Smart mechanobiological systems using force-adaptive biomaterials

Abstract

Mechanobiology has emerged as a critical framework for understanding how physical forces regulate cell behavior, tissue homeostasis, regeneration, and disease progression. This review examines the development of smart mechanobiological systems, defined as force-responsive biomaterials that can sense, transmit, and adapt to dynamic mechanical cues in living tissues. First, the mechanobiological foundations relevant to material design are discussed, including tissue stiffness, viscoelasticity, stress relaxation, mechanotransduction pathways, and the role of dynamic microenvironments in repair and pathology. Next, major classes of engineered smart biomaterials are reviewed, with emphasis on mechanically responsive polymers, hydrogels, multifunctional materials, mechanoresponsive drug delivery systems, and programmable self-adaptive platforms. The review further summarizes applications in regenerative medicine, including wound healing, musculoskeletal repair, cardiovascular regeneration, neural repair, and stem-cell engineering, followed by disease-focused applications in fibrosis, cancer, cardiovascular disorders, and chronic wounds. Across these contexts, smart materials are shown to offer advantages over passive systems by enabling spatiotemporal control, adaptive mechanical regulation, and improved therapeutic precision.

Introduction

Background and motivation

Smart mechanobiological systems have been recently established incipient works. ¹ Rajeev et al. ² discuss mechanoresponsive biomaterials which demonstrate strain-stiffening, supramolecular adaptation, and force-induced conformational changes in constituent proteins. For example, in Jin et al., ³ elaborate mechanotransduction pathways, including integrin–FAK–RhoA/ROCK, Piezo signaling and YAP/TAZ activation, orchestrate mechanical loading in regulating tissue regeneration. At the same time, Wang et al. ⁴ emphasized piezoelectric materials in their review as a platform that converts the mechanical stimulation into electrical signal for the repair of the tissue; Yarali et al. ⁵ focused on the review of 4D-printed biomedical systems, which includes dynamic stents, microneedles, wound-closure devices, and regenerative cellular microenvironments. Collectively, these studies provide evidence that next-generation biomaterials need to be structural scaffolds that sense, transduce, and respond to mechanical signals in live tissues. Hence, there is a growing need for smart mechanobiological systems to link material responsiveness to cellular mechanotransduction and precision regenerative medicine. Figure 1. Smart MechanoBiological Systems Derived from Force-Adaptive Biomaterials Based on the mechanical cues including stiffness, viscoelasticity, stress relaxation, shear stress, compression, cyclic strain, and remote magnetic/mechanical stimulation, the expected adaptive material responses consist of strain-stiffening, stress relaxation, self-healing, mechanoresponsive drug release, piezoelectric conversion, magnetic actuation and programmable remodelling. These responses however may turn-off mechanotransduction pathways in cells such as integrin–FAK signaling, Piezo activation, RhoA/ROCK contractility, cytoskeletal tension, and YAP/TAZ nuclear translocation as well as nuclear mechanosignaling and direct the outcomes of regenerative versus disease-modifying therapeutics.

Figure 1.

Conceptual framework of smart mechanobiological systems using force-adaptive biomaterials.

Figure 1 summarizes the cue–material–cell–therapy framework used in this review, showing how mechanical inputs are translated by force-adaptive biomaterials into cellular mechanotransduction responses and therapeutic outcomes.

Why smart mechanobiological systems matter

Cells are embedded in an active biological tissue, and the extracellular matrix has been referred to as a system that continuously provides physical, chemical, and biological signals to cells by Xie et al. ⁶ Static biomaterials can be used for the study of adhesion, migration, growth and differentiation but they show very little control once implanted. Mechanobiology encompasses events that occur over very different temporal and spatial scales (from organism-, organ-, cell-to protein- and gene-level), such that failure of the system to respond mechanically may lead to inhibited integration into a tissue or even initiate pathological signaling in some cases. ⁷ To that end, dynamic hydrogel systems have been developed transitioning from classical 2D into 3D and 4D tunable niches, as delineated by Gharios et al., ⁸ whereas Xiang et al. ⁹ focused on programmable hydrogels endowed with self-stimulated, self-swellable and self-powered activities. Such systems have increasingly been proven in terms of oral regeneration translational relevance, where layered gradient nonwovens and polymer-modified biomaterials were connected to mechanotransductive tissue repair. ¹⁰ The main ideas of mechanobiological systems with intelligent biomaterials for precision regenerative medicine are depicted in Figure 1.

Limitations of current understanding and need for this review

Despite rapid advances, these developments in mechanobiology and biomaterials engineering have only rarely progressed as a unified field. Dong et al. ¹¹ outlined programmable and mechanically active materials that respond to optical, thermal, magnetic, electrical, chemical, and mechanical stimuli however Huang and Fussenegger ¹² utilized this principle in synthetic gene circuits that are modulated by at least six physical cues: light, magnetic fields, temperature, mechanical forces (shortly after), ultrasound and electricity. Yet such disease-specific coupling of force generation, material response, and remodeling remains incompletely integrated. For instance, Jin ¹³ demonstrated localized stiffening in early on set superficial zones and softening in deeper or advanced regions of osteoarthritic cartilage, while Velusamy ¹⁴ showed force responsive DNA mechanocapsules for traction dependent HIF1α knockdown. Likewise, Guo et al. ¹⁵ reported that articular cartilage is >80% water and contains only one cell type, explaining much of the poor regenerative capacity. These examples highlight the underrepresentation for a review integrating mechanisms, materials, pathology and therapy. Figure 2 illustrates how integrins, focal adhesion complexes, cytoskeletal elements, and the nucleoskeleton convey mechanical cues to the nucleus. Mechanotransduction signals are indicated by the yellow shadow. ¹⁰

Figure 2.

Diagrammatic representation of mechanobiology’s molecular foundation. Reproduced with permission from Argentati et al., International journal of molecular sciences, 20(21), 5337. (2018). Copyright 2018 authors, licensed under a creative commons attribution (CC BY) license.

Aim, scope, and organization of the review

The present review seeks to bridge the gaps between mechanobiological tenets, smart material design, and clinical translation via an unambiguous cue–material–cell–therapy framework. In this perspective, it correlates mechanical stimuli like stiffness, viscoelasticity, stress relaxation, shear stress, compression, cyclic strain, and externally applied forces with materials actions such as strain-stiffening, self-healing, mechanoresponsive drug release, piezoelectric conversion, magnetic actuation and programmable remodeling. These responses regulate mechanotransduction pathways in the cell, such as integrin–FAK signaling, Piezo-ion-channel activation, RhoA/ROCK contractility, YAP/TAZ nuclear translocation and mechanotransduction pathways in the tissue, such as cytoskeletal tension and nuclear mechanosignaling, and ultimately affect stem-cell fate, tissue repair, disease remodeling and therapeutic outcomes.

Thus, the current review aims to link mechanobiological principles with smart material engineering and clinical translation. Examples of force-guided regenerative systems were summarized in the categories of mechanically loaded stem-cell niches, comprising four types of oral stem-cells (DPSCs, PDLSCs, SHEDs and GMSCs) from Zhou et al. ¹⁶ On top of that, Gharios et al. ¹⁷ generated biomaterial logic architectures with 17 YES/AND/OR operators mediated by three orthogonal proteases and Tan and colleagues identified five mesenchymal subsets plus another 14 cell types involved under force-induced root resorption, indicating the comprehensive nature of mechano-immune regulation. On the tool side, Kumar et al. ¹⁸ developed a mechanoactuated hydrogel interface for real-time force probing and Müller and Van de Voorde ¹⁹ have reported responsive hydrogels capable of cellular tension sensing at the piconewton scale. Thus, this review will cascade from mechanobiological underpinnings to force-responsive biomaterials classes, to cellular–material interactions, regenerative and disease applications, and finally to translation and future directions (Table 1).

Table 1.

Overview of smart mechanobiological systems with problem addressed, key findings, and research gap.

Author	Focus area	Problem addressed	Key findings	Research gap	Relevance to review
Liu et al. 1	Mechanomedicine	Mechanical changes in disease are underused in diagnosis and therapy	Mechanical forces act across organ-to-molecular scales; altered mechanics can serve as biomarkers	Need standardization of mechanical biomarkers and better translation	Strong foundation for why mechanobiology matters
Rajeev et al. 2	Mechanoresponsive biomaterials	Passive biomaterials cannot adapt to living tissues	Hydrogels, elastomers, and piezoelectric composites respond via strain stiffening and force-induced changes; 4D bioprinting and AI noted	Scalability, long-term biocompatibility, clinical translation	Good for introducing smart biomaterials
Xie et al. 6	Dynamic ECM-mimicking biomaterials	Static culture materials poorly mimic real cell microenvironments	Dynamic materials can spatiotemporally regulate cell fate; static vs dynamic cues affect adhesion, migration, growth, differentiation	More precise control of dynamic cues still needed	Excellent for “why smart systems matter”
Velusamy 14	Mechano-triggered drug delivery	Drug delivery rarely targets cell mechanical phenotype	DNA mechanocapsules released cargo under cellular force; HIF1α mRNA knockdown was force-dependent	Needs in vivo expansion and broader disease validation	Strong example of mechanically triggered therapy
Tan et al. 20	Force-sensitive therapeutic hydrogel	Excessive orthodontic force causes root resorption; cell heterogeneity unclear	5 mesenchymal subsets and 14 other cell types identified; GelMA@siRNA hydrogel reduced root resorption	Need broader validation in skeletal mechanotherapy	Strong disease-intervention example
Müller and Van de Voorde 19	Responsive hydrogels	Need materials for strain accommodation and force sensing	Smart hydrogels developed for SASS, on-demand assembly, and piconewton-level cellular force sensing	More characterization and broader biomedical application needed	Useful for future smart hydrogel design

Mechanobiological foundations for smart material design

Mechanical properties of biological tissues

In a biological setting, the mechanical properties of tissues are active controllers of cell behaviour, tissue organisation, repair and pathology progression. As stated by Pishvar and Harne, ²¹ natural tissues incorporate structure along with sensing, control and adaptive behavior over relevant length scales, and as noted by Donati et al., ²² biomaterials can profit from extensive knowledge acquired for designing extracellular-matrix-like physical and surface material properties. Thus, tissue mechanics is not a single value of stiffness for a smart biomaterial but should be approached as a design framework. Cell spreading, focal adhesion formation, cytoskeletal tension, migration, proliferation, and lineage specification are regulated by stiffness and elasticity. Nonetheless, native tissues possess non-zero tokens of viscous behavior. Evans et al. ²³ demonstrated the inhomogeneous and isotropic mechanics of the periosteum varying by species, anatomical site, and stress state; Holzapfel et al. ²⁴ developed a constitutive relations based on the concept that soft tissues are nonlinear, anisotropic, and inelastic systems. Thus, biomaterials should closely resemble not just tissue modulus but also site-specific, nonlinear, and quantitatively load-dependent behavior. Since living tissues dissipate and remodel mechanical energy over time, it is important to study viscoelasticity and stress relaxation both in parity with each other. They provide support for cell spreading, ligand clustering, traction-force generation and matrix remodeling, e.g. hyper elastic stress-relaxing hydrogels and dynamic polymer networks. In the same way, anisotropy and mechanical gradients are required for the guidance of cellular alignment and hence function in tissues like tendon, muscle, myocardium, blood vessels, nerves, periosteum, and osteochondral interfaces.

Finally, changes in tissue mechanics during injury, inflammation, aging, repair, fibrosis, cancer and degeneration. As the mechanical mismatch can limit regeneration, Shi et al. ²⁵ also highlighted the importance of biomaterials that can mimic the dynamic myocardial microenvironment towards cardiac repair. Thus, polymeric biomaterials with programmable properties such as tunable stiffness, viscoelasticity, stress relaxation, anisotropic properties and remodeling ability into biomimicking scaffolds are desired to deliver mechanical signals and then adapt with the repairing or diseased tissue.

Mechanisms of cellular mechanosensing and force generation

Each of these cellular responses to force has been demonstrated to be dependent on coordinated sensing and transduction machinery. Lucariello et al. ²⁶ illustrated detection of external and internal forces via mechanosensor proteins and membrane–organelle networks, which leads to cytoskeletal remodeling and downstream transcriptional change. In revolving systems, Wang et al. ²⁷ published information regarding blood cells and their ability to sense shear, stretch, rigidity through receptors including but not limited to Piezo1, glycoprotein Ib-IX-V and integrins that act in association with YAP/TAZ and NF-κB signaling. Yang et al. ²⁸ further characterized stem-cell responses to stiffness, nanotopography, shear stress, and dynamic stimuli-responsive properties that affect proliferation, differentiation, migration and apoptosis. Nims et al. ²⁹ proposed the therapeutic implementation of these constructs, describing “mechanogenetics” as mechanotransduction-nexus + synthetic gene expression control. At the material level, Dong et al. ³⁰ noted that mechanical force can directly trigger chemical reactions and connect force sensing with interfacial adhesion regulation and biological stimulation. Therefore, it is established that cells not only respond to force via integrins, focal adhesions and ion channels, but also generate and maintain this force with contractility and cytoskeletal tension. An outline of the mechanosensing procedure is shown in Figure 3. The scheme shows the several membrane proteins involved in the detection of mechanical stimuli.

Figure 3.

An outline of the mechanosensing process. The several membrane proteins involved in the sensing of mechanical stimuli are depicted in the scheme. Mechanosensitive ion channels like TWIK-related potassium channels and Piezo1, as well as adhesion receptors like integrin and cadherin, may be activated by changes in extracellular signals, mechanical stimuli, and ECM stiffness. These channels then interact with cytoskeletal proteins like talin, vinculin, paxillin, and focal adhesion kinase, connecting F-actin filaments and transmitting the tensions within the cells. ²⁶ Reproduced with permission from Lucariello et al., Biomolecules, 15(6), 848. (2025). Copyright 2025 authors, licensed under a creative commons attribution (CC BY) license.

Dynamic mechanical microenvironments in tissue repair and disease

Tissue microenvironments are indeed not static but rather responding through incremental modifications during repair and disease. Mechanical cues govern physiology and pathology in at least 10 systems (Li et al. ³¹ ) yet their clinical translation is by no means complete. Lin et al. ³² define mechano-active biomaterials, in the context of tissue repair systems that could adapt in vivo to endogenous forces and mediate spatially and temporally defined repair. According to Garatikar et al., ³³ although advanced scaffolds and 4D bioprinted constructs can adapt to the body physiological environment, it remains challenging to develop a single material that fulfills both mechanical requirements, as well as safety and dynamic responsiveness in tissue regeneration strategies. In cancer, Peng et al. ³⁴ demonstrated that biomechanical alterations in the tumor microenvironment modulate immune surveillance and progression via checkpoints including PIEZO1, DDR1, YAP/TAZ and TRPV4. In bone repair, fracture healing was proposed to be a spatiotemporal “force-cell-matrix” coupling process by Ich et al., ³⁵ during which YAP/TAZ, Piezo1/2, Integrin-FAK-ERK and RhoA/ROCK pathways modulate osteogenesis, angiogenesis and immune transformation. These discoveries are compatible with the perspective that tissues can indeed stiffen, soften or remodel during repair and as such materials must respond dynamically to retrogressive states.

Design principles for mechanobiology-informed biomaterials

This mechanobiological understanding has increasingly been incorporated into engineering guidelines for smart biomaterials. Indeed, both static and dynamic physical properties have been shown to direct skeletal stem and progenitor cell fate, ³⁶ making controllable biomaterial mechanics a key determinant of success in tissue engineering. Sojdeh et al. ³⁷ bring a strong step forward by noting not just the role of adaptive biomaterals to support structure, but also adjust stiffness, self-repair and transmit cellular mechanical signal in real-time. In cardiovascular regeneration, they argued that fabricating mature tissue-engineered heart valves with sufficient levels of functional maturity depends on synchronized control of anisotropy, immune modulation and mechanical conditioning rather than solely material replacement. ³⁸ Freeman emphasized that mechanically graded architecture is essential for an effective load transfer, which then preserves the mechanobiological homeostasis necessary to achieve osteochondral repair. ³⁹ Lastly, a regenerative design approach was suggested by Gallego and Cheu ⁴⁰ for 3D-printed hip prostheses that combined patients’ imaging data, mechanobiology-based architecture optimization, porosity and stiffness control with regulatory compliance. In summary, it has been highlighted that ideal mechanobiology-informed biomaterials supply tunable and time-variant stiffness, viscoelasticity and stress-relaxation responses as well as spatial-temporal programmability, and provide bidirectional force transfer between cells and materials. The schematic representation of different mechanical properties applied to cells is shown in Figure 4.

Figure 4.

Diagrammatic depiction of various mechanical characteristics applied to cells. (a) Distinctions between 3D and traditional 2D cell culture. (b) The depiction of mechanical forces applied to cells and the models that follow to investigate them. (c) The scheme illustrates the distinctions between biodevices and biomaterials. ²⁶ Reproduced with permission from Lucariello et al., Biomolecules, 15(6), 848. (2025). Copyright 2025 authors, licensed under a creative commons attribution (CC BY) license.

Engineering force-responsive biomaterials and smart systems

Mechanically responsive polymers and hydrogels

Among them, hydrogels and polymers have been the most widely used as a principal biomaterial because of their structural and functional similarity to the extracellular matrix. Another approach involves mechanical force-responsive systems: drug release has been accomplished through rupture of chemical bonds or structural destabilization when subjected to compressive, tensile, or shear forces, mechanophore-based signaling for a-stretch dysfunction (Ma et al. ⁴¹ ). Wu et al. ⁴² demonstrated that hydrogel microspheres with micrometer-scale architecture, high porosity and large surface area allow for spatiotemporally controlled release and enhanced regeneration. In another example, Zhang et al. ⁴³ presented controlled drug delivery platforms between mechanical forces to show responsiveness not only to direct force but also remote triggers like ultrasound and magnetic fields. Moreover, Xin et al. ⁴⁴ have demonstrated that light-based 3D printable hydrogels enable high environmental adaptability and precise fabrication methods. Such dynamic systems allow for adaptive environments at the cellular level, and reversible crosslinking, stress relaxation, and structural tunability contribute to tissue repair/regeneration (Table 2).

Table 2.

Overview of key mechanical properties, and biological significance.

Author	Tissue/system	Key mechanical property	Biological significance	Corresponding material design target	Research gap
Evans et al. 23	Periosteum/bone surface	Stress-state dependence; site-specific mechanics	Regulates mechanosensitive progenitor niche	Biomimetic periosteum with adaptive, location-specific mechanics	Multiscale structure-function still unclear
Holzapfel et al. 24	10 soft tissues/organs	Nonlinear elasticity, inelasticity, multiaxial response	Governs local cell environment in load-bearing tissues	Tissue-specific constitutive matching; nonlinear, anisotropic scaffolds	Need models for evolving properties in disease/healing
Shi et al. 25	Myocardium/cardiac tissue	Dynamic microenvironment; progressive mechanical change	Influences cardiomyogenesis, maturation, regeneration	Stimuli-responsive hydrogels and nanoparticles for cardiac repair	Better native-heart mimicry still needed
Yang et al. 28	Stem-cell niches	Stiffness, nanotopography, shear stress, dynamic cues	Controls proliferation, differentiation, migration, apoptosis	Dynamic mechanomodulatory biomaterials with tunable cues	Clinical translation remains limited
Ich et al. 35	Fracture microenvironment	Spatiotemporal biomechanics; force-cell-matrix coupling	Regulates osteogenesis, angiogenesis, immune transition	Adjustable-stiffness scaffolds; gradient and load-responsive systems	Real-time dual-signal monitoring still limited
Freeman 39	Osteochondral tissue	Mechanical gradient; compressive and shear loading	Supports load transfer and joint homeostasis	Graded osteochondral scaffolds matching cartilage-bone transition	Better integration of inflammation + mechanics needed

Stimuli-responsive, magneto-active, and multi-functional biomaterials

Moreover, these smart biomaterials have been rapidly engineered with the prospect of adapting ability to several physical and chemical stimuli simultaneously. External mechanisms bridging between electricity, light, ultrasound and magnetism were shown to regulate cellular pathways including biochemical signaling and mechanical stress modulation. ⁴⁵ Gao et al. ⁴⁶ also reported advances in biosensing to enhance sensitivity and real-time biomarker detection by design of multi-stimuli responsive materials. Shahi et al. ⁴⁷ designed interpenetrating polymer network (IPN) hydrogels with improved mechanical properties and responsiveness to conquer the limitations of ordinary hydrogels. There has been successful work in integrating mechanochromic and self-healing properties; Zhao et al. ⁴⁸ reported of a PDMS elastomer with mechanical properties: tensile strength 10.5 MPa, elongation at break 785%, and received the high self-healing efficiency (92.1%) after 24 h at 60°C. Ultrasound-responsive polymeric micelles have also been developed by Xia et al., ⁴⁹ showing reversible or irreversible release of drug encapsulated within them. Soares and Besenius ⁵⁰ also reported mechanophoric hydrogels that respond visibly to mechanical stimuli, indicating the implementation of molecularly-responsive segments into polymeric networks. Magneto-active systems are an important group of multifunctional smart biomaterials due to their ability in wireless and remote-controllable mechanical stimulation. Garcia-Gonzalez, Raman, Schuerle and Tay ⁵¹ described magnetic actuation as a novel mechanomedicine strategy, whereby external fields and magnetic materials produce controlled deformation, deformation, displacement, torque, compression or oscillatory stimulation. More recently, Garcia-Gonzalez ⁵² elaborated on force transmission to cells and extracellular matrix mediated by magneto-mechanics including magnetic particles, magnetoresponsive hydrogels, magnetoelastic substrates, and magnetic scaffolds to modulate cell shape, cytoskeletal tension, focal adhesion activity, and downstream mechanotransduction. These systems go beyond passive stiffness control towards smart mechanobiological design, by allowing for externally programmable, reversible, spatiotemporally controlled force inputs. They can thus serve as a platform for stem-cell engineering, vascular remodeling, neural and muscle interfaces, organoid mechanobiology, and disease modeling. At the same time Cedillo-Servin, Raman, Castilho and co-workers ⁵³ proposed meta-adaptive biomaterials, where multiscale organization, spatiotemporal actuation and cell-material feedback were combined to build adaptive engineered tissues.

Mechanoresponsive drug delivery and therapeutic systems

Mechanical and pathological cue responsive drug delivery systems have been extensively studied. The authors designed autonomous triggering of the drug release by endogenous factors like pH, stiffness, strain and temperature which allows for precise spatial as well as temporal control. ⁵⁴ Gao et al. ⁵⁵ emphasized on bio-based polymeric systems with multiple/single responsive behavior, which can enhance the effectiveness of intelligent drug delivery. Shahi et al. ⁵⁶ proposed a novel concept of smart microneedles incorporating multiple stimuli-responsive polymers for localized therapy and better patient compliance. Maier et al. ⁵⁷ developed a mechanoresponsive hydrogel system where the difference in protein release was enhanced by 32% under an applied pressure of 1.3 N cm⁻² with tunable composition between 100 and 150 mg mL⁻¹. Moreover, Jia et al. ⁵⁸ noted that dynamic biomaterials able to mimic ECM feedback mechanisms are critical in modulating cell behavior and enhancing therapeutic effects.

Dynamic, programmable, and self-adaptive systems

Programmable biomaterials have increasingly been engineered to not only this end, but also adapt to their surroundings. A two-component system based on cryogels with interconnected micrometer-scale pores was further reported by Jain et al., ⁵⁹ allowing to achieve not only high mechanical resilience, rapid hydration and efficient mass transport. Multifunctional nanocarriers are designed with added benefits (such as stimuli-controlled systems) that make them more efficient in target delivery and less effective to off-target sites. ⁶⁰ For cardiovascular application, Liu et al. ⁶¹ have shown nanotheranostic systems that allow for spatiotemporal controlled drug release and multimodal imaging. The use of supramolecular biomaterials with reversible interactions was emphasized by Hu et al., ⁶² allowing the precise tuning of morphology and drug release for cancer intervention. Lastly, Zhang et al. ⁶³ presented a tri-stimuli-responsive material that undergoes a reversible phase transition under light, humidity and mechanical force while displaying self-healing behavior and greater wound healing ability. Overall, these systems demonstrate that programmable, feedback-responsive biomaterials can adapt their properties with great dynamic range and potentially be integrated with sensing and control elements toward next-generation therapeutic applications.

Smart mechanobiological systems should be chosen based on the prevailing mechanical cue and target tissue from a design viewpoint. Stiffness and stress relaxation are crucial for stem-cell fate, wound repair, fibrosis, and matrix remodeling through their regulation of focal adhesion formation, cytoskeletal tension, and YAP/TAZ signaling. Dynamic force transmission is essential for cartilage, bone, tendon, ligament, skeletal muscle, and myocardium, where matrix deposition, load-bearing function, and cellular alignment are central to their function. Shear stress is especially relevant for vascular and cardiovascular tissues as flow-induced mechanotransduction has a prominent influence on endothelial function, angiogenesis, and thrombosis. Each of them has specific domains of utility; tunable and stress-relaxing hydrogels suit stiffness- and viscoelasticity-sensitive niches; mechanically reinforced scaffolds sustain compression- and strain-bearing tissues; flow-responsive materials are applicable in vascular systems; and magneto-active or piezoelectric biomaterials facilitate wireless, reversible, or dynamic stimulation. Thus, future smart biomaterial design should match the intrinsic mechanical cue, material response, mechanotransduction pathway, tissue type and translational goal rather than simply report on single material examples (Table 3).

Table 3.

Cue-to-material design map of smart mechanobiological systems.

Author	Mechanical cue/stimulus	Material type	Response mechanism	Biological target/application	Evidence level/translational readiness	Key limitation
Wu et al. 42	Internal/external stimuli; microenvironmental cues	Smart responsive hydrogel microspheres	Stimulus-triggered swelling, degradation, or controlled release	Tissue regeneration; delivery of cells, drugs, or bioactive factors	Mainly in vitro and preclinical	Clinical translation and long-term in vivo performance remain limited
Zhao et al. 48	Stretch, heat, UV, and visible light	Mechanochromic self-healing PDMS elastomer	Color change under mechanical deformation and self-healing through reversible interactions	Mechanical sensing and soft-material monitoring	Material-level validation	Biomedical and in vivo validation are still limited
Xia et al. 49	Ultrasound-induced mechanical stimulation	Ultrasound-responsive polymeric micelles	Reversible or irreversible micelle disruption and drug release	Remotely triggered drug delivery	In vitro and preclinical	Ultrasound sensitivity, penetration control, and release precision require improvement
Maier et al. 57	External pressure/compression	Supramolecular hyaluronic acid hydrogel	Pressure-induced network rearrangement and protein release	Mechano-triggered biomolecule delivery for regenerative applications	In vitro/early preclinical	Force threshold, release kinetics, and in vivo validation need further optimization
Jain et al. 59	Compression, deformation, and hydration-associated mechanical cues	Cryogels with interconnected pores	Elastic recovery, rapid hydration, and mass transport through porous architecture	Tissue engineering, biosensing, and delivery platforms	Material and preclinical validation	Structure–function relationships and clinical performance remain insufficiently defined
Zhang et al. 63	Light, humidity, and shear force	Azobenzene-containing alginate-based biomaterial	Reversible phase transition, self-healing, and adaptive mechanical response	Wound healing and dynamic tissue repair	Preclinical	Long-term safety, degradation, and translational testing are still required
Garcia-Gonzalez, Raman, Schuerle and Tay 51	Magnetic field-induced force, torque, compression, and oscillation	Magneto-active materials and magnetic actuation systems	Wireless mechanical actuation through magnetic components and external magnetic fields	Mechanomedicine, remote cell stimulation, and mechanotherapeutic applications	Emerging preclinical/early translational	Force quantification, heating, targeting, and safety standardization are required
Garcia-Gonzalez 52	Remote magnetic force transmission	Magnetic particles, magneto-responsive hydrogels, magnetoelastic substrates, and magnetic scaffolds	Remote deformation of cells and extracellular matrix to regulate mechanotransduction	Cell–matrix mechanics, organoid mechanobiology, and disease modeling	Mainly in vitro and preclinical	Local force distribution and in vivo mechanical output remain difficult to quantify
Cedillo-Servin, Raman, Castilho and co-workers 53	Multiscale mechanical actuation and adaptive tissue remodeling	Meta-adaptive biomaterials	Spatiotemporal actuation, hierarchical organization, and cell–material feedback	Engineered tissues and adaptive regenerative platforms	Conceptual and emerging preclinical	Complex fabrication, control, and clinical translation remain challenging

Applications in regenerative medicine

Wound healing and skin regeneration

Regenerative medicine has gained traction as a strategy for wound healing and skin repair, notably as chronic wounds still represent a high unmet clinical demand. As reported by Nilforoushzadeh et al., ⁶⁴ despite billions of dollars spent worldwide in the last 20 years on wound treatment and skin regeneration, no commercially available regenerative therapy is used globally, and clinical outcomes have not been standardized. Thereafter, Shimizu et al. ⁶⁵ listed safer and more efficient regenerative strategies which could be divided by cell-based (MSCs, iPSCs) or cell-free approaches (fibroblast derived products including platelet-rich plasma, exosomes and conditioned media). The study also highlighted the demand for more personalized and specific wound interventions, especially acute and chronic wounds. ⁶⁶ In the case of aged skin, where healing is significantly impaired, Duscher et al. ⁶⁷ reported that scaffold-based delivery systems are able to boost stem-cell engraftment and paracrine activity with an adaptive wound dressing or a mechanically supporting scaffold becoming critical for chronically hostile wound conditions.

Bone and musculoskeletal regeneration

Load-responsive materials and stiffness-guided regeneration have been actively explored in the field of musculoskeletal repair. Mesenchymal stem based cell therapies show promise, though none has become standard of care in orthopaedics yet. ⁶⁸ This translational challenge was elaborated upon by Holzapfel et al., ⁶⁹ who analyzed tissue engineering and regenerative medicine approaches to musculoskeletal tumors, noting the potential role of multifunctional biomaterials and drug-delivery nanomaterial in promoting both regeneration and anti-cancer effects. Smith and Grande ⁷⁰ elaborated on requirements for musculoskeletal scaffolds, explaining that shape fidelity, biomechanical performance, and biocompatibility must always be balanced in creating a scaffold; still bone scaffolds are limited because vascularization and biomechanical optimization are hard to accomplish together. Notably, El Miedany et al. ⁷¹ highlighted the significance of modulating the tissue microenvironment to promote progenitor function and suggested that regenerative rehabilitation coupled with stiffness-dependent niche engineering may be fundamental components of future musculoskeletal therapeutic approaches.

Cardiovascular and vascular applications

Full restoration of tissue remains hard to perform, and as such, cardiovascular regeneration has been approached with hesitance. The prediction of Lee and Walsh ⁷² anticipated that most rigorously powered cardiac cell-therapy trials in the upcoming 10 years are likely to return null results, although long-term regenerative advances remain probable sometime during the first half of this century. In a parallel effort, Tomov et al. ⁷³ investigated biomaterial-based, cell based and hybrid approaches to engineer functional cardiac constructs. The critical bottleneck of vascularization was pointed out as a significant constraint by Kim et al., ⁷⁴ highlighting that the 3D myocardium engineered from cells will need constant flow of oxygen and nutrients. Hinderer et al. ⁷⁵ also mentioned that other clinical unmet goals include small-diameter vascular substitutes <6 mm, thrombus-free grafts, and growth-capable pediatric valves. Overall, these discoveries bolster the significance of flow-responsive scaffolds, vascular grafts and mechanothermally regulated cardiovascular constructs.

Neural and soft tissue regeneration

Soft biomaterials have also been extremely well-investigated in the field of neural and soft tissue repair. The use of MSCs in craniofacial, vascular, muscular, fibrous and nerve regeneration was summarized by Rehman et al. ⁷⁶ Atala [794] more broadly stated that tissue engineering integrates cell transplantation, material science and bioengineering to solve the increasing scarcity of donor organs. Li et al. ⁷⁷ reported engineered grafts that consist of biomaterials, growth factors, and stem cells that could support repair in brain injury, stroke and spinal cord injury as a special series in neural regeneration; six papers out of 10 submissions were published as part of that series, another indication of interest in this area. Finally, according to McMurtrey, ⁷⁸ the design of biomaterial has potential to control neurite elongation in addition to influence causes that affect stem-cell survival, differentiation and tissue architecture; hence the importance of soft, mechanosensitive neural interfaces.

Stem cell engineering platforms

Mechanically tunable stem-cell platforms have emerged as integral agents for regenerative medicine, because successful repair relies on ensuring that stem-cell behavior is compatible with disease-specific niches. Two types of regenerative strategies were framed as replacement and regeneration/rejuvenation ⁷⁹ ; each requires environmental matching. Next, Mahla ⁸⁰ highlighted that ex vivo remodeling, 3D organoid engineering and source-specific stem-cell selection have broadened personalized applications. Nirmalanandhan and Sittampalam ⁸¹ suggested that combination strategies are necessary because simply using stem-cell therapy may not suffice, but rather stem-cell therapy should be augmented with molecular adjuvants, high-throughput screening and 3D tissue engineering. Lastly, Akhtar and Gupta ⁸² pointed out the convergence of biomaterials/organ-on-a-chip systems/immune engineering/bioprinting/molecular engineering in creating advanced stem-cell-engineering platforms which could more finely control cell fate for regenerative applications (Table 4).

Table 4.

Representative smart biomaterial strategies for regenerative medicine applications.

Author	Regenerative application	Material/engineering strategy	Main regenerative goal	Key note/numerical point	Limitation/gap
Duscher et al. 67	Wound healing/aged skin	Scaffold-based stem cell delivery	Improve engraftment and paracrine repair in chronic wounds	Focus on aged wounds with reduced healing capacity	Clinical adoption still limited
Smith and Grande 70	Bone, cartilage, tendon, meniscus, muscle	3D scaffolds using natural/synthetic materials	Structural replacement with biomechanical support	Cartilage scaffolds have strongest clinical experience	Bone vascularization and biomechanical optimization remain difficult
Kim et al. 74	Cardiac regeneration/heart failure	Vascularized 3D tissue engineering; micropatterning; sacrificial materials; bioprinting	Maintain viability and function of engineered myocardium	Constant oxygen/nutrient supply is essential	Efficient vascularization remains a major bottleneck
Hinderer et al. 75	Myocardium, heart valves, blood vessels	Off-the-shelf biomaterials; scalable biomaterial processing	Functional cardiovascular tissue replacement	Small-diameter vascular grafts <6 mm are still challenging	Translation to clinical standard remains far off
Li et al. [95]	Neural tissue regeneration	Biomaterial scaffolds + stem cells + growth factors	Repair brain, spinal cord, and peripheral nerve injury	Special issue included 6 papers from 10 submissions	Tumorigenicity and integration issues remain
Nirmalanandhan and Sittampalam 81	Stem cell engineering platforms	Stem cells + molecular adjuvants + 3D tissue engineering	Improve regenerative efficacy and preclinical translation	Stem cells used as tools over the past 2 decades	Stem cells alone may be insufficient

Conclusion and future outlook

Here, we have highlighted that mechanical forces cannot be simply viewed as background phenomena in the cell microenvironment but instead serve as a fundamental regulator of cell fate, tissue organization and repair, and disease progression. In fact, biological tissues have always been described as both mechanically heterogeneous and time-dependent systems, in which stiffness, viscoelasticity, stress-relaxation, anisotropy and dynamic force transmission mold migration, proliferation, differentiation and immune response and matrix remodelling. It was also shown that cells detect these signals with receptors like integrins, focal adhesions, mechanosensitive ion channels, direct cytoskeletal tension and nucleus-tethered signaling pathways but in turn produce traction forces that often fall into the pN–nN span over nm–μm distances. This illustrates a clear shift in the biomaterials field from passive materials to smart mechanobiological systems, including strain-stiffening and stress-relaxing hydrogels, self-healing polymers, mechanoresponsive delivery systems, piezoelectric platforms, as well as programmable 4D constructs. It has been repeatedly shown has been demonstrated in both regenerative and disease-intervention contexts across disease intervention and regenerative approaches that enhanced biological control is a function of how materials are designed to measure, transfer and adapt to force rather than simply provide static support. ⁸³

In the future, we may transition past responsive materials into closed-loop mechanotherapeutic systems in which sensing, actuation, prediction and intervention are harmonized. Great opportunities will originate from the merge of AI-augmented analysis, intelligent biosensors, organoid-on-chip (Organs-on-Chip), magneto-mechanical actuation, programmable biofabrication and tailor-made computational models. In such a framework, multi-scale predictive strategies inspired by the concept of digital twins may enable us to anticipate tissue mechanics, remodeling behavior, and therapeutic response prior to or during treatment while adaptive biomaterials are tuned in real time based on the evolving biological state of the patient. Meanwhile, this will continue to need deeper mechanistic insight to connect molecular force events with emergent tissue-scale behavior, especially in such diverse biological pathways as fibrosis, cancer, cardiovascular remodeling and chronic non-healing repair. Thus, the next steps are only to be made in an integrated translational pathway that combines mechanobiology, materials science, systems engineering and computation with clinical medicine. In that future, smart mechanobiological systems may be positioned not just as supportive biomaterials but rather as active programmable therapeutic partners directing regeneration to overcome disease progression and redefine precision medicine.