Ioana-Cristina Băncilă- Biomedical Engineering, Vienna University of Technology (TU Wien), Vienna, Austria
Hydrogels are key materials in bone tissue engineering due to their high water content, biocompatibility, and tunable mechanics. Mechanically adaptive hydrogels, a class of smart biomaterials, can dynamically adjust stiffness and viscoelasticity in response to environmental cues, closely mimicking bone extracellular matrix behavior. This review critically synthesizes the hydrogel types, biomechanical properties, and scaffold fabrication strategies, with a focus on mechanically responsive systems. Finite element modeling (FEM) is highlighted as a predictive tool for scaffold design, while bone-on-chip (BoC) platforms provide physiologically relevant in vitro evaluation. Recent advances in composite hydrogels, reinforcement methods, and multi-scale modeling are analysed to identify gaps in standardization, mechanical mapping and biological outcomes. By linking mechanical adaptability to clinical scenarios such as craniofacial reconstruction, spinal fusion, and osteochondral repair, this review provides a concise framework for the rational design and translation and future research in mechanically adaptive hydrogels in bone regeneration.
1 Introduction
Hydrogels have emerged as highly promising materials in tissue engineering and biomechanics due to their capacity to mimic key structural and functional aspects of the extracellular matrix (ECM). These three-dimensional (3D) polymeric networks possess a high water content—typically between 70% and 99% by weight—offering a hydrated environment conducive to cellular adhesion, proliferation, and differentiation. Furthermore, their intrinsic viscoelastic behavior and tunable mechanical properties allow them to closely replicate the biomechanical microenvironments encountered in native tissues. These characteristics render hydrogels suitable for a broad spectrum of biomedical applications, including regenerative medicine, localized drug delivery, and biofabrication techniques such as 3D bioprinting (Rana and De la Hoz Siegler, 2021; Tavakoli and Klar, 2020).
While numerous reviews have summarized hydrogel properties, few critically integrate mechanical adaptivity and computational modeling with organ-on-chip, giving a translational perspective for bone regenration. This is meant for highlighting mechanobiological performance and correlation of scaffold properties with clinical applications.
Recent advances in the field have highlighted the critical role of mechanically adaptive hydrogels—materials capable of altering their stiffness or mechanical response in reaction to dynamic environmental stimuli. Such adaptivity is particularly advantageous in bone tissue engineering, where mechanoresponsive behavior is essential for recapitulating the complex biophysical cues that influence osteogenesis and tissue remodeling. These stimuli-responsive hydrogels are designed to undergo real-time mechanical modulation under physiological loading conditions, aligning scaffold performance with the evolving needs of regenerating tissues (Lin et al., 2023).
This review synthesizes current developments in the classification, mechanical characterization, and biomedical applications of hydrogels engineered for bone tissue regeneration. A special emphasis is placed on hydrogel systems exhibiting mechanoresponsiveness, with discussions centered around their role in enhancing cellular mechanotransduction, supporting angiogenesis, and promoting mineralization. Additionally, the integration of computational modeling approaches—such as finite element modeling (FEM)—and microfluidic platforms (e.g., bone-on-chip systems) is explored. These technologies serve as critical tools for optimizing scaffold geometry, predicting in vivo performance, and establishing more physiologically relevant in vitro testing environments.
The body of literature reviewed spans publications from 2011 to 2025, encompassing over a decade of scientific advancements in hydrogel-based systems. Studies were selected based on rigorous inclusion criteria: publication in peer-reviewed journals, citation impact (minimum 10 citations for studies older than 2 years), and relevance to key themes in mechanobiology and regenerative medicine. Particular attention was given to research on injectable hydrogels, cartilage and bone repair scaffolds, mechanically dynamic materials, computational modeling of mechanical environments, and organ-on-chip technologies. This review also incorporates critical insights into vascularization strategies, rheological profiling methods, and emerging 3D bioprinting modalities that support the development of biofunctional scaffolds. Considering all these together, the analysis provides a comprehensive framework for advancing future research at the intersection of tissue biomechanics, responsive biomaterials, and translational regenerative therapies.
1.1 Literature selection
A total of 241 articles were initially identified through database searches, complemented by 38 additional studies from reference lists. After removing duplicates and screening titles/abstracts for relevance, 86 articles were retained for full-text review and inclusion in this manuscript. The selection process focused on studies relevant to mechanically adaptive hydrogels, finite element modeling, and bone-on-chip systems, with an emphasis on peer-reviewed articles and experimental rigor.
Each study was systematically evaluated for hydrogel type, mechanical properties, stimuli responsiveness and biological outcomes. Comparative tables and figures were generated to emphasize the main differences, advantages and limitations. This aspect provides an analytical synthesis rather than a simple summary literature.
2 Responsive and mechanically adaptive hydrogels
Table 1 summarizes the main hydrogel subclasses, their stimuli, crosslinking modalities, and resulting mechanical properties relevant for bone tissue engineering (Nain et al., 2024; Gao et al., 2021; Farasati Far et al., 2023; Zhang et al., 2005; Chen et al., 2022; Wang et al., 2018; Maitra and Shukla, 2014; Chen et al., 2024; Akhtar et al., 2015; Romischke et al., 2022).
Table 1. The stimuli effect and resulting mechanical property changes.
2.1 Overview of stimuli-responsive systems
Stimuli-responsive hydrogels represent an emerging class of smart biomaterials capable of dynamically altering their physical state or material properties in response to environmental cues such as temperature, pH, enzymatic activity, or mechanical forces. Among these, mechanically adaptive hydrogels are particularly relevant for bone tissue engineering. They can modulate their stiffness according to the evolving mechanical environment during tissue repair and regeneration (Romischke et al., 2022; Subramani et al., 2020; Ding et al., 2023). This adaptive behavior not only enhances scaffold integration with host tissues but also allows precise control and simulation through computational approaches, such as finite element modeling (FEM). These tools facilitate the design of optimized scaffolds and organ-on-chip platforms (Subramani et al., 2020).
2.2 Natural, synthetic and hybrid hydrogel systems
Natural hydrogels, including collagen and hyaluronic acid, exhibit excellent biocompatibility and biodegradability but generally lack the mechanical strength necessary for load-bearing applications. Synthetic hydrogels—such as polyethylene glycol (PEG) and polyvinyl alcohol (PVA)—offer tunable stiffness and enhanced structural stability, making them suitable for advanced biomedical applications, including controlled drug delivery and bone scaffold fabrication. Hybrid hydrogels, which combine natural and synthetic polymers, aim to balance biological functionality with mechanical robustness to meet the complex demands of bone regeneration (Onaciu et al., 2019; Hoffman, 2012; Zhao et al., 2015; Highley et al., 2015).
2.3 Crosslinking strategies
Crosslinking modality critically influences hydrogel behavior and performance. Chemical crosslinking establishes covalent bonds, producing stable and mechanically resilient networks. In contrast, physical crosslinking relies on reversible interactions, providing injectability and environmental responsiveness. This distinction dictates hydrogel suitability for specific biomedical contexts, particularly regarding mechanical performance and degradation profiles (Chen et al., 2022; Chen et al., 2024; Subramani et al., 2020; Ding et al., 2023).
Emerging strategies also integrate mechanosensitive elements to better mimic the dynamic viscoelasticity of bone tissue and enhance scaffold adaptability.
2.4 Structure-function relationship
The subsequent section will explore how these intrinsic material properties translate into functional outcomes within bone tissue engineering. Emphasis will be placed on the interplay between hydrogel mechanics, cellular response, and scaffold design optimization. A comparative summary of hydrogel subclasses, crosslinking approaches, and biomechanical effects is shown in Figure 1.
Figure 1. Classification scheme of hydrogels-created by author with the help of AI-based tools under the supervision and guidance of author illustrativelly for educational purposes. Classification scheme showing the three main categories of hydrogels used in biomedical applications. Natural hydrogels are derived from biological sources and typically form through physical crosslinking mechanisms. Synthetic hydrogels are chemically synthesized polymers with tunable properties achieved through chemical crosslinking. Hybrid hydrogels combine natural and synthetic components to leverage advantages of both systems while minimizing individual limitations. Each category exhibits distinct mechanical properties and biological compatibility profiles that determine their suitability for specific tissue engineering applications. Original image created by author with the help of AI-based tools.
As illustrated in Figure 1, hydrogel subclasses differ in their composition and their stimuli-responsiveness. The quantitative details from Table 2 on their biomechanical parameters, correlating material properties and functional outcomes, are provided.
Table 2. Main biomechanical parameters that influence the hydrogel performance în tissue engineering.
3 Biomechanical properties of hydrogels
Hydrogels play a critical role in the field of biomechanics due to their inherent viscoelasticity, responsiveness to mechanical stimuli, and tunable stiffness. Their performance in bone tissue engineering is influenced by several interrelated parameters, including swelling ratio, degradation rate, elastic modulus, and overall mechanical integrity (Zhao et al., 2015). A high swelling ratio generally corresponds to a reduction in stiffness by lowering the elastic modulus, and it can accelerate material degradation, ultimately shortening scaffold lifespan and compromising its structural function during tissue remodeling (Subramani et al., 2020; Gupta and Shivakumar, 2012). Achieving an elastic modulus that closely matches native bone tissue is essential to minimize mechanical mismatch, reduce interfacial stress, and promote functional integration (Lee et al., 2018; Yang, 2022).
The elastic modulus (E) and shear modulus (G) are interrelated material constants, linked through Poisson’s ratio, whereas tensile strength is a separate property reflecting the maximum stress a material can withstand. All three parameters are critical for assessing mechanical stability in load-bearing applications. Hydrogels intended for such uses must maintain functional integrity under physiological stress, which requires careful tuning of their mechanical properties (Tan et al., 2011). Additionally, controlled degradation is essential for scaffold performance: a slower degradation maintains mechanical support during early bone healing while allowing gradual remodeling and tissue ingrowth (Savić Gajić et al., 2023; Siqueira et al., 2023).
Viscoelastic properties—such as stress relaxation and creep—are fundamental to replicating the deformation and recovery behaviors of native tissue under mechanical load. These time-dependent mechanical responses vary with hydrogel stiffness and have a direct impact on scaffold performance in dynamic physiological environments. Properly engineered viscoelasticity promotes the capacity of the scaffold to dissipate mechanical energy and adapt to repetitive loading, making it a key factor in the long-term success of bone tissue engineering constructs (Li X. et al., 2024; López-Serrano et al., 2024; Pérez-Calixto et al., 2021).
Porosity and pore interconnectivity are other essential design parameters affecting both mechanical strength and biological performance (Lee et al., 2018; Yang, 2022; Tan et al., 2011). Highly porous structures enhance cell migration, vascularization, and nutrient transport, but excessive porosity can compromise the scaffold’s mechanical integrity. Thus, a balance must be achieved between mechanical robustness and biological functionality, especially in scaffolds intended for large or load-bearing bone defects (Piao et al., 2021; Seyedmajidi et al., 2023; Lin and Chen, 2022; Sacks et al., 2009; Chen et al., 2025; Nerger et al., 2024; Alheib et al., 2022; Ghiasi Tabari et al., 2024).
Table 2 summarizes the key biomechanical parameters that influence hydrogel performance in tissue engineering. Swelling ratio, elastic modulus (E), shear modulus (G), tensile strength, porosity, and viscoelastic properties collectively determine a scaffold’s ability to mimic the mechanical behavior of native tissues. Generally, higher swelling reduces stiffness, whereas increased crosslinking density enhances structural stability. Controlled degradation ensures short-term mechanical support during early healing while allowing long-term tissue remodeling. Porosity and interconnectivity facilitate nutrient diffusion, cellular infiltration, and vascularization without compromising load-bearing capacity. Viscoelastic behaviors, including stress relaxation and creep, enable hydrogels to adapt to dynamic physiological loading. Together, these characteristics guide the rational design of mechanically adaptive hydrogels, capable of responding to mechanical cues and evolving biological environments throughout tissue regeneration (Zhao et al., 2015; Tan et al., 2011; Savić Gajić et al., 2023; Siqueira et al., 2023; Nerger et al., 2024).
Hydrogels with an elastic modulus E of 0.1–0.5 MPa (Lee et al., 2018; Yang, 2022; Tan et al., 2011) are suitable for promoting osteogenic differentiation but it may not provide adequate mechanical support for load bearing bone deffect. Swelling ratios above 40x (Zhao et al., 2015; Highley et al., 2015; Subramani et al., 2020) are associated with 20%–30% reduction in scaffold stiffness.
Stiffness range mimics the native bone extracellular matrix, facilitating mediated mechanotransduction and activation of osteogenic signaling pathways. Hydrogels with porosity higher than 80% facilitate enhanced cell filtration and vascularisation, but it may compromise tensile strength (Seyedmajidi et al., 2023; Lin and Chen, 2022; Sacks et al., 2009). Creep values of 5%–30% reflect long term adaptation ensuring scaffold durability during remodeling of tissues. This behaviour arises from molecular chain rearrangements under sustained stress (Tan et al., 2011; Pérez-Calixto et al., 2021; Jeon et al., 2021).
4 Mechanically adaptive hydrogels
Mechanically adaptive hydrogels are a class of smart biomaterials capable of modulating stiffness, elasticity, and stress-relaxation behavior in response to stimuli such as temperature, pH, enzymatic degradation, and mechanical load (Jeon et al., 2021; Yang et al., 2022; Azizi et al., 2023; Bergkvist et al., 2008). By emulating the dynamic nature of the native ECM, they provide essential cues for cellular mechanotransduction, guiding proliferation and lineage specification in tissue engineering applications. Stiffer microenvironments promote osteogenesis, whereas softer matrices favor chondrogenic or neurogenic pathways (Jeon et al., 2021; Bergkvist et al., 2008).
Among notable examples, PBNPs@OBG combines oxidized hyaluronic acid, gelatin, borax, and Prussian blue nanoparticles to form a dual-crosslinked, injectable hydrogel with self-healing capacity. It scavenges reactive oxygen species, exhibits antibacterial activity, and maintains mechanical integrity under physiologically relevant loads (Nerger et al., 2024; Alheib et al., 2022; Lima et al., 2021; Tegas, 2014). Comparable mechanically adaptive hydrogels include hydrogels with dynamic covalent bonds, supramolecular crosslinks, or shear-thinning networks, which have been applied in cartilage, bone, and intervertebral disc regeneration (Jeon et al., 2021; Al-Tamimi et al., 2020; Lee, 1985).
Despite these advantages, challenges remain. Time-dependent viscoelasticity complicates standard mechanical characterization, scalability and nanoparticle toxicity pose translational barriers, and heterogeneity in dynamic behavior requires careful optimization (Jeon et al., 2021; Al-Tamimi et al., 2020; Lee, 1985; Wu et al., 2023). Advanced computational modeling, including finite element analysis and machine learning-based prediction, helps to simulate scaffold performance and guide rational design. Moreover, sensor-integrated hydrogels enabling real-time monitoring of mechanical changes, degradation, and cellular responses represent a promising direction for personalized regenerative therapies (Boccaccio et al., 2011; Uth et al., 2017). Figure 2 schematically illustrates this interaction mechanism, highlighting how the hydrogel matrix supports cell adhesion, proliferation, and differentiation. The image was created for educational purposes using AI-based tools under the strict supervision and guidance of the author.
Figure 2. Schematic representation of hydrogel and cellular interaction mechanism. The image is created for educational purposes using AI-based tools under the strict supervision and guidance of the author. Schematic representation of hydrogel formation and cellular interaction mechanisms. (A) Polymer network formation and gelation process showing progression from individual polymer chains through crosslinking to hydrated hydrogel state. (B) Comparison between static covalent crosslinks and dynamic reversible crosslinks, highlighting their impact on mechanical properties. (C) Cellular interaction and nutrient transport through interconnected pores within the hydrogel matrix and interface formation with native tissue. Image created by author with the help of Al-based tools.
5 Biomechanical analysis and FEM modeling of scaffolds
Boccaccio et al. (2011) demonstrated an integrative approach that combines the Finite Element Method (FEM) with mechanobiological principles to design hydrogel scaffolds for bone regeneration. Their work utilized three-dimensional FEM simulations to evaluate the mechanical performance of hydrogel scaffolds and surrounding bone tissue under physiological loading conditions. The computational model assigned Young’s modulus values ranging from 1 to 5 MPa to represent the mechanical properties of hydrogels, while trabecular and cortical bone characteristics were also incorporated. To replicate in vivo axial loading, compressive forces of approximately 1000 N were applied, and boundary conditions were defined to closely represent the scaffold–bone interface (Boccaccio et al., 2011) (see Figure 3 with computational representations of the study).
Figure 3. FEM used for mandible. Reproduced from Boccaccio et al. (2011), under CC BY-NC (Boccaccio et al., 2011). Figure 3 is presenting the stages of the computational model. Thus, firstly an epoxy-resin model is built using Rapid Protyping techniques (a), then FEM model of mandible with tooth borne device and boundary conditions and FEM model of osteomized regions followed (b,c).
The study highlights the significance of scaffold stiffness, geometry, and porosity distribution in shaping the local mechanical environment—factors that significantly influence osteogenic differentiation and scaffold integration. By embedding mechanobiological modeling into the FEM framework, the authors were able to simulate localized mechanical stimuli such as stress and strain, which are known to regulate bone remodeling in accordance with Wolff’s Law. The findings indicate that scaffold designs arranged to deliver favorable mechanical cues promote more effective bone formation, whereas designs lacking such augmentation may lead to insufficient regeneration or even bone resorption (Boccaccio et al., 2011).
Despite its valuable contributions, the study is constrained by several notable limitations. Foremost, the absence of experimental validation significantly limits the translational relevance of the findings. The simulations, while sophisticated, remain theoretical without corroboration from in vitro or in vivo data. Furthermore, the model assumes material homogeneity and does not account for critical dynamic behaviors of hydrogels in biological environments, such as swelling, biodegradation, and viscoelastic response over time. These omissions reduce the predictive power of the simulations under real-world conditions (Uth et al., 2017; Scocozza et al., 2023).
Similarly, biological outcomes, such as angiogenesis and osteogenesis discussed by Liu et al. (2023) cannot be fully predicted by computational modeling, thus emphasizing the importance of in vivo and in vitro experiments.
Additionally, the boundary conditions applied in the model are overly simplified, focusing solely on axial compression. In clinical scenarios—particularly in craniofacial or load-bearing orthopedic applications—scaffolds are subject to complex multiaxial loading regimes, including shear, torsion, and bending. Neglecting these components limits the generalization of the results. The model also presumes a perfectly bonded scaffold–bone interface, overlooking core interfacial phenomena such as fluid transport, adhesion dynamics, and cellular infiltration (Musthafa et al., 2024).
To sum up, the work by Boccaccio et al. (2011) provides a foundational framework for integrating FEM and mechanobiological feedback in scaffold design. However, it remains a static and idealized model. Future research should aim to extend this framework by incorporating time-dependent scaffold degradation, evolving mechanical stimuli, and experimental validation through biological assays. Only through such integrative and multidisciplinary efforts can FEM-based interpretations be translated into clinically viable scaffold designs (Boccaccio et al., 2011).
Table 3 highlights the versatility of the Finite Element Method (FEM) in bone tissue engineering, encompassing scaffold degradation, stiffness analysis, and modeling of fluid flow in bioreactors. For instance, injectable HA-Fmoc-diphenylalanine hydrogels have been shown to promote bone regeneration in vivo, illustrating the importance of scaffold mechanics and immunomodulatory properties (Huang et al., 2025), (Halperin-Sternfeld et al., 2023). Similarly, copper-incorporated chitosan scaffolds enhance osteogenesis in calvarial defect models, highlighting the relevance of scaffold composition and mechanical integrity for bone healing (D'Mello et al., 2015). Integrating computational modeling with biological assessment remains critical for translating scaffold designs into clinical applications.
Table 3. FEM applications în scaffold design for tissue engineering.
FEM enables prediction of scaffold behavior under physiological loading, supporting the design of scaffolds optimized for osteointegration. In craniofacial bone regeneration, FEM can help assess whether bioactive scaffolds, such as BMP-loaded hydrogels or metal-enhanced chitosan scaffolds, withstand masticatory forces while maintaining structural integrity (Halperin-Sternfeld et al., 2023; D'Mello et al., 2015; Yu Y. et al., 2022). Nevertheless, these models often oversimplify dental biomechanics and rarely account for anatomical variability. In spinal fusion applications, FEM contributes to developing hydrogels capable of bearing compressive loads and promoting mineralization (Wang and Wu, 2023; Oku et al., 2023; Cedd et al., 2025), although torsional and cyclic loading scenarios are still rarely incorporated.
Hydrogel–bioceramic composites incorporating hydroxyapatite have shown advanced mechanical strength and mineralization potential for cranial bone regeneration (Lacroix et al., 2006; Milan et al., 2009; Lee et al., 2018), yet model limitations persist regarding degradation dynamics and biological variability.
Emerging directions including the development of mechanically adaptive “smart” hydrogels (Eshraghi and Das, 2010; Prendergast et al., 1997) and injectable hydrogels—such as those based on hyaluronic acid combined with mesenchymal stem cells (MSCs)—are currently under investigation for osteoarthritis treatment, aiming to reduce pain and improve joint function (Guilak and Mow, 2000; Fernandes et al., 2024; Vikingsson et al., 2015). However, FEM simulations in this context rarely capture real-time tissue remodeling or joint biomechanics.
The integration of FEM with 3D bioprinting technologies is advised to improve construct design (Moxon et al., 2017; Castro et al., 2015). Nonetheless, experimental validation of such computational models remains a significant challenge. To address this, bone-on-chip (BoC) systems are gaining attention for their ability to represent with fidelity the mechanobiological microenvironment under physiologically relevant conditions (Castro et al., 2024; Da Silva et al., 2024).
6 Mechanically adaptive hydrogel-based organ-on-chip systems
Organ-on-chip (OoC) systems, including bone-on-chip (BoC) platforms, have emerged from recent advances in microfluidics and bioengineering (Zauchner et al., 2024; Lipreri et al., 2023; Blache et al., 2022). These systems aim to reproduce the physiological microenvironment in vitro. A central component of these platforms is the incorporation of hydrogels, which serve as scaffolds mimicking the extracellular matrix (ECM) to support cell adhesion, proliferation, and differentiation (Blache et al., 2022).
Mechanically adaptive hydrogels are particularly suitable for BoC models because they respond to biomechanical stimuli such as compression, shear stress, or cyclic deformation—mechanical forces crucial to bone physiology (Blache et al., 2022; Castro et al., 2024). These hydrogels can dynamically alter their stiffness or viscoelastic behavior, allowing the simulation of physiological processes like bone remodeling, or pathological conditions such as osteoporosis and intervertebral disc degeneration (IVDD) (Castro et al., 2024; Xue et al., 2025). Studies on stress-relaxing hydrogels have shown advanced osteogenic differentiation, cytoskeletal organization, and cell–matrix interactions in 3D culture environments (Zauchner et al., 2024; Blache et al., 2022; Castro et al., 2024).
Photocrosslinkable hydrogels, such as GelMA and PEGDA, are widely used in BoC systems due to their tunable mechanical properties and compatibility with microfabrication techniques (Xue et al., 2025; Wang et al., 2018; Yu C. et al., 2024; Chen et al., 2024). These materials permit the generation of spatial stiffness gradients, effectively mimicking the heterogeneity of trabecular and cortical bone, and enabling localized mechanotransduction (Wang et al., 2018; Yu C. et al., 2024). Additionally, hydrogel composites incorporating hydroxyapatite nanoparticles or carbon-based nanomaterials can emulate the mineralized bone matrix without significantly compromising viscoelastic behavior (Wang et al., 2018; Yu C. et al., 2024; Chen et al., 2024).
BoC systems integrating mechanically adaptive hydrogels represent a robust alternative to static 2D in vitro cultures and traditional in vivo animal models (Lipreri et al., 2023; Blache et al., 2022; Zhang et al., 2024). These platforms can conduct real-time monitoring of cellular behavior, matrix remodeling, and drug responses under physiologically relevant mechanical loading (Zauchner et al., 2024; Castro et al., 2024; He et al., 2025). Furthermore, the integration of biosensors and advanced imaging techniques facilitates quantitative assessment of bone tissue formation, mineralization, and mechanotransduction pathways, such as Wnt/β-catenin and YAP/TAZ signaling (Blache et al., 2022; Xue et al., 2025; He et al., 2025).
Table 4 provides a summary of the recent studies (Zauchner et al., 2024; Lipreri et al., 2023; Blache et al., 2022; Castro et al., 2024; Xue et al., 2025; Wang et al., 2018; Yu C. et al., 2024; Wang J. et al., 2023; Zhang et al., 2024; He et al., 2025; Mei et al., 2021; Gandin et al., 2024) utilizing mechanically adaptive hydrogels in BoC platforms, highlighting their applications, material formulations, and biomechanical features. This section evaluates the role of mechanically adaptive hydrogels within bone-on-chip (BoC) systems, focusing on how variations in material formulation, mechanical stimuli, and system integration influence osteogenic behavior under physiomimetic conditions (Blache et al., 2022; Castro el al., 2024). Although promising, the field still grapples with insufficient standardization, poor cross-study comparability, and a lack of multiscale mechanical characterization, all of which hinder clinical translation.
Table 4. Hydrogels and BoC applications.
Castro et al. (2024) introduced a laser-based actuation platform to deliver controlled mechanical stimuli to human mesenchymal stem cells (hMSCs) seeded on thermoresponsive hydrogels (Castro el al., 2024). Notably, their investigation centered not on characterizing hydrogel mechanics, but on assessing mechanotransduction-driven osteogenesis in the absence of biochemical factors. This approach reflects a novel mechanobiological testing paradigm, decoupling mechanical cues from biochemical complexity. However, a major limitation is the absence of quantitative metrics describing the amplitude, frequency, or duration of mechanical stimulation, making it difficult to reproduce or scale the results. Beyond issues of reproducibility, these parameters are essential for understanding the dose–response relationship between mechanical cues and cellular behavior, influencing important processes such as osteogenic differentiation, cell polarization, and focal adhesion dynamics. Without such data, experimental replication and technology scaling become difficult to achieve. Future work should integrate real-time force quantification and correlate cellular outcomes with defined mechanical inputs, possibly by embedding force sensors or using traction force microscopy within BoC constructs.
In contrast, Xue et al. (2025) applied standard uniaxial compression tests to GelMA/PEGDA hydrogels to evaluate their compressive behavior and enzymatic degradation (Xue et al., 2025; Wang et al., 2018). While their study offered valuable data on initial mechanical performance, it omitted essential mechanical parameters such as tensile strength, shear resistance, fatigue behavior, and stress-relaxation capacity, all of which are vital for mimicking the multiaxial mechanical environment of bone. Moreover, the scarcity of methodological transparency—e.g., sample preparation, boundary conditions, and post-processing techniques—reduces confidence in reproducibility. To ensure robust conclusions, future studies should provide full test protocols, including loading geometry, strain rates, boundary constraints, and error analysis, in alignment with ASTM F2450 or ISO 527 guidelines for hydrogels.
Zhang et al. (2024) emphasized the necessity of standardized mechanical testing protocols, particularly for hydrogels functionalized with cells or bioactive compounds (Chen et al., 2024; Zhang et al., 2024). While their call for adherence to ASTM and ISO standards is commendable, it also implicitly highlights a persistent and problematic fragmentation in the field: despite repeated advocacy, actual implementation of such protocols remains sporadic at best. The lack of enforceable methodological benchmarks continues to generate a body of literature that is difficult to reconcile or compare, undermining efforts toward cumulative scientific progress.
Moreover, the authors only partially addressed the complexities introduced by biofunctionalization. While they acknowledged that the incorporation of cells or signaling molecules can introduce local heterogeneities—altering stiffness or triggering microphase separation—they did not quantify or model these effects. This omission leaves a critical gap, as such heterogeneities profoundly distort bulk mechanical readouts, leading to potentially misleading interpretations if only averaged metrics (e.g., Young’s modulus from uniaxial tests) are reported (Chen et al., 2024; Zhang et al., 2024).
A more robust approach would require not just the recommendation but the systematic application of high-resolution spatially resolved techniques—such as atomic force microscopy (AFM) nanoindentation, Brillouin light scattering microscopy, or scanning acoustic microscopy. These tools are not merely “promising” but increasingly indispensable for accurately resolving intra-gel mechanical gradients in cell-laden or dynamically remodeling hydrogels. Without their integration, the mechanical behavior of biofunctional hydrogels will remain undercharacterized, compromising both mechanistic understanding and translational viability in tissue engineering contexts (Blache et al., 2022; Chen et al., 2024; Zhang et al., 2024).
Bulk mechanical tests (e.g., uniaxial compression, tensile testing, or rheometry) inherently average the response of the entire sample volume, assuming mechanical homogeneity throughout the material. However, biofunctionalized hydrogels are rarely homogeneous (López-Serrano et al., 2024; Alheib et al., 2022; Jeon et al., 2021; Blache et al., 2022; Yu C. et al., 2024). The presence of cells, growth factors, micro/nanoparticles, or gradients in crosslinking density introduces microscale variations in stiffness, viscoelasticity, and poroelastic behavior (Lin et al., 2023; Subramani et al., 2020; Wu et al., 2024; López-Serrano et al., 2024; Nerger et al., 2024; Yu C. et al., 2024). These local variations are not trivial—they profoundly influence cellular fate decisions such as proliferation, differentiation, and migration, particularly in 3D culture systems that attempt to replicate the physiological microenvironment (Seyedmajidi et al., 2023; Chen et al., 2025; Alheib et al., 2022; Zauchner et al., 2024).
Without spatially resolved techniques, critical microdomains of altered mechanics—resulting from cell clustering, matrix remodeling, or local degradation—remain undetected (López-Serrano et al., 2024; Nerger et al., 2024; Alheib et al., 2022; Jeon et al., 2021). This leads to major limitations:
• False negatives, by overlooking stiffened or degraded regions that critically modulate cell–matrix interactions (López-Serrano et al., 2024; Chen et al., 2025; Jeon et al., 2021).
• Misleading averages, where reported values of Young’s modulus or relaxation time fail to reflect what cells actually “feel” at their interface (Subramani et al., 2020; Lee et al., 2018; López-Serrano et al., 2024).
• Poor reproducibility, since subtle variations in gel architecture—common in biofunctional or cell-laden systems—can cause widely divergent biological outcomes, even under nominally identical mechanical testing conditions (Siqueira et al., 2023; Lin and Chen, 2022; Wu et al., 2024; López-Serrano et al., 2024).
In contrast, AFM nanoindentation provides nanometric precision in quantifying surface and local stiffness, enabling direct interrogation of the cell–matrix interface (López-Serrano et al., 2024; Jeon et al., 2021; Blache et al., 2022). Brillouin microscopy, a non-invasive and label-free method, allows 3D viscoelastic mapping of hydrated gels and living tissues (Jeon et al., 2021; Blache et al., 2022). Scanning acoustic microscopy offers complementary spatial resolution through acoustic impedance contrasts, revealing internal structures often missed by conventional mechanical tests.
Therefore, excluding these high-resolution tools from the characterization pipeline not only results in an incomplete mechanical profile, but also severely limits the translational potential of hydrogels in regenerative medicine (Ding et al., 2023; López-Serrano et al., 2024; Blache et al., 2022; He et al., 2025). For materials intended to recapitulate the complex and spatially heterogeneous mechanical environment of native tissues—such as bone or cartilage—this is not a minor methodological oversight, but a critical flaw in experimental design (Ding et al., 2023; Wu et al., 2024; Alheib et al., 2022; Ghiasi Tabari et al., 2024; Zhang and Khademhosseini, 2017; Wang and Heilshorn, 2015; Yu et al., 2025; Bai et al., 2018).
Zhou et al. (2024) provided a comprehensive review of GelMA hydrogels, identifying mechanical fragility, lack of testing standardization, and insufficient vascularization as key translational bottlenecks (Yu C. et al., 2024). Their recommendation to enhance mechanical robustness through composite engineering—e.g., with hydroxyapatite nanoparticles, nanocellulose, or graphene oxide—is fundamental for extending GelMA applications into load-bearing contexts. However, further studies should systematically compare these composite variants under dynamic mechanical conditions, mimicking loading cycles typical of in vivo bone environments. Additionally, the interplay between angiogenic signaling and mechanical adaptation remains underexplored. Incorporating dual gradients (mechanical and biochemical) within 3D-printed hydrogel scaffolds, combined with vascularized BoC platforms, represents a promising but underutilized frontier.
While Yu et al. (2024) rightly emphasize the mechanical and vascular limitations of GelMA hydrogels, their review falls short in proposing quantitative benchmarks or comparative performance data for the suggested nanocomposite reinforcements. Claims about improved robustness through incorporation of hydroxyapatite, nanocellulose, or graphene oxide remain largely qualitative or anecdotal, lacking direct mechanical metrics under physiologically relevant loading regimes. Moreover, the review does not address the potential trade-offs introduced by such additives, such as altered degradation kinetics, reduced bioactivity, or compromised printability. These aspects are needed to be pointed when targeting load-bearing applications, where structural integrity must coexist with cellular integration and remodeling capacity.
Equally, while the concept of integrating dual gradients—mechanical and biochemical—within 3D-printed constructs is theoretically sound, Zhou et al. fail to engage with the technical and biological complexities of such integration. Gradient generation in hydrogels remains highly sensitive to print resolution, crosslinking kinetics, and local diffusion phenomena, which are seldom harmonized in existing platforms. Additionally, the role of mechanoresponsive angiogenic pathways, such as YAP/TAZ or VEGF/Notch interplay under cyclic strain, is omitted from their analysis. Without these mechanistic insights, the proposed vascularized constructs risk remaining proof-of-concept demonstrations rather than clinically viable systems (Onaciu et al., 2019; Zhao et al., 2015; Highley et al., 2015; Subramani et al., 2020).
7 Discussions
Bone tissue engineering using hydrogel-based scaffolds shows great promise but faces several critical challenges limiting clinical translation.
7.1 Dynamic mechanical adaptation and real-time monitoring
Despite significant progress, current hydrogel systems often fail to replicate the dynamic mechanical environment encountered during bone healing. One key limitation is their inability to adapt stiffness or viscoelasticity in response to evolving mechanical and biochemical cues in vivo. To address this, next-generation stimulus-responsive hydrogels—especially those based on reversible dynamic bonds (e.g., Schiff base or host–guest interactions)—are being engineered to modulate their mechanical properties in real time, closely mimicking the adaptive behavior of the extracellular matrix (Jeon et al., 2021; Xue et al., 2025).
The integration of functional nanostructures and embedded nanosensors within these adaptive hydrogels has emerged as a powerful strategy to monitor scaffold integrity, cellular mechanotransduction, and microenvironmental changes (Wang et al., 2018; Zhang and Khademhosseini, 2017). These nanocomposite systems not only enhance the mechanical strength and bioactivity of the scaffold but also support real-time feedback mechanisms, enabling closed-loop control of tissue regeneration processes.
Furthermore, studies on hydrogels with programmable spatiotemporal cues demonstrate their ability to direct stem cell fate and bone formation via mechanosensitive pathways, without relying exclusively on biochemical factors (Castro et al., 2024; Xue et al., 2025). In parallel, engineered 4D hydrogels, capable of time-dependent transformations under specific stimuli, offer a promising avenue for synchronizing scaffold mechanics with tissue maturation (Nain et al., 2024; Romischke et al., 2022).
Together, these developments mark a critical shift toward intelligent hydrogel scaffolds capable of responding to and monitoring the bone healing microenvironment in real time, enhancing both safety and efficacy in clinical translation.
7.2 Modeling and multiscale integration
Finite Element Modeling (FEM) has long been a cornerstone in predicting the macroscopic mechanical behavior of scaffolds and surrounding bone tissue. Its application has yielded valuable insights into stress distribution, load transfer, and structural optimization for bone regeneration (Boccaccio et al. (2011); Uth et al. (2017)). However, FEM alone is insufficient to fully describe the complex biological phenomena involved in bone healing, particularly cell–scaffold interactions, degradation kinetics, and matrix remodeling.
To address these gaps, integrating FEM with molecular dynamics (MD) simulations is increasingly recognized as essential. This multiscale strategy enables a more comprehensive understanding of scaffold behavior by linking molecular-level phenomena (e.g., bond breakage, hydrogel swelling, degradation pathways) to macroscale mechanical performance (Yu et al., 2025; Da Silva et al., 2024).
Moreover, the experimental Bone-on-Chip (BoC) platforms have emerged as powerful tools for mimicking the dynamic bone microenvironment with high physiological relevance. Despite their promise, data generated from BoC systems remains underutilized in computational model validation (Lipreri et al., 2023; Blache et al., 2022). There is a pressing need to develop validated multiscale computational frameworks that integrate BoC-derived biomechanical data, FEM simulations, and molecular modeling—an approach that could significantly enhance the predictive power and clinical relevance of scaffold design processes.
Such frameworks would also facilitate feedback-informed design iterations, reducing reliance on costly and time-consuming in vivo testing, and accelerating translational timelines in bone tissue engineering.
7.3 Limitations of current FEM–BoC integration
Despite the growing recognition of both Finite Element Modeling (FEM) and Bone-on-Chip (BoC) systems as essential tools in bone tissue engineering, their integration remains underdeveloped and presents several limitations.
Firstly, current FEM models are primarily macroscopic, simulating global scaffold deformation under physiological loads (e.g., axial compression or shear), but often lack molecular-scale resolution necessary to predict degradation dynamics, local cell–matrix interactions, or viscoelastic changes in real time (Da Silva et al., 2024; Blache et al., 2022; Yu et al., 2025). Most FEM frameworks do not account for time-dependent hydrogel behavior such as swelling, stress relaxation, or fatigue, which are central to adaptive materials and influence mechanotransduction over prolonged periods (Castro et al., 2024; Xue et al., 2025; Chen et al., 2024).
Secondly, very few studies combine experimental BoC outputs with multiscale FEM validation. Existing BoC platforms often measure cell differentiation, matrix mineralization, or signaling (e.g., Wnt/β-catenin, YAP/TAZ) (Blache et al., 2022; He et al., 2025), but these biological metrics are rarely translated into parameters that inform or calibrate FEM simulations. This results in a disconnect between computational predictions and biological outcomes, reducing the capacity for predictive modeling and scaffold optimization (Lipreri et al., 2023; Yu C. et al., 2024).
Thirdly, standardization is lacking in both domains. While organizations like ASTM and ISO recommend rigorous mechanical testing protocols for hydrogels (Chen et al., 2024), few studies apply these systematically before FEM integration. Without quantitative experimental inputs, FEM simulations often rely on static or idealized assumptions that do not reflect the dynamic, multi-axial mechanical environment of BoC systems (Xue et al., 2025; Yu C. et al., 2024). To address the lack of standardization in bone-on-chip (BoC) platforms, initial efforts should prioritize key parameters that strongly influence tissue responses, including physiologically relevant flow rates and shear stresses, mechanical loading protocols that mimic bone microenvironments, and hydrogel geometry with consistent scaffold dimensions. Cross-laboratory reproducibility can be facilitated through standardized reporting guidelines, open-access device blueprints, and the use of reference hydrogels and cell lines, enabling more reliable comparisons and accelerated optimization of BoC systems for bone tissue engineering (Lipreri et al., 2023; Blache et al., 2022; Liu et al., 2023).
Lastly, most FEM studies assume ideal interfaces between scaffold and host tissue or culture medium, neglecting realistic boundary conditions, such as fluid flow, interfacial bonding, and localized mechanical gradients, which are increasingly accessible in advanced BoC systems (Da Silva et al., 2024; Blache et al., 2022; He et al., 2025). Additionally, scaling BoC platforms to test multiple hydrogel conditions in parallel, while feeding into a unified FEM model, remains technically challenging and resource-intensive (Lipreri et al., 2023; He et al., 2025).
To overcome these limitations, future efforts should prioritize the development of validated, multiscale computational–experimental frameworks, in which BoC-derived mechanobiological data directly inform FEM simulations. Such integration would significantly improve the physiological relevance and predictive accuracy of scaffold design for regenerative medicine.
7.4 Bone-on-chip platforms: stability, vascularization, and scalability
The integration of mechanically adaptive hydrogels into Bone-on-Chip (BoC) platforms represents a promising direction for modeling bone physiology and regeneration under controlled in vitro conditions. However, this approach faces several unresolved challenges. One key issue is ensuring the long-term mechanical stability of hydrogels subjected to continuous or cyclic loading, a requirement for simulating bone’s dynamic environment (Xue et al., 2025; Lipreri et al., 2023).
Another major limitation is the incomplete recapitulation of angiogenesis within hydrogel matrices. Although recent hydrogel formulations have been designed to promote vascular ingrowth and endothelial cell behavior, their performance within BoC systems remains suboptimal, often lacking functional perfusable networks that sustain long-term culture and mimic in vivo vascularization (Yu C. et al., 2024; He et al., 2025).
For mechanically adaptive hydrogels in load-bearing bone defects, vascularization can be most effectively promoted by a combination of angiogenic factor incorporation and pre-formed capillary networks (Ding et al., 2023, Chen et al., 2025, Wu et al., 2023, Xue et al., 2025). The dynamic modulation of hydrogel stiffness supports both osteogenesis and vascular ingrowth by providing a mechanically favorable microenvironment: softer regions facilitate endothelial cell migration and network formation, while stiffer regions maintain load-bearing capacity. This synergistic interplay ensures that vascularization progresses alongside tissue regeneration without compromising mechanical functionality (Ding et al., 2023, Chen et al., 2025, Wu et al., 2023, Xue et al., 2025).
Additionally, BoC systems incorporating hydrogel-based scaffolds often face scalability constraints, particularly regarding standardization, automation, and integration with high-throughput screening platforms. Overcoming these barriers is essential to enhance the physiological relevance, reproducibility, and translational applicability of BoC models in drug testing and mechanistic studies (Zauchner et al., 2024; Lipreri et al., 2023).
Addressing these challenges through smart hydrogel engineering, microfluidic design optimization, and modular BoC architectures will be critical to realizing the full potential of hydrogel-based BoC systems in bone tissue engineering and regenerative medicine.
7.5 Mechanical, biological, and translational challenges
Hydrogel-based scaffolds hold promise for bone regeneration but face persistent mechanical, biological, and translational hurdles. Their mechanical properties—low elastic and shear moduli, poor tensile/compressive strength, and susceptibility to creep/fatigue—are inferior to native bone, risking stress shielding and suboptimal mechanotransduction (Nain et al., 2024; Gao et al., 2021; Farasati Far et al., 2023; Wang et al., 2018; Subramani et al., 2020; Onaciu et al., 2019). Strategies like nanoparticle reinforcement, electrospun fibers, or 3D-printed lattices enhance stiffness and stress distribution (Zhang et al., 2005; Wang et al., 2018; Chen et al., 2024; Subramani et al., 2020; Zhao et al., 2015; Subramani et al., 2020) but may compromise viscoelasticity, injectability, or uniform cell/nutrient distribution (Wang et al., 2018; Zhao et al., 2015; Lee et al., 2018).
Biologically, inadequate vascularization, immune reactions, fibrous capsule formation, and mismatched degradation rates can impair scaffold integration and tissue remodeling (Nain et al., 2024; Gao et al., 2021; Farasati Far et al., 2023; Zhang et al., 2005; Onaciu et al., 2019; Hoffman, 2012; Zhao et al., 2015; Highley et al., 2015; Subramani et al., 2020; Gupta and Shivakumar, 2012; Lee et al., 2018; Yang, 2022; Piao et al., 2021). Suboptimal stress relaxation or creep reduces cell mechanosensing and long-term structural stability (Pérez-Calixto et al., 2021; López-Serrano et al., 2024; Jeon et al., 2021). Crosslinking strategies must balance stiffness and brittleness to optimize mechanical integrity and biocompatibility (Maitra and Shukla, 2014; Akhtar et al., 2015; Yang et al., 2022; Wang and Heilshorn, 2015).
Translationally, regulatory uncertainties, long-term in vivo data gaps, and GMP-compliant manufacturing pose major barriers. Preclinical and early clinical candidates, such as GelrinC (PEG–fibrinogen), demonstrate promise but highlight ongoing challenges in scalability, vascularization, and standardized evaluation (Rana and De la Hoz Siegler, 2021; Lin et al., 2023; Chen et al., 2022; Romischke et al., 2022; Piao et al., 2021; Jeon et al., 2021).
This consolidated view underscores that mechanical mismatch, immune compatibility, degradation kinetics, viscoelasticity, vascularization, and regulatory alignment are interconnected factors critical for successful hydrogel scaffold translation. Integrated strategies—combining composite design, dynamic crosslinking, vascularized constructs, and robust standardization—are essential to overcome these persistent challenges.
7.6 Interdisciplinary collaboration and future directions
Advancing the field of hydrogel-based bone tissue engineering necessitates robust interdisciplinary collaboration among bioengineers, materials scientists, clinicians, and computational modelers. Such integration is critical to bridge the gap between experimental models and clinical applicability. For instance, Azizi et al. (2023) developed a mechanically adaptive nanocomposite hydrogel within a bone-on-chip (BoC) platform, demonstrating enhanced osteogenesis through the combined application of mechanical stimulation, biological assessment, and computational modeling.
Similarly, Savić Gajić et al. (2023) emphasized the importance of tailoring hydrogel stiffness through dynamic crosslinking strategies to mimic the evolving mechanical cues of native bone, while Ding et al. (2023) highlighted the integration of vascular networks in engineered constructs using microfluidic technologies. The convergence of such approaches points to the necessity of developing next-generation BoC platforms that not only replicate the biomechanical and biochemical microenvironment of bone, but also allow controlled perfusion, real-time data acquisition, and long-term stability under mechanical loading.
Main future directions involve:
• Engineering hydrogels with extended functional longevity and tunable degradation profiles to match bone regeneration timelines (Farasati Far et al., 2023; Savić Gajić et al., 2023; Sacks et al., 2009);
• Incorporating vascularized compartments using advanced bioprinting or endothelial co-culture systems to support nutrient diffusion and angiogenesis (Ding et al., 2023; Ghiasi Tabari et al., 2024; Lee, 1985);
• Establishing validated finite element method (FEM)–BoC coupled models for precise mechanobiological simulations (Wu et al., 2024; Pérez-Calixto et al., 2021; Azizi et al., 2023);
• Designing high-throughput BoC platforms for drug screening and personalized regenerative therapy development (Hoffman, 2012; Yang et al., 2022);
• Embedding biosensing technologies for real-time monitoring of mechanical stress, pH, and cellular activity to enable dynamic adjustments of scaffold properties during tissue maturation (Nerger et al., 2024; Jeon et al., 2021).
• Inclusion of biosafety measures meant to maintain the function parameters. He et al. (2025) stated in their study that 2 weeks after the injection, no abnormal changes in liver and kidney function parameters could be seen; thus, they emphasize that after 4 weeks the hydrogel exhibited low toxicity in rats. Also, these facts are meant to adress the biosafety and stability of chitosan hydrogels (He et al., 2025).
• Utilizing AI technology to predict and optimize the properties of prepared hydrogels decreases the time and expenses associated to individual experiments. Obtaining insight from generated data using ML algorithms helps to accelerate the process of designing and optimizing hydrogels with desired outcomes, by also integrating with FEM and BoC (Li Z. et al., 2024).
• Compliance with ISO 10993 standards is essential for assessing the biocompatibility, cytotoxicity, sensitization and FDA classification are a regulatory requirements for hydrogels as the mechanical performance, degradation rates an cellular interactions must meet strict criteria for safety and efficacy before clinical use (He et al., 2025; ISO 10993-1, 2018).
• Use of multi-responsive hydrogels, that are capable to response to thermal and biochemical cues in order to replicate the dynamic microenvironment. This can bring control on degradation rate and scaffold mechanics, especially during remodeling phases (Xue et al., 2025; Castro et al., 2024; Jeon et al., 2021).
• Clinical translation that requires careful evaluation of ethical safety and regulatory aspects. Patient safety, long-term biocompatibility and potential immune reactions prevention should be ensured through standardized reporting, rigorous testing and transparent documentation (He et al., 2025).
The Table 5 summarizes the mechanically adaptive hydrogels discussed in this review; this comparative analysis provides a clear overview of practical merits and limitations.
Table 5. The types of hydrogels from studies used in review.
While PBNPs@OBG hydrogels shows self-healing ability, maintaining stiffness under load, supporting also osteogenic differentiation,the stimuli-responsive hydrogels is subjected to real-time stiffness modulation. On the other hand, computationally assisted ones provide predictive tool for current experimental gaps (Nerger et al., 2024; Jeon et al., 2021; Zhang et al., 2024; Yu C. et al., 2024; He et al., 2025; Boccaccio et al., 2011).
Achieving these milestones will require not only technical innovation but also standardization of evaluation protocols, open data integration, and regulatory alignment—critical steps toward the clinical translation of hydrogel-based regenerative systems (Chen et al., 2022; Subramani et al., 2020; Piao et al., 2021).
8 Conclusions
Hydrogels play a fundamental role in bone tissue engineering due to their tunable physicochemical properties and inherent biocompatibility. Their unique characteristics allow for the creation of scaffolds that can closely mimic the natural bone environment, promoting cellular activities essential for bone regeneration. The synergistic combination of mechanically adaptive hydrogels, computational modeling, and experimental validation accelerates scaffold optimization and promotes the translational potential of regenerative therapies. Such interdisciplinary strategies are imperative to bridge the gap between hydrogel scaffold design, their effective clinical application in bone regeneration, AI -ML approaches, while the ethical considerations are addressed.
Author contributions
I-CB: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.
Funding
The authors declare that financial support was received for the research and/or publication of this article. The author acknowledges TU Wien Bibliothek for financial support through its Open Access Funding Programme.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that Generative AI was used in the creation of this manuscript. Text formulation assistance and literature reference identification were supported by Claude (Anthropic, 2024) and ChatGPT (OpenAI, 2024). All scientific content, critical analysis, and final interpretations were independently developed and verified by the author. Figures were generated using AI-based tools, strictly under the author’s concept and supervision, for educational and illustrative purposes. The tables were created using Microsoft Excel.
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Keywords: hydrogels, bone tissue engineering, mechanical adaptation, finite element modeling, bone-on-chip, smart biomaterials
Citation: Băncilă I-C (2025) Mechanically adaptive hydrogels for bone tissue engineering: from classification and biomechanics to modeling and translational applications. Front. Med. Eng. 3:1703555. doi: 10.3389/fmede.2025.1703555
Received: 11 September 2025; Accepted: 24 November 2025;
Published: 18 December 2025.
Edited by:
Dinesh Kumar, Centre of Bio-Medical Research (CBMR), IndiaReviewed by:
Kamatchi Sankaranarayanan, Ministry of Science and Technology, IndiaKarthick Velu, Sathyabama Institute of Science and Technology, India
Jyoti Pandey, Babasaheb Bhimrao Ambedkar University, India
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*Correspondence: Ioana-Cristina Băncilă, Y3Jpc3RpbmFiYW5jaWxhMDNAeWFuZGV4LmNvbQ==