Bioengineering structural anisotropy in living tissues

References

Liesche, J., Ziomkiewicz, I. & Schulz, A. Super-resolution imaging with pontamine fast scarlet 4BS enables direct visualization of cellulose orientation and cell connection architecture in onion epidermis cells. BMC Plant. Biol. 13, 226 (2013).

Google Scholar
Flemming, H. C. & Wingender, J. The biofilm matrix. Nat. Rev. Microbiol. 8, 623–633 (2010).

Google Scholar
Rozario, T. & DeSimone, D. W. The extracellular matrix in development and morphogenesis: a dynamic view. Dev. Biol. 341, 126–140 (2010).

Google Scholar
Hoffmann, G. A., Wong, J. Y. & Smith, M. L. On force and form: mechano-biochemical regulation of extracellular matrix. Biochemistry 58, 4710–4720 (2019).

Google Scholar
Scarr, G. Fascial hierarchies and the relevance of crossed-helical arrangements of collagen to changes in the shape of muscles. J. Bodyw. Mov. Ther. 20, 377–387 (2016).

Google Scholar
Anderson, R. H., Niederer, P. F., Sanchez‐Quintana, D., Stephenson, R. S. & Agger, P. How are the cardiomyocytes aggregated together within the walls of the left ventricular cone? J. Anat. 235, 697–705 (2019).

Google Scholar
Bontempi, M. et al. Understanding the structure-function relationship through 3D imaging and biomechanical analysis: a novel methodological approach applied to anterior cruciate ligaments. Biomimetics 9, 477 (2024).

Google Scholar
Franchi, M., Trirè, A., Quaranta, M., Orsini, E. & Ottani, V. Collagen structure of tendon relates to function. Sci. World 7, 404–420 (2007).

Google Scholar
Hooks, D. A. et al. Laminar arrangement of ventricular myocytes influences electrical behavior of the heart. Circ. Res. 101, 103–112 (2007).

Google Scholar
Holmes, D. F. et al. Corneal collagen fibril structure in three dimensions: structural insights into fibril assembly, mechanical properties, and tissue organization. Proc. Natl Acad. Sci. USA. 98, 7307–7312 (2001).

Google Scholar
Feinberg, A. W. et al. Controlling the contractile strength of engineered cardiac muscle by hierarchal tissue architecture. Biomaterials 33, 5732–5741 (2012).

Google Scholar
Zhang, L. & Szeri, A. Z. Transport of neutral solute in articular cartilage: effect of microstructure anisotropy. J. Biomech. 41, 430–437 (2008).

Google Scholar
Kim, K. et al. Dynamic hierarchical ligand anisotropy for competing macrophage regulation in vivo. Bioact. Mater. 47, 121–135 (2025).

Google Scholar
Bril, M. et al. Shape-morphing photoresponsive hydrogels reveal dynamic topographical conditioning of fibroblasts. Adv. Sci. 10, 2303136 (2023).

Google Scholar
Ghonim, S. et al. Myocardial architecture, mechanics, and fibrosis in congenital heart disease. Front. Cardiovasc. Med. 4, 258682 (2017).

Google Scholar
Santodomingo-Rubido, J. et al. Keratoconus: an updated review. Contact Lens Anterior Eye 45, 101559 (2022).

Google Scholar
Brazile, B. L. et al. Biomechanical properties of acellular scar ECM during the acute to chronic stages of myocardial infarction. J. Mech. Behav. Biomed. Mater. 116, 1–23 (2021).

Google Scholar
Liew, L. C., Ho, B. X. & Soh, B. S. Mending a broken heart: current strategies and limitations of cell-based therapy. Stem Cell Res. Ther. 11, 138 (2020).

Google Scholar
Tompkins, B. A., Natsumeda, M., Balkan, W. & Hare, J. M. What is the future of cell-based therapy for acute myocardial infarction. Circ. Res. 120, 252–255 (2017).

Google Scholar
van den Boom, N. A. C., Winters, M., Haisma, H. J. & Moen, M. H. Efficacy of stem cell therapy for tendon disorders: a systematic review. Orthop. J. Sports Med. 8, 4 (2020).

Google Scholar
Wissing, T. B. et al. Biomaterial-driven in situ cardiovascular tissue engineering — a multi-disciplinary perspective. NJP Regen. Med. 2, 18 (2017).

Google Scholar
Hwang, D. G., Choi, Y. M. & Jang, J. 3D bioprinting-based vascularized tissue models mimicking tissue-specific architecture and pathophysiology for in vitro studies. Front. Bioeng. Biotechnol. 9, 685507 (2021).

Google Scholar
Uiterwijk, M. et al. In situ remodeling overrules bioinspired scaffold architecture of supramolecular elastomeric tissue-engineered heart valves. JACC Basic Transl. Sci. 5, 1187 (2020).

Google Scholar
Mercer, S. E. et al. Multi-tissue microarray analysis identifies a molecular signature of regeneration. PLoS One 7, e52375 (2012).

Google Scholar
Torrent-Guasp, F. et al. Towards new understanding of the heart structure and function. Eur. J. Cardiothorac. Surg. 27, 191–201 (2005).

Google Scholar
Takebayashi-Suzuki, K. & Suzuki, A. Intracellular communication among morphogen signaling pathways during vertebrate body plan formation. Genes 24, 341 (2020).

Google Scholar
Kim, S., Uroz, M., Bays, J. L. & Chen, C. S. Harnessing mechanobiology for tissue engineering. Dev. Cell. 56, 180–191 (2021).

Google Scholar
Kahane, N. & Kalcheim, C. Neural tube development depends on notochord-derived sonic hedgehog released into the sclerotome. Development 147, dev183996 (2020).

Google Scholar
Lui, L. et al. Nodel is a short-range morphogen with activity that spreads through a relay mechanism in human gastruloids. Nat. Commun. 13, 497 (2022).

Google Scholar
Nonaka, S., Shiratori, H., Saijoh, Y. & Hamada, H. Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418, 96–99 (2002).

Google Scholar
Gros, J., Feistel, K., Viebahn, C., Blum, M. & Tabin, C. J. Cell movements at Hensen’s node establish left/right asymmetric gene expression in the chick. Science 324, 941–944 (2009).

Google Scholar
Strutt, D., Madder, D., Chaudhary, V. & Artymiuk, P. J. Structure-function dissection of the frizzled receptor in Drosophila melanogaster suggests different mechanisms of action in planar polarity and canonical wnt signaling. Genetics 192, 1295–1313 (2012).

Google Scholar
Vetter, R. & Iber, D. Precision of morphogen gradients in neural tube development. Nat. Commun. 13, 1145 (2022).

Google Scholar
Adelmann, J. A., Vetter, R. & Iber, D. Patterning precision under non-linear morphogen decay and molecular noise. eLife 12, e84757 (2023).

Google Scholar
Dickmann, J. E. M., Rink, J. C. & Jülicher, F. Long-range morphogen gradient formation by cell-to-cell signal propagation. Phys. Biol. 7, 19 (2022).

Google Scholar
Ho, R. D. J. G. et al. Dynamics of morphogen source formation in a growing tissue. PLoS Comput. Biol. 14, e1012508 (2024).

Google Scholar
Mosby, L. S., Bowen, A. E. & Hadjivasiliou, Z. Morphogens in the evolution of size, shape and patterning. Development 15, dev202412 (2024).

Google Scholar
Travascio, F., Devaux, F., Volz, M. & Jackson, A. R. Molecular and macromolecular diffusion in human meniscus: relationships with tissue structure and composition. Osteoarthr. Cartil. 28, 375–382 (2020).

Google Scholar
Kenny, F. N. et al. Autocrine IL-6 drives cell and extracellular matrix anisotropy in scar fibroblasts. Matrix Biol. 123, 1–16 (2023).

Google Scholar
Canse, C., Yildirim, E. & Yaba, A. Overview of junctional complexes during mammalian early embryonic development. Front. Endocrinol. 14, 1150017 (2023).

Google Scholar
Sánchez-Iranzo, H., Halavatyi, A. & Diz-Muñoz, A. Strength of interactions in the notch gene regulatory network determines patterning and fate in the notochord. eLife 6, e75429 (2022).

Google Scholar
Bocci, F., Onuchic, J. N. & Jolly, M. K. Understanding the principles of pattern formation driven by notch signaling by integrating experiments and theoretical models. Front. Physiol. 31, 929 (2020).

Google Scholar
Mammoto, T. & Ingber, D. E. Mechanical control of tissue and organ development. Development 137, 1407–1420 (2010).

Google Scholar
Duclos, G., Garcia, S., Yevick, H. G. & Silberzan, P. Perfect nematic order in confined monolayers of spindle-shaped cells. Soft Matter. 14, 2346–2353 (2014).

Google Scholar
Luo, Y. et al. Molecular-scale substrate anisotropy, crowding and division drive collective behaviours in cell monolayers. J. R. Soc. Interface. 20, 20230160 (2023).

Google Scholar
Park, D. et al. Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions. Nat. Mater. 19, 227–238 (2020).

Google Scholar
Alert, R. & Trepat, X. Living cells on the move. Phys. Today 74, 30–36 (2021).

Google Scholar
Kim, J. et al. Stress-induced plasticity of dynamic collagen networks. Nat. Commun. 8, 842 (2017).

Google Scholar
Leivo, I., Vaheri, A., Timpl, R. & Wartiovaara, J. Appearance and distribution of collagens and laminin in the early mouse embryo. Dev. Biol. 76, 100–114 (1980).

Google Scholar
Legerstee, K., Geverts, B., Slotman, J. A. & Houtsmuller, A. B. Dynamics and distribution of paxillin, vinculin, zyxin and VASP depend on focal adhesion location and orientation. Sci. Rep. 9, 10460 (2019).

Google Scholar
Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410 (2017).

Google Scholar
Wu, X., Cesarovic, N., Falk, V., Mazza, E. & Giampietro, C. Mechanical factors influence β-catenin localization and barrier properties. Integr. Biol. 16, zyae013 (2024).

Google Scholar
Tan, H. & Tan, S. The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining α-tubulin acetylation. J. Biol. Chem. 295, 5928–5943 (2020).

Google Scholar
Shang, N. et al. Focal adhesion kinase and β-catenin cooperate to induce hepatocellular carcinoma. Hepatology. 70, 1631–1645 (2019).

Google Scholar
Fisher, R. S. et al. Contractility, focal adhesion orientation, and stress fiber orientation drive cancer cell polarity and migration along wavy ECM substrates. Proc. Natl Acad. Sci. USA. 118, e2021135118 (2021).

Google Scholar
Buskermolen, A. B. C. et al. Cellular contact guidance emerges from gap avoidance. Cell Rep. Phys. Sci. 1, 100055 (2020).

Google Scholar
Ray, A. et al. Anisotropic forces from spatially constrained focal adhesions mediate contact guidance directed cell migration. Nat. Commun. 8, 14923 (2017).

Google Scholar
Böhringer, D. et al. Dynamic traction force measurements of migrating immune cells in 3D biopolymer matrices. Nat. Phys. 20, 1816–1823 (2024).

Google Scholar
Jones, D. L. et al. Mechanoepigenetic regulation of extracellular matrix homeostasis via Yap and Taz. Proc. Natl Acad. Sci. USA. 30, e2211947120 (2023).

Google Scholar
Karamanos, N. K. et al. A guide to the composition and functions of the extracellular matrix. FEBS J. 228, 6850–6912 (2021).

Google Scholar
Wartiovaara, J., Leivo, I. & Vaheri, A. Expression of the cell surface-associated glycoprotein, fibronectin, in the early mouse embryo. Dev. Biol. 69, 247–257 (1979).

Google Scholar
Gelse, K., Pöschl, E. & Aigner, T. Collagens — structure, function, and biosynthesis. Adv. Drug Deliv. Rev. 55, 1531–1546 (2003).

Google Scholar
Guo, X. et al. Morphologic characterization of organized extracellular matrix deposition by ascorbic acid-stimulated human corneal fibroblasts. Invest. Ophthalmol. Vis. Sci. 48, 4050–4060 (2007).

Google Scholar
Hasenzahl, M., Müsken, M., Mertsch, S., Schrader, S. & Reichl, S. Cell sheet technology: influence of culture conditions on in vitro‐cultivated corneal stromal tissue for regenerative therapies of the ocular surface. J. Biomed. Mater. Res. B Appl. Biomater. 109, 1488–1504 (2021).

Google Scholar
Leclech, C. & Villard, C. Cellular and subcellular contact guidance on microfabricated substrates. Front. Bioeng. Biotechnol. 8, 1198 (2020).

Google Scholar
Niu, Y. et al. Compressive stress improves mechanical properties of mineralized collagen by dynamically regulating its mineralization — a closed-loop regulation mechanism. Mater. Des. 239, 112830 (2024).

Google Scholar
Hammerman, M., Pierantoni, M., Isaksson, H. & Eliasson, P. Deprivation of loading during rat achilles tendon healing affects extracellular matrix composition and structure, and reduces cell density and alignment. Sci. Rep. 14, 23380 (2024).

Google Scholar
Potekaev, N. N. et al. The role of extracellular matrix in skin wound healing. J. Clin. Med. 10, 5947 (2021).

Google Scholar
Humphrey, J. D., Dufresne, E. R. & Schwartz, M. A. Mechanotransduction and extracellular matrix homeostasis. Nat. Rev. Mol. Cell Biol. 15, 802–812 (2014).

Google Scholar
Chow, M., Turcotte, R., Lin, C. P. & Zhang, Y. Arterial extracellular matrix: a mechanobiological study of the contributions of interactions of elastin and collagen. Biophys. J. 106, 2684–2692 (2014).

Google Scholar
Cabral-Pacheco, G. A. et al. The roles of matrix metalloproteinases and their inhibitors in human disease. Int. J. Mol. Sci. 21, 9739 (2020).

Google Scholar
Wang, W. Y., Davidson, C. D., Lin, D. & Baker, B. M. Actomyosin contractility-dependent matrix stretch and recoil induces rapid cell migration. Nat. Commun. 10, 1186 (2019).

Google Scholar
De Jonge, N., Kanters, F. M. W., Baaijens, F. P. T. & Bouten, C. V. C. Strain-induced collagen organization at the micro-level in fibrin-based engineered tissue constructs. Ann. Biomed. Eng. 41, 763–774 (2013).

Google Scholar
Yeganegi, A., Whitehead, K., de Castro Brás, L. E. & Richardson, W. J. Mechanical strain modulates extracellular matrix degradation and byproducts in an isoform-specific manner. Biochim. Biophys. Acta Gen. Subj. 1867, 130286 (2022).

Google Scholar
Humphrey, J. D. & Schwartz, M. A. Vascular mechanobiology: homeostasis, adaptation, and disease. Annu. Rev. Biomed. Eng. 13, 1–27 (2021).

Google Scholar
Tschumperlin, D. J., Ligresti, G., Hilscher, M. B. & Shah, V. H. Mechanosensing and fibrosis. J. Clin. Invest. 128, 74–84 (2018).

Google Scholar
Contessotto, P. et al. Reproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model. Nat. Commun. 127, 995 (2023).

Google Scholar
Zhou, Z. et al. Reorganized collagen in the tumor microenvironment of gastric cancer and its association with prognosis. J. Cancer. 8, 1466–1476 (2017).

Google Scholar
Paidi, S. K. et al. Label-free Raman spectroscopy detects stromal adaptations in premetastatic lungs primed by breast cancer. Cancer Res. 77, 247–256 (2017).

Google Scholar
Mierke, C. T. Extracellular matrix cues regulate mechanosensing and mechanotransduction of cancer cells. Cells 2, 96 (2024).

Google Scholar
Hsu, K. S. et al. Cancer cell survival depends on collagen uptake into tumor-associated stroma. Nat. Commun. 13, 7078 (2022).

Google Scholar
Yuan, Z. et al. Extracellular matrix remodeling in tumor progression and immune escape: from mechanics to treatments. Mol. Cancer. 22, 48 (2023).

Google Scholar
Thorseth, M.-L. et al. Uncovering mediators of collagen degradation in the tumor microenvironment. Matrix Biol. Plus 13, 100101 (2022).

Google Scholar
Ermis, M., Antmen, E. & Hasirci, V. Micro and nanofabrication methods to control cell-substrate interactions and cell behavior: a review from the tissue engineering perspective. Bioact. Mater. 3, 355–369 (2018).

Google Scholar
Pramotton, F. M. et al. Accelerated epithelial layer healing induced by tactile anisotropy in surface topography. Sci. Adv. 9, eadd1581 (2023).

Google Scholar
Strale, P. O. et al. Multiprotein printing by light-induced molecular adsorption. Adv. Mater. 28, 2024–2029 (2016).

Google Scholar
Perl, A., Reinhoudt, D. N. & Huskens, J. Microcontact printing: limitations and achievements. Adv. Mater. 21, 2257–2268 (2009).

Google Scholar
Liu, C. et al. Sustained biochemical signaling and contact guidance by electrospun bicomponents as promising scaffolds for nerve tissue regeneration. ACS Omega 6, 33010–33017 (2021).

Google Scholar
Flores-Rojas, G. G. et al. Electrospun scaffolds for tissue engineering: a review. Macromol 3, 524–553 (2023).

Google Scholar
Teixeira, A. I., Abrams, G. A., Bertics, P. J., Murphy, C. J. & Nealey, P. F. Epithelial contact guidance of well-defined micro- and nanostructured substrates. J. Cell Sci. 116, 1881–1892 (2003).

Google Scholar
Hamilton, D. W., Oates, C. J., Hasanzadeh, A. & Mittler, S. Migration of periodontal ligament fibroblasts on nanometric topographical patterns: influence of filopodia and focal adhesions on contact guidance. PLoS One 5, e15129 (2010).

Google Scholar
Kim, D. H. et al. Mechanosensitivity of fibroblast cell shape and movement to anisotropic substratum topography gradients. Biomaterials 30, 5433–5444 (2009).

Google Scholar
Linke, P. et al. Dynamic contact guidance of myoblasts by feature size and reversible switching of substrate topography: orchestration of cell shape, orientation, and nematic ordering of actin cytoskeletons. Langmuir 35, 7538–7551 (2019).

Google Scholar
Sun, Q., Qiu, T., Liu, X. & Wei, Q. Cellular spatial sensing determines cell mechanotransduction activity on the aligned nanofibers. Small 21, e2410351 (2025).

Google Scholar
Serbo, J. V. et al. Patterning of fibroblast and matrix anisotropy within 3D confinement is driven by the cytoskeleton. Adv. Healthc. Mater. 5, 146–158 (2015).

Google Scholar
Ilina, O. et al. Cell–cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion. Nat. Cell Biol. 22, 1103–1115 (2020).

Google Scholar
Yamada, K. M., Doyle, A. D. & Lu, J. Cell-3D matrix interactions: recent advances and opportunities. Trends Cell Biol. 32, 883–895 (2022).

Google Scholar
van der Putten, C. et al. Dimensionality matters: exploiting UV-photopatterned 2D and two-photon-printed 2.5D contact guidance cues to control corneal fibroblast behavior and collagen deposition. Bioengineering 11, 402 (2024).

Google Scholar
Bian, W., Jackman, C. P. & Bursac, N. Controlling the structural and functional anisotropy of engineered cardiac tissues. Biofabrication 6, 024109 (2015).

Google Scholar
Jia, X. et al. A multifunctional anisotropic patch manufactured by microfluidic manipulation for the repair of infarcted myocardium. Adv. Mater. 36, 2404071 (2024).

Google Scholar
Werner, M., Petersen, A., Kurniawan, N. A. & Bouten, C. V. C. Cell‐perceived substrate curvature dynamically coordinates the direction, speed, and persistence of stromal cell migration. Adv. Biosyst. 3, 1900080 (2019).

Google Scholar
Connon, C. J. & Gouveia, R. M. Milliscale substrate curvature promotes myoblast self‐organization and differentiation. Adv. Biol. 5, 2000280 (2021).

Google Scholar
Schamberger, B. et al. Curvature in biological systems: its quantification, emergence, and implications across the scales. Adv. Mater. 35, e2206110 (2023).

Google Scholar
Callens, S. J. P., Uyttendaele, R. J. C., Fratila-Apachitei, L. E. & Zadpoor, A. A. Substrate curvature as a cue to guide spatiotemporal cell and tissue organization. Biomaterials 232, 119739 (2020).

Google Scholar
Baptista, D., Teixeira, L., van Blitterswijk, C., Giselbrecht, S. & Truckenmüller, R. Overlooked? Underestimated? Effects of substrate curvature on cell behavior. Trends Biotechnol. 37, 838–854 (2019).

Google Scholar
Werner, M. et al. Surface curvature differentially regulates stem cell migration and differentiation via altered attachment morphology and nuclear deformation. Adv. Sci. 4, 1600347 (2017).

Google Scholar
Werner, M., Kurniawan, N. A. & Bouten, C. V. C. Cellular geometry sensing at different length scales and its implications for scaffold design. Materials 13, 963 (2020).

Google Scholar
Werner, M., Kurniawan, N. A., Korus, G., Bouten, C. V. C. & Petersen, A. Mesoscale substrate curvature overrules nanoscale contact guidance to direct bone marrow stromal cell migration. J. R. Soc. Interface. 15, 20180162 (2018).

Google Scholar
Fioretta, E. S., Simonet, M., Smits, A. I. P. M., Baaijens, F. P. T. & Bouten, C. V. C. Differential response of endothelial and endothelial colony forming cells on electrospun scaffolds with distinct microfiber diameters. Biomacromolecules 15, 821–829 (2014).

Google Scholar
Liu, C. et al. Collective cell polarization and alignment of curved surfaces. J. Mech. Behav. Biomed. Mater. 88, 330–339 (2018).

Google Scholar
Gouveia, R. M., Koudouna, E., Jester, J., Figueiredo, F. & Connon, C. J. Template curvature influences cell alignment to create improved human corneal tissue equivalents. Adv. Biosyst. 1, 1700135 (2017).

Google Scholar
Wohlgemuth, R. P. et al. Strain-dependent dynamic re-alignment of collagen fibers in skeletal muscle extracellular matrix. Acta Biomaterialia 187, 227–241 (2024).

Google Scholar
Ristori, T. et al. Modelling the combined effects of collagen and cyclic strain on cellular orientation in collagenous tissues. Sci. Rep. 8, 8518 (2018).

Google Scholar
Kaunas, R., Nguyen, P., Usami, S. & Chien, S. Cooperative effects of Rho and mechanical stretch on stress fiber organization. Proc. Natl Acad. Sci. USA 102, 15895–15900 (2005).

Google Scholar
Tamiello, C. et al. Cellular strain avoidance is mediated by a functional actin cap — observations in an Lmna-deficient cell model. J. Cell Sci. 130, 779–790 (2017).

Google Scholar
Nava, M. M. et al. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell 181, 800–817.e22 (2020).

Google Scholar
Tamiello, C., Bouten, C. V. C. & Baaijens, F. P. T. Competition between cap and basal actin fiber orientation in cells subjected to contact guidance and cyclic strain. Sci. Rep. 5, 8752 (2015).

Google Scholar
Wang, J. H. C. & Grood, E. S. The strain magnitude and contact guidance determine orientation response of fibroblasts to cyclic substrate strains. Connect. Tissue Res. 41, 29–36 (2000).

Google Scholar
Tondon, A. & Kaunas, R. The direction of stretch-induced cell and stress fiber orientation depends on collagen matrix stress. PLoS One 9, 89592 (2014).

Google Scholar
Chen, K. et al. Role of boundary conditions in determining cell alignment in response to stretch. Proc. Natl Acad. Sci. USA 115, 986–991 (2018).

Google Scholar
Gaul, R. T. et al. Pressure-induced collagen degradation in arterial tissue as a potential mechanism for degenerative arterial disease progression. J. Mech. Behav. Biomed. Mater. 109, 103771 (2020).

Google Scholar
Pei, D. et al. Remodeling of aligned fibrous extracellular matrix by encapsulated cells under mechanical stretching. Acta Biomater. 112, 202–212 (2020).

Google Scholar
Ingber, D. E. Tensegrity I. Cell structure and hierarchical systems biology. J. Cell Sci. 116, 1157–1173 (2003).

Google Scholar
Foolen, J., Deshpande, V. S., Kanters, F. M. W. & Baaijens, F. P. T. The influence of matrix integrity on stress-fiber remodeling in 3D. Biomaterials 33, 7508–7518 (2012).

Google Scholar
Mostert, D. et al. Human pluripotent stem cell-derived cardiomyocytes align under cyclic strain when guided by cardiac fibroblasts. APL Bioeng. 6, 046108 (2022).

Google Scholar
Van Haaften, E. E. et al. Decoupling the effect of shear stress and stretch on tissue growth and remodeling in a vascular graft. Tissue Eng. Part C Methods 24, 418–429 (2018).

Google Scholar
Ando, J. & Yamamoto, K. Vascular mechanobiology endothelial cell responses to fluid shear stress. Circ. J. 73, 1983–1992 (2009).

Google Scholar
Levesque, M. J. & Nerem, R. M. The elongation and orientation of cultured endothelial cells in response to shear stress. J. Biomech. Eng. 107, 341–347 (1985).

Google Scholar
Egorova, A. D. et al. Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition. Circ. Res. 108, 1093–1101 (2011).

Google Scholar
Jones, T. J. et al. Primary cilia regulates the directional migration and barrier integrity of endothelial cells through the modulation of hsp27 dependent actin cytoskeletal organization. J. Cell Physiol. 227, 70–76 (2012).

Google Scholar
van der Meer, A. D., Poot, A. A., Feijen, J. & Vermes, I. Analyzing shear stress-induced alignment of actin filaments in endothelial cells with a microfluidic assay. Biomicrofluidics 4, 11103 (2010).

Google Scholar
Vion, A. C. et al. Endothelial cell orientation and polarity are controlled by shear stress and VEGF through distinct signaling pathways. Front. Physiol. 11, 1743 (2021).

Google Scholar
Nerger, B. A., Brun, P. T. & Nelson, C. M. Marangoni flows drive the alignment of fibrillar cell-laden hydrogels. Sci. Adv. 6, eaaz7748 (2020).

Google Scholar
Kim, S. et al. Recent technological advances in lab-on-a-chip for bone remodeling. Biosens. Bioelectron. X 14, 100360 (2023).

Google Scholar
Nerger, B. A., Brun, P. T. & Nelson, C. M. Microextrusion printing cell-laden networks of type i collagen with patterned fiber alignment and geometry. Soft Matter 15, 5728–5738 (2019).

Google Scholar
Muncie, J. M. & Weaver, V. M. The physical and biochemical properties of the extracellular matrix regulate cell fate. Curr. Top. Dev. Biol. 130, 1–37 (2018).

Google Scholar
Yue, B. Biology of the extracellular matrix: an overview. J. Glaucoma 23, S20–S23 (2014).

Google Scholar
Wang, Y., Wang, X., Wohland, T. & Sampath, K. Extracellular interactions and ligand degradation shape the nodal morphogen gradient. eLife 5, e13879 (2016).

Google Scholar
Lin, B. & Levchenko, A. Spatial manipulation with microfluidics. Front. Bioeng. Biotechnol. 3, 39 (2015).

Google Scholar
Mathieu, M., Isomursu, A. & Ivaska, J. Positive and negative durotaxis — mechanisms and emerging concepts. J. Cell Sci. 137, jcs261919 (2024).

Google Scholar
McGuigan, A. P. & Javaherian, S. Tissue patterning: translating design principles from in vivo to in vitro. Annu. Rev. Biomed. Eng. 18, 1–24 (2016).

Google Scholar
Zhao, F. et al. Fibroblast alignment and matrix remodeling induced by a stiffness gradient in a skin-derived extracellular matrix hydrogel. Acta Biomater. 1, 67–80 (2024).

Google Scholar
van der Putten, C. et al. Protein micropatterning in 2.5D: an approach to investigate cellular responses in multi-cue environments. ACS Appl. Mater. Interfaces 13, 25589–25598 (2021).

Google Scholar
Vartanian, K. B., Kirkpatrick, S. J., Hanson, S. R. & Hinds, M. T. Endothelial cell cytoskeletal alignment independent of fluid shear stress on micropatterned surfaces. Biochem. Biophys. Res. Commun. 371, 787–792 (2008).

Google Scholar
Ristori, T., Vigliotti, A., Baaijens, F. P. T., Loerakker, S. & Deshpande, V. S. Prediction of cell alignment on cyclically strained grooved substrates. Biophys. J. 111, 2274–2285 (2016).

Google Scholar
Bliley, J. M. et al. Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype. Sci. Transl. Med. 13, eabd1817 (2021).

Google Scholar
Dede Eren, A. et al. The loop of phenotype: dynamic reciprocity links tenocyte morphology to tendon tissue homeostasis. Acta Biomater. 163, 275–286 (2023).

Google Scholar
Jing, J. et al. Reciprocal interaction between mesenchymal stem cells and transit amplifying cells regulates tissue homeostasis. eLife 10, e59459 (2021).

Google Scholar
Bril, M., Fredrich, S. & Kurniawan, N. A. Stimuli-responsive materials: a smart way to study dynamic cell responses. Smart Mater. Med. 3, 257–273 (2022).

Google Scholar
Madl, C. M. et al. Hydrogel biomaterials that stiffen and soften on demand reveal that skeletal muscle stem cells harbor a mechanical memory. Proc. Natl Acad. Sci. USA. 121, e2406787121 (2024).

Google Scholar
Rosales, A. M. et al. Hydrogels with reversible mechanics to probe dynamic cell microenvironments. Angew. Chem. 129, 12300–12304 (2017).

Google Scholar
Scott, S. et al. Dynamic and reversible tuning of hydrogel viscoelasticity by transient polymer interactions for controlling cell adhesion. Adv. Mater. 37, 2408616 (2025).

Google Scholar
Li, T. et al. Bioprinted anisotropic scaffolds with fast stress relaxation bioink for engineering 3D skeletal muscle and repairing volumetric muscle loss. Acta Biomater. 156, 21–36 (2023).

Google Scholar
Wang, Z. et al. Functional regeneration of tendons using scaffolds with physical anisotropy engineered via microarchitectural manipulation. Sci. Adv. 4, 10 (2018).

Google Scholar
Yao, S. et al. Co-effects of matrix low elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth. Nanoscale 8, 10252–10265 (2016).

Google Scholar
Han, J., Wu, Q., Xia, Y., Wagner, M. B. & Xu, C. Cell alignment induced by anisotropic electrospun fibrous scaffolds alone has limited effect on cardiomyocyte maturation. Stem Cell Res. 16, 740–750 (2016).

Google Scholar
Fomovsky, G. M. et al. Anisotropic reinforcement of acute anteroapical infarcts improves pump function. Circ. Heart Fail. 5, 515–522 (2012).

Google Scholar
Clarke, S. A. et al. Effect of scar compaction on the therapeutic efficacy of anisotropic reinforcement following myocardial infarction in the dog. J. Cardiovasc. Transl. Res. 8, 353–361 (2015).

Google Scholar
Mondrinos, M. J. et al. Surface-directed engineering of tissue anisotropy in microphysiological models of musculoskeletal tissue. Sci. Adv. 7, eabe9446 (2021).

Google Scholar
Xu, F. et al. Architecture design and advanced manufacturing of heart-on-a-chip: scaffolds, stimulation and sensors. Microsyst. Nanoeng. 10, 96 (2024).

Google Scholar
Herrera-Perez, R. M. et al. Tissue flows are tuned by actomyosin-dependent mechanics in developing embryos. PRX Life 1, 013004 (2023).

Google Scholar
Chandrasekar, S., Beach, J. R. & Oakes, P. W. Shining a light on RhoA: optical control of cell contractility. Int. J. Biochem. Cell Biol. 161, 106442 (2023).

Google Scholar
Shoyer, T. C. et al. Coupling during collective cell migration is controlled by a vinculin mechanochemical switch. Proc. Natl Acad. Sci. USA. 120, e2316456120 (2023).

Google Scholar
Mauretti, A. et al. Cardiomyocyte progenitor cell mechanoresponse unrevealed: strain avoidance and mechanosome development. Integr. Biol. 8, 991–1001 (2016).

Google Scholar
Carton, F. et al. Cardiac differentiation promotes focal adhesions assembly through vinculin recruitment. Int. J. Mol. Sci. 24, 2444 (2023).

Google Scholar
Mittal, N. et al. Myosin-independent stiffness sensing by fibroblasts is regulated by the viscoelasticity of flowing actin. Commun. Mater. 5, 6 (2024).

Google Scholar
Meinert, C. et al. A novel bioreactor system for biaxial mechanical loading enhances the properties of tissue-engineering human cartilage. Sci. Rep. 7, 16997 (2017).

Google Scholar
Rama, E. et al. In vitro and in vivo evaluation of biohybrid tissue-engineered vascular grafts with transformative 1H/19F MRI traceable scaffolds. Biomaterials 311, 122669 (2024).

Google Scholar
Wang, X. et al. Anisotropy links cell shapes to tissue flow during convergent extension. Proc. Natl Acad. Sci. USA 117, 13541–13551 (2020).

Google Scholar
Aper, S. J. A. et al. Colorful protein-based fluorescent probes for collagen imaging. PLoS One 9, e114983 (2014).

Google Scholar
Fiore, A. et al. Live imaging of the extracellular matrix with a glycan-binding fluorophore. Nat. Methods 22, 1070–1080 (2025).

Google Scholar
Daetwyler, S. et al. Imaging of cellular dynamics from a whole organism to subcellular scale with self-driving, multiscale microscopy. Nat. Methods 22, 569–578 (2025).

Google Scholar
Punoyuori, K. et al. Multiparameter imaging reveals clinically relevant cancer cell-stroma interaction dynamics in head and neck cancer. Cell 187, 7267–7284 (2024).

Google Scholar
Loveless, T. B. et al. Open-ended molecular recording of sequential cellular events into DNA. Nat. Chem. Biol. 21, 512–521 (2025).

Google Scholar
Godivier, J., Lawrence, E. A., Wang, M., Hammond, C. L. & Nowlan, N. C. Compressive stress gradients direct mechanoregulation of anisotropic growth in the zebrafish jaw joint. PLoS Comput. Biol. 20, e1010940 (2024).

Google Scholar
Pacary, A. et al. A computational model reveals an early transient decrease in fiber cross-linking that unlocks adult regeneration. NPJ Regen. Med. 9, 29 (2024).

Google Scholar
Humphrey, J. D. Mechanisms of vascular remodeling in hypertension. Am. J. Hypertens. 34, 432–441 (2020).

Google Scholar
Loerakker, S. et al. Mechanosensitivity of Jagged–Notch signaling can induce a switch-type behavior in vascular homeostasis. Proc. Natl Acad. Sci. USA 115, 3682–3691 (2018).

Google Scholar
Best, C. A. et al. Differential outcomes of venous and arterial tissue engineered vascular grafts highlight the importance of coupling long-term implantation studies with computational modeling. Acta Biomater. 94, 183–194 (2019).

Google Scholar
Emmert, M. Y. et al. Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model. Transl. Med. 10, eaan4587 (2018).

Google Scholar
Tan, W., Boodagh, P., Selvakumar, P. P. & Keyser, S. Strategies to counteract adverse remodeling of vascular graft: A 3D view of current graft innovations. Front. Bioeng. Biotechnol. 10, 1097334 (2023).

Google Scholar
Xing, J. et al. Engineering complex anisotropic scaffolds beyond simply uniaxial alignment for tissue engineering. Adv. Funct. Mater. 32, 2110676 (2022).

Google Scholar
Skillin, N. P. et al. Stiffness anisotropy coordinates supracellular contractility driving long-range myotube-ECM alignment. Sci. Adv. 10, eadn0235 (2024).

Google Scholar
Jorba, I. et al. Steering cell orientation through light-based spatiotemporal modulation of the mechanical environment. Biofabrication 16, https://doi.org/10.1088/1758-5090/ad3aa6 (2024).

Google Scholar
Xue, Y. et al. Biomimetic conductive hydrogel scaffolds with anisotropy and electrical stimulation for in vivo skeletal muscle reconstruction. Adv. Healthc. Mater. 13, e2302180 (2024).

Google Scholar
Liu, N., Becton, M., Zhang, L., Tang, K. & Wang, X. Mechanical anisotropy of two-dimensional metamaterials: a computational study. Nanoscale Adv. 8, 2891–2900 (2019).

Google Scholar
Burdick, J. A., Khademhosseini, A. & Langer, R. Fabrication of gradient hydrogels using a microfluidics/photopolymerization process. Langmuir 20, 5153–5156 (2004).

Google Scholar
Boyden, S. The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J. Exp. Med. 115, 453–466 (1962).

Google Scholar
Evans, E. B., Brady, S. W., Tripathi, A. & Hoffman-Kim, D. Schwann cell durotaxis can be guided by physiologically relevant stiffness gradients. Biomater. Res. 22, 14 (2018).

Google Scholar
Keenan, T. M. & Folch, A. Biomolecular gradients in cell culture systems. Lab. Chip 8, 34–57 (2007).

Google Scholar
Shirure, V. S. et al. Low levels of physiological interstitial flow eliminate morphogen gradients and guide angiogenesis. Angiogenesis 20, 493–504 (2017).

Google Scholar
Guo, T. et al. Mitochondrial fission and bioenergetics mediate human lung fibroblast durotaxis. JCI Insight 8, e157348 (2023).

Google Scholar
Ferre-Torres, J. et al. Modelling of chemotactic sprouting endothelial cells through an extracellular matrix. Front. Bioeng. Biotechnol. 11, 1145550 (2023).

Google Scholar
Mohammed, M. et al. Studying the response of aortic endothelial cells under pulsatile flow using a compact microfluidic system. Anal. Chem. 91, 12077–12084 (2019).

Google Scholar
Driessen, R. et al. Computational characterization of the dish-in-a-dish, a high yield culture platform for endothelial shear stress studies on the orbital shaker. Micromachines 11, 552 (2020).

Google Scholar
Nakayama, K. H. et al. Nanoscale patterning of extracellular matrix alters endothelial function under shear stress. Nano Lett. 16, 410–419 (2016).

Google Scholar
Yevick, H. G. et al. Architecture and migration of an epithelium on a cylindrical wire. Proc. Natl Acad. Sci. USA 112, 5944–5949 (2015).

Google Scholar
Ye, M. et al. Brain microvascular endothelial cells resist elongation due to curvature and shear stress. Sci. Rep. 4, 4681 (2014).

Google Scholar
Tamiello, C., Buskermolen, A. B. C., Baaijens, F. P. T., Broers, J. L. V. & Bouten, C. V. C. Heading in the right direction: understanding cellular orientation response to complex biophysical environments. Cell Mol. Bioeng. 9, 12–37 (2016).

Google Scholar
Chen, Y. et al. Single-cell migration chip for chemotaxis-based microfluidic selection of heterogeneous cell populations. Sci. Rep. 5, 9980 (2015).

Google Scholar
Kohn, J. C. et al. Cooperative effects of matrix stiffness and fluid shear stress on endothelial cell behavior. Biophysical J. 108, 471–478 (2015).

Google Scholar
Schmidt, A., Greenhalgh, A., Jockenhoevel, S., Fernandez-Colino, A. & Frydrych, M. Manufacturing of anisotropic protein-based scaffolds to precisely mimic native-tissue mechanics. Adv. Mater. Technol. 10, 2400946 (2025).

Google Scholar
Wei, X. et al. Hierarchically biomimetic scaffolds with anisotropic micropores and nanotopological patterns to promote bone regeneration via geometric modulation. Adv. Healthc. Mater. 13, e2304178 (2024).

Google Scholar
Garrido, C. A. et al. Hydrogels with stiffness-degradation spatial patterns control anisotropic 3D cell response. Biomater. Adv. 151, 213423 (2023).

Google Scholar
Vedaraman, S. et al. Bicyclic RGD peptides enhance nerve growth in synthetic PEG-based anisogels. Biomater. Sci. 9, 4329–4342 (2021).

Google Scholar
Gaspar, V. M. et al. Advanced bottom-up engineering of living architectures. Adv. Mater. 32, 6 (2020).

Google Scholar
Wu, H. et al. Advancing Scaffold-assisted modality for in situ osteochondral regeneration: a shift from biodegradable to bioadaptable. Adv. Mater. 36, 47 (2024).

Google Scholar

Download references