Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review)

Introduction

Orthopedic rehabilitation has long relied on mechanical interventions, such as physical therapy, exercise and load-bearing activities, to promote tissue repair and functional recovery (1,2). However, the biological mechanisms underlying these therapies have only recently been elucidated through advances in understanding mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals (3,4). This intricate interplay between physical forces and cellular responses plays a pivotal role in tissue regeneration, particularly in the bone, cartilage, tendons and ligaments (5,6). As regenerative medicine continues to evolve, understanding mechanotransduction offers new opportunities to enhance healing, optimize rehabilitation protocols and develop novel bioengineered therapies (7,8).

Mechanotransduction is a fundamental biological phenomenon that enables cells to sense and respond to mechanical cues such as tension, compression and shear stress (9,10). In orthopedic tissues, specialized cells including osteocytes, chondrocytes, tenocytes and mesenchymal stem cells (MSCs) possess mechanosensitive receptors (such as integrins, ion channels and primary cilia) that detect extracellular mechanical forces (11,12). These signals trigger intracellular cascades, such as the activation of Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), Wnt/β-catenin and mitogen-activated protein kinase (MAPK) pathways, ultimately influencing gene expression, extracellular matrix (ECM) remodeling and tissue adaptation (13-15). The ECM itself acts as a dynamic scaffold that transmits and amplifies mechanical signals, further modulating cellular behavior (16,17).

Distraction histogenesis is the biological process that regenerates bone and soft tissue (18). In bone regeneration, mechanical loading stimulates the osteogenic differentiation of MSCs and osteoblasts while inhibiting osteoclast activity, thereby promoting bone formation and preventing resorption (19,20). Low-magnitude high-frequency vibration and controlled cyclic loading have shown promise in accelerating fracture healing and mitigating osteoporosis-related bone loss (21,22). Similarly, in cartilage repair, chondrocytes respond to dynamic compression by upregulating anabolic factors (such as aggrecan and collagen type II) while suppressing catabolic enzymes [such as matrix metalloproteinases (MMPs)] (23,24). However, excessive or aberrant loading can induce degenerative changes, highlighting the need for precise mechanotherapeutic strategies (25). Tendon and ligament healing, often hindered by poor vascularity and slow ECM turnover, also depends on mechanotransduction (26,27). Controlled mechanical stimulation enhances collagen alignment and tensile strength, whereas immobilization leads to tissue atrophy and fibrosis (28). Emerging evidence suggests that tendon stem/progenitor cells exhibit load-dependent differentiation, offering potential targets for regenerative interventions (29). The integration of mechanotransduction principles into regenerative medicine has led to innovative approaches in orthopedic rehabilitation (7,25).

Biomechanically optimized scaffolds, embedded with growth factors and designed to mimic native tissue mechanics, enhance stem cell recruitment and differentiation (30,31). Additionally, dynamic bioreactor systems apply physiologically relevant mechanical stimuli to engineered tissues, improving their functional maturation before implantation (32). Clinically, mechanotherapy, the therapeutic application of mechanical forces, has gained traction. Techniques such as extracorporeal shockwave therapy (ESWT) and pulsed electromagnetic fields (PEMFs) harness mechanotransduction to stimulate tissue repair, while personalized rehabilitation protocols leverage patient-specific loading regimens to maximize recovery (3,33). The optimal magnitude, frequency and duration of mechanical stimuli vary across tissues and individuals, necessitating further research into precision mechanotherapies. Additionally, the crosstalk between mechanical and biochemical signaling pathways must be deciphered to develop synergistic treatment strategies. Future advancements in biofabrication, smart biomaterials and artificial intelligence (AI)-driven biomechanical modeling hold promise for tailoring regenerative therapies to individual patient needs (34).

The present review comprehensively examines the fundamental mechanisms of mechanotransduction, detailing how specialized sensors convert physical forces into biochemical signals that direct cellular behavior. The present review explores the critical role of the ECM as a dynamic mediator of mechanical signaling and investigates tissue-specific responses in bone, cartilage, tendon and ligament regeneration. The discussion extends to the notable impact of mechanical loading on stem cell differentiation and the development of innovative biomechanical strategies in regenerative medicine, including advanced biomaterials and bioreactor systems. Clinically, the present review focuses on translating these principles into effective mechanotherapy protocols and personalized rehabilitation approaches. Finally, the prevailing challenges in defining optimal loading parameters are addressed and future directions are explored, emphasizing the potential of emerging technologies such as smart biomaterials and AI-driven modeling to create precise, biologically-driven interventions. By synthesizing these elements, the present review aims to highlight the transformative potential of integrating mechanobiology with regenerative medicine to advance orthopedic rehabilitation outcomes.

Cellular sensors and fundamental mechanisms of mechanotransduction

The conversion of mechanical forces into biochemical signals, a process fundamental to tissue repair, is initiated by specialized cellular structures known as mechanosensors. These sensors detect physical cues including compression, tension and fluid shear stress within the musculoskeletal environment (35). Principal among these are integrins, transmembrane receptors that form focal adhesion complexes, creating a critical link between the ECM and the intracellular cytoskeleton. These complexes act as primary force transduction hubs, sensing deformation and matrix stiffness. Additionally, stretch-activated ion channels (such as Piezo1) embedded in the cell membrane respond to mechanical perturbation by rapidly altering ion flux, particularly Ca2+, to initiate immediate electrochemical signaling (36). On the surface of cells such as osteocytes and chondrocytes, primary cilia project as non-motile antennae, exquisitely tuned to sense subtle changes in fluid flow and pressure. Force detection by these sensors triggers a sophisticated cascade of intracellular signaling pathways. The mechanical signal is first propagated through the dynamic cytoskeleton, a network that distributes tension from the membrane to the nucleus (37). This mechanical energy is then converted into chemical signals through the activation of key mediators.

Mechanotransduction is the sophisticated process through which cells perceive external mechanical forces and convert them into intracellular biochemical responses (4,9). This fundamental mechanism is initiated by mechanosensors, which are specialized cellular structures that detect mechanical perturbations. Key sensors include integrins, which tether the intracellular cytoskeleton to the ECM, forming focal adhesion complexes that act as primary force transduction hubs (38,39). Additionally, stretch-activated ion channels (such as Piezo1) rapidly alter ion flux upon membrane deformation, while primary cilia on chondrocytes and osteocytes function as cellular antennae, sensing fluid shear stress and compression (40). Force detection triggers a cascade of intracellular signaling pathways. The mechanical signal is propagated via the cytoskeleton, a dynamic network that distributes tension throughout the cell (37). This leads to the activation of key mediators such as the Hippo pathway effectors YAP and TAZ, which translocate to the nucleus to regulate genes responsible for proliferation and matrix synthesis (41,42). Fig. 1 depicts the key signaling cascades (such as the Wnt/β-catenin and MAPK pathways) activated by mechanosensitive ion channels, which further modulate cell fate decisions, including differentiation and apoptosis (43,44). Crucially, mechanotransduction is bidirectional. Cells not only respond to forces but also actively exert contractile forces on their surroundings through actomyosin activity, a concept known as mechanoreciprocity (45,46). This continuous dialogue between cells and their biomechanical environment is essential for maintaining tissue homeostasis and is a critical target for guiding regenerative outcomes in orthopedic tissues (47). Key cellular mechanosensors and signaling pathways are shown in Table I (48-56).

Figure 1 Mechanotransduction is fundamental to distraction histogenesis. Mechanotransduction begins when mechanical forces are applied to the ECM and cellular membranes, which in turn stimulate mechanosensitive ion channels, including Piezo1. The activation of these channels initiates downstream signaling cascades such as the Wnt/β-catenin, MAPK, PI3K/AKT and mTOR pathways that regulate critical cellular processes, including proliferation and differentiation. Concurrently, this mechanosensitive signaling stimulates the production of growth factors, namely TGF-β1, PDGF-BB and VEGF. These factors are then released into the circulation and transported to the injury site, where they promote bone lengthening and regeneration, in addition to supporting the repair and neogenesis of vascular and cutaneous tissues. ECM, extracellular matrix; LRP, lipoprotein receptor-related protein; GSK-3β, glycogen synthase kinase 3β; CKIα, casein kinase 1α; APC, adenomatous polyposis coli; TCF/LEF, T-cell factor and lymphoid enhancer-binding factor; RAS, rat sarcoma; Raf, rapidly accelerated fibrosarcoma; ERK, extracellular signal-regulated kinase; shc, SHC-adaptor protein; GRB2, growth factor receptor-bound protein; RTK, receptor tyrosine kinase; TSC1, tuberous sclerosis complex 1; Rheb, Ras homolog enriched in brain; PDGF-BB, platelet-derived growth factor-BB.

Table I Key cellular mechanosensors and signaling pathways.

Table I

Key cellular mechanosensors and signaling pathways.

Mechanosensor or pathway	Description	Function in mechanotransduction	(Refs.)
Integrins and focal adhesions	Transmembrane receptors that link the extracellular matrix to the intracellular cytoskeleton.	Form primary force transduction hubs; detect tension and stiffness (mechanoreciprocity) by sensing ECM deformation.	(38,48,49)
Stretch-activated ion channels (such as Piezo1)	Channels embedded in the cell membrane that open in response to membrane deformation.	Rapidly alter ion flux (such as Ca2+ influx) upon mechanical stress, initiating immediate signaling cascades.	(36)
Primary cilia	Non-motile, hair-like microtubule-based organelles projecting from the cell surface.	Act as cellular antennae sensing fluid shear stress, compression and osmotic pressure.	(50,51)
YAP/TAZ (Hippo pathway)	Transcriptional coactivators that shuttle between the cytoplasm and nucleus.	Act as central mediators; translocate to the nucleus upon mechanical stimulation to regulate genes for proliferation and matrix synthesis.	(14,52)
Wnt/β-catenin pathway	A highly conserved signaling pathway crucial for development and homeostasis.	Activated by mechanical loading (such as in bone, via sclerostin inhibition) to promote osteogenic differentiation.	(53,54)
Cytoskeleton	A dynamic network of actin filaments, microtubules and intermediate filaments.	Distributes and transmits tension throughout the cell, from the membrane to the nucleus.	(55,56)

Role of the extracellular matrix in mechanical sensing

The ECM is far more than a passive structural scaffold; it is a dynamic and active mediator essential for cellular mechanical sensing. The composition, architecture and physical properties of the ECM fundamentally govern how mechanical forces are transmitted, attenuated or amplified before reaching cellular mechanosensors (57). The stiffness of the ECM, or elastic modulus, provides a critical physical cue that directly influences cell fate. For instance, MSCs can sense this rigidity through integrin-mediated adhesions, a process known as durotaxis, which directs them toward osteogenic differentiation on stiffer, bone-mimetic substrates or adipogenesis on softer substrates (58). Beyond static properties, the viscoelasticity of the ECM, its ability to exhibit both elastic solid and viscous fluid behaviors, allows it to absorb and distribute energy from dynamic loading (59). This time-dependent response protects cells from sudden, damaging impacts while facilitating the transfer of beneficial, rhythmic strains. Furthermore, the molecular organization of the ECM is pivotal. The specific arrangement of fibrillar collagens, proteoglycans and glycoproteins creates a unique architectural landscape that filters mechanical signals (60). This organized network ensures that forces such as tension or compression are not merely felt as blunt pressure but are translated into specific, spatially guided biochemical instructions.

Crucially, the matrix acts as a biochemical reservoir that works in concert with mechanical inputs. Embedded growth factors and bioactive peptides are often sequestered within the ECM and can be released or activated in response to mechanical deformation (61). The mechanosensitive signaling triggers the production of growth factors including TGF-β1, platelet-derived growth factor-BB and VEGF, which are released into the circulation and transported to the injury site to promote bone lengthening and regeneration (62). This process, termed mechano-chemo transduction, creates a synergistic effect where physical forces directly modulate the local biochemical microenvironment. For example, mechanical strain can liberate TGF-β from its latent binding proteins in the matrix, thereby simultaneously providing a mechanical and a chemical stimulus for tissue repair (63). Therefore, the ECM is an indispensable partner in mechanotransduction; it functions as a sophisticated signal processor that contextualizes external mechanical loads, ensuring that the subsequent intracellular signaling cascades and transcriptional responses are appropriate for maintaining tissue homeostasis or initiating regeneration (60). This central role makes the rational design of ECM-mimetic biomaterials a paramount strategy in regenerative orthopedics.

Mechanotransduction in bone and cartilage regeneration

The regenerative processes in bone and cartilage are guided by mechanotransduction, although the specific cellular responses differ due to the distinct physiological demands of each tissue (64-66). In bone regeneration, mechanical loading is a potent anabolic stimulus (67). Osteocytes, embedded within the mineralized matrix, act as the primary mechanosensors, detecting interstitial fluid flow shear stress generated during loading (68,69). This detection inhibits sclerostin expression, thereby unleashing the Wnt/β-catenin signaling pathway. This cascade promotes osteoblastic bone formation and suppresses osteoclastic resorption, making targeted mechanical stimulation a critical therapeutic strategy for enhancing fracture healing and combating osteoporosis (53,70,71). By contrast, cartilage regeneration presents a more complex mechanobiological challenge due to its avascular nature and low cellularity (72). Chondrocytes within the proteoglycan-rich ECM respond optimally to dynamic compression and hydrostatic pressure, which upregulate anabolic genes for type II collagen and aggrecan (73,74). However, the response is dependent on the nature, magnitude and frequency of the load. While physiological, dynamic loading promotes matrix synthesis and the chondrogenesis of MSCs, aberrant loading such as high-impact shear or prolonged static compression induces a catabolic state characterized by the release of inflammatory cytokines and matrix-degrading enzymes such as MMP-13, accelerating degeneration (74). This nuanced understanding is directly applied in rehabilitative medicine. For bone, low-magnitude high-frequency vibration and controlled weight-bearing protocols are used to stimulate healing (75). For cartilage, motion therapies and continuous passive motion devices are designed to provide beneficial dynamic compression while avoiding detrimental shear forces, thereby creating a pro-regenerative mechanical microenvironment (76).

Osteogenic responses to mechanical stimuli

Mechanical loading is a fundamental regulator of bone mass and architecture, with osteogenic responses following a well-established principle whereby bone forms in areas of high stress and resorbs in areas of disuse (77,78). This adaptive process, governed by mechanotransduction, is crucial for fracture healing and preventing osteoporosis (79). Osteocytes, comprising >90% of bone cells and entombed within lacunae, act as the orchestrators of this response; they detect minute deformations of the bone matrix, which cause interstitial fluid to flow within the canalicular network, generating shear stress across their extensive dendritic processes (69,80). This mechanical stimulation triggers a rapid biochemical response. Osteocytes downregulate the secretion of sclerostin, a key inhibitor of the Wnt/β-catenin signaling pathway (81,82). The subsequent activation of Wnt signaling in pre-osteoblasts and lining cells promotes their proliferation, differentiation and ultimately, bone formation (83). Concurrently, mechanical signals suppress osteocyte-supported receptor activator of nuclear factor κ-B ligand expression, thereby inhibiting osteoclastogenesis and bone resorption (84). Mechanical stimulation directs MSCs toward becoming bone-forming osteoblasts. This occurs by activating osteogenic transcription factors [such as β-catenin and Runt-related transcription factor 2 (RUNX2)] and suppressing regulators of other cell fates (such as fat or cartilage). As the cells mature from precursors into functional osteoblasts, they sequentially express specific marker genes (such as alkaline phosphatase, collagen type I α1 chain and osteocalcin). The final outcome for an osteoblast is either programmed cell death or embedding into bone as a lining cell. This mechanically driven process is essential for bone growth and healing in rehabilitation (85-87) (Fig. 2). The net result is a powerful anabolic shift favoring net bone deposition. Therapeutic strategies in rehabilitation leverage this knowledge. Controlled, dynamic loading regimens such as those achieved through specific weight-bearing exercises or low-magnitude, high-frequency vibration are designed to exceed the minimal effective strain threshold needed to initiate this anabolic cascade. This targeted 'mechanotherapy' provides a non-pharmacological means to accelerate fracture callus maturation, enhance bone density around implants and counteract the bone loss associated with immobilization, making it a cornerstone of modern orthopedic rehabilitation (88,89).

Figure 2 Osteogenic differentiation pathway driven by mechanotransduction. Mechanical signals promote the commitment of MSCs to the osteoblast lineage by activating key transcription factors (such as β-catenin, RUNX2 and MSX2) while inhibiting drivers of alternative fates (such as PPARγ, MyoD and SOX9). The progression from osteoprogenitor to pre-osteoblast to functional osteoblast is marked by the sequential expression of characteristic genes (such as ALP, COL1A1, BSP and OCN). The final fate of the osteoblast is either apoptosis or incorporation into the bone structure as a lining cell. This mechanically-induced osteogenesis is crucial for bone formation and regeneration in orthopedic rehabilitation. MSC, mesenchymal stem cell; PPAR-γ, peroxisome proliferator-activated receptor γ; MyoD, myoblast determination protein; SOX9, SRY-box transcription factor 9; RUNX2, Runt-related transcription factor 2; MSX2, Msh homeobox 2; FOXP1, forkhead box P1, MAF, macrophage-activating factor; ATF4, activating transcription factor 4; FAR1, fatty acyl-CoA reductase 1; ALP, alkaline phosphatase; COL1A1, collagen type I α1 chain; BSP, bone sialoprotein; OCN, osteocalcin; OSX, osterix.

Chondrocyte mechanobiology in cartilage repair

Chondrocyte mechanobiology is a critical determinant of success or failure in cartilage repair, presenting a unique therapeutic paradox (90,91). Residing within an avascular, aneural ECM, chondrocytes are sensitive to their mechanical environment (92). The application of physiological dynamic compression and hydrostatic pressure, mimicking joint loading during movement, promotes an anabolic response (67). This stimulates the synthesis of essential matrix components such as aggrecan and type II collagen, crucial for restoring the load-bearing functionality of the tissue (93,94). Such mechanical cues are vital for guiding the chondrogenic differentiation of implanted MSCs in tissue engineering strategies (95,96). However, the beneficial effects are critically dependent on load characteristics. Deviations into abnormal loading patterns, such as high-magnitude impact, shear stress or prolonged static compression, trigger a starkly different, catabolic fate. These detrimental forces activate inflammatory pathways (such as the NF-κB pathway) and upregulate matrix-degrading enzymes (MMPs and ADAMTS), leading to the breakdown of the very matrix regenerative therapies aim to build (97,98). This dichotomy underscores the importance of precise rehabilitative loading. Protocols employing motion therapy and continuous passive motion are designed to deliver pro-anabolic stimuli while meticulously avoiding the destructive shear and inflammatory stress that hinder repair and accelerate post-traumatic osteoarthritis.

Mechanotransduction in tendon and ligament healing

Tendon and ligament healing are a mechanosensitive process where the precise application of load is paramount for restoring functional strength and preventing dysfunctional scar tissue (99-101). These densely collagenous, hypovascular tissues rely on mechanotransduction to guide repair (102). Tenocytes and ligament fibroblasts possess an array of mechanosensors, including integrins and stretch-activated ion channels, which detect changes in tension and strain during movement (103). Early, controlled mechanical loading stimulates the production and organized alignment of collagen fibrils, enhancing the tensile properties of the repair and promoting a more regenerative rather than purely scar-forming outcome (104,105). Conversely, the absence of load (immobilization) leads to tissue atrophy, matrix disorganization and adhesion formation (104). As shown in Fig. 3, physical force is converted into a biochemical signal by bone cells through mechanotransduction, and surface sensors stimulate the intracellular cascade that activates transcription factors to upregulate osteogenic gene expression. However, excessive or premature loading can be equally detrimental, provoking reinjury, inflammation and metaplasia (106). The therapeutic window is narrow. Therefore, rehabilitation protocols are designed to leverage mechanotransduction carefully. Techniques such as early controlled motion and progressive loading regimens apply precise biomechanical cues to activate pro-reparative signaling pathways in tenocytes and resident stem cells. This promotes collagen synthesis and maturation while steering the healing process away from the weak, fibrotic scar tissue that characterizes poor functional recovery, making mechanotherapy a cornerstone of effective tendon and ligament rehabilitation (107,108).

Figure 3 Mechanosignaling in bone cells. This schematic depicts how bone cells perceive mechanical forces and translate them into biological activity, both within themselves and across cell-to-cell junctions. The pathway initiates with mechanical signals being detected by sensors on the cell surface (such as integrins and ion channels) and the cytoskeleton. This triggers mechanotransduction via signaling pathways (such as Hippo and Wnt), leading to the generation of signaling molecules. Intracellularly, key TFs (such as YAP/TAZ, β-catenin and RUNX2) are activated and translocate to the nucleus to mediate transcriptional regulation of target genes (such as BGLAP and SPP1) essential for bone formation. Furthermore, these signals are communicated to neighboring cells via receptor-mediated cell-cell interactions (such as through gap junctions or paracrine signaling), coordinating a synchronized anabolic response across the bone tissue. ECM; extracellular matrix; TF, transcription factor; YAP, Yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding motif; RUNX2, Runt-related transcription factor 2; BGLAP, bone γ-carboxyglutamate protein; SPP1, secreted phosphoprotein 1.

Impact of mechanical loading on stem cell differentiation

Mechanical loading is a potent regulator of stem cell fate, serving as a critical determinant in their commitment to specific lineages essential for musculoskeletal repair (30). The differentiation of MSCs is not solely governed by biochemical cues; the physical forces present in their microenvironment provide instructive signals that can override soluble factors (109). For instance, substrate stiffness is a primary mechanical cue. MSCs cultured on substrates mimicking the stiffness of bone tissue tend to undergo osteogenesis, upregulating RUNX2 and osteocalcin expression (110). By contrast, softer substrates that resemble brain or fat tissue promote neurogenesis or adipogenesis, respectively (111). This phenomenon, known as durotaxis, highlights how cells sense and migrate along stiffness gradients, a principle vital for designing biomaterials in tissue engineering (112,113). Beyond static stiffness, dynamic mechanical forces such as cyclic tensile strain, compression and fluid shear stress directly activate mechanosensitive pathways that dictate lineage specification (114,115). Applied cyclic strain promotes tenogenic and osteogenic differentiation by activating pathways such as focal adhesion kinase/MAPK and RhoA/Rho-associated coiled-coil-containing protein kinase, which influence cytoskeletal tension and nuclear translocation of transcription factors (116). Fluid shear stress, crucial in vascular and bone environments, enhances osteogenesis by stimulating prostaglandin release and activating Wnt/β-catenin signaling (117,118). Even low-intensity vibrations have been shown to promote osteogenic differentiation while suppressing adipogenesis, illustrating the finely tuned nature of mechanical input (119). Mechanical forces are transmitted from the cell cytoskeleton (F-actin) to the nucleus through the linker of nucleoskeleton and cytoskeleton complex, causing the nucleus to deform (120). This strain increases the permeability of nuclear pores, allowing for faster import of critical transcription factors (120). As a result, mechanosensitive regulators such as YAP/TAZ and β-catenin accumulate in the nucleus (121). There, they initiate osteogenic genetic programs. At the same time, phosphorylated RUNX2 binds to DNA, prompting chromatin to remodel into an open state. This open conformation further activates the transcription of genes that are essential for bone formation (Fig. 4). The implications for regenerative medicine are profound. In bioreactors for tissue engineering, mechanical conditioning such as cyclic stretching of tendon grafts or fluid flow perfusion in bone scaffolds is used to pre-condition stem cell-seeded constructs, promoting differentiation and matrix maturation before implantation (122). In clinical rehabilitation, understanding how specific exercise-induced loading regimens influence endogenous stem cell pools can lead to targeted therapies that harness mechanical cues to guide tissue repair, offering a non-invasive strategy to enhance regenerative outcomes in orthopedic healing (123,124).

Figure 4 Nuclear mechanotransduction drives osteogenic transcription. Mechanical forces are transduced from the cytoskeleton (F-actin) to the nucleus via the LINC complex, inducing nuclear deformation. This strain enhances the permeability of nuclear pore complexes, facilitating the accelerated nuclear import of key transcription factors and coactivators. The mechanosensitive regulators YAP/TAZ and β-catenin accumulate within the nucleus, where they orchestrate the upregulation of osteogenic gene programs. Concurrently, phosphorylated RUNX2 binds to target sites, inducing chromatin remodeling to an open conformation, which further potentiates the transcriptional activation of genes essential for bone formation. LINC; linker of nucleoskeleton and cytoskeleton; SUN, Sad1-UNC-84 homology; KASH, Klarsicht, ANC-1, syne homology; ERK, extracellular signal-regulated kinase; YAP, Yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding motif; RUNX2, runt-related transcription factor 2; TCF, T-cell factor; LEF, lymphoid enhancer factor; LCF, transcription cofactor; TEAD, transcriptional enhanced associate domain.

Biomechanical strategies in regenerative medicine

The integration of mechanobiology principles into regenerative medicine has given rise to innovative biomechanical strategies designed to orchestrate tissue repair by harnessing the power of mechanical forces (125,126). These approaches move beyond passive structural support, aiming to actively direct cellular behavior through precisely controlled physical cues. A central strategy involves the development of smart biomaterial scaffolds. These are not inert structures but are engineered with specific mechanical properties such as tunable stiffness, viscoelasticity and microtopography that mimic the native ECM of the target tissue (127,128). For instance, a scaffold designed for bone regeneration is designed to be rigid to promote osteogenesis, while a cartilage scaffold requires a compliant, hydrogel-based environment to support chondrogenesis (129). Furthermore, these scaffolds can be functionalized with tethered bioactive molecules that are mechanically activated upon cell adhesion or scaffold stretching, creating a dynamic feedback loop with resident cells (130,131). Beyond static design, dynamic bioreactor systems are a cornerstone of in vitro tissue engineering. These devices apply biomimetic mechanical stimuli including cyclic compression, tensile strain and fluid shear stress to cell-seeded constructs during cultivation (132,133). This process of mechanical preconditioning promotes stem cell differentiation, enhances ECM synthesis and organization and yields a more functional and robust tissue graft prior to implantation (134). For example, tensile bioreactors are used to generate aligned collagen fibers in engineered ligaments, significantly improving their ultimate tensile strength (135,136). Translating these principles to the clinic, advanced mechanotherapy is revolutionizing rehabilitation. Techniques such as ESWT and low-intensity pulsed ultrasound (LIPUS) deliver targeted mechanical energy to injury sites, activating pro-regenerative mechanotransduction pathways, enhancing angiogenesis and stimulating stem cell recruitment (137,138). These biomechanical strategies, which work in concert with biological cues, represent a paradigm shift from merely replacing damaged tissue to actively instructing the innate healing mechanisms of the body, thereby significantly improving functional outcomes in orthopedic rehabilitation (139,140).

Physical therapies and exercise-induced mechanotransduction

Physical therapies represent the deliberate clinical application of mechanotransduction principles, utilizing controlled mechanical stimuli to directly influence cellular behavior and guide tissue repair (25,141). Therapeutic exercise is not merely about strengthening muscles; it is a precise modality that delivers targeted biomechanical cues to injured bones, cartilage, tendons and ligaments (25,142). Each movement, whether it is weight-bearing, resistance training or dynamic motion, generates specific forces that are detected by cellular mechanosensors, such as integrins and ion channels (1). This initiates intracellular signaling cascades that promote anabolic processes, including collagen synthesis, matrix organization and stem cell differentiation (143,144). The efficacy of these interventions hinges on the careful calibration of mechanical dosing. Rehabilitation protocols are designed to apply loads within a therapeutic window that stimulate repair without exacerbating damage. For instance, eccentric loading of tendons promotes aligned collagen fibril formation, while controlled motion following cartilage procedures delivers essential dynamic compression that enhances chondrocyte activity and nutrient diffusion (23,145). By harnessing the body's innate responsiveness to physical forces, exercise-based therapies provide a powerful, non-invasive strategy to optimize the regenerative microenvironment, making them a cornerstone of modern orthopedic rehabilitation.

Clinical applications in orthopedic rehabilitation

The principles of mechanotransduction are directly applied in orthopedic rehabilitation to enhance healing and functional recovery (7,25). Clinicians utilize controlled mechanical loading through tailored exercise regimens to stimulate cellular repair processes across various tissues. Following fracture fixation, progressive weight-bearing is prescribed to generate osteogenic fluid shear stress, promoting callus formation and bone remodeling (146,147). This approach harnesses the mechanosensitivity of osteocytes to guide structural adaptation. In soft tissue injuries, specific loading protocols are fundamental (141,148). For tendinopathies, eccentric strengthening exercises apply controlled tensile strains that upregulate collagen production in tenocytes, improving tendon fibril alignment and tensile strength (149). Similarly, postoperative rehabilitation after cartilage repair procedures incorporates continuous passive motion and carefully graded active exercises (150,151). These interventions deliver essential dynamic compression and hydrostatic pressure to chondrocytes, supporting matrix synthesis while preventing the formation of adhesions and fibrous tissue (23,152). These clinical strategies exemplify mechanotherapy, where externally applied forces are translated into biochemical signals that drive anabolic cellular activity. By modulating the intensity, frequency and type of mechanical stimulus, rehabilitation specialists can optimize the tissue microenvironment to support regeneration, reduce recovery time and improve long-term functional outcomes for patients with musculoskeletal injuries (Table II) (153-158).

Table II Clinical applications of mechanotransduction in orthopedic rehabilitation.

Table II

Clinical applications of mechanotransduction in orthopedic rehabilitation.

Tissue	Clinical application or therapy	Mechanism of action (based on mechanotransduction)	Intended outcome	(Refs.)
Bone	Controlled weight-bearing and low-magnitude high-frequency vibration	Generates interstitial fluid flow and shear stress, detected by osteocytes. Inhibits sclerostin, activating Wnt/β-catenin pathway to promote bone formation.	Accelerate fracture healing and mitigate osteoporosis-related bone loss.	(81,82,153)
Cartilage	Motion therapy and continuous passive motion	Applies dynamic compression and hydrostatic pressure to chondrocytes. Upregulates anabolic factors (such as aggrecan, collagen II) and suppresses catabolic enzymes (such as matrix metalloproteinases).	Enhance cartilage repair, support chondrogenesis and prevent adhesions and degeneration.	(154,155)
Tendon and ligament	Eccentric strengthening exercises and progressive loading	Applies controlled tensile strain detected by tenocytes via integrins and ion channels. Promotes aligned collagen fibril formation and improves tensile strength.	Improve collagen alignment, enhance tensile properties of repair and prevent dysfunctional scarring and atrophy.	(156)
General (multiple tissues)	Low-intensity pulsed ultrasound and extracorporeal shockwave therapy	Deliver targeted mechanical energy (sound waves and shockwaves) to the injury site. Activates pro-regenerative mechanosensitive pathways, enhances angiogenesis and stimulates stem cell recruitment.	Stimulate tissue repair, accelerate healing and treat delayed unions or non-unions.	(138,157)
Tissue engineering	Bioreactor conditioning (such as cyclic strain and compression)	Applies biomimetic mechanical stimuli to stem cell-seeded constructs in vitro. Directs stem cell differentiation and promotes extracellular matrix synthesis and organization prior to implantation.	Create more functional and robust engineered tissue grafts (such as bone, cartilage and tendon) with improved mechanical properties.	(31,158)

Mechanotherapy for fracture healing

Mechanotherapy is a targeted therapeutic approach that applies controlled mechanical forces to directly influence the biological process of fracture repair (159,160). Following a fracture, the carefully timed introduction of specific mechanical stimuli is crucial for guiding callus formation, mineralization and eventual remodeling. This strategy harnesses the innate mechanosensitivity of bone cells, particularly osteocytes, which act as primary sensors of changes in their mechanical environment. Clinical applications begin with an initial period of relative stabilization to allow early callus formation, followed by the progressive introduction of load (161). Controlled weight-bearing and resistance exercises are prescribed to generate intermittent hydrostatic pressure and fluid shear stress within the porous network of the bone (162,163). These mechanical cues are detected by osteocytes, triggering intracellular signaling cascades that downregulate sclerostin expression. The subsequent activation of the Wnt/β-catenin pathway promotes osteoblast differentiation and activity, accelerating bone formation while simultaneously inhibiting osteoclastic bone resorption (53,164). Advanced modalities such as LIPUS and PEMFs provide non-invasive mechanical and electrical stimulation to the fracture site (165). These techniques enhance cellular proliferation, angiogenesis and matrix synthesis, particularly in cases of delayed union or non-union. By precisely modulating the mechanical microenvironment, mechanotherapy offers a powerful, non-pharmacological method to optimize the innate healing capacity of the body, reduce recovery time and improve structural outcomes in fracture management.

Mechanically assisted tissue engineering

Mechanically assisted tissue engineering represents a paradigm shift in regenerative medicine, moving beyond passive scaffolds to dynamic systems that actively instruct cellular behavior through applied physical forces. This approach recognizes that mechanical cues are as critical as biochemical signals in directing stem cell differentiation and fostering the development of functional, load-bearing tissues. In vitro, this is achieved through the use of bioreactors that deliver biomimetic mechanical conditioning such as cyclic strain for tendons, fluid shear for bone and dynamic compression for cartilage to cell-seeded constructs (166). This preconditioning promotes ECM synthesis, improves structural organization and enhances the mechanical properties of the engineered tissue before implantation. The principles extend to smart scaffold design, where materials are engineered with specific mechanical properties such as tailored stiffness, elasticity and degradability that mimic the native tissue environment and provide ongoing mechanical cues in vivo (167). These scaffolds can be designed to respond to body movements, thereby continuously stimulating integrated cells post-implantation. By harnessing mechanotransduction to guide cellular activity at every stage, mechanically assisted tissue engineering creates more robust and biologically integrated grafts, significantly improving their functional outcomes and success rates in orthopedic repair and rehabilitation (125,168).

Personalized mechanotransduction-based therapies

The future of orthopedic rehabilitation lies in personalizing interventions based on individual mechanobiological profiles. Personalized mechanotransduction-based therapies move beyond one-size-fits-all protocols by accounting for patient-specific factors such as age, genetics, tissue viability and biomechanics (169). Advanced imaging and diagnostic technologies enable clinicians to assess the unique mechanical microenvironment and cellular responsiveness of the patient, creating a foundation for tailored rehabilitation strategies. For instance, real-time feedback systems and wearable sensors can monitor load distribution and movement patterns during therapeutic exercises. This data, combined with genetic profiling that identifies variations in mechanosensitive pathways, allows for the optimization of mechanical dosing prescribing specific intensities, frequencies and types of loading that are most likely to stimulate anabolic responses in that individual (67). In tissue engineering, this approach translates to 3D-bioprinted scaffolds customized to match the anatomical and mechanical requirements of the patient, potentially seeded with autologous cells primed ex vivo using patient-specific mechanical conditioning (170). By aligning therapeutic mechanical inputs with the cellular responsiveness of the individual, these precision interventions maximize regenerative potential, minimize the risk of re-injury and significantly improve functional recovery, heralding a new era of truly personalized orthopedic medicine.

Challenges and future directions in optimizing mechanical stimulation protocols

Despite significant advances, translating mechanotransduction research into clinical practice faces notable challenges. A primary hurdle is defining the optimal mechanical dosage, such as the precise intensity, frequency and duration of loading, required to stimulate anabolic repair without provoking catabolic damage or inflammation (171). This therapeutic window varies significantly between tissues, individuals and even stages of healing. Furthermore, the complex, interdependent nature of mechanosignaling pathways makes it difficult to isolate specific therapeutic targets (65). Future progress hinges on developing more sophisticated smart biomaterials that can dynamically respond to in vivo mechanical cues and deliver bioactive factors in a feedback-controlled manner (172).

The ultimate objective is to create a closed-loop system where AI-driven algorithms analyze this multifaceted data to prescribe and dynamically adjust mechanical dosing in real-time (173). This will ensure that the stimulus remains within the patient-specific therapeutic window throughout the healing process, which evolves from the inflammatory phase to remodeling. Furthermore, this principle extends to ex vivo tissue engineering, where bioreactors can apply patient-specific mechanical conditioning to stem cell-seeded constructs, pre-adapting them to the mechanical demands they will encounter upon implantation (174). By moving beyond a one-size-fits-all model, these optimized, data-driven protocols will maximize regenerative potential, minimize the risk of re-injury and significantly accelerate functional recovery, heralding a new era of precision orthopedics.

Conclusion and perspectives

The present review established mechanotransduction as the pivotal mechanism linking mechanical forces to cellular regeneration in orthopedic rehabilitation. The sophisticated interplay between cellular sensors, signaling pathways and the ECM enables physical stimuli to direct tissue repair and adaptation. The translation of these principles into mechanotherapy and biomechanically-informed biomaterials represents a notable advancement beyond traditional rehabilitation. Looking forward, the field must overcome the challenge of defining optimal, personalized mechanical dosing. The future lies in integrating real-time biomechanical monitoring with patient-specific profiling to create dynamic, adaptive treatment protocols. The convergence of smart biomaterials, AI-driven modeling and a deeper systems-level understanding of mechanobiological networks will enable truly predictive and personalized regenerative interventions. This evolution towards precision mechanotherapy promises to revolutionize musculoskeletal care by optimally harnessing the innate healing mechanisms of the body. This will ultimately enable clinicians to precisely harness the innate mechanoresponsive capacity, offering more effective, non-invasive strategies to restore function and revolutionize patient outcomes in musculoskeletal medicine.

Availability of data and materials

Not applicable.

Authors' contributions

BW and XZ conceived the review, designed the manuscript writing structure and drafted the manuscript. HL, LL and TL edited and revised the manuscript. YL, QF, YC and BD participated in the literature search and analysis of literature content to be included in the review. All authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Funding

No funding was received.

References