed a sponge-like hydrogel system (HG/MPA) by surface-modifying poly(dopamine)-coated Ti₃C₂T_x MXene (MP) nanosheets with acidic fibroblast growth factor (aFGF) and a hydroxypropyl chitosan/gelatin (HG) hydrogel, wherein PDA served as an interlayer. The abundant amine and 1,2-dihydroxybenzene moieties of PDA enhanced the stability and photothermal performance of the MXene nanosheets, while providing a stable adhesive interface for linking aFGF molecules [96]. Wu et al. developed a sponge-like hydrogel system (HG/MPA) by surface-modifying poly(dopamine)-coated Ti₃C₂T_x MXene (MP) nanosheets with acidic fibroblast growth factor (aFGF) and a hydroxypropyl chitosan/gelatin (HG) hydrogel, wherein PDA served as an interlayer. The abundant amine and 1,2-dihydroxybenzene moieties of PDA enhanced the stability and photothermal performance of the MXene nanosheets, while providing a stable adhesive interface for linking aFGF molecules [70].

Layered double hydroxides (LDHs) have emerged as effective near-infrared (NIR) photothermal agents due to their layered structures and high specific surface area, and have been widely applied in drug delivery, tumor therapy, and tissue engineering [57]. By adjusting the composition and ratio of doped metal ions, LDHs can release metal ions during degradation, creating an alkaline microenvironment that promotes cellular mineralization and osteogenesis. Li et al. designed a core–shell composite hydrogel consisting of a shell of magnesium–iron-based layered double hydroxide (LDOX) loaded with doxorubicin (DOX) and a core of liquid crystal hydrogel (LCgel-L) containing LDH. During the early treatment phase, moderate hyperthermia (45–50 °C) induced shell dissociation, triggering thermosensitive release of LDOX. This facilitated DOX delivery via LDH-mediated endocytosis, enabling targeted release into osteosarcoma cells. The synergistic effect of photothermal therapy (PTT) and DOX allowed timely clearance of residual tumor cells following surgery and prevented postoperative bacterial infection. Following shell dissociation, the exposed core synergistically activated HSP70 expression and the ERK-Wnt/β-catenin signaling pathway through the interaction of the liquid crystal hydrogel with LDH-induced mild hyperthermia (40–42 °C) and released metal ions (Mg²⁺, Fe³⁺), thereby achieving temporally controlled treatment of osteosarcoma-associated bone defects(Fig. 4c) [58].

When local temperatures exceed 50 °C, tumor cell proteins undergo denaturation, thereby enhancing treatment efficacy and therapeutic outcomes [97,98] Gold nanorods (GNRs) have been widely employed as highly efficient photothermal agents owing to their strong near-infrared (NIR) absorption, biocompatibility, and photothermal stability [99]. Liao et al. fabricated a GNRs/nano-hydroxyapatite (nHA) composite hydrogel via photo-induced polymerization, embedding GNRs with excellent photothermal properties and nHA with strong osteogenic activity within a gelatin-based three-dimensional hydrogel matrix. This design enabled dual functionality for tumor photothermal therapy and bone repair. Under NIR laser irradiation, the hydrogel core temperature rapidly increased to approximately 53.8 °C, effectively eliminating residual tumor cells, while the surrounding tissue temperature remained around 40 °C, preventing damage to healthy tissue and simultaneously promoting differentiation of mesenchymal stem cells (MSCs) into osteoblasts [71]. In addition, micro–nano bioactive glass (MNBG) is a biodegradable, bioactive material exhibiting favorable mineralization properties [100]. The ions released, including silicon and calcium, stimulate cell proliferation and enhance the expression of genes associated with osteogenesis and angiogenesis [101]. The copper-doped bioactive glass microsphere (CuBGM) hydrogel developed by Chen et al. incorporates Cu ions into the micro–nano bioactive glass (MNBG) network, which sinter to form a metal oxide structure. This design not only endowed the hydrogel with favorable photothermal properties but also accelerated the Diels–Alder (DA) reaction during hydrogel formation. During photothermal therapy, the hydrogel significantly elevated local temperatures, effectively eliminating tumor cells at the excision site. Concurrently, gradual hydrogel degradation released Cu ions that activated signaling pathways, including Wnt/β-catenin and Shh, which synergized with the release of Ca²⁺ and Si⁴⁺ ions to promote cellular proliferation and bone matrix deposition [72]. Similarly, Zhang et al. fabricated a core–shell scaffold by 3D printing β-tricalcium phosphate (β-TCP)/SrCuSi₄O₁₀ (SC) nanosheet composites as the hollow fiber shell (hTCP/SC) and encapsulating drug-loaded gelatin as the hollow fiber core. The SC nanosheets exhibited exceptional photothermal conversion efficiency (∼46.3%). Upon near-infrared irradiation, the generated heat induced a gel-to-sol transition in DOX-loaded gelatin, triggering its release from the hollow channels and enabling chemotherapeutic–photothermal synergistic treatment of residual cancer cells in bone and surrounding tissues. Following complete gelatin release and degradation, the core–shell gelatin–TCP/SC scaffold transformed into a hollow-channel TCP/SC structure, providing enhanced space and structural guidance for nutrient transport and cell migration. Simultaneously, degradation of SC nanosheets continuously released bioactive ions (Sr²⁺, Cu²⁺, Si⁴⁺), with Sr²⁺ and Si⁴⁺ promoting osteogenesis-related gene expression (OCN, RUNX2), and Cu²⁺ enhancing VEGF expression to stimulate angiogenesis(Fig. 4d) [73].

3.1.1.2. BP

Black phosphorus (BP) nanosheets, as an emerging two-dimensional nanomaterial, have attracted considerable attention due to their favorable biocompatibility and degradability [102]. Under near-infrared (NIR) irradiation, BP exhibits outstanding photothermal conversion efficiency, enabling mild hyperthermia strategies that promote bone regeneration [74,103] Its degradation products, primarily phosphate ions, capture calcium ions to form calcium phosphate minerals, thereby accelerating cellular biomineralization [95,104] Hydrogels incorporating BP as a photothermal agent have demonstrated significant potential in bone repair applications. For instance, Shen et al. developed a fish-derived scaffold composed of fish scales and fish gelatin methacrylate (fGelMA), which exhibited excellent osteoinductive capability and biocompatibility. By incorporating BP nanosheets, the fGelMA hydrogel was able to achieve efficient photothermal conversion under NIR irradiation, enabling precise temperature regulation to 41–45 °C within 10 min. This mild hyperthermia promoted HSP70 expression and activated the Wnt/β-catenin signaling pathway, enhancing osteogenesis [74]. However, BP nanosheets exhibit weak interactions with scaffold matrices and are susceptible to oxidative degradation under physiological conditions, limiting their long-term photothermal therapeutic performance [105,106] To overcome the limitations of black phosphorus (BP) nanosheets, researchers have employed surface modification and composite stabilization strategies to improve their performance. Wu et al. developed a GA/BPPD hydrogel platform based on a gelatin methacrylate (GelMA)/sodium alginate methacrylate (Alg-MA) hybrid hydrogel (GA) system, combined with BP-based nanocomposites (BPPD) coated with dopamine (PDA) and loaded with deferoxamine (DFO) (Fig. 5a). This approach protected BP from rapid degradation, enabling sustained release of PO₄³⁻ to promote bone regeneration, while enhancing interfacial bonding between BP nanosheets and the polymer matrix to improve hydrogel stability [107]. The hydrogel responds to dual stimuli—internal pH and external NIR laser irradiation—generating mild thermal stimulation (∼45 °C) to induce macrophage M2 polarization and improve the local immune microenvironment(Fig. 5b,c,d,e,f). Concurrently, it facilitates the sequential release of DFO (angiogenic factor) and PO₄³⁻ (osteogenic factor), activating HIF-1α and VEGF signaling pathways to enhance osteogenic and angiogenic capabilities(Fig. 5g) [75]. Similarly, Li et al. incorporated layered double hydroxide (LDH) onto BP nanoplates (LDH@BP), which enhanced the photothermal performance and biocompatibility of the phosphate matrix while creating a favorable mineralization microenvironment within the hydrogel. Incorporation of LDH@BP into a liquid crystal (LC) gel endowed the organically derived ECM-like surface with phosphate mineralization nucleation sites, closely mimicking the mineralization microenvironment of native bone ECM. Mild hyperthermia induced by photothermal effects modulated ERK and Wnt/β-catenin signaling and heat shock responses, facilitating the release of phosphate anions and Mg²⁺ ions to accelerate biomineralization and osteogenic differentiation within bone defects [57].

Fig. 5.

a) Schematic illustration for fabrication and application of smart-responsive multifunctional therapeutic system with mild photothermal activity for augmented bone regeneration through spatiotemporal manipulation of the immune microenvironment, stem cell recruitment and vascular development, and osteogenic differentiation throughout the whole healing process. b) Schematic diagram of the NIR/pH dual-triggered drug/ion release behavior of the GA/BPPDM hydrogel. c, d) Cumulative release of DFO from the GA/BPPDM hydrogel at different pH values with or without NIR irradiation (808 nm, 1 W cm−2). Data are presented as the mean ± SD (n = 3). e, f) Immunohistochemical staining of iNOS and CD206 in different hydrogels on day 7 after implantation in the rat subcutaneous model (M: material residue). Scale bar: 50 μm (f). Data are presented as the mean ± SD (n = 3). ∗p < 0.05 and ∗∗p < 0.01 indicate significant differences compared with the control group. #p < 0.05 and # #p < 0.01 indicate significant differences compared with the GA/BPPDM + NIR group. g) Relative mRNA expression of angiogenesis-related genes in HUVECs, including Ang-1, bFGF, eNOS, HIF-1α, and VEGF. Data are presented as the mean ± SD (n = 3). ∗p < 0.05 and ∗∗p < 0.01 indicate significant differences compared with the GA group. #p < 0.05 and # #p < 0.01 indicate significant differences compared with the GA/BPPDM + NIR group. Reproduced with permission [75]. Copyright 2023, Publisher Wiley-VCH GmbH.

Inspired by the protective and defensive envelopes of natural chloroplasts, which not only convert light into chemical energy but also provide intrinsic protection, Li et al. developed a self-defensive bone scaffold. By mimicking the thylakoid and matrix lamellae structures of chloroplasts, poly(dopamine) (PDA) was encapsulated as an “envelope” around BP. Additionally, BP was integrated within a chitosan and polycaprolactone fiber network. This design not only improved the photothermal stability of the BP-based scaffold but also enabled in situ growth and anchoring of silver nanoparticles (AgNPs) as antimicrobial agents. Under mild thermal stimulation (40–42 °C), the hydrogel promoted upregulation of osteogenesis-related genes, including Runx2, ALP, and COL1, via activation of the Wnt/β-catenin and HSP signaling pathways. Concurrently, the AgNPs provided a biomimetic “self-defense” function, enhancing the scaffold's antimicrobial performance [76].

3.1.1.3. Carbon nanomaterials

Carbon nanomaterials, including graphene oxide [108], carbon nanotubes [109] carbon dots [110], and their derivatives, have been widely employed as photothermal agents. These materials efficiently convert near-infrared (NIR) laser energy into thermal energy, enabling antibacterial and antitumor therapies [111,112] while simultaneously promoting tissue regeneration, cell proliferation, and osteogenic differentiation. However, carbon nanomaterials below 200 nm are susceptible to rapid immune clearance or removal by organ-level physical targeting mechanisms, potentially reducing therapeutic efficacy [113,114] To overcome these limitations, Wei et al. developed an injectable thermosensitive hydrogel composed of chitosan (CS), hyaluronic acid (HA), and sodium β-glycerophosphate (GP), incorporating large carbon particles (CPs) with an average diameter of 491 nm as photothermal agents. Upon irradiation with 808 nm NIR light, the hydrogel exhibited rapid heating with excellent photothermal stability, effectively eliminating residual tumor cells, and simultaneously promoted new bone formation through the surface mineralization capability of CPs [77].

Graphene oxide (GO), a two-dimensional carbonaceous material, exhibits considerable potential in tissue engineering and drug delivery due to its excellent photothermal conversion efficiency, biocompatibility, and ability to promote osteoblast differentiation [115,116] Notably, graphene-based hydrogels can function as sustained drug delivery platforms, leveraging GO's high specific surface area and diverse interaction mechanisms—including π–π stacking, electrostatic interactions, hydrophobic interactions, and hydrogen bonding—to achieve high drug loading without compromising therapeutic efficacy [117]. Furthermore, photothermal stimulation can induce microstructural changes within the hydrogel, enabling precise and controlled modulation of drug release pathways. For infectious bone defects, Wu et al. developed a GelMA/PNIPAM/PAAM/GO-PL@BBR (GNAG@BBR) nanocomposite hydrogel, integrating mild photothermal therapy (PTT) nanomaterials with a pulsed drug release strategy (Fig. 6a and b). Berberine (BBR) exhibits concentration-dependent effects, functioning as an antibacterial agent at high concentrations and promoting osteogenic differentiation at low concentrations. Under near-infrared (NIR) irradiation, the GNAG@BBR hydrogel displays a pulsed release profile: approximately 60% of BBR is released during the initial antibacterial phase (first 24 h), effectively suppressing both Staphylococcus aureus and Escherichia coli. In the subsequent bone repair phase, sustained low-dose BBR release synergizes with photothermal stimulation to upregulate heat shock protein HSP70, activate the Ras/Raf/MEK/ERK signaling pathway, and enhance the expression of angiogenesis-related genes in human umbilical vein endothelial cells (HUVECs), thereby promoting osteoblast differentiation and neovascularization(Fig. 6c and d) [78]. Under physiological conditions, parathyroid hormone (PTH) secretion follows a diurnal rhythm, characterized by a morning peak, a late-morning trough, and a smaller afternoon peak [118]. This pulsatile secretion is essential for PTH to exert anabolic effects on bone metabolism [119,120] playing a critical role in restoring bone defects in osteoporotic patients. Wang et al. fabricated near-infrared (NIR) light-triggered reduced graphene oxide-loaded chitosan (CS/rGO) hydrogel films via electrodeposition. Leveraging rGO for NIR photothermal conversion, these films enabled biomimetic pulsatile drug delivery under 808 nm irradiation. The hydrogel achieved drug loading exceeding 85% at an rGO content of 0.7 % (w/v). Upon 10 min of 808 nm, 0.5 W cm⁻² laser exposure, approximately 40% of teriparatide was released, supporting repeatable daily pulsatile administration (Fig. 6e, f, g, h). Following hydrogel application, RANKL expression remained largely unchanged, whereas the OPG/RANKL ratio increased and PDGF gene expression was upregulated, demonstrating the hydrogel's potential for promoting bone defect repair [79].

Fig. 6.

a) The preparation of the photothermal sensitive nanocomposite hydrogel. b) The photothermal sensitive nanocomposite hydrogel for in vivo infectious bone defect repair in rats and its potential mechanism. c) Concentration curve depicting intermittent drug release from the hydrogel. d) Cumulative release curve for the continuously released drug from the hydrogel. Reproduced with permission [78]. Copyright 2025, Publisher Springer Nature. e) Teriparatide (100 μg mL− 1) loading capacity of CS/rGO as a function of rGO content (w/v) in PBS; f) Photothermal heating curves of CS hydrogel film (black, 0% content rGO), and different rGO contents of CS/rGO (blue, green, purple and red, 0.1%-0.7% content rGO) under NIR light irradiation (808 nm) at 0.5 W cm− 2 using a continuous wave laser. g) Percentage of Teriparatide released with NIR light irradiation time. h) In vitro pulsatile drug release curves from CS/rGO hydrogel films with (red line) or without (black line) NIR light irradiation (808 nm) at 0.5 W cm− 2 for 10 min. Concentration of drug released into PBS was detected before and after NIR light treat. Reproduced with permission [79]. Copyright 2020, Publisher Elsevier B.V.

3.1.1.4. Organic polymers

Organic polymers, owing to their versatile properties and facile processability, serve as ideal platforms for drug delivery and biomimetic scaffolds in near-infrared (NIR) light-mediated photothermal therapy. Among these, polydopamine (PDA) exhibits exceptional photothermal conversion efficiency, facile synthesis, minimal photobleaching, and excellent biocompatibility [121]. Furthermore, PDA modification enhances cell adhesion, proliferation, and osteogenic differentiation, while upregulating the expression of osteogenesis- and angiogenesis-related genes [122]. Given these advantages, PDA has been widely applied in anti-infective and anti-tumor therapies, diabetic bone repair, and sustained-release drug delivery. In preliminary studies, Wu et al. observed that incorporating PDA nanoparticles led to reduced mechanical properties of the hydrogel. To overcome this limitation, polymethyl methacrylate (PMMA) was incorporated as a stabilizing additive, enhancing the hydrogel's structural integrity and mechanical strength without compromising biocompatibility. At 40–43 °C, the resulting GelMA/PMMA/PDA composite hydrogel, synthesized via radical polymerization, promotes osteogenic differentiation and maturation of bone marrow mesenchymal stem cells (BMSCs), enhances local blood flow and nutrient exchange, and accelerates bone tissue regeneration [80].

For the treatment of bone defects associated with bone tumors, Lai et al. developed bioactive nanoparticles (MDA-NPs) comprising magnesium oxide nanoparticles (M-NPs) as the core and 2-aminoethyl methacrylate (2-AM)-grafted PDA as the shell. These nanoparticles were incorporated into NP/CMP@PAM dual-network hydrogels, exhibiting superior photothermal activity, mechanical properties, and osteogenic activity. Under near-infrared irradiation, the photothermal effect effectively suppressed the proliferation of human osteosarcoma cells (143B), achieving complete inhibition of tumor recurrence, while the released Mg²⁺ ions promoted osteogenic differentiation of mouse embryonic osteoblast precursor cells (MC3T3-E1) [81]. Similarly, Yao et al. developed an injectable SOH1(CP)1 hydrogel system integrating Se-Mg co-doped hydroxyapatite nanorods (Se15%/Mg30%-HAp) with PDA-coated CaO₂ nanospheres. Upon NIR irradiation, the hydrogel maintained stable temperatures of 41–44 °C for 10 min, suppressing tumor cell metabolism and inducing apoptosis without damaging surrounding healthy tissue. During degradation, Ca²⁺, Mg²⁺, and PO₄³⁻ ions were continuously released, providing mineralization nucleation sites for osteoblasts and activating the Wnt/β-catenin signaling pathway to enhance osteogenic differentiation. Concurrently, SeO₃²⁻ release accelerated in acidic microenvironments, inducing G₁ phase cell cycle arrest and increasing TUNEL-positive apoptotic cells, thereby synergistically enhancing antitumor efficacy(Fig. 7a) [82].

Fig. 7.

a) Diagram of the SOH1(CP)1 injectable hydrogel with mild photothermal effects combined with ion release for osteosarcoma-related bone defect repair. Preparation process of the injectable hydrogel. Schematic illustration of the injectable hydro gel for postoperative treatment of osteosarcoma through anti-osteosarcoma and promoting bone defect repair sequential therapy. The application method of the injectable hydrogel and its mechanisms of action for anti-tumor, promoting osteogenic differentiation and mineralization. Reproduced with permission [82]. Copyright 2024, Publisher Wiley-VCH GmbH. b) Schematic illustration of b) the synthesis of the PGCZ scaffold with c) multifunctional properties for d) potential application in diabetic bone healing and reconstruction through programmed regulation of the regeneration process. e) Schematic diagram of synthesis of MION-RGD/Agarose (MRA) hydrogels, and its mechanism of osteogenesis, biomineralization and angiogenesis in the bone defect site under mild magnetic hyperthermia. Reproduced with permission [84]. Copyright 2022, Publisher Elsevier Ltd. f) A schematic illustration of the preparation of FND-ZHD hydrogel and its molecular mechanism in treating infectious bone defects. Reproduced with permission [86]. Copyright 2025, Publisher The Author(s). Advanced Healthcare Materials published by Wiley-VCH GmbH.

For infectious bone defects, Wei et al. employed a Schiff base reaction to encapsulate plant progesterone (Pht)-loaded PDA within ZIF-8 nanoparticles, integrating these into a hydrogel composed of hyaluronic acid and carboxymethyl chitosan to form a smart co-regulated system. Under mild photothermal conditions (42.5 ± 1.2 °C), near-infrared (NIR) irradiation activated PDA, inducing sustained release of Pht and Zn²⁺ and simultaneously enhancing their release rate, while avoiding thermal damage to surrounding healthy tissue, of which Pht exerts pro-osteogenic, anti-inflammatory, and antibacterial effects, whereas Zn²⁺ promotes calcium-phosphorus deposition and osteoblast differentiation, synergistically establishing a microenvironment conducive to bone regeneration. This dual-functional system effectively enhances both antibacterial activity and osteogenesis, activating the BMP/SMAD signaling pathway and facilitating bone matrix mineralization [83]. Similarly, Wu et al. noticed that combining PDA with ZIF-8 nanoparticles not only supports osteogenesis and angiogenesis but also leverages photothermal activation and Zn²⁺ release to mitigate local inflammation and oxidative stress, thereby promoting tissue regeneration under chronic inflammatory conditions, such as those associated with diabetes [123,124] Wu et al. incorporated poly(dopamine)-modified zeolitic imidazolate framework-8 (ZIF-8@PDA) into a dual-network hydrogel (soft matrix) and integrated it within a 3D-printed polycaprolactone (PCL) scaffold (hard matrix) to construct a multifunctional PGCZ scaffold. In terms of osteogenesis, Zn²⁺ released from ZIF-8@PDA activates the MAPK pathway, promoting proliferation and differentiation of pre-osteoblasts. Mild near-infrared (NIR) irradiation induces low-grade hyperthermia, enhancing heat shock protein (HSP) expression and activating the PI3K/AKT and integrin signaling pathways. These pathways regulate cytoskeletal dynamics and adhesion molecules, thereby facilitating osteogenic differentiation (Fig. 7b, c, d). Furthermore, mild hyperthermia not only upregulates HSPs and activates PI3K/AKT and adhesion-mediated signaling to enhance immune regulation and suppress pro-inflammatory cascades, but also modulates immune responses by inhibiting the NF-κB pathway, thereby protecting cells from ROS-induced oxidative damage. Also, Zn²⁺ additionally promotes macrophage polarization from the pro-inflammatory M1 phenotype to the healing-associated M2 phenotype through inhibition of NF-κB and activation of the JAK-STAT pathway. Beyond immunomodulation, zinc ions exhibit broad-spectrum antibacterial activity, inhibiting bacterial growth and biofilm formation, collectively establishing a favorable osteoimmunomodulatory microenvironment that supports bone defect repair(Fig. 7e) [84]. D-cysteine is an essential precursor for bacterial peptidoglycan metabolism, and previous studies have shown that fluorescently labelled D-amino acids can bind peptidoglycan chains for bacterial targeting and tracking [125]. Inspired by this, Li et al. developed a methacrylate-gelatin composite hydrogel incorporating zinc ion- and D-cysteine-modified polydopamine nanoparticles (PZC), enabling a “camouflage strategy” for bacteria targeting. Upon bacterial uptake, PZC particles exert antibacterial effects via the release of Zn²⁺ ions and photothermal activity under near-infrared (NIR) irradiation. These bacteria-targeting nanoparticles preferentially aggregate within bacterial regions, avoiding excessive temperature increases and allowing controlled Zn²⁺ release within surrounding bone tissue cells. After bacterial clearance, the system further promotes repair of infected bone defects through synergistic photothermal and Zn²⁺-mediated osteogenic effects [85]. Beyond conventional bacterial infections, methicillin-resistant Staphylococcus aureus (MRSA) represents a major challenge in infectious bone defects. A critical factor underlying MRSA virulence is its ability to form biofilms on implant and bone surfaces, encapsulating bacteria within an extracellular matrix and conferring high resistance to antibiotics and host immune responses. Yang et al. developed an injectable nano-hybrid hydrogel (FND-ZHD) based on Pluronic F-127, which incorporates dopamine-coated nano-hydroxyapatite and zinc oxide nanoparticles encapsulated with dopamine and hyaluronic acid (Fig. 7f). Under near-infrared (NIR) irradiation, the zinc oxide nanoparticles exhibit potent anti-biofilm activity, synergistically eliminating MRSA via precise low-temperature photothermal therapy. This photothermal process generates reactive oxygen species (ROS) to enhance antimicrobial efficacy, while the hydrogel design allows self-elimination of excess ROS to minimize cytotoxicity. Moreover, the hydrogel promotes bone regeneration by upregulating heat shock protein 70 (HSP70), thereby facilitating osteogenic differentiation and accelerating bone repair [86].

Beyond applications in antitumor, anti-infective, and immunomodulatory therapies, as well as in promoting bone function, photothermal effects have also been leveraged to control the sustained release of signaling molecules with transient activity and limited diffusion [126]. Nitric oxide (NO), for example, plays a pivotal role in diverse physiological and pathological processes—including vasodilation, neuromodulation, and tumorigenesis—and exerts important regulatory effects on vascularization and bone regeneration at defect sites [[127], [128], [129]] Pan et al. developed an ultrasonic self-assembly system encapsulating indocyanine green (ICG)-loaded mPEG-P nanoparticles (NO-NPs@ICG), which were incorporated into an injectable thermosensitive hydrogel composed of mPEG-PA-PP. Under near-infrared irradiation, the photothermal effect of ICG induces dissociation of –SNO bonds within the nanoparticles, enabling controlled, sustained NO release. This activates the NO–soluble guanylate cyclase (SGC)–cyclic guanosine monophosphate (cGMP) signaling pathway, thereby enhancing proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs) and promoting vascular endothelial function, ultimately accelerating bone defect repair [87].

In conclusion, photothermal hydrogels offer a promising solution for bone defect repair by combining thermal stimulation with the localized delivery of photothermal energy. The optimal parameter range for photothermal therapy typically involves near-infrared (NIR) light with wavelengths in the 800–1064 nm range, where the ideal temperature range is 40–45 °C for promoting °Costeogenesis while minimizing cytotoxicity. For instance, CuS-based hydrogels can achieve optimal thermal effects under NIR irradiation at 808 nm, reaching 45–50 °C in just 10 min, effectively stimulating osteoblast activity and angiogenesis. However, excessive temperatures above 55 °C may cause tissue damage.

The key mechanisms underlying photothermal hydrogels in bone regeneration include the activation of heat shock proteins (HSPs), upregulation of Wnt/β-catenin signaling, and enhanced cellular biomineralization. Additionally, the controlled release of bioactive ions (e.g., Ca²⁺, Mg²⁺) and therapeutic agents in response to NIR irradiation further promotes osteogenesis and accelerates bone healing. Importantly, these hydrogels also exhibit dual functionality, combining antibacterial and antitumor effects via localized hyperthermia and reactive oxygen species (ROS) generation.

Nevertheless, the unresolved challenges discussed above continue to constrain precise thermal control and translational scalability. The NIR-I window (650–950 nm), while capable of penetrating several millimeters of soft tissue, remains insufficient for deep bone structures such as the acetabulum and spine, limiting its efficacy in treating large or deep defects [130]. The NIR-II window (1000–1700 nm) offers slightly increased tissue penetration, yet the biocompatibility, safety, and photostability of corresponding photothermal agents require further validation [131,132] Additionally, most inorganic photothermal materials—such as gold nanostructures, MXenes, and black phosphorus nanosheets—demonstrate high photothermal conversion efficiency but face size-dependent metabolic constraints during prolonged in vivo use [133]. Metallic nanoparticles larger than 5 nm are cleared slowly via the hepatobiliary pathway, potentially leading to tissue accumulation and chronic toxicity [134], whereas downsizing particles for renal clearance shifts their surface plasmon resonance out of the near-infrared range, reducing photothermal efficiency [135].

3.1.2. Magnetothermal hydrogels

Unlike near-infrared light, alternating magnetic fields (AMF) can penetrate deep tissues, enabling magnetic hyperthermia therapy (MHT) [136]. As a non-invasive modality, MHT has been widely applied in clinical oncology due to its unrestricted tissue penetration, remote controllability, and versatility in therapeutic modes(Table 2) [143,144] Studies have demonstrated that AMF can penetrate porcine skin up to 3 cm in thickness, highlighting the potential of MHT for the treatment of deep bone defects [145].

Table 2.

Advanced hydrogel strategies for magnetothermal in bone repair.

Hydrogel Scaffold Structure	Photothermal Agent	Thermal Treatment Conditions			Functional agents	Animal Models	Applicable diseases	Reference
		Thermal Treatment Parameters	Radiation Time	Maximum Temperature
Fe3O4/Chitosan/PEG	Fe3O4 nanoparticles	12 kA m−1: Rapidly heat to 43 °C; 9.6 kA m−1: Maintain at 43 °C.	12 kA m−1/2.5min; 9.6 kA m−1/15min	43 °C	Fe3O4 nanoparticles act as magnetic heat agents, producing heat under an AMF to enable magnetic hyperthermia treatment.	/	Bone defects	[137]
Fe3O4@GO (MGO)/PVA/SA/HA	MGO	300 Gs	10min	∼45 °C	HA boosts hydrogel osteoconductivity and strength, aids bone matrix mineralization and BMSC osteogenesis; MGO's magnetothermal effect kills tumors and its iron ions and GO promote BMSC osteogenesis	Balb/c nude mice, subcutaneous	Tumour-related bone defects and tumor	[138]
CoFe2O4@MnFe2O4(MION)/RGD/Agarose(MRA)	MION	1.35 kA m−1	5min	41 °C	MION offers magnetothermal effect, boosts osteogenic differentiation and mineralization, and releases iron and cobalt ions.	Rat, calvarium	Bone defects	[139]
Fe3O4/GOx/MgCO3@PLGA(MBRs)	Fe3O4 nanoparticles	5.72 kA m−1	Applied an “on-off” mode in 5 cycles, each lasting approximately 5 min.	40-45 °C	Fe3O4 induces GOx release via mild heating, reducing tumor heat resistance; Fe3+ converts H2O2 to O2; GOx consumes glucose, starving tumors; MgCO3 provides Mg2+ to promote bone formation.	Osteogenesis: SD rat calvaria; residual tumor therapy: NZ rabbit tibial plateau.	Osteosarcoma	[140]
HAp/SiO2/PLMC/Fe3O4	Fe3O4 nanoparticles	5.0 kW	1min	51 °C	Fe3O4 nanoparticles supply dual hyperthermia and ROS via Fenton for CDT; PLMC exhibits shape memory for precise scaffold conformability and minimally invasive delivery.	Tumor model: nude mice, right dorsal subcutaneous; osteogenesis: SD rats, calvarium.	Osteosarcoma	[141]
GelMA/MNPs(ZnCoFe2O4@ZnMnFe2O4)/PEI-COOH/siCkip-1	MNPs	1.35 kA m−1	10 min	infection period:≈50 °C; repair stage:41.5 °C	MNPs generate heat under alternating magnetic fields for magneto-thermal therapy; siCkip-1 silences Ckip-1 and activates Akt, promoting osteogenesis, M1→M2 polarization, and inflammation reduction, while particle degradation releases Fe2+, Zn2+, and Mn2+ to assist chemodynamic therapy and bone formation.	SD rats, femur	Infected bone defects	[142]

Superparamagnetic nanoparticles (MNPs), such as Fe₃O₄ nanoparticles, exhibit pronounced heating under high-frequency alternating magnetic fields. This thermal effect arises from energy dissipation during magnetization and demagnetization processes. Specifically, heat generation occurs via the Néel relaxation mechanism, in which reversal of magnetic moments within the crystal lattice is impeded by anisotropic energy, or via the Brownian relaxation mechanism, in which the physical rotation of nanoparticles in suspension is restricted by the medium's viscosity [146]. As nanomaterials, magnetic ferrite nanoparticles combine favorable biocompatibility and degradability with strong cell surface coupling capabilities, allowing precise regulation of cellular functions under external magnetic field control [147,148] In 2018, Cao et al. pioneered the integration of magnetothermal therapy (MHT) with injectable hydrogels for bone defect repair by developing a nanocomposite magnetothermal hydrogel containing Fe₃O₄ nanoparticles. Under a 20 A current magnetic field, the hydrogel rapidly reached the optimal temperature of 43 °C within 2.5 min and maintained this temperature stably at 15.5 A, effectively promoting osteogenic differentiation of mesenchymal stem cells (MSCs) [137]. Leveraging graphene's macrostructural advantages in bioengineering and its antibacterial properties through bacterial membrane disruption [149], Li et al. employed additive manufacturing (AM) to fabricate a polyvinyl alcohol/sodium alginate/hydroxyapatite (PVA/SA/HA) hydrogel composite scaffold at low temperatures. Magnetic graphene oxide (MGO)@Fe₃O₄ nanoparticles were incorporated into the scaffold matrix, combining Fe₃O₄'s magnetothermal conversion for antitumor effects with MGO's antibacterial membrane-disruptive activity. This synergistic system promotes bone marrow-derived MSC differentiation and mineralization via calcium ions in the scaffold, iron ions (Fe²⁺/Fe³⁺) in MGO, and graphene oxide functional groups (-COOH, -OH) [138]. Wang et al. fabricated core-shell structured magnetic iron oxide nanoparticles (MIONs; CoFe₂O₄@MnFe₂O₄) via coprecipitation as MHT generators for bone defect hyperthermia, further modified with RGD (arginine-glycine-aspartic acid) to enhance MSC adhesion. The MIONs exhibit exceptional magnetothermal efficiency due to exchange-coupled magnetism between the CoFe₂O₄ core and MnFe₂O₄ shell [150]. MION-RGD particles released from MRA hydrogels were internalized by bone marrow-derived MSCs, promoting osteogenic differentiation via the MAPK pathway. Under MHT stimulation, the hydrogel upregulates heat shock protein 90 (HSP90) expression, stabilizes p-Akt, and activates the PI3K/Akt pathway, thereby enhancing osteogenesis and biomineralization. Additionally, elevated HSP90 expression, through p-Akt stabilization, upregulates hypoxia-inducible factor-1α (HIF-1α), which synergizes with iron and cobalt ion release from MION degradation to promote angiogenesis and improve local blood supply [139]. Subsequently, synergistic integration with sustained-release therapeutics further enhances the efficacy of magnetothermal therapy (MHT) in both suppressing tumor growth and accelerating bone defect reconstruction. Yu et al. developed a trifunctional magnetic hydrogel (Fe₃O₄/GOx/MgCO₃@PLGA) for bone repair (MBRs), achieving dual functions of antitumor activity and osteogenesis. MHT directly induces tumor cell apoptosis while simultaneously triggering the release of glucose oxidase (GOx) from the hydrogel. In the presence of Fe³⁺ and under controlled thermal conditions, glucose is converted into gluconic acid and hydrogen peroxide (H₂O₂), which subsequently generates oxygen (O₂). This process depletes glucose, thereby limiting ATP production and suppressing tumor cell heat shock protein (HSP) expression, reducing hyperthermia resistance. Concurrently, MHT promotes the sustained release of magnesium ions, serving as a bone-inducing agent that enhances osteogenic differentiation and mineralization in osteoblast-like cells (e.g., iMEFs)(Fig. 8a and b) [140].

Fig. 8.

a) Synthesis of PLGA gels and the encapsulation of glucose oxidase and Fe₃O₄/MgCO₃ nanoparticles. b) Mild hyperthermia-triggered GOx release to induce starvation-magnetic synergistic therapy in 143B bone tumors. The enzymatic activity of GOx was reserved under mild thermal conditions and accelerated the enzyme-promoting reaction, and HSP70 was inhibited by simultaneously decreasing ATP for enhanced magnetic hyperthermia therapy. The irregular bone defect was repaired by the porous structure of the MBRs, enhanced osteogenic differentiation and calcium salt deposition to achieve a treatment and repair two-in-one strategy. Reproduced with permission [140]. Copyright 2023, The Author(s) Publisher Journal of Nanobiotechnology. c) Synthesis of MNP-PEI-siCkip-1 (MPSC) Nanoparticles and the Further Encapsulation of MPSCs into GelMA To Form MSG Hydrogels; d) Schematics Illustrating IBDs in Femoral Condyles under the Treatments by cMHT. Reproduced with permission [142]. Copyright 2025, Publisher American Chemical Society.

Furthermore, Fe₃O₄ nanoparticles can simultaneously mediate magnetothermal therapy (MHT) and photothermal therapy (PTT), effectively overcoming the limitations associated with each modality. Wang et al. employed Pickering emulsions combined with 4D printing to fabricate a hierarchical porous shape-memory scaffold (HSP-Fe₃O₄) incorporating hydroxyapatite, silica, and Fe₃O₄ nanoparticles. This scaffold generates dual-mode heating under both near-infrared (NIR) irradiation and alternating magnetic fields, while its shape-memory properties enable precise adaptation to complex bone defects following minimally invasive implantation. Concurrently, the scaffold activates Wnt/β-catenin, MAPK, and TGF-β/BMP signaling pathways to promote osteogenesis and bone repair. In addition, Fe₃O₄ nanoparticles can generate highly cytotoxic reactive oxygen species (ROS) within tumor cells via the Fenton reaction, exploiting overexpressed H₂O₂ to eliminate cancer cells. Hydroxyapatite nanoparticles mimic natural bone tissue and, upon cellular uptake, gradually release Ca²⁺ and PO₄³⁻ ions, which trigger Ca²-dependent signaling pathways to further enhance osteogenic differentiation in mesenchymal stem cells [141]. Similarly, Wang et al. observed that magnetothermal therapy (MHT), through synergistic interaction with magnetic nanoparticles, not only disrupts biofilm structures during the catalyzed generation of hydroxyl radicals (·OH) from H₂O₂, but also enhances the Fenton reaction. This leads to elevated reactive oxygen species (ROS) production, reactivating macrophages suppressed by the biofilm and generating a synergistic antibacterial effect. To exploit this mechanism, ZnCoFe₂O₄@ZnMnFe₂O₄ nanoparticles were first coated with siRNA targeting casein kinase-2 interacting protein-1 (siCkip-1) and polyethyleneimine-carboxylic acid (PEI-COOH), forming a magnetothermal nanoscale platform. These MPSCs were then incorporated into gelatin methacrylate (GelMA) to construct a nanocatalytic nanoparticle–hydrogel composite (MSG) exhibiting potent magnetothermal effects, establishing a cascading magnetothermal therapy (CMHT) strategy for infected bone defects. During infection, the hydrogel generates heat (∼50 °C) upon exposure to an alternating magnetic field (AMF), effectively disrupting dense biofilm structures. The elevated temperature, in combination with chemo dynamic therapy (CDT) mediated by magnetic nanoparticles, reacts with overexpressed H₂O₂ in the infected microenvironment, producing substantial ·OH locally to eradicate bacteria. This synergistic effect also enhances ·OH production, thereby activating neutrophil extracellular trap (NETosis) formation, which in turn polarizes M1 macrophages and promotes dendritic cell maturation to enhance antigen presentation. Following infection clearance, accelerated hydrogel degradation facilitates MPSCs release. Upon internalization by osteoblasts and M1 macrophages, MPSCs escape lysosomes, which then allows siCkip-1 to be released and transported into the nucleus via PEI's proton sponge effect. Controlled AMF irradiation raises the defect site temperature to approximately 41 °C, which, together with siCkip-1, synergistically activates the Akt signaling pathway, enhancing biomineralization and promoting M2 macrophage polarization(Fig. 8c and d) [142].

Magnetothermal hydrogels provide a non-invasive, remotely controllable approach for bone defect repair by converting alternating magnetic fields (AMF) into localized heat. Optimal therapeutic temperatures range between 41 and 45 °C, with 43 °C being the most commonly used. At this temperature, osteogenesis is promoted while minimizing cytotoxicity. For example, Fe₃O₄-based hydrogels can reach the desired temperature within 2-3 min under AMF currents of 1–15 kA m⁻¹. Excessive heating beyond 45 °C may lead to protein denaturation and impaired cell function. Magnetothermal conversion efficiency depends on nanoparticle composition, particle size, and magnetic coupling, which together influence heat delivery precision.

Mechanistically, magnetothermal therapy enhances osteogenesis through PI3K/Akt and MAPK signaling, upregulating HSP90, stabilizing p-Akt, and activating HIF-1α, which aids angiogenesis. Additionally, it regulates macrophage polarization (M1 to M2), facilitating tissue remodeling. In multifunctional systems, the combination of heat, reactive oxygen species (ROS) generation, and controlled ion release enables antibacterial, antitumor, and osteogenic effects, offering broad therapeutic potential.

Despite their attractive features, including remote controllability and synergistic therapeutic effects, magnetothermal hydrogels still face significant challenges toward clinical translation. The limited magnetothermal conversion efficiency and the poor precision of heat distribution remain key obstacles, as most Fe₃O₄ or composite ferrite nanoparticles fail to achieve adequate specific absorption rates (SAR) under clinically safe magnetic field intensities [151]. Moreover, the long-term biodegradation and metabolic fate of magnetic nanoparticles are not yet fully elucidated, and the release of metal ions (e.g., Fe, Co, Mn) may induce oxidative stress or inflammatory responses, compromising local tissue integrity [152]. Structural limitations, such as inadequate mechanical strength and mismatched degradation kinetics with bone formation, also hinder their application [153]. Furthermore, uneven nanoparticle dispersion can generate localized hotspots, leading to protein denaturation, cellular necrosis, and impaired tissue regeneration [154]. The underlying molecular mechanisms remain to be comprehensively defined, though the activation of MAPK, PI3K/Akt, and HIF-1α pathways has been reported [155]. Additionally, excessive local hyperthermia may disrupt immune homeostasis and attenuate the long-term regenerative potential of bone-associated cells [156].

Future research should aim to optimize magnetothermal efficiency, enhance spatial–temporal control of heat generation, and minimize cytotoxicity, thereby improving biosafety and accelerating the clinical translation of magnetothermal hydrogel systems.

3.2. Electrical stimulation and energy metabolism regulation

Bioelectricity underpins the functional activity of electrically active organs and tissues, and bone tissue is no exception [157]. The endogenous electric field (EnEF) refers to the naturally occurring electric field within living tissues, generated by the collective electrical activity of cells and tissues. EnEF is influenced by multiple factors, including cell membrane potential, ion concentrations, and tissue architecture. In bone tissue, the primary manifestation of EnEF is its piezoelectric properties, reflecting the material's capacity to convert mechanical stimuli into electrical signals [158]. Collagen molecules within bone adopt a helical triple-helix structure, self-assembling via hydrogen bonds into a quasi-hexagonal lattice that establishes the non-centrosymmetric architecture required for piezoelectricity [159]. Under physiological compressive loads, bone tissue generates a charge density of approximately 7 × 10⁻¹¹ mC/cm², producing a negative piezoelectric potential [160]. This negative charge is believed to promote osteoclast activity, thereby maintaining the dynamic equilibrium between bone resorption and formation. Beyond piezoelectricity, Heng et al. reviewed the dielectric, pyroelectric, and ferroelectric properties of bone tissue, attributing these characteristics primarily to interactions between inorganic components (e.g., hydroxyapatite) and organic constituents (e.g., collagen fibers, proteoglycans) under biomechanical stresses associated with daily physical activity (Fig. 9). The three principal cellular lineages within bone tissue—osteoblasts, osteocytes, and osteoclasts—are also recognized as electrically sensitive and electroactive. Their transmembrane potentials are altered by mechanical or electrical stimulation through mechanosensitive and voltage-gated ion channels, activating downstream pathways such as the calmodulin–calcineurin–NFAT cascade and the extracellular signal-regulated kinase (ERK) pathway. These mechanisms exert extensive regulatory effects on cellular metabolism and diverse biological processes, thereby profoundly influencing the dynamic equilibrium and remodeling of bone tissue. In addition, electrical stimulation has been demonstrated to induce the redistribution of several cell-surface receptors, including fibronectin, epidermal growth factor (EGF), and lectins, which govern cell migration, adhesion, and proliferation [161].

Fig. 9.

Bone is an electroactive, electrosensitive and electroresponsive tissue. Reproduced with permission [161]. Copyright 2022, Publisher The Authors. Advanced Science published by Wiley-VCH GmbH.

Following the occurrence of bone defects, the endogenous electric field (EnEF) within the defect region is disrupted, impairing the self-restoration of the disordered electrophysiological microenvironment and ultimately delaying bone tissue repair [162]. To address this challenge, strategies such as implanting conductive materials to restore bone electrophysiological function have been explored, alongside the application of electrical stimulation (ES) as an effective approach to promote bone defect repair. Extensive studies have demonstrated that ES can mimic the electrophysiological characteristics of excitable tissues, thereby facilitating the regeneration of cells and tissues—including cardiomyocytes and neurons [163]—and contributing to functional recovery [164,165] For bone defects, electrical stimulation (ES) promotes bone repair and restores the local microenvironment through multiple mechanisms. Firstly, during the early inflammatory phase, ES modulates the inflammatory response by regulating immune cell recruitment and polarization, notably promoting the transition of macrophages from the pro-inflammatory M1 to the pro-healing M2 phenotype. This creates an immunological microenvironment conducive to osteoblast adhesion, migration, and differentiation. Mechanistically, ES activates signaling pathways such as RhoA/ROCK and AKT2-IRF5/HIF-1α, while mitigating chronic inflammation by inhibiting TNF and MAPK/JNK cascades, thereby accelerating tissue repair [166,167] Secondly, ES enhances angiogenesis by upregulating pro-angiogenic factors including VEGF, MMP2 and IL-8. It regulates endothelial cell migration and lumen formation via the SDF-1/CXCR4 axis and PI3K/Akt/eNOS pathways, improving nutrient and oxygen delivery to the defect site and supporting osteoblast survival and function [168]. Moreover, during the osteogenic phase, ES directly influences osteoprogenitor cells and mesenchymal stem cells (MSCs), promoting their adhesion, migration, and differentiation. This results in elevated expression of osteogenesis-related genes and markers such as RUNX2, COL1A1, and SPP1.The underlying mechanism involves electric-field–mediated modulation of surface charge distribution, which induces conformational changes in adsorbed fibronectin. This enhances integrin receptor binding and clustering, thereby promoting focal adhesion complex assembly and activating focal adhesion kinase (FAK). Subsequent activation of the YAP/TAZ transcriptional co-activators upregulates key osteogenesis-associated genes, ultimately driving osteogenic differentiation [[169], [170], [171], [172]] Ca²⁺ influx, activation of NFAT and SMAD signaling, and synergistic regulation via TGF-β/BMP and Wnt/β-catenin pathways. Furthermore, ES enhances extracellular matrix (ECM) protein expression and spatial organization, facilitating bone-like tissue deposition and mineralization(Fig. 10) [173].

Fig. 10.

Electrical stimulation–enhanced immunomodulation, angiogenesis, and osteogenesis in bone defect repair.

In summary, hydrogel materials that restore the bioelectrical microenvironment in bone defects and deliver electrical stimulation to promote osteogenesis have emerged as a key research focus. These materials can be broadly categorized into two main types—conductive hydrogels and piezoelectric hydrogels—and representative strategies are comparatively summarized in Table 3. It should be noted that although key electrical signal parameters are summarized, several critical descriptors—such as electrode geometry, detailed waveform definitions, duty cycle, and in vivo electric field distribution—are not consistently reported across studies, which currently limits direct quantitative comparison and standardization.

Table 3.

Advanced Hydrogel Strategies for Conductive hydrogels and Piezoelectric Hydrogels in Bone Repair.

Classification	Hydrogel Scaffold Structure	Electroactive Structures	Electrical Stimulation Parameters/Electrical Output Characteristics	mechanical properties	Functional Agents	Animal Models	applicable diseases	Reference
Conductive hydrogels	GelMA/AlgMA/BP@Mg	BP@Mg	Electric field strength:200 mV mm−1, Frequency: 100 Hz, Stimulation duration: 1 h/day, 50% duty cycle	/	BP@Mg provides electrical conductivity to mimic endogenous electric fields, promoting angiogenesis and osteogenesis.	C57BL/6 mice; calvaria	Senile bone defects	[174]
	GelMA/BP@Mg	BP@Mg	Stimulation duration: 5min	Elastic modulus:2.09 ± 0.07 MPa	BP@Mg: Exhibits antibacterial effects, promotes Schwann cell migration and neurotrophic factor secretion to enhance neural regeneration; stimulates osteogenic differentiation of BMSCs.	SD rat; calvaria	Infected bone defects	[175]
	MXene/RSF	MXene nanosheets and RSF construct a dual-crosslinked network.	Electric field strength: 100 mV mm−1, Frequency: 20 Hz, Stimulation duration: 0.5 h, repeated every two days.	/	RSF: inhibits MXene restacking and oxidation; MXene nanosheets: metallic conductivity.	SD rat, calvaria	Bone defects	[176]
	GelMA/ppyNWs	Polypyrrole nanowires (ppyNWs).	Voltage: 2 V (DC), Duration: 20 min, Stimulation frequency: once daily.	Elastic modulus:58.2 kPa; Fracture toughness:29.81 mPa,60%	Polypyrrole nanowires create ordered conductive tracks, improving hydrogel electrical conductivity and strength.	SD rat BMSCs from femur and tibia	Bone defects	[162]
	CaP-PEDOT:PSS-MgTiO3@MA(CPM@MA)	PEDOT:PSS/MgTiO3	Voltage: 100 mV mm−1, Frequency: 100 Hz, Duration: 30 min, applied once daily.	Fracture toughness:35.60 Mpa	PEDOT:PSS enhances conductivity, mimics bioelectric environment, and drives cell signaling; CaP supplies calcium phosphate, accelerating HAp formation and mineralization; MgTiO3 induces piezoelectric polarization, promoting phosphate aggregation and osteogenesis.	Rat; femur	Bone defects	[177]
	PLGA/HA/PLA-AP/phBMP-4(pSTAR - hBMP - 4)	PLA-AP	Voltage: 500 mV; Frequency: 100 Hz; Duration: 30 min; Duty cycle: 50%.	Compressive strength:1.68 MPa	pSTAR-hBMP-4: delivers hBMP-4, drives osteoblasts; PLA-AP: electroactive, boosts gene expression and release via ES.	Osteogenesis: New Zealand White rabbits; gene modulation: radial dorsal muscle.	Bone defects	[178]
Piezoelectric hydrogels	Gel/OCS/KBTO	KBTO	Voltage: −41.16 to 61.82 mV.	/	KBTO: ultrasound-induced piezoelectricity drives ES, enhancing BMSC osteogenesis.	SD rat, calvaria	Bone defects	[179]
	ZnO/RSF	ZnO and RSF	Voltage: approximately 80 mV; Current: approximately 32 nA.	Elastic modulus:2.09 ± 0.07 MPa	ZnO: boosts piezoelectricity, emits ES, drives BMSC osteogenesis; RSF: bio-compatible, stiffens hydrogel, reinforces piezo effect.	SD rat, femoral condyle	Bone defects	[180]
	Piezoelectric Module:PCL/γ-glycine; Conductive Hydrogel Module: VA/Gelatin/LiAc/B(OH)4-/nHAp	LiAc, nHAp and B(OH)4-	Voltage: approximately 260 mV	Elastic modulus:5.18 Mpa	γ-glycine: provides piezoelectric properties; LiAc: provides Li+ ions, enhances ionic conductivity, and activates β-catenin pathway; nHAp: enhances pore connectivity, releases Ca2+/PO43-, and promotes osteogenesis	SD rat; calvaria	Bone defects	[181]
	Upper: dECM/FF; lower: PEDOT/Gel-C.	Piezoelectric structure:FF and dECM; Conductive structure:PEDOT with Gel-C.	Voltage: approximately 20 mV; Current: approximately 0.8 μA.	Tensile strength:60%;	FF: force-induced potential tunes dECM, raises piezoelectricity; Gel-C/PEDOT: basal layer, raises conductivity, promotes osteogenesis.	Parma pig, femoral trochlear sulcus	Osteochondral defect	[182]
	BP@PDA/AlgMA/ECM	BP@PDA	Open-circuit voltage ≈35 V; Short-circuit current 3.7 μA; Charge transfer 23 nC	/	BP@PDA boosts conductivity and mineralization, enhancing hydrogel electrical performance.	SD rat, femur	Bone defect	[183]

For conductive hydrogels, the listed electrical parameters represent externally applied stimulation conditions. For piezoelectric and self-powered systems, the reported values correspond to measured electrical outputs (e.g., open-circuit voltage or short-circuit current) generated under mechanical or ultrasonic excitation.

3.2.1. Conductive hydrogels

Conductive implants have emerged as promising platforms for tissue regeneration, demonstrating notable advancements in cardiac tissue engineering [184] and neural prosthetics [185]. Although natural bone exhibits intrinsic bioelectric activity, regions of bone defects typically lack endogenous electric fields, disrupting the local microenvironment and hindering osteoblast migration from defect margins toward the center [186]. To address this, conductive materials incorporated into hydrogels have been designed to restore bioelectric signaling. Research on conductive hydrogels that emulate endogenous electrical cues to stimulate osteogenesis remains nascent. Ageing and other pathological conditions exacerbate this challenge by increasing the electrical resistance of bone defect zones through structural discontinuity and ionic dysregulation, thereby impairing signal transmission and delaying repair. Wu et al. addressed this limitation by developing an AGBM conductive hydrogel functionalized with magnesium-doped black phosphorus (Mg²⁺-BP). This system leverages BP's superior conductivity and Mg²⁺ release to reduce defect impedance, elevate local voltage, restore bioelectric signals, promote Ca²⁺ influx, and activate calcium/calmodulin-dependent kinase II (CaMKII) phosphorylation, collectively enhancing osteogenic differentiation. Concurrently, this hydrogel upregulated the expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR2, activating the PI3K-AKT-eNOS signaling pathway and markedly enhancing the angiogenic capacity of vascular endothelial cells under ageing conditions(Fig. 11a) [174].

Fig. 11.

a) Schematic illustration of the ability of the AGBM conductive hydrogel to promote vascular bone healing in aged mice. Owing to their unique electrical and chemical properties, conductive hydrogels increase bioelectric signals and VEGF chemical signal transduction, addressing the challenge of poor vascular bone healing in bone defects. Reproduced with permission [174]. Copyright 2025, Publisher Wiley-VCH GmbH. b) Construction of a smart electroactive tissue engineering scaffold with ability to control release and expression of hBMP-4 for efficient bone repair [178]. Copyright 2019, Publisher Elsevier Ltd.

Emerging evidence indicates that sensory nerve regeneration is indispensable for bone repair [187,188] peaking within the first 24 h post-fracture and preceding vascularization, ossification, and mineralization, thereby initiating bone defect regeneration. In this context, Jing et al. developed a similar hydrogel system, GelMA-BP@Mg (GBM). This hydrogel not only exploits the photothermal effect of BP at 48.5 °C to eliminate pathogens but also promotes ion migration within the hydrogel via local temperature elevation, restoring bioelectrical communication at the defect site. Beyond activating the BMP-2 signaling pathway to stimulate osteogenesis, the conductive nanosheets and released bioactive ions synergistically enhance Schwann cell proliferation and nerve growth factor (NGF) secretion. NGF subsequently binds to its receptor TrkA, triggering downstream signaling cascades that facilitate coupled osteogenic and neural regeneration [175].

Beyond restoring endogenous bioelectric signals, exogenous electrical stimulation (ES) has been extensively shown to promote bone repair by modulating the electro-microenvironment and facilitating intercellular ion flux and signaling pathway communication [189]. However, the invasive nature of conventional ES approaches may induce additional tissue injury, limiting their broader clinical application [190]. In recent years, the development of exogenous ES devices with precisely controllable stimulation intensity and conductivity, together with conductive bioactive materials, has rapidly advanced the field of conductive hydrogels. Among these, MXenes—novel two-dimensional nanomaterials composed of transition metal complexes—exhibit metallic conductivity, piezoelectric effects, exceptional hydrophilicity, and versatile surface chemistry, rendering them highly attractive for biomedical conductive platforms [191]. Moreover, the abundant tunable functional groups on MXene surfaces mitigate oxidation during storage and use, improving their water dispersibility and plasticity, and enabling the formation of diverse composites and microstructures through integration with other materials [192,193] Nevertheless, MXenes remain prone to oxidation in humid environments and tend to stack or restack in aqueous solutions, resulting in substantial reductions in electrical conductivity [194]. To overcome these limitations, Hu et al. assembled biocompatible regenerated sericin fibers (RSF) onto MXene nanosheets, forming β-lamellar nanofibers that effectively suppress restacking and oxidation. This strategy facilitated the fabrication of an electroactive RSF/MXene hydrogel capable of delivering pulsed electrical signals via embedded needle-like metal electrodes. The hydrogel activates the Ca²⁺/calmodulin (Ca²⁺/CALM) signaling pathway to promote osteogenic differentiation, while concurrently facilitating M2 macrophage polarization and endothelial cell proliferation and migration, thereby enhancing osteogenesis through both direct and indirect mechanisms [176]. Xia et al. prepared a nano-conductive polymer featuring high conductivity, facile shape adaptability, and favorable biocompatibility. By incorporating highly conductive polypyrrole nanowires (PPyNWs) into a methacrylate-modified gelatin (GelMA) hydrogel, they constructed an integrated conductive composite network. This platform markedly enhanced osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) under externally applied direct current microcurrents delivered via a precision-controlled electrical stimulation device, engaging key signaling pathways including Notch, BMP/Smad, and calcium-mediated cascades [162]. Additionally, Xia et al. synthesized a nano-conductive hydrogel (CaP–PEDOT:PSS–MgTiO₃@MA, CPM@MA) via sequential crosslinking and ionic chelation, comprising calcium phosphate nanoclusters, PEDOT: PSS, and magnesium titanate nanoparticles integrated within methacrylated alginate. Among these, calcium phosphate nanoclusters guide the formation of oriented hydroxyapatite (HAp) crystals within the fibers, thereby enhancing the hydrogel's mechanical strength and osteogenic potential [195,196] PEDOT:PSS serves as a conductive modifier, while magnesium titanate (MgTiO₃) confers favorable piezoelectric and polarization properties, promoting phosphate aggregation and osteogenesis [197]. Upon application of an external square-wave alternating voltage, the hydrogel induces intracellular calcium accumulation, activates the CaMKII pathway to drive osteogenic differentiation, and upregulates endogenous TGF-β1 expression, subsequently stimulating the TGF-β/Smad2 signaling cascade to enhance cellular function [177].

Furthermore, electrically stimulated, controlled-release drug delivery systems have been explored to enhance bone formation. For example, the poly(L-lactic acid)-block-aniline pentamer-block-poly(L-lactic acid) (PLA-AP) triblock copolymer undergoes reversible interconversion among its lowest, intermediate, and highest oxidation states under pulsed electrical stimulation [198]. This redox-active behavior modulates gene release, enabling controlled delivery, while exhibiting excellent electrical activity, solubility, biocompatibility, and biodegradability [199]. Cui et al. incorporated a human bone morphogenetic protein-4 (hBMP-4) gene fragment into a non-viral recombinant plasmid vector (pSTAR) to construct the pSTAR-hBMP-4 plasmid (phBMP-4). The pSTAR vector is positively regulated by doxycycline (Dox), and the carried DNA does not integrate into the host genome, ensuring precise temporal and dosage control of hBMP-4 expression. This plasmid was subsequently embedded into an electroactive tissue hydrogel composed of PLA-AP and poly (lactic-co-glycolic acid)/hydroxyapatite (PLGA/HA). Within this platform, a Dox-inducible switch precisely regulates the timing and dosage of hBMP-4 expression, while externally applied electrical pulses trigger the controlled release of phBMP-4, thereby activating the BMP/Smad signaling pathway and promoting osteogenic differentiation. This system achieved favorable bone regeneration outcomes in a rabbit radial defect model, highlighting its potential for temporally and spatially regulated gene therapy in bone repair(Fig. 11b) [178].

Overall, conductive hydrogels provide a versatile and effective platform for restoring disrupted bioelectrical microenvironments and delivering localized electrical stimulation to accelerate bone regeneration. Representative studies have demonstrated that mild and continuous electrical cues can effectively enhance osteogenic differentiation without inducing cytotoxicity. These parameter ranges have been shown to upregulate osteogenic markers (RUNX2, ALP, COL1A1, OCN) and promote matrix mineralization, while excessive or prolonged stimulation may instead induce oxidative stress or membrane depolarization, thereby impairing cell viability.

Mechanistically, conductive hydrogels facilitate bone repair through multi-level electro-biological regulation. Electrical stimulation modulates transmembrane potential and Ca²⁺ influx, activating CaMKII, calcineurin–NFAT, and SMAD cascades, which synergize with TGF-β/BMP and Wnt/β-catenin signaling to promote osteogenic differentiation. Concurrently, ES enhances macrophage polarization (M1→M2), activates PI3K/Akt–eNOS and SDF-1/CXCR4 axes to promote angiogenesis, and upregulates YAP/TAZ-mediated mechanotransduction to stimulate focal adhesion formation and osteogenesis. Moreover, the use of conductive nanofillers such as black phosphorus (BP), MXene, and PEDOT:PSS not only improves charge transport and Ca²⁺-dependent signaling but also couples electrical, ionic, and biochemical cues, enabling synchronized osteogenic, angiogenic, and neurogenic regeneration.

Although conductive hydrogels hold significant promise in bone defect repair, particularly in remodeling the bioelectrical environment and enhancing osteogenic signals, their clinical translation faces several challenges. First, the lack of conductive stability remains a major bottleneck. For instance, while polypyrrole (PPy) demonstrates excellent initial conductivity, it is prone to uncontrollable degradation, flaking, and disruption of conductive pathways under physiological conditions. This leads to a decrease in long-term conductivity, which compromises the continuity of electrical stimulation (ES) and impairs osteogenesis [200,201] Second, some conductive hydrogels exhibit issues with immunocompatibility and tissue reactivity, potentially inducing mild local inflammation, which may hinder the establishment of a conducive osteogenic environment [200,202] Finally, standardized electrical stimulation parameters (such as frequency, current intensity, and duration) have yet to be established, with significant variations in these parameters across different studies. This lack of uniformity results in issues related to the repeatability and controllability of ES in clinical applications [203,204] Additionally, the deep positioning of hydrogels in vivo and ensuring a long-term stable conductive connection remain unresolved challenges [183].

3.2.2. Piezoelectric hydrogels

Piezoelectric materials are a class of substances capable of converting mechanical energy into electrical energy and vice versa, enabling the in situ regeneration of local electrical signals without the need for external electrodes or power sources. The crystal structures of piezoelectric materials are inherently non-centrosymmetric, meaning their lattices lack inversion symmetry—an essential prerequisite for the manifestation of the piezoelectric effect [205]. Upon application of mechanical stimuli, such as compressive, tensile, or ultrasonic stress, the internal lattice undergoes deformation, resulting in the separation of positive and negative ionic charge centers. This generates electric dipole moments and an internal electric potential, thereby producing a piezoelectric response.

Extensive studies have demonstrated that piezoelectric ceramics, including barium titanate (BaTiO₃), potassium titanate, and strontium titanate, can generate electrical stimulation under mechanical force while exhibiting favorable biocompatibility and degradability in vivo [206]. Nevertheless, their intrinsic brittleness and limited flexibility restrict their conformity to irregular fracture sites, constraining their application in electrically stimulated bone repair. To overcome these limitations, researchers have incorporated piezoelectric ceramics as functional additives to confer piezoelectric properties while enhancing the mechanical performance of hydrogel scaffolds. For instance, Zhou et al. embedded amino-modified barium titanate nanoparticles (KBTO) within a bioadhesive gelatin–chondroitin sulfate network to fabricate an injectable, ultrasound-driven bone adhesive hydrogel. Under ultrasonic stimulation, the KBTO nanoparticles experience mechanical stress, producing controllable electrical outputs ranging from −41.16 to 61.82 mV. This, in turn, promotes calcium ion influx and activates the PI3K/AKT and MEK/ERK signaling pathways, thereby enhancing the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (MSCs) [179]. Zinc oxide (ZnO) exhibits remarkable piezoelectric properties and biocompatibility. When integrated with regenerated silk fibroin (RSF), it alleviates the intrinsic brittleness of RSF while substantially enhancing the piezoelectric performance of the composite. Zhang et al. developed a self-powered piezoelectric hydrogel (ZnO/RSF) through a straightforward enzymatic cross-linking approach. The incorporation of ZnO increased the hydrogel's mechanical strength by 1.7-fold and amplified piezoelectric output by 2.8-fold, while concurrently slowing degradation. Under physiological loading, such as human movement or in vivo mechanical stress, directional alignment of ZnO nanoparticles generates a potential difference across the hydrogel surfaces, inducing current flow. This endogenous electrical stimulation markedly promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells (MSCs) and supports vascular network formation [180]. Lithium ions (Li⁺) not only possess excellent electrical conductivity but also modulate the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) via the β-catenin pathway, highlighting their potential in tissue regeneration [[207], [208], [209]] Nevertheless, Li⁺ delivery at the tissue level remains inefficient due to the absence of effective targeting strategies. To address this, Min et al. developed a biodegradable lithium-ion-doped piezoelectric hydrogel assembly (PIHA) that integrates dual-stimulus therapy—electrical stimulation and Li⁺ release. PIHA consists of two components: (1) an injectable conductive hydrogel composed of a polyvinyl alcohol-Li⁺-doped gelatin matrix, forming a conformal conductive scaffold at bone defect sites to facilitate targeted lithium ion delivery; and (2) a piezoelectric hydrogel layer was fabricated via electrospinning γ-glycine/polycaprolactone (PCL-Gly) nanofibers, integrated with the conductive layer via interfacial borate ion cross-linking. Upon ultrasound (US) activation, the piezoelectric component generates an endogenous electric field (∼200 mV) transmitted through the conductive hydrogel, stimulating osteogenic pathways (e.g., PI3K/AKT) in BMSCs and enhancing calcium signaling. Simultaneously, Li⁺ released from the conductive module activates the β-catenin/TCF7/CCN4 pathway, further upregulating osteogenic markers such as RUNX2 and promoting bone regeneration(Fig. 12a) [181].

Fig. 12.

a) Schematic illustration of bone defect repairing by the combined effect of electro-acoustic stimulation and Li-ions. Reproduced with permission [181]. Copyright 2025, Publisher Wiley-VCH GmbH. b) Schematic diagram of biodegradable piezoelectric-conductive scaffolds for repair and reconstruction of osteochondral defects. Reproduced with permission [182]. Copyright 2024, Publisher Wiley-VCH GmbH. c) Schematic of the reconstruction of the electrical microenvironment to accelerate bone regeneration in the bone defect region using ES. d) Schematic of a fully implantable battery-free BD--ES system for patients performing active or passive functional exercise under guidance. e) Possible mechanism by which the BD--ES system promotes bone repair. f) Voltage signals generated by the triboelectric module, piezoelectric module, and hybrid module of the HTP-NG. g) The applied pressure (∼6 kPa) and output voltage of the HTP-NG were monitored in real time. Reproduced with permission [183]. Copyright 2024, The Author(s), Publisher the American Association for the Advancement of Science (AAAS). h) The piezoelectric output performance of dECM, FF peptide-modified dECM (dECM-P), and FF peptide-modified bilayer hydrogels.Data in panel (h) were analyzed for statistical significance using one-way ANOVA. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. Reproduced with permission [182]. Copyright 2024, Publisher Wiley-VCH GmbH.

Previous studies have demonstrated that mesenchymal stem cell (MSC) differentiation is closely regulated by piezoelectric activity, with lower voltage outputs promoting chondrogenic differentiation and higher outputs favoring osteogenesis [210]. Building upon this principle, Liu et al. developed a dual-layer hydrogel carrier system to address the distinct electrical stimulation requirements of osteochondral injury layers. The upper layer comprises decellularized extracellular matrix (dECM), while the lower layer consists of modified gelatin (Gel-C). PEDOT was incorporated into the lower layer to reduce resistance and enhance conductivity, thereby amplifying the potential difference between the two layers. Both layers were further modified with diphenylalanine (FF) to impart piezoelectric functionality. Piezoelectric functionality was further introduced via diphenylalanine (FF)-modified dECM and conductive gelatin (Gel-C) (Fig. 12b). During joint motion, compressive deformation of the upper layer generates an approximate 50 mV potential difference, adequately meeting the electrical stimulation demands of both cartilage and bone tissues (Fig. 12h). The positive charge on the upper layer attracts MSCs, activating the PI3K/Akt and MAPK signaling pathways to promote chondrogenic differentiation. Conversely, the negative charge on the lower layer induces MSC osteogenic differentiation by increasing calcium ion influx, activating calmodulin kinase CaMK2D, and enhancing osteogenic signaling [182].

Emerging nanogenerators (NGs) convert mechanical energy into electrical energy through triboelectric or piezoelectric effects [211], generating pulsed electrical signals synchronously with human movement and demonstrating considerable potential for self-powered, self-stimulative electrical stimulation therapies [212]. Wang et al. integrated a flexible hybrid triboelectric/piezoelectric nanogenerator (HTP-NG) with a conductive injectable hydrogel to construct a composite system for implantation in knee joint bone defects. This system harnesses piezoelectric and triboelectric potentials generated by walking or joint movement to provide sustained electrical stimulation at the defect site without the need for an external power source. Specifically, under mechanical pressure, the PVDF and PTFE films generate piezoelectric and triboelectric potentials, respectively, which are transduced into electrical current via electrodes, achieving an open-circuit voltage (VOC) of 35 V and a short-circuit current (ISC) of 3.7 μA (Fig. 12f and g). The conductive hydrogel comprises a cross-linked network of modified black phosphorus nanosheets (BP@PDA) and alginate methacrylate (AlgMA). BP confers electronic conductivity and promotes mineralization, while PDA enhances BP stability and supports cell adhesion. AlgMA provides structural integrity, facilitating three-dimensional bone tissue repair and establishing an optimal regenerative microenvironment. Electrical stimulation delivered by this system induces calcium influx through mechanosensitive channels (e.g., PIEZO1/2), upregulates osteogenesis-related protein expression, and activates signaling pathways including PI3K/AKT, Wnt/β-catenin, and MAPK, thereby effectively promoting angiogenesis and bone regeneration(Fig. 12c,d,e) [183].

In summary, piezoelectric hydrogels offer a promising strategy for bone regeneration by converting mechanical energy into electrical stimulation, promoting osteogenesis and tissue repair. The optimal parameter range for piezoelectric hydrogels typically involves mechanical stress such as ultrasonic stimulation or compressive/tensile forces, with the voltage output ranging from 50 mV to 200 mV, which is sufficient to activate osteogenic signaling pathways. For instance, piezoelectric composites like ZnO/RSF hydrogels generate a piezoelectric potential under physiological loading, inducing calcium influx and enhancing osteogenic differentiation of mesenchymal stem cells (MSCs). The mechanical environment plays a critical role in the force-to-electricity conversion efficiency of these hydrogels, which should be optimized for different tissue types.

The key mechanisms behind piezoelectric hydrogels include the generation of endogenous electric fields due to mechanical deformation, which activates ion channels (e.g., PIEZO1/2) and triggers calcium ion influx. This electrical stimulation, combined with Li⁺ release and β-catenin pathway activation, enhances osteogenesis. Furthermore, piezoelectric hydrogels can promote macrophage polarization from the pro-inflammatory (M1) to the healing (M2) phenotype, aiding tissue remodeling. The ability of piezoelectric hydrogels to provide self-powered stimulation through triboelectric or piezoelectric nanogenerators also adds to their potential for continuous, low-energy electrical stimulation without external power sources.

Despite the significant advantages of piezoelectric hydrogels in bone repair, their future development and clinical applications face several challenges [213]. For instance, piezoelectric nanoparticles such as BaTiO₃ and ZnO are prone to lattice fatigue and polarization decay under prolonged dynamic loading, leading to a gradual weakening of the electrical signal output and reduced stability [214,215] Additionally, the biodegradation products of these materials may interfere with osteogenesis-related signaling pathways [216]. Furthermore, the complex mechanical environment resulting from varying exercise habits and environmental factors introduces biological uncertainty into the force-to-electricity conversion efficiency of hydrogels [213].

Although hydrogel strategies based on electrical stimulation have demonstrated remarkable results in bone defect repair—particularly in modulating the electrophysiological microenvironment and activating osteogenic signaling pathways—the reliance on a single mechanism of electrical stimulation limits the potential for more comprehensive tissue regeneration. Therefore, there is an urgent need to incorporate "non-traditional electrical stimulation" technologies, such as semiconductor materials (e.g., black phosphorus, bismuth telluride) that leverage the photothermal effect to drive photovoltaic conversion [[217], [218], [219]] or magneto-electric coupling through nanomagneto-electric structures. Electrical stimulation generated via multiple excitation pathways provides a theoretical foundation for the diversified design of future hydrogels and their precise regulation in various application scenarios. This approach is expected to shift electrostimulated hydrogels from a "single-driven" to a "multiple synergistic" paradigm, thereby enhancing the efficiency and precision of bone tissue regeneration.

4. Safety considerations and translational potential of thermo- and electro-stimulative hydrogels

4.1. Biocompatibility, degradation, and toxicity

Thermo- and electro-stimulative hydrogels designed for bone regeneration must balance functionality with biosafety. Natural polymers such as gelatin, chitosan, and hyaluronic acid have demonstrated excellent biocompatibility and biodegradability, making them suitable for clinical translation [220]. However, when combined with metallic nanoparticles—such as gold (AuNPs), MXene, or Fe₃O₄—to impart thermo- or electroactive properties, potential cytotoxicity and oxidative stress due to metal ion release must be considered [221]. Surface modification strategies, such as PEGylation or coating with biopolymers, can reduce nanoparticle aggregation and mitigate toxicity. Moreover, degradable inorganic nanomaterials (e.g., black phosphorus or calcium phosphate) provide safer alternatives as their degradation products are osteoinductive and non-toxic [222].

4.2. Thermal and electrical stimulation safety

Photothermal or magnetothermal therapies rely on mild hyperthermia (40–45 °C) to stimulate osteogenesis without inducing necrosis, while excessive heat (>50 °C) causes irreversible damage [223]. Similarly, safe electrical stimulation typically remains below 200 mV cm⁻¹ and 100 μA cm⁻² to avoid membrane disruption and ROS overproduction [177]. Integrating feedback circuits for temperature and current control can ensure stable, localized stimulation within therapeutic windows.

4.3. Immunological and systemic effects

Immune modulation plays a pivotal role in the in vivo response to multifunctional hydrogels. Properly designed thermo- and electro-stimulative systems can promote M2 macrophage polarization and anti-inflammatory signaling, facilitating osteogenesis [224]. However, persistent M1 activation or ROS accumulation may lead to fibrotic encapsulation and failure of tissue integration. Long-term in vivo testing in large animal models remains essential for understanding chronic immune responses and systemic safety.

4.4. Translational and regulatory perspectives

Despite promising preclinical data, the clinical translation of multifunctional stimulative hydrogels remains limited by manufacturing reproducibility, sterilization, and regulatory uncertainty [225]. Standardized guidelines for biodegradation, chronic toxicity, and immune evaluation are urgently needed. Simplified modular hydrogel architectures and GMP-compatible fabrication may accelerate clinical adoption. Moreover, bioinspired injectable hydrogels integrating real-time feedback sensors are likely to bridge the gap between laboratory and clinical application [226].

Thermo- and electro-stimulative hydrogels exhibit strong regenerative efficacy and multifunctionality but require further optimization in terms of biodegradability, systemic biosafety, and stimulation precision. Establishing standardized safety evaluation and translational frameworks will be key to advancing these intelligent hydrogel systems toward clinical practice.

5. Conclusion and future outlook

Overall, hydrogel technology has progressed from serving as a simple passive scaffold to functioning as an intelligent platform capable of actively responding to environmental changes, controllably releasing bioactive factors, and integrating multiple physical stimuli. By mimicking the microenvironment, functional hydrogels provide an ideal three-dimensional scaffold for osteocyte adhesion, proliferation, and differentiation. These materials exhibit significant research value and translational potential in repairing bone defects caused by trauma, tumors, inflammation, and other etiologies. Their excellent biocompatibility and precisely tunable mechanical properties allow adaptation to diverse repair requirements across varying defect morphologies and physiological conditions.

his paper focuses on elucidating the pivotal role of advanced multifunctional hydrogels incorporating thermotherapeutic and electrical stimulation strategies in bone repair, with emphasis on the following key functions.

• (1)Precise spatiotemporal controlled release: enabling on-demand and programmable delivery of diverse bioactive molecules (including growth factors, pharmaceuticals, ions, and others) to align with the biological requirements of distinct stages of the bone regeneration process.
• (2)Intelligent on-demand therapy: achieving targeted intervention for specific pathological conditions by responding to endogenous pathological signals (such as reactive oxygen species, pH, or enzymes) or by integrating exogenous physical stimuli (such as photothermal, magnetothermal, or electrical stimulation), thereby addressing major challenges during repair.
• (3)Multidisciplinary physical interventions: employing thermotherapy to induce precise, localized temperature elevation to eradicate residual pathological foci (including tumor cells and pathogenic bacteria), while utilizing conductive or piezoelectric materials to recreate the skeletal microcurrent environment through electrical stimulation, thereby directly promoting osteogenic differentiation and bone tissue regeneration.

To further clarify the correlations between stimulation parameters, biological mechanisms, and safety windows of thermo- and electro-stimulative hydrogel systems, Table 4 provides a concise summary of representative optimal parameter ranges, dominant regulatory pathways, and major limitations.

Table 4.

Parameter–effect–safety comparison of energy-stimulative hydrogels for bone regeneration.

Modality	Key Stimulation Parameters (Representative Range)	Dominant Biological Effects	Safety Window & Potential Risks	References
Photothermal Therapy (PTT)	•Temperature: 40–45 °C (mild hyperthermia) •NIR wavelength: 808–1064 nm •Power density: 0.5–1.5 W cm−2(adjusted to achieve mild or moderate hyperthermia) •Irradiation time: 3–10 min	•Activation of HSPs (HSP47, HSP70) •Osteogenic differentiation (Runx2, ALP, OCN) •Wnt/β-catenin-mediated osteoblast support •Angiogenesis via HIF-1α/VEGF •Antibacterial and antitumor effects (≥45 °C, short exposure) •Immunomodulation (M1→M2 macrophage polarization)	•Safe window: 40–43 °C promotes regeneration •45–50 °C: therapeutic for tumors/bacteria but time-dependent •>50–55 °C: protein denaturation, thermal necrosis, burn risk, depending on exposure duration and tissue context •Risk of nanoparticle accumulation and off-target heating	[59,68,70,71,75,76,84,86]
Magnetothermal Therapy (MHT)	•Alternating magnetic field (AMF): 1–15 kA m−1 •Frequency: 100–500 kHz (typical) •Target temperature: 40–43 °C •Exposure mode: continuous or on–off cycles •Electric field strength: 50–300 mV mm−1 •Frequency: 20–100 Hz	•Deep-tissue hyperthermia without optical attenuation •Enhanced osteogenesis via HSP90, PI3K/Akt, MAPK •Angiogenesis via HIF-1α stabilization •Synergistic antitumor and antibacterial effects (via ROS/Fenton reactions)	•Safe window: stable maintenance at ∼41–43 °C •Overheating under high field strength → tissue damage •Long-term biosafety of magnetic nanoparticles (Fe, Co, Mn) remains under evaluation •Heating efficiency strongly depends on particle distribution	[138,139,141]
Electrical Stimulation (ES) – Conductive Hydrogels	•Electric field strength: 50–300 mV mm−1 •Frequency: 20–100 Hz •Duration: 20–60 min per session •Mode: DC or pulsed AC	•Restoration of endogenous electrical microenvironment •Enhanced MSC adhesion, migration, and osteogenesis •Activation of Ca2+ influx, CaMKII, YAP/TAZ, BMP/Smad, Wnt/β-catenin pathways •Promotion of angiogenesis and immunoregulation	•Safe window: low-amplitude microcurrents •Excess voltage/current → oxidative stress, membrane depolarization •Conductivity decay and electrode integration remain challenges	[162,174,176,178]
Piezoelectric Stimulation (Self-Powered)	•Mechanical loading/ultrasound stimulation •Output voltage: ∼20–260 mV (material-dependent) •Current: nA–μA range	•Autonomous generation of endogenous-like electrical signals •Osteogenic differentiation via Ca2+ signaling and PI3K/Akt •Coupled angiogenesis and osteogenesis •No external power source required	•Output instability under irregular mechanical loading •Polarization decay and fatigue of piezoelectric ceramics (e.g., BaTiO3, ZnO) •Degradation by-products may affect long-term signaling	[179,181,183]

However, to transform hydrogels into clinically effective platforms capable of addressing complex pathological scenarios and achieving functionally complete bone regeneration, future research must advance towards intelligent, precise, and integrated strategies. The following directions represent the primary developmental trends in this field.

• 1.Multi-module integrated hydrogel systems with temporal coordination

Although monofunctional hydrogels exhibit potential in specific contexts, the pathological microenvironment of bone defects—often characterized by concurrent inflammation, hypoxia, infection, and aberrant bone resorption—requires synergistic modulation of multiple biological processes. As a result, single-function strategies are insufficient to achieve optimal outcomes. Current work largely focuses on single- or dual-functional systems; future development should prioritize temporally coordinated, multi-module hydrogels capable of concurrent and sequential regulation.

For example, by incorporating implantable biosensors to continuously monitor local parameters such as temperature, pH, and mechanical strain, intelligent closed-loop “sensing–diagnosis–treatment” platforms could be established. These systems would subsequently modulate the spatiotemporal delivery of both physical stimuli, including thermotherapy and electrical stimulation, and therapeutic agents that promote bone defect repair, such as pro-angiogenic, osteogenic, and neurogenic regenerative factors, as well as immunomodulators. Such systems would enable precision-targeted intervention, simultaneously eliminating pathological factors and maximizing regenerative support. Nonetheless, challenges remain regarding modular compatibility, sensing stability and accuracy, and insufficient understanding of biological mechanisms, all of which require further investigation to facilitate clinical translation.

• 2.Spatially engineered hydrogels for multi-tissue interfaces

Existing research predominantly targets bone regeneration alone. However, many clinically challenging defects—such as osteochondral lesions, bone–ligament/tendon junctions, and periodontal tissues—involve intricate multi-tissue interfaces with distinct cellular compositions, extracellular matrices, mechanical properties, and biochemical gradients. Successful repair requires coordinated regeneration of multiple tissues with highly heterogeneous structures and functions. Homogeneous or single-phase hydrogel scaffolds are unable to address these demands.

Accordingly, the development of spatially engineered hydrogels with precise compartmentalization represents a critical direction. Advanced fabrication approaches—including multi-material 3D bioprinting, microfluidic patterning, field-guided assembly, and segmented cross-linking—should be employed to control matrix composition, cell distribution, physicochemical parameters, and bioactive molecule gradients across discrete regions. These systems not only enable customizable geometry but also provide physical cues involving gradient electrical and thermal cues across interfaces while reproducing physiological transition zones, thereby guiding cell behavior and promoting tissue integration. More importantly, robust integration between distinct functional regions within hydrogels must be ensured. This can be achieved by engineering interlocking microarchitectures to enhance mechanical anchoring, or by employing interface-specific bioadhesives (e.g., catechol-based chemistries, transglutaminase-mediated crosslinking) and molecular recognition motifs (e.g., antibody–antigen interactions, DNA hybridization) to reinforce chemical and biological connectivity.

• 3.Deep integration with emerging biotechnologies

Effective and precise bone regeneration will require close integration between hydrogel engineering and frontier biotechnologies. Hydrogels may be utilized to deliver CRISPR/Cas9 cargos for in situ genome editing of osteogenic, angiogenic (e.g., Runx2, VEGF, and inflammation-associated genes), or inflammation-related targets, thereby restructuring the regenerative microenvironment at the molecular level. Likewise, sustained delivery of bioactive extracellular vesicles through hydrogel matrices may enhance angiogenesis, immune modulation, and osteogenesis.

In addition, artificial intelligence and data-driven modelling will accelerate hydrogel composition optimization and architectural design, enabling patient-specific formulation. Integration of in situ biosensing modules to monitor pH, oxygen tension, strain, and molecular biomarkers will support real-time efficacy assessment and risk prediction, further advancing hydrogels toward personalized and adaptive therapeutic platforms.

Despite the substantial progress achieved at the laboratory scale, the clinical translation of advanced hydrogels continues to encounter critical challenges.

First, the modulation of cellular fate via thermal and electrical stimulation involves highly intricate signaling networks, and the mechanisms through which specific stimulation parameters precisely influence cellular responses at different stages of repair remain insufficiently clarified. In parallel, reliable delivery devices and standardized long-term biosafety evaluation systems must be established to ensure experimental reproducibility and compliance with regulatory standards.

Second, personalized design represents an inevitable trend for clinical implementation. This requires the integration of medical imaging with 3D bioprinting technologies to fabricate scaffolds that accurately reproduce patient-specific defect geometries, coupled with individual biological information to tailor functional modules within hydrogel systems.

Finally, research must progress beyond healthy animal models and consider more clinically relevant comorbid contexts. A key focus is the development and validation of hydrogel platforms capable of maintaining therapeutic efficacy under pathological states that impair bone regeneration, such as diabetes and osteoporosis. These systems must undergo rigorous preclinical evaluation in large-animal models, followed by clinical trial designs incorporating appropriate patient stratification strategies.

In summary, future advances will depend not only on the continued development of smarter and more precise multifunctional hydrogel systems in the laboratory, but also on deep integration between fundamental research and clinical needs. Only through close interdisciplinary collaboration can the ambitious objective of transforming the therapeutic landscape of bone defect repair through advanced hydrogel technology be achieved.

CRediT authorship contribution statement

Yuheng Zhang: Conceptualization, Investigation, Project administration, Supervision, Visualization, Writing – original draft, Writing – review & editing. Yi Wang: Conceptualization, Software, Visualization, Writing – review & editing. Jiahu Zou: Methodology, Software, Visualization, Writing – original draft. Jiandang Huang: Data curation, Visualization, Writing – original draft. Qiang Zhong: Conceptualization, Data curation, Writing – original draft. Yixin Xu: Data curation, Visualization. Mingyuan Lei: Validation, Writing – review & editing. Rong Chen: Validation, Writing – review & editing. Ding Wang: Validation, Writing – review & editing. Hao Li: Validation, Writing – review & editing. Hongyu Wang: Validation, Writing – review & editing. Jian Wang: Conceptualization, Funding acquisition, Supervision, Validation, Writing – review & editing. Zhanjun Shi: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing. Hao Cheng: Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.