Nanotopography-guided cellular mechanobiology: Mechanotransduction pathways and applications in tissue engineering

Abstract

Nanotopography has emerged as a powerful tool for regulating cellular behavior through mechanotransduction. This review explores how engineered nanoscale features, including grooves, ridges, and pillars, modulate integrin clustering, cytoskeletal organization, and nuclear signaling via YAP/TAZ and PIEZO1, ultimately influencing cell fate, epigenetic remodeling, and tissue regeneration. We discuss the hierarchical pathways linking extracellular topographies to chromatin regulation, emphasizing cell-type–specific responses in mesenchymal stem cells, fibroblasts, and myoblasts. Advances in nanofabrication, including electron-beam lithography, nanoimprinting, electrospinning, and self-assembly, have enabled reproducible topographical platforms to mimic extracellular matrix geometry. These have been applied across diverse biomedical fields, including bone, nerve, skin, and liver tissue engineering, as well as for implant surface optimization. Despite the growing clinical potential of these, challenges remain in topography standardization, biomarker development, sterilization resilience, and in vivo integration. Future directions include AI-driven design, dynamic topography, and integrated physical–biochemical cue delivery. Together, these strategies will drive next-generation mechanotherapeutic materials and deepen our understanding of cell–material interactions at the nanoscale.

Keywords

nanotopography mechanotransduction stem cell differentiation YAP/TAZ signaling tissue engineering

Introduction

Mechanobiology is an interdisciplinary field that investigates how physical forces and mechanical characteristics of the cellular microenvironment modulate cellular- and tissue-level behaviors. Mechanical cues, such as tensile strain, shear, and matrix stiffness, influence intracellular signaling pathways through mechanotransduction mechanisms involving integrins, the cytoskeleton, and stretch-activated ion channels. These mechanical inputs can critically affect cell adhesion, proliferation, migration, differentiation, and gene expression, even in the absence of biochemical stimuli, by engaging force-sensitive complexes, such as focal adhesions and cytoskeletal networks, that couple to the nucleus and extracellular matrix.^1–3 Mechanical inputs are transduced into biochemical signals via integrin-mediated coupling between the extracellular matrix (ECM) and the actin cytoskeleton, triggering focal adhesion formation. These dynamic complexes function as mechanosensitive signaling hubs that activate cascades involving FAK and RhoA, reinforcing cytoskeletal tension and promoting the nuclear localization of transcriptional regulators such as YAP and TAZ. This mechanotransduction axis orchestrates cellular responses in development and homeostasis and is dysregulated in diseases, such as fibrosis and cancer.⁴

Among the diverse mechanical stimuli, nanoscale features of the extracellular matrix, such as those formed by collagen fibrils and fibronectin bundles, have emerged as critical regulators of cell fate decisions by modulating integrin clustering, cytoskeletal tension, and mechanotransduction cascades.⁵ Cells exhibit remarkable sensitivity to nanoscale surface patterns, typically ranging from 10 to several hundred nanometers, that modulate their morphology, alignment, and functional behavior by altering focal adhesion dynamics, cytoskeletal architecture, and gene expression profiles.⁶ Recent advances in fabrication methods, including electron-beam lithography, nanoimprinting, and electrospinning, have enabled the creation of biomimetic surfaces with precisely controlled nanoscale architectures, including pits, grooves, and fibers, facilitating the systematic investigation of how distinct topographical features influence cell adhesion, spreading, and lineage commitment.⁷

The integration of mechanobiological principles with precisely engineered micro- and nanoscale topographies presents a paradigm-shifting strategy to modulate cellular behavior and guide tissue regeneration, thereby enabling next-generation biomaterial designs for regenerative medicine.⁷ Designing biomaterials with specific nanotopographical features can guide cell behavior and fate, often without chemical inducers.^8,9 Nanostructured substrates with defined topographies have demonstrated the ability to direct mesenchymal stem cell (MSC) differentiation toward osteogenic or neurogenic lineages in the absence of exogenous biochemical cues by modulating cytoskeletal tension, mechanotransduction pathways, and nuclear architecture through dimension-specific contact guidance and substrate mechanics.^10–12 Engineered nanostructured substrates with defined topographical features, including grooves, pillars, and nanopits, modulate fibroblast and myoblast behavior by altering adhesion strength, cytoskeletal organization, alignment, and differentiation potential in a cell type–specific manner and to elicit distinct functional responses in fibroblasts and myoblasts.^5,13

This review explores the molecular mechanisms driving nanotopography-mediated mechanotransduction, delineates cell-type-specific responses, including those observed in fibroblasts and myoblasts, assesses recent advances in micro- and nanofabrication technologies, and critically discusses their translational relevance, existing limitations, and future opportunities for regenerative medicine and tissue engineering.

Nanofabrication technologies and nanotopography design

Engineering biologically relevant nanotopographies requires precise, reproducible, and scalable methods. Advances in nanofabrication allow for controlled surface patterns that are essential for mechanotransduction and cell guidance. This section introduces four key techniques, namely electron-beam lithography, nanoimprint lithography, electrospinning, and chemical etching/self-assembly, along with emerging hybrid strategies.

Electron-beam lithography (EBL)

Electron beam lithography (EBL) enables custom nanopatterning with sub-10 nm resolution on PMMA resists, especially when paired with cold development, to enhance the resolution, trench quality, and reproducibility of nanobiological studies.¹⁴ Despite its low throughput, EBL has inspired scalable nanoimprint lithography approaches that replicate high-aspect-ratio nanopillars, effectively modulating mechanosensing and actin organization in human hepatic cells.¹⁵ Complementary methods, including focused ion beam (FIB) milling and laser machining, also produce deep- or high-aspect-ratio features suited for biomechanical research.¹⁶

Nanoimprint lithography (NIL)

Nanoimprint lithography (NIL) is a high-throughput and cost-effective technique for replicating nanoscale features using mold-based resist deformations. Variants including thermal-, UV-, and laser-assisted NIL achieve sub-10 nm resolution, with UV and roll-to-roll (R2R) NIL offering rapid, scalable patterning. R2R-NIL and flexible stamps enable the nanofabrication of large or curved biomedical surfaces. Using UV-NIL with OSTE + resins, high-aspect-ratio nanopillars were reliably fabricated and shown to modulate hepatic cell mechanotransduction by enhancing actin ring formation and focal adhesion.^15,17,18

Electrospinning

Electrospinning leverages electrohydrodynamic forces to produce nanofibrous scaffolds that recapitulate ECM architecture with tunable fiber diameters (40–2000 nm) and alignments. Aligned electrospun scaffolds from decellularized ECM (dECM) or graphene-based composites guide C2C12 myoblast elongation and fusion, whereas platforms incorporating PCL/graphene or GO-RGD-PLGA enhance myotube alignment, maturation, and electrical responsiveness for skeletal muscle regeneration.¹⁹

Chemical etching & self-assembly

Surface engineering methods, including wet etching and reactive ion etching (RIE), generate nanoscale grooves on TiO₂ surfaces, enhancing osteogenic differentiation by regulating integrin clustering, focal adhesion dynamics, and signaling via YAP and PIEZO1 pathways.^20,21 Nanosphere lithography (NSL) is a low-cost, scalable, self-assembly technique that fabricates nanodot or nanopillar arrays with tunable sizes and chemistry using polystyrene or silica colloids. These nanostructures, formed on silicon, sapphire, or flexible polymers, modulate protein adsorption and mechanotransductive signaling, promoting focal adhesion and immunomodulatory responses.²² Collectively, these strategies support biosensing, responsive substrates, and regenerative interface designs.

Representative nanoscale surface topographies (nanogrooves, nanopillars, and nanopits) and their subsequent functionalization processes are schematically illustrated in Figure 1 to highlight typical strategies for engineering nanobiointerfaces.

Figure 1.

Schematic illustration of representative nanoscale surface topographies and their functional modification. (A) Fabrication of well-defined nanotopographies, including parallel nanogrooves, nanopillar, and nanopits (nanoholes) on a solid substrate. (B) Subsequent surface functionalization steps, including localized material deposition or patterning, coating with a bioactive hydrogel or polymer layer, and syringe-based delivery or loading of bioactive agents onto the nanostructured surface, illustrating typical strategies for engineering nano–biointerfaces.

Molecular mechanisms of nanotopography-mediated mechanotransduction

Nanotopography modulates cellular behavior through a multiscale mechanotransduction cascade involving integrin signaling, cytoskeletal remodeling, ion channel activation, and nuclear transcriptional regulation. Integrins cluster at focal adhesions, anchoring ECM ligands to the actin cytoskeleton and initiating signaling via FAK and Src kinases. These complexes reorganize dynamically in response to nanoscale features, such as ridges and pillars, altering adhesion strength and activating downstream RhoA-mediated actomyosin contractility through the ROCK and formin pathways.^23–27

The mechanotransduction process involves direct physical transmission of force, known as mechanochemical coupling. Nanotopography-induced focal adhesion maturation increases actomyosin contractility, generating cytoskeletal tension.²⁸ This tension is transmitted physically from the cytoskeleton to the nuclear interior via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which connects the actin filaments to the nuclear lamina.^29,30 The resulting mechanical stress on the nuclear envelope induces nuclear flattening and stretches the Nuclear Pore Complexes (NPCs). This physical dilation of NPCs reduces the energetic barrier for molecular transport, thereby facilitating the active nuclear import of YAP and TAZ, independent of their phosphorylation state.³ Consequently, the distinct nanoscale geometries directly dictate gene expression by mechanically regulating the permeability of the nuclear envelope to transcription factors.

Scaffold proteins, such as BNIP-2, help fine-tune adhesion nanoarchitecture by integrating topographical and tensile inputs, whereas FAK serves as a mechanosensitive transducer of these structural cues through force-induced conformational activation.^31,32 Mechanical inputs are further transduced through the LINC complex into the nucleus, promoting YAP/TAZ activation and directing mesenchymal stem cell fate decisions.^33–35 Nanotopography-induced nuclear deformation enhances chromatin accessibility via histone acetylation, upregulating key osteogenic and neurogenic markers, such as RUNX2 and SOX9.^36,37 PIEZO1 functions as a specialized mechanotransducer that senses membrane tension and curvature through a unique biophysical mechanism.^38,39 Structurally, the PIEZO1 trimer induces a dome-like curvature in the plasma membrane in its closed resting state. Nanotopographical features, such as nanopillars or ridges, impose high local curvature on the cell membrane, which alters the membrane tension distribution. According to the membrane dome mechanism, this topography-induced deformation lowers the free energy barrier required for the channel’s conformational transition from a closed to an open state.⁴⁰ By reducing the mechanical work needed to flatten the membrane dome, the nanotopography effectively primes the PIEZO1 channels, facilitating rapid calcium influx even under low global tension. This calcium surge subsequently boosts mitochondrial metabolism and focal adhesion maturation.^41,42

The YAP/TAZ axis and PIEZO1 channel function within complex signaling networks and play a central role in mechanosignaling. Specifically, the myosin-related transcription factor A (MRTF-A)/serum response factor (SRF) pathway synergistically detects nanotopographic signals. The polymerization of globular actin (G-actin) into filamentous actin (F-actin), induced by nanotopography, releases MRTF-A from G-actin monomers. This enables nuclear translocation, thereby inducing the expression of cytoskeletal genes essential for cell stiffening and maturation.⁴³ Furthermore, Wnt/β-catenin signaling is frequently activated by specific nanoscale geometric structures, often through cross-talk with integrin-linked kinase (ILK) or by inhibiting the degradation complex, thereby stabilizing β-catenin and promoting osteogenic differentiation.⁴⁴ These pathways collectively orchestrate the cellular response to physical inputs, ensuring robust adaptation to the engineered microenvironment.

To synthesize these multiscale events, Figure 2 highlights that nanotopography may not simply activate multiple mechanosensitive pathways in parallel; rather, it can bias the dominant mode of mechanosensing by reshaping the cell’s physical energy landscape. Distinct geometric features modulate local membrane curvature and force distribution, thereby shifting the balance between adhesion-mediated force transmission and curvature-facilitated PIEZO1 gating. Under low-to-moderate curvature conditions, integrin clustering and FAK-mediated cytoskeletal tension dominate mechanical sensing, whereas high curvature or constrained topography lowers the energy barrier for PIEZO1 channel opening, triggering calcium influx. These physically distinct sensing modes converge at the cytoskeleton-nucleus axis, where force transmission via the LINC complex expands nuclear pores, promoting YAP/TAZ translocation and chromatin remodeling. This framework highlights mechanical signaling as an energy-regulated physical process rather than a purely biochemical signaling pathway.

Figure 2.

Nanotopography-mediated biasing of mechanotransduction pathways. By modulating membrane curvature and force transmission, nanotopographical features can bias PIEZO1- or integrin-driven mechanosensing, which converges on nuclear mechanoregulation to control YAP/TAZ activity and chromatin accessibility. This image was designed using https://www.biorender.com/.

Cell-specific responses to nanotopographical cues

While Figure 2 provides a unifying physical framework, the resulting biological outputs remain highly context-dependent across cell types. Nanotopography serves as a universal physical signal, yet cellular responses vary greatly depending on the context and differ significantly between different lineages. These divergent behaviors stem from inherent differences in the mechanical sensitivity of cells. Specifically, the baseline level of cytoskeletal tension (pre-stress), the specific composition of integrin subtypes expressed on the cell membrane, and the intrinsic stiffness of the nucleus determine how cells perceive and transmit physical signals.^2,45,46 For example, cells with different nuclear lamina compositions exhibit varying sensitivities to nuclear deformation caused by topography, which differentially regulates mechanosensory gene expression.³⁰ Therefore, the same nanotexture plays a role in determining the differentiation pathway in stem cells sensitive to mechanical stimulation, whereas in fully differentiated fibroblasts and myoblasts, it primarily induces alignment or migration.^47–49

Mesenchymal stem cells (MSCs)

Mesenchymal stromal cells (MSCs), which are known for their mechanosensitivity and therapeutic potential, respond strongly to defined nanotopographies. Square-arranged nanopits (∼120 nm) reduce intracellular tension and focal adhesion maturation, preserving MSC proliferation and immunomodulatory functions without inducing differentiation.⁵⁰ TiO₂ nanotube surfaces created by anodic oxidation enhance YAP nuclear localization and upregulate PIEZO1, collectively increasing ALP and RUNX2 expression in MSCs both in vitro and in vivo.²¹ In addition, geometric cues, such as aligned grooves or nanofibers, align MSCs and promote osteogenesis through actomyosin tension and Wnt/β-catenin signaling.⁴⁴

Fibroblasts

Fibroblasts, which are key regulators of ECM remodeling and fibrosis, are highly sensitive to nanoscale features. Polymer-demixed nanoisland arrays (∼13–27 nm) enhance adhesion and lamellipodial extension via Rac1, highlighting the role of nanoscale roughness in early cytoskeletal remodeling and focal adhesion dynamics.^51,52 Accumulating evidence indicates that nanoscale topographical and mechanical cues regulate fibroblast behavior through force-dependent focal adhesion maturation and actomyosin contractility. In this context, defined nanotopographies modulate integrin clustering and activate FAK–RhoA signaling, thereby promoting cellular contractility, ECM synthesis, and fibroblast activation.⁵³ Recent experimental evidence demonstrates that introducing nanoscale topological features onto microfiber surfaces effectively suppresses fibroblast activation and fibrosis by attenuating integrin-mediated mechanotransduction, reducing actomyosin contractility, and limiting YAP-dependent profibrotic signaling.⁵

Myoblast

C2C12 myoblasts aligned along nanogrooved substrates (∼100 nm width, 20 nm depth) showed ∼28% higher fusion and ∼21% greater maturation indices, along with improved sarcomere organization. Upon electrical stimulation, myotubes on grooved substrates contracted ∼3 times more than those on flat controls, indicating enhanced functionality.⁵⁴ The aligned electrospun nanofibers similarly enhanced myofiber elongation, multinucleation, and sarcomere alignment, correlating with elevated myosin heavy chain and titin expression.⁵⁵ Random cellulose acetate nanofibers promoted myogenesis via YAP/TAZ-driven mechanotransduction, upregulating MyoD, myogenin, and myosin heavy chain expression, even without biochemical cues.⁵⁶ Moreover, cell-scale curvature regulates focal adhesion tension and nuclear mechanics via RhoA-driven actomyosin contractility, thereby enabling curvotaxis. These responses coordinate cytoskeletal alignment and gene expression, highlighting the role of topography in muscle tissue engineering and organ-on-chip models.⁵⁷ Table 1 demonstrates the quantitative relationship between nanostructure dimensions and cellular responses across multiple cell types. To further generalize this relationship, endothelial and immune cell responses to defined nanotopographies can also be incorporated, highlighting the angiogenic and osteoimmune dimensions of mechanoregulation.

Table 1.

Representative quantitative correlations between nanotopographical dimensions and cellular responses.

Cell type	Topography type	Critical dimensions	Key quantitative/Biological outcome	Reference
Mesenchymal stem cells	Square-arranged nanopits	Diameter: ∼120 nm	Associated with reduced intracellular tension, helping maintain phenotype and proliferation without overt differentiation.	⁵⁰
Mesenchymal stem cells	TiO₂ nanotubes (anodic oxidation)	Diameter: ∼100 nm	Increased YAP nuclear localization and PIEZO1 expression; associated with higher ALP and RUNX2 expression in vitro and in vivo.	²¹
Mesenchymal stem cells	Aligned nanogrooves (photolithography)	Width: 12.5 μm	Promoted MSC alignment and osteogenic bias, consistent with actomyosin tension and Wnt/β-catenin involvement.	⁴⁴
Mesenchymal stem cells	Aligned nanogrooves (photolithography)	Depth: 540 nm		⁴⁴
Mesenchymal stem cells	Nano-grooved waves	Peak height: ∼211 nm	Increased chromatin accessibility and osteogenic priming	³⁷
Mesenchymal stem cells	Nano-grooved waves	Pitch distance: ∼890 nm	Increased chromatin accessibility and osteogenic priming	³⁷
Fibroblasts	Polymer-demixed nanoislands	Height: 13–27 nm	Enhanced adhesion and lamellipodial extension, consistent with Rac1-associated cytoskeletal remodeling.	^51,52
Fibroblasts	Nanoscale protrusions on microfiber	Length: 200 – 500 nm	Reduced α-SMA expression and attenuated fibrotic activation, consistent with dampened integrin β1–Rho/ROCK–YAP signaling.	⁵
C2C12 myoblasts	Nanogrooves	Width: ∼100 nm	∼28% higher fusion index and ∼21% greater maturation index compared to flat controls; enhanced sarcomere organization.	⁵⁴
C2C12 myoblasts	Nanogrooves	Depth: 20 nm		⁵⁴
C2C12 myoblasts	Nanogrooves (under electrical stimulation)	Width: ∼100 nm	Induced ∼3-fold higher contraction compared to flat substrates, indicating functional maturation.	⁵⁴
C2C12 myoblasts	Nanogrooves (under electrical stimulation)	Depth: 20 nm		⁵⁴
C2C12 myoblasts	Electrospun nanofibers (aligned)	Diameter: 40 –2000 nm	Guided myoblast elongation and fusion; mimicked native muscle architecture for regeneration.	¹⁹
Endothelial cells (HUVECs)	Nanogrooves	Width: 100–800 nm	Enhanced alignment and ∼2–3× increase in migration speed; increased VEGFR2-related signaling	⁵⁸
Macrophages (RAW264.7)	Nanotubes (TiO₂)	Diameter: 20–120 nm	Smaller nanotubes favored adhesion/proliferation, whereas larger nanotubes were associated with reduced inflammatory responses.	⁵⁹
Macrophages	Nano-rough surfaces (AuNPs)	Ra: 20–50 nm	Reduced pro-inflammatory cytokine secretion and improved osteoimmune coupling.	⁶⁰

Applications of nanotopography in regenerative medicine and biomaterials

Nanotopography has advanced from basic research to tools for controlling cell fate in regenerative medicine. Engineered surfaces regulate adhesion, differentiation, migration, and immune responses to mimic ECM architecture. The following sections outline their applications in tissue regeneration, implant design, disease modeling, and translational platforms.

Scaffold design and tissue regeneration

Bone regeneration

Nanotopographically engineered 3D-printed PCL scaffolds enhance osteogenesis by modulating surface roughness and activating mechanotransductive pathways, including cytoskeletal remodeling and YAP/TAZ signaling, promoting MSC proliferation, osteogenic gene expression, and bone regeneration.^61,62 Compared to microstructures, needle-like nanostructures on bioglass and calcium silicate scaffolds improved osteointegration by enhancing stem cell adhesion and mineral deposition compared to microstructures. In addition, multifunctional GelMA hydrogels incorporating dendrimer-functionalized nanoceria integrated antioxidants and nanotopographical cues to boost rMSC adhesion, proliferation, and osteogenesis under oxidative stress through Wnt-related gene activation and mineralization.⁶³

Muscle and nerve regeneration

Electrospun PCL nanofibers aligned with graphene oxide promote C2C12 myoblast alignment and elongation, mimicking the native muscle architecture of the muscle-on-chip system.⁶⁴ Similarly, aligned nanofiber nerve conduits replicated ECM anisotropy to guide Schwann cell migration and axonal growth, aiding peripheral nerve regeneration across defects.^65,66 A nano neuro-knitting strategy using self-assembling peptide nanofibers fosters CNS tissue reconnection and axonal regeneration, enabling functional recovery, including vision restoration, in preclinical models.⁶⁷

Skin regeneration and wound healing

Nanozyme-engineered hydrogels that integrate ROS-scavenging activity and surface nanotopography are emerging as promising skin repair constructs that can reduce oxidative stress and reprogram macrophages toward an M2-like anti-inflammatory phenotype to accelerate chronic wound healing.⁶⁸ Cobalt-doped nanoglass nanozymes accelerate diabetic wound healing by simultaneously scavenging ROS and promoting angiogenesis via cobalt ion-mediated HIF-1α activation, enhancing neovascularization and extracellular matrix formation.⁶⁹

Nanotopographical surfaces for implant integration

Titanium implants engineered with ordered TiO₂ nanotube arrays enhanced osseointegration and modulated osteoimmune responses by promoting osteogenic differentiation and reducing inflammation, offering improved outcomes in patient-specific scenarios, including diabetes and orthopedic applications.⁷⁰ Nanostructured TiO₂ nanotube arrays on titanium implants mimicked the native bone extracellular matrix, enhanced biocompatibility, promoted osteogenic differentiation, and improved osseointegration through multidimensional regulation of protein adsorption, immune modulation, and mechanotransduction.⁷¹ In addition, micro-/nanotextured titanium implants enhanced osseointegration by promoting BMSC adhesion, exosome release, and ECM formation, outperforming smooth and microtextured surfaces in vitro and in vivo.⁷² Hydrothermally grown TiO₂ nanoneedles create hierarchical surfaces that improve mechanical strength, antimicrobial effects, and osteoimmune modulation, leading to better bone integration.⁷³ Matrix stiffness, viscoelasticity, and nanotopography influenced macrophage mechanotransduction, directing M2 polarization via cytoskeletal and YAP/PIEZO1 signaling.⁷⁴ Additionally, nano-roughened surfaces reduced interfacial shear stress and local strain, improved implant fixation, and minimized bone resorption under load-bearing conditions.^75,76

Nanotopography in regenerative and pathological microenvironments

Electrospun hybrid scaffolds combining decellularized liver ECM and nanoscale topographies promoted HepG2 hepatocyte proliferation, metabolism, and albumin secretion, highlighting the synergy between biochemical and topographical cues in hepatic tissue engineering.⁷⁷ Nanotopographical cues also modulated the cargo of EVs from skeletal muscle progenitors, enhancing their regenerative capacity by stimulating proliferation and differentiation of aged muscle.⁷⁸ Moreover, engineered micro/nanotopographical substrates can recreate fibrotic and tumor-like microenvironments, enabling precise studies on fibroblast activation, ECM remodeling, and cancer cell invasiveness.⁵

Therapeutic implications and translational potential

Integrating 3D printing with nanofibrous microsphere-based patterning enabled the fabrication of hierarchical porous scaffolds that enhanced stem cell infiltration, osteogenic differentiation, and bone regeneration, thereby offering a versatile strategy for musculoskeletal repair.⁷⁹ The micro/nano hierarchical topographies of bioceramics actively regulate immune responses by promoting M2 macrophage polarization, thereby reducing inflammation, minimizing fibrotic reactions, and enhancing osteogenic and angiogenic integration.⁸⁰ Multiple nanoengineered implants have been clinically used in the dental and orthopedic fields because of the validated mechanical interlocking strength and ability to promote early stage osteoblastic differentiation and osseointegration of these, despite persistent challenges in achieving full bone–implant contact and resolving osteoblast kinetic discrepancies.^75,76

Current challenges and limitations in nanotopography-guided mechanobiology

Technical and biological limitations

Despite substantial progress, several key challenges have impeded the clinical translation of nanotopographically engineered biomaterials. Achieving uniform nanotopography over large areas remains technically difficult because slight deviations can affect cell behavior, requiring precise control and metrology. Batch-to-batch and inter-laboratory variability limit reproducibility, highlighting the need for standardized protocols for surface geometry and chemistry.^81,82 Furthermore, mechanosensitive, cell-specific responses demand robust phenotypic validation; however, the lack of standardized assays for traction force, focal adhesions, and imaging complicates cross-study comparison.^83,84 Static in vitro models fail to reflect the dynamic in vivo cues, contributing to fibrosis and mechanical mismatch.⁸⁵ Addressing these limitations requires physiomimetic models and predictive biomarkers that better represent human physiology and predict treatment outcomes.

Regulatory and practical barriers to clinical translation

Beyond fabrication challenges, the clinical translation of nanotopography-guided biomaterials faces key obstacles. First, the lack of regulatory frameworks for nanoscale architectures highlights the need for biomechanical biomarkers, such as YAP/TAZ translocation or traction force profiles, to predict in vivo responses, as no clear approval pathways exist.⁸⁶ Second, sterilization methods, including autoclaving or gamma irradiation, can alter nanoscale geometry, impairing focal adhesion formation and YAP/TAZ signaling in MSCs, thereby reducing their osteoinductive potential.⁸⁷ Third, long-term degradation or biofouling may disrupt integrin signaling, weaken cytoskeletal tension, destabilizing cell phenotypes.⁸⁸ A significant barrier that is often underestimated in translating pure results obtained from in vitro experiments to in vivo applications is the phenomenon of biological contamination. When implanted into a physiological environment, the surface of an engineered biomaterial immediately undergoes competitive adsorption of serum proteins, forming a dense, dynamic layer known as the protein corona. This protein layer can effectively inhibit direct cell-surface interactions with nanostructures by creating masking effects.^89,90 When the thickness of the adsorbed protein layer exceeds the critical dimensions of the underlying structure—for example, when filling nano-grooves or burying nano-pillars—cells may perceive the surface as functionally flat. Consequently, the precise mechanical signaling cues intended by nanoscale engineering are weakened or completely nullified by this disordered protein interface, leading to the loss of biological functions within the living organism.

From a regulatory perspective, the approval process for nanotopography-based medical devices presents unique obstacles compared to traditional pharmaceuticals. The primary challenge lies in defining a clear mechanism of action (MOA). Unlike drugs that target specific biochemical receptors, nanotopography exerts its effects through complex, multifaceted mechanical signaling pathways. This makes it extremely difficult to pinpoint a single, definable mechanism of action as required by regulatory bodies like the FDA or EMA.⁹¹ Furthermore, there is a critical absence of standardized metrology and international consensus standards for establishing manufacturing tolerances at the nanoscale. Validating batch-to-batch consistency with nanometer precision for quality control remains a significant technological and regulatory bottleneck for clinical translation.⁹² Addressing these issues requires physiologically relevant preclinical models and early regulatory engagements to support clinical adoption.

Future perspectives of nanotopography-guided mechanobiology

Recent advances in materials science, computational modeling, and cellular biology have transformed the field of nanotopography-guided mechanobiology. The following emerging directions hold significant promise.

AI-driven design and predictive modeling

Artificial intelligence (AI) and machine learning (ML) are increasingly being used in mechanobiology to optimize nanotopographical designs that modulate cellular mechanotransduction. These tools predict cell-type-specific responses, including YAP/TAZ localization, focal adhesion dynamics, and lineage-specific gene expression, based on surface geometry, stiffness, and biochemical cues.^93,94 AI-integrated platforms, including robotic synthesis systems, enable iterative refinement of topographical signals to enhance outcomes, such as osteogenesis or myogenesis.^95,96 This reduces trial-and-error, improves reproducibility, and facilitates systematic analysis of topography–mechanotransduction interactions.

Development of dynamic nanotopographies

A static nanotopography cannot completely replicate the dynamic mechanical environment of cells in vivo. Stimuli-responsive nanomaterials that reversibly alter topography or stiffness in response to cues, such as light, temperature, or pH allow spatiotemporal control of mechanotransduction.⁹⁷ These dynamic surfaces regulate cytoskeletal tension and focal adhesion remodeling, activating downstream responses, including YAP/TAZ translocation, PIEZO1 activation, and chromatin modification. Thermoresponsive titanium surfaces, for instance, produce stage-specific effects, including osteogenesis and antimicrobial activity.^98,99 Such systems can mimic sequential mechanical cues during development and repair, enabling precise regulation of mechanosensitive gene expression.

Integration of physical and biochemical cues

Next-generation biomaterials are expected to integrate spatially resolved nanotopographical features with localized biochemical cues, such as ECM-derived peptides and growth factors to synergistically enhance cell adhesion, lineage commitment, and tissue regeneration. Hybrid platforms employing nanoscale patterning and biochemical gradients, often achieved through advanced 4D fabrication, serve as “signal meshes” that spatially and temporally coordinate cellular responses to promote complex tissue morphogenesis.^100,101

Mechanoregulation of epigenetics and metabolism

Nanotopography and cyclic mechanical stimuli influence core cellular processes including chromatin organization and metabolism. Mechanotransduction via YAP/TAZ and cytoskeletal–nuclear coupling induces epigenetic remodeling, particularly by reducing repressive histone marks, such as H3K9me3, to promote chromatin accessibility and enhance reprogramming efficiency. These insights underscore the need for integrated metabolomic and epigenomic profiling to decode mechanically driven gene regulation and support multimodal therapeutic strategies.¹⁰²

Summary

Nanotopography-guided mechanobiology offers a powerful platform for directing cellular behavior through integrin clustering, cytoskeletal remodeling, and nuclear mechanotransduction. This review highlights how engineered nanoscale features modulate stem cell fate, fibroblast activation, and myoblast maturation via YAP/TAZ, PIEZO1, and epigenetic remodeling. Advances in nanofabrication have enabled precise biointerface designs that enhance tissue regeneration and implant integration. Despite their translational potential, challenges remain in terms of scalability, assay standardization, and regulatory frameworks. Future research should focus on AI-based designs, dynamic topographies, and integrative biochemo-mechanical cues to develop next-generation mechanotherapeutic biomaterials.

Footnotes

ORCID iD

Seunghan Oh

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the National Research Foundation of Korea (NRF), Grant Number 2022R1A2C1006565, funded by the Korean government (MSIT).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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