·
REVIEW
·

Cellular modulation by the mechanical cues from biomaterials for tissue engineering

Qiang Wei1 Shenghao Wang1 Feng Han1 Huan Wang1 Weidong Zhang1 Qifan Yu1 Changjiang Liu2 Luguang Ding2 Jiayuan Wang2 Lili Yu2 Caihong Zhu2* Bin Li1,2,3*
Show Less
1 Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
2 College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, Jiangsu Province, China
3 China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, Zhejiang Province, China
Submitted: 5 April 2021 | Revised: 13 June 2021 | Accepted: 10 July 2021 | Published: 28 December 2021
Copyright © 2021 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution–NonCommercial–ShareAlike 4.0 License.
Abstract

Mechanical cues from the extracellular matrix (ECM) microenvironment are known to be significant in modulating the fate of stem cells to guide developmental processes and maintain bodily homeostasis. Tissue engineering has provided a promising approach to the repair or regeneration of damaged tissues. Scaffolds are fundamental in cell-based regenerative therapies. Developing artificial ECM that mimics the mechanical properties of native ECM would greatly help to guide cell functions and thus promote tissue regeneration. In this review, we introduce various mechanical cues provided by the ECM including elasticity, viscoelasticity, topography, and external stimuli, and their effects on cell behaviours. Meanwhile, we discuss the underlying principles and strategies to develop natural or synthetic biomaterials with different mechanical properties for cellular modulation, and explore the mechanism by which the mechanical cues from biomaterials regulate cell function toward tissue regeneration. We also discuss the challenges in multimodal mechanical modulation of cell behaviours and the interplay between mechanical cues and other microenvironmental factors.

Keywords
cell behaviour ; mechanical cues ; multi-modal ; stiffness ; viscoelasticity
References

Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.

1. Wolff, J. Concept of the Law of Bone Remodelling. In The Law of Bone Remodelling, Wolff, J., ed. Springer Berlin Heidelberg: Berlin, Heidelberg. 1986; p 1.  
2. Doyle, A. D.; Carvajal, N.; Jin, A.; Matsumoto, K.; Yamada, K. M. Local 3D matrix microenvironment regulates cell migration through spatiotemporal dynamics of contractility-dependent adhesions. Nat Commun. 2015, 6, 8720.  
3. Hadden, W. J.; Young, J. L.; Holle, A. W.; McFetridge, M. L.; Kim, D. Y.; Wijesinghe, P.; Taylor-Weiner, H.; Wen, J. H.; Lee, A. R.; Bieback, K.; Vo, B. N.; Sampson, D. D.; Kennedy, B. F.; Spatz, J. P.; Engler, A. J.; Choi, Y. S. Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels. Proc Natl Acad Sci U S A. 2017, 114, 5647-5652.  
4. Mao, A. S.; Shin, J. W.; Mooney, D. J. Effects of substrate stiffness and cell-cell contact on mesenchymal stem cell differentiation. Biomaterials. 2016, 98, 184-191.  
5. Nisenholz, N.; Rajendran, K.; Dang, Q.; Chen, H.; Kemkemer, R.; Krishnan, R.; Zemel, A. Active mechanics and dynamics of cell spreading on elastic substrates. Soft Matter. 2014, 10, 7234-7246.  
6. Shin, J. W.; Mooney, D. J. Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias. Proc Natl Acad Sci U S A. 2016, 113, 12126-12131.  
7. Bonnans, C.; Chou, J.; Werb, Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014, 15, 786-801.  
8. Handorf, A. M.; Zhou, Y.; Halanski, M. A.; Li, W. J. Tissue stiffness dictates development, homeostasis, and disease progression. Organogenesis. 2015, 11, 1-15.  
9. Chaudhuri, O. Viscoelastic hydrogels for 3D cell culture. Biomater Sci. 2017, 5, 1480-1490.  
10. Yang, Y.; Wang, K.; Gu, X.; Leong, K. W. Biophysical regulation of cell behavior—cross talk between substrate stiffness and nanotopography. Engineering (Beijing). 2017, 3, 36-54.  
11. Panciera, T.; Azzolin, L.; Cordenonsi, M.; Piccolo, S. Mechanobiology of YAP and TAZ in physiology and disease. Nat Rev Mol Cell Biol. 2017, 18, 758-770.  
12. Chaudhuri, O.; Cooper-White, J.; Janmey, P. A.; Mooney, D. J.; Shenoy, V. B. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature. 2020, 584, 535-546.  
13. Levental, I.; Georges, P. C.; Janmey, P. A. Soft biological materials and their impact on cell function. Soft Matter. 2007, 3, 299-306.  
14. Vining, K. H.; Mooney, D. J. Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol. 2017, 18, 728-742.  
15. Sharabi, M.; Wertheimer, S.; Wade, K. R.; Galbusera, F.; Benayahu, D.; Wilke, H. J.; Haj-Ali, R. Towards intervertebral disc engineering: Biomimetics of form and function of the annulus fibrosus lamellae. J Mech Behav Biomed Mater. 2019, 94, 298-307.  
16. Kleemann, R. U.; Krocker, D.; Cedraro, A.; Tuischer, J.; Duda, G. N. Altered cartilage mechanics and histology in knee osteoarthritis: relation to clinical assessment (ICRS Grade). Osteoarthritis Cartilage. 2005, 13, 958-963.  
17. Zhang, X.; Cai, D.; Zhou, F.; Yu, J.; Wu, X.; Yu, D.; Zou, Y.; Hong, Y.; Yuan, C.; Chen, Y.; Pan, Z.; Bunpetch, V.; Sun, H.; An, C.; Yi-Chin, T.; Ouyang, H.; Zhang, S. Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis. Biomaterials. 2020, 232, 119724.  
18. Han, F.; Zhu, C.; Guo, Q.; Yang, H.; Li, B. Cellular modulation by the elasticity of biomaterials. J Mater Chem B. 2016, 4, 9-26.  
19. Sherratt, M. J. Tissue elasticity and the ageing elastic fibre. Age (Dordr). 2009, 31, 305-325.  
20. Engler, A. J.; Sen, S.; Sweeney, H. L.; Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell. 2006, 126, 677-689.  
21. Erickson, A. E.; Lan Levengood, S. K.; Sun, J.; Chang, F. C.; Zhang, M. Fabrication and characterization of chitosan-hyaluronic acid scaffolds with varying stiffness for glioblastoma cell culture. Adv Healthc Mater. 2018, 7, e1800295.  
22. Vorwald, C. E.; Gonzalez-Fernandez, T.; Joshee, S.; Sikorski, P.; Leach, J. K. Tunable fibrin-alginate interpenetrating network hydrogels to support cell spreading and network formation. Acta Biomater. 2020, 108, 142-152.  
23. Narkhede, A. A.; Crenshaw, J. H.; Manning, R. M.; Rao, S. S. The influence of matrix stiffness on the behavior of brain metastatic breast cancer cells in a biomimetic hyaluronic acid hydrogel platform. J Biomed Mater Res A. 2018, 106, 1832-1841.  
24. Sun, Y.; Zhang, K.; Deng, R.; Ren, X.; Wu, C.; Li, J. Tunable stiffness of graphene oxide/polyacrylamide composite scaffolds regulates cytoskeleton assembly. Chem Sci. 2018, 9, 6516-6522.  
25. Corbin, E. A.; Vite, A.; Peyster, E. G.; Bhoopalam, M.; Brandimarto, J.; Wang, X.; Bennett, A. I.; Clark, A. T.; Cheng, X.; Turner, K. T.; Musunuru, K.; Margulies, K. B. Tunable and reversible substrate stiffness reveals a dynamic mechanosensitivity of cardiomyocytes. ACS Appl Mater Interfaces. 2019, 11, 20603-20614.  
26. Mi, H. Y.; Jing, X.; Yilmaz, G.; Hagerty, B. S.; Enriquez, E.; Turng, L. S. In situ synthesis of polyurethane scaffolds with tunable properties by controlled crosslinking of tri-block copolymer and polycaprolactone triol for tissue regeneration. Chem Eng J. 2018, 348, 786-798.  
27. Buitrago, J. O.; Patel, K. D.; El-Fiqi, A.; Lee, J. H.; Kundu, B.; Lee, H. H.; Kim, H. W. Silk fibroin/collagen protein hybrid cell-encapsulating hydrogels with tunable gelation and improved physical and biological properties. Acta Biomater. 2018, 69, 218-233.  
28. Crocini, C.; Walker, C. J.; Anseth, K. S.; Leinwand, L. A. Three-dimensional encapsulation of adult mouse cardiomyocytes in hydrogels with tunable stiffness. Prog Biophys Mol Biol. 2020, 154, 71-79.  
29. Yi, B.; Shen, Y.; Tang, H.; Wang, X.; Li, B.; Zhang, Y. Stiffness of aligned fibers regulates the phenotypic expression of vascular smooth muscle cells. ACS Appl Mater Interfaces. 2019, 11, 6867-6880.  
30. Wu, Y.; Xiang, Y.; Fang, J.; Li, X.; Lin, Z.; Dai, G.; Yin, J.; Wei, P.; Zhang, D. The influence of the stiffness of GelMA substrate on the outgrowth of PC12 cells. Biosci Rep. 2019, 39, BSR20181748.  
31. Jiang, P.; Mao, Z.; Gao, C. Combinational effect of matrix elasticity and alendronate density on differentiation of rat mesenchymal stem cells. Acta Biomater. 2015, 19, 76-84.  
32. Berger, A. J.; Linsmeier, K. M.; Kreeger, P. K.; Masters, K. S. Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen. Biomaterials. 2017, 141, 125-135.  
33. Ansari, S.; Sarrion, P.; Hasani-Sadrabadi, M. M.; Aghaloo, T.; Wu, B. M.; Moshaverinia, A. Regulation of the fate of dental-derived mesenchymal stem cells using engineered alginate-GelMA hydrogels. J Biomed Mater Res A. 2017, 105, 2957-2967.  
34. Ansari, S.; Chen, C.; Hasani-Sadrabadi, M. M.; Yu, B.; Zadeh, H. H.; Wu, B. M.; Moshaverinia, A. Hydrogel elasticity and microarchitecture regulate dental-derived mesenchymal stem cell-host immune system cross-talk. Acta Biomater. 2017, 60, 181-189.  
35. Wang, X.; Ding, Z.; Wang, C.; Chen, X.; Xu, H.; Lu, Q.; Kaplan, D. L. Bioactive silk hydrogels with tunable mechanical properties. J Mater Chem B. 2018, 6, 2739-2746.  
36. Zhu, C.; Li, J.; Liu, C.; Zhou, P.; Yang, H.; Li, B. Modulation of the gene expression of annulus fibrosus-derived stem cells using poly(ether carbonate urethane)urea scaffolds of tunable elasticity. Acta Biomater. 2016, 29, 228-238.  
37. Günay, K. A.; Ceccato, T. L.; Silver, J. S.; Bannister, K. L.; Bednarski, O. J.; Leinwand, L. A.; Anseth, K. S. PEG-anthracene hydrogels as an on-demand stiffening matrix to study mechanobiology. Angew Chem Int Ed Engl. 2019, 58, 9912-9916.  
38. Young, J. L.; Engler, A. J. Hydrogels with time-dependent material properties enhance cardiomyocyte differentiation in vitro. Biomaterials. 2011, 32, 1002-1009.  
39. Fu, L.; Haage, A.; Kong, N.; Tanentzapf, G.; Li, H. Dynamic protein hydrogels with reversibly tunable stiffness regulate human lung fibroblast spreading reversibly. Chem Commun (Camb). 2019, 55, 5235-5238.  
40. Zhang, D.; Zhou, C.; Wang, Q.; Cai, L.; Du, W.; Li, X.; Zhou, X.; Xie, J. Extracellular matrix elasticity regulates osteocyte gap junction elongation: involvement of paxillin in intracellular signal transduction. Cell Physiol Biochem. 2018, 51, 1013-1023.  
41. Xie, J.; Zhang, Q.; Zhu, T.; Zhang, Y.; Liu, B.; Xu, J.; Zhao, H. Substrate stiffness-regulated matrix metalloproteinase output in myocardial cells and cardiac fibroblasts: implications for myocardial fibrosis. Acta Biomater. 2014, 10, 2463-2472.  
42. Yeung, T.; Georges, P. C.; Flanagan, L. A.; Marg, B.; Ortiz, M.; Funaki, M.; Zahir, N.; Ming, W.; Weaver, V.; Janmey, P. A. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil Cytoskeleton. 2005, 60, 24-34.  
43. Hansen, T. D.; Koepsel, J. T.; Le, N. N.; Nguyen, E. H.; Zorn, S.; Parlato, M.; Loveland, S. G.; Schwartz, M. P.; Murphy, W. L. Biomaterial arrays with defined adhesion ligand densities and matrix stiffness identify distinct phenotypes for tumorigenic and nontumorigenic human mesenchymal cell types. Biomater Sci. 2014, 2, 745-756.  
44. Melica, M. E.; La Regina, G.; Parri, M.; Peired, A. J.; Romagnani, P.; Lasagni, L. Substrate stiffness modulates renal progenitor cell properties via a ROCK-mediated mechanotransduction mechanism. Cells. 2019, 8, 1561.  
45. Peyton, S. R.; Putnam, A. J. Extracellular matrix rigidity governs smooth muscle cell motility in a biphasic fashion. J Cell Physiol. 2005, 204, 198-209.  
46. Bangasser, B. L.; Shamsan, G. A.; Chan, C. E.; Opoku, K. N.; Tüzel, E.; Schlichtmann, B. W.; Kasim, J. A.; Fuller, B. J.; McCullough, B. R.; Rosenfeld, S. S.; Odde, D. J. Shifting the optimal stiffness for cell migration. Nat Commun. 2017, 8, 15313.  
47. Lo, C. M.; Wang, H. B.; Dembo, M.; Wang, Y. L. Cell movement is guided by the rigidity of the substrate. Biophys J. 2000, 79, 144-152.  
48. Okimura, C.; Sakumura, Y.; Shimabukuro, K.; Iwadate, Y. Sensing of substratum rigidity and directional migration by fast-crawling cells. Phys Rev E. 2018, 97, 052401.  
49. Hartman, C. D.; Isenberg, B. C.; Chua, S. G.; Wong, J. Y. Vascular smooth muscle cell durotaxis depends on extracellular matrix composition. Proc Natl Acad Sci U S A. 2016, 113, 11190-11195.  
50. Liu, N.; Zhou, M.; Zhang, Q.; Yong, L.; Zhang, T.; Tian, T.; Ma, Q.; Lin, S.; Zhu, B.; Cai, X. Effect of substrate stiffness on proliferation and differentiation of periodontal ligament stem cells. Cell Prolif. 2018, 51, e12478.  
51. Ansardamavandi, A.; Tafazzoli-Shadpour, M.; Shokrgozar, M. A. Behavioral remodeling of normal and cancerous epithelial cell lines with differing invasion potential induced by substrate elastic modulus. Cell Adh Migr. 2018, 12, 472-488.  
52. Leipzig, N. D.; Shoichet, M. S. The effect of substrate stiffness on adult neural stem cell behavior. Biomaterials. 2009, 30, 6867-6878.  
53. Robinson, K. G.; Nie, T.; Baldwin, A. D.; Yang, E. C.; Kiick, K. L.; Akins, R. E., Jr. Differential effects of substrate modulus on human vascular endothelial, smooth muscle, and fibroblastic cells. J Biomed Mater Res A. 2012, 100, 1356-1367.  
54. Eroshenko, N.; Ramachandran, R.; Yadavalli, V. K.; Rao, R. R. Effect of substrate stiffness on early human embryonic stem cell differentiation. J Biol Eng. 2013, 7, 7.  
55. Arshi, A.; Nakashima, Y.; Nakano, H.; Eaimkhong, S.; Evseenko, D.; Reed, J.; Stieg, A. Z.; Gimzewski, J. K.; Nakano, A. Rigid microenvironments promote cardiac differentiation of mouse and human embryonic stem cells. Sci Technol Adv Mater. 2013, 14, 025003.  
56. Macrí-Pellizzeri, L.; Pelacho, B.; Sancho, A.; Iglesias-García, O.; Simón-Yarza, A. M.; Soriano-Navarro, M.; González-Granero, S.; García-Verdugo, J. M.; De-Juan-Pardo, E. M.; Prosper, F. Substrate stiffness and composition specifically direct differentiation of induced pluripotent stem cells. Tissue Eng Part A. 2015, 21, 1633-1641.  
57. Fu, J.; Chuah, Y. J.; Liu, J.; Tan, S. Y.; Wang, D. A. Respective effects of gelatin-coated polydimethylsiloxane (PDMS) substrates on self-renewal and cardiac differentiation of induced pluripotent stem cells (iPSCs). ACS Biomater Sci Eng. 2018, 4, 4321-4330.  
58. Janmey, P. A.; Fletcher, D. A.; Reinhart-King, C. A. Stiffness sensing by cells. Physiol Rev. 2020, 100, 695-724.  
59. Lantoine, J.; Grevesse, T.; Villers, A.; Delhaye, G.; Mestdagh, C.; Versaevel, M.; Mohammed, D.; Bruyère, C.; Alaimo, L.; Lacour, S. P.; Ris, L.; Gabriele, S. Matrix stiffness modulates formation and activity of neuronal networks of controlled architectures. Biomaterials. 2016, 89, 14-24.  
60. Chen, G.; Dong, C.; Yang, L.; Lv, Y. 3D scaffolds with different stiffness but the same microstructure for bone tissue engineering. ACS Appl Mater Interfaces. 2015, 7, 15790-15802.  
61. Zhang, Q.; Yu, Y.; Zhao, H. The effect of matrix stiffness on biomechanical properties of chondrocytes. Acta Biochim Biophys Sin (Shanghai). 2016, 48, 958-965.  
62. Sun, A. X.; Lin, H.; Fritch, M. R.; Shen, H.; Alexander, P. G.; DeHart, M.; Tuan, R. S. Chondrogenesis of human bone marrow mesenchymal stem cells in 3-dimensional, photocrosslinked hydrogel constructs: Effect of cell seeding density and material stiffness. Acta Biomater. 2017, 58, 302-311.  
63. Sarem, M.; Arya, N.; Heizmann, M.; Neffe, A. T.; Barbero, A.; Gebauer, T. P.; Martin, I.; Lendlein, A.; Shastri, V. P. Interplay between stiffness and degradation of architectured gelatin hydrogels leads to differential modulation of chondrogenesis in vitro and in vivo. Acta Biomater. 2018, 69, 83-94.  
64. Zhan, X. Effect of matrix stiffness and adhesion ligand density on chondrogenic differentiation of mesenchymal stem cells. J Biomed Mater Res A. 2020, 108, 675-683.  
65. Takaza, M.; Moerman, K. M.; Gindre, J.; Lyons, G.; Simms, C. K. The anisotropic mechanical behaviour of passive skeletal muscle tissue subjected to large tensile strain. J Mech Behav Biomed Mater. 2013, 17, 209-220.  
66. Asbach, P.; Klatt, D.; Hamhaber, U.; Braun, J.; Somasundaram, R.; Hamm, B.; Sack, I. Assessment of liver viscoelasticity using multifrequency MR elastography. Magn Reson Med. 2008, 60, 373-379.  
67. Balleyguier, C.; Canale, S.; Ben Hassen, W.; Vielh, P.; Bayou, E. H.; Mathieu, M. C.; Uzan, C.; Bourgier, C.; Dromain, C. Breast elasticity: principles, technique, results: an update and overview of commercially available software. Eur J Radiol. 2013, 82, 427-434.  
68. Kearney, S. P.; Khan, A.; Dai, Z.; Royston, T. J. Dynamic viscoelastic models of human skin using optical elastography. Phys Med Biol. 2015, 60, 6975-6990.  
69. Yang, X.; Muthukumaran, P.; DasDe, S.; Teoh, S. H.; Choi, H.; Lim, S. K.; Lee, T. Positive alterations of viscoelastic and geometric properties in ovariectomized rat femurs with concurrent administration of ibandronate and PTH. Bone. 2013, 52, 308-317.  
70. Cameron, A. R.; Frith, J. E.; Cooper-White, J. J. The influence of substrate creep on mesenchymal stem cell behaviour and phenotype. Biomaterials. 2011, 32, 5979-5993.  
71. Charrier, E. E.; Pogoda, K.; Wells, R. G.; Janmey, P. A. Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation. Nat Commun. 2018, 9, 449.  
72. Chaudhuri, O.; Gu, L.; Darnell, M.; Klumpers, D.; Bencherif, S. A.; Weaver, J. C.; Huebsch, N.; Mooney, D. J. Substrate stress relaxation regulates cell spreading. Nat Commun. 2015, 6, 6364.  
73. Chaudhuri, O.; Gu, L.; Klumpers, D.; Darnell, M.; Bencherif, S. A.; Weaver, J. C.; Huebsch, N.; Lee, H. P.; Lippens, E.; Duda, G. N.; Mooney, D. J. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat Mater. 2016, 15, 326-334.  
74. Nam, S.; Stowers, R.; Lou, J.; Xia, Y.; Chaudhuri, O. Varying PEG density to control stress relaxation in alginate-PEG hydrogels for 3D cell culture studies. Biomaterials. 2019, 200, 15-24.  
75. Vining, K. H.; Stafford, A.; Mooney, D. J. Sequential modes of crosslinking tune viscoelasticity of cell-instructive hydrogels. Biomaterials. 2019, 188, 187-197.  
76. Nam, S.; Hu, K. H.; Butte, M. J.; Chaudhuri, O. Strain-enhanced stress relaxation impacts nonlinear elasticity in collagen gels. Proc Natl Acad Sci U S A. 2016, 113, 5492-5497.  
77. Rosales, A. M.; Rodell, C. B.; Chen, M. H.; Morrow, M. G.; Anseth, K. S.; Burdick, J. A. Reversible control of network properties in azobenzene-containing hyaluronic acid-based hydrogels. Bioconjug Chem. 2018, 29, 905-913.  
78. Marozas, I. A.; Anseth, K. S.; Cooper-White, J. J. Adaptable boronate ester hydrogels with tunable viscoelastic spectra to probe timescale dependent mechanotransduction. Biomaterials. 2019, 223, 119430.  
79. Tang, S.; Ma, H.; Tu, H. C.; Wang, H. R.; Lin, P. C.; Anseth, K. S. Adaptable fast relaxing boronate-based hydrogels for probing cell-matrix interactions. Adv Sci (Weinh). 2018, 5, 1800638.  
80. Hui, E.; Gimeno, K. I.; Guan, G.; Caliari, S. R. Spatiotemporal control of viscoelasticity in phototunable hyaluronic acid hydrogels. Biomacromolecules. 2019, 20, 4126-4134.  
81. Lou, J.; Stowers, R.; Nam, S.; Xia, Y.; Chaudhuri, O. Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture. Biomaterials. 2018, 154, 213-222.  
82. Sánchez-Morán, H.; Ahmadi, A.; Vogler, B.; Roh, K. H. Oxime cross-linked alginate hydrogels with tunable stress relaxation. Biomacromolecules. 2019, 20, 4419-4429.  
83. McKinnon, D. D.; Domaille, D. W.; Cha, J. N.; Anseth, K. S. Biophysically defined and cytocompatible covalently adaptable networks as viscoelastic 3D cell culture systems. Adv Mater. 2014, 26, 865-872.  
84. Brown, T. E.; Carberry, B. J.; Worrell, B. T.; Dudaryeva, O. Y.; McBride, M. K.; Bowman, C. N.; Anseth, K. S. Photopolymerized dynamic hydrogels with tunable viscoelastic properties through thioester exchange. Biomaterials. 2018, 178, 496-503.  
85. Loebel, C.; Ayoub, A.; Galarraga, J. H.; Kossover, O.; Simaan-Yameen, H.; Seliktar, D.; Burdick, J. A. Tailoring supramolecular guest-host hydrogel viscoelasticity with covalent fibrinogen double networks. J Mater Chem B. 2019, 7, 1753-1760.  
86. Zhao, X.; Huebsch, N.; Mooney, D. J.; Suo, Z. Stress-relaxation behavior in gels with ionic and covalent crosslinks. J Appl Phys. 2010, 107, 63509.  
87. Lee, H. P.; Gu, L.; Mooney, D. J.; Levenston, M. E.; Chaudhuri, O. Mechanical confinement regulates cartilage matrix formation by chondrocytes. Nat Mater. 2017, 16, 1243-1251.  
88. Ryan, A. J.; O’Brien, F. J. Insoluble elastin reduces collagen scaffold stiffness, improves viscoelastic properties, and induces a contractile phenotype in smooth muscle cells. Biomaterials. 2015, 73, 296-307.  
89. Bauer, A.; Gu, L.; Kwee, B.; Li, W. A.; Dellacherie, M.; Celiz, A. D.; Mooney, D. J. Hydrogel substrate stress-relaxation regulates the spreading and proliferation of mouse myoblasts. Acta Biomater. 2017, 62, 82-90.  
90. Zheng, J. Y.; Han, S. P.; Chiu, Y. J.; Yip, A. K.; Boichat, N.; Zhu, S. W.; Zhong, J.; Matsudaira, P. Epithelial monolayers coalesce on a viscoelastic substrate through redistribution of vinculin. Biophys J. 2017, 113, 1585-1598.  
91. Sommerfeld, S. D.; Elisseeff, J. H. Time to relax: mechanical stress release guides stem cell responses. Cell Stem Cell. 2016, 18, 166-167.  
92. Ghosh, P.; Rameshbabu, A. P.; Dhara, S. Citrate cross-linked gels with strain reversibility and viscoelastic behavior accelerate healing of osteochondral defects in a rabbit model. Langmuir. 2014, 30, 8442-8451.  
93. Ghosh, P.; Rameshbabu, A. P.; Das, D.; Francis, N. K.; Pawar, H. S.; Subramanian, B.; Pal, S.; Dhara, S. Covalent cross-links in polyampholytic chitosan fibers enhances bone regeneration in a rabbit model. Colloids Surf B Biointerfaces. 2015, 125, 160-169.  
94. Darnell, M.; Young, S.; Gu, L.; Shah, N.; Lippens, E.; Weaver, J.; Duda, G.; Mooney, D. Substrate stress-relaxation regulates scaffold remodeling and bone formation in vivo. Adv Healthc Mater. 2017, 6, 1601185.  
95. Richardson, B. M.; Wilcox, D. G.; Randolph, M. A.; Anseth, K. S. Hydrazone covalent adaptable networks modulate extracellular matrix deposition for cartilage tissue engineering. Acta Biomater. 2019, 83, 71-82.  
96. Li, W.; Wu, D.; Hu, D.; Zhu, S.; Pan, C.; Jiao, Y.; Li, L.; Luo, B.; Zhou, C.; Lu, L. Stress-relaxing double-network hydrogel for chondrogenic differentiation of stem cells. Mater Sci Eng C Mater Biol Appl. 2020, 107, 110333.  
97. Mandal, K.; Gong, Z.; Rylander, A.; Shenoy, V. B.; Janmey, P. A. Opposite responses of normal hepatocytes and hepatocellular carcinoma cells to substrate viscoelasticity. Biomater Sci. 2020, 8, 1316-1328.  
98. Chen, J.; Wright, K. E.; Birch, M. A. Nanoscale viscoelastic properties and adhesion of polydimethylsiloxane for tissue engineering. Acta Mech Sin. 2014, 30, 2-6.  
99. Trappmann, B.; Gautrot, J. E.; Connelly, J. T.; Strange, D. G.; Li, Y.; Oyen, M. L.; Cohen Stuart, M. A.; Boehm, H.; Li, B.; Vogel, V.; Spatz, J. P.; Watt, F. M.; Huck, W. T. Extracellular-matrix tethering regulates stem-cell fate. Nat Mater. 2012, 11, 642-649.  
100. Wen, J. H.; Vincent, L. G.; Fuhrmann, A.; Choi, Y. S.; Hribar, K. C.; Taylor-Weiner, H.; Chen, S.; Engler, A. J. Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat Mater. 2014, 13, 979-987.  
101. Sadtler, K.; Wolf, M. T.; Ganguly, S.; Moad, C. A.; Chung, L.; Majumdar, S.; Housseau, F.; Pardoll, D. M.; Elisseeff, J. H. Divergent immune responses to synthetic and biological scaffolds. Biomaterials. 2019, 192, 405-415.  
102. Chu, G.; Yuan, Z.; Zhu, C.; Zhou, P.; Wang, H.; Zhang, W.; Cai, Y.; Zhu, X.; Yang, H.; Li, B. Substrate stiffness- and topography-dependent differentiation of annulus fibrosus-derived stem cells is regulated by Yes-associated protein. Acta Biomater. 2019, 92, 254-264.  
103. Shvedova, A. A.; Kisin, E. R.; Mercer, R.; Murray, A. R.; Johnson, V. J.; Potapovich, A. I.; Tyurina, Y. Y.; Gorelik, O.; Arepalli, S.; Schwegler-Berry, D.; Hubbs, A. F.; Antonini, J.; Evans, D. E.; Ku, B. K.; Ramsey, D.; Maynard, A.; Kagan, V. E.; Castranova, V.; Baron, P. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol. 2005, 289, L698-708.  
104. Suki, B.; Sato, S.; Parameswaran, H.; Szabari, M. V.; Takahashi, A.; Bartolák-Suki, E. Emphysema and mechanical stress-induced lung remodeling. Physiology (Bethesda). 2013, 28, 404-413.  
105. Nguyen, A. T.; Sathe, S. R.; Yim, E. K. From nano to micro: topographical scale and its impact on cell adhesion, morphology and contact guidance. J Phys Condens Matter. 2016, 28, 183001.  
106. Wu, S.; Duan, B.; Qin, X.; Butcher, J. T. Living nano-micro fibrous woven fabric/hydrogel composite scaffolds for heart valve engineering. Acta Biomater. 2017, 51, 89-100.  
107. Wang, S.; Zhong, S.; Lim, C. T.; Nie, H. Effects of fiber alignment on stem cells-fibrous scaffold interactions. J Mater Chem B. 2015, 3, 3358-3366.  
108. Fu, X.; Wang, H. Spatial arrangement of polycaprolactone/collagen nanofiber scaffolds regulates the wound healing related behaviors of human adipose stromal cells. Tissue Eng Part A. 2012, 18, 631-642.  
109. Moffa, M.; Sciancalepore, A. G.; Passione, L. G.; Pisignano, D. Combined nano- and micro-scale topographic cues for engineered vascular constructs by electrospinning and imprinted micro-patterns. Small. 2014, 10, 2439-2450.  
110. Yan, J.; Qiang, L.; Gao, Y.; Cui, X.; Zhou, H.; Zhong, S.; Wang, Q.; Wang, H. Effect of fiber alignment in electrospun scaffolds on keratocytes and corneal epithelial cells behavior. J Biomed Mater Res A. 2012, 100, 527-535.  
111. Stevens, M. M.; George, J. H. Exploring and engineering the cell surface interface. Science. 2005, 310, 1135-1138.  
112. Dalby, M. J.; Gadegaard, N.; Oreffo, R. O. Harnessing nanotopography and integrin-matrix interactions to influence stem cell fate. Nat Mater. 2014, 13, 558-569.  
113. Hou, Y.; Yu, L.; Xie, W.; Camacho, L. C.; Zhang, M.; Chu, Z.; Wei, Q.; Haag, R. Surface roughness and substrate stiffness synergize to drive cellular mechanoresponse. Nano Lett. 2020, 20, 748-757.  
114. Jahanmard, F.; Baghban Eslaminejad, M.; Amani-Tehran, M.; Zarei, F.; Rezaei, N.; Croes, M.; Amin Yavari, S. Incorporation of F-MWCNTs into electrospun nanofibers regulates osteogenesis through stiffness and nanotopography. Mater Sci Eng C Mater Biol Appl. 2020, 106, 110163.  
115. Qu, F.; Guilak, F.; Mauck, R. L. Cell migration: implications for repair and regeneration in joint disease. Nat Rev Rheumatol. 2019, 15, 167-179.  
116. Liu, W.; Thomopoulos, S.; Xia, Y. Electrospun nanofibers for regenerative medicine. Adv Healthc Mater. 2012, 1, 10-25.  

117. Song, K. H.; Heo, S. J.; Peredo, A. P.; Davidson, M. D.; Mauck, R. L.; Burdick, J. A. Influence of fiber stiffness on meniscal cell migration into dense fibrous networks. Adv Healthc Mater. 2020, 9, e1901228.  
118. Davidson, M. D.; Song, K. H.; Lee, M. H.; Llewellyn, J.; Du, Y.; Baker, B. M.; Wells, R. G.; Burdick, J. A. Engineered fibrous networks to investigate the influence of fiber mechanics on myofibroblast differentiation. ACS Biomater Sci Eng. 2019, 5, 3899-3908.  
119. Northey, J. J.; Przybyla, L.; Weaver, V. M. Tissue force programs cell fate and tumor aggression. Cancer Discov. 2017, 7, 1224-1237.  
120. Brusatin, G.; Panciera, T.; Gandin, A.; Citron, A.; Piccolo, S. Biomaterials and engineered microenvironments to control YAP/TAZ-dependent cell behaviour. Nat Mater. 2018, 17, 1063-1075.  
121. Hove, J. R.; Köster, R. W.; Forouhar, A. S.; Acevedo-Bolton, G.; Fraser, S. E.; Gharib, M. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature. 2003, 421, 172-177.  
122. Yang, Y.; Beqaj, S.; Kemp, P.; Ariel, I.; Schuger, L. Stretch-induced alternative splicing of serum response factor promotes bronchial myogenesis and is defective in lung hypoplasia. J Clin Invest. 2000, 106, 1321-1330.  
123. Lefebvre, V.; Bhattaram, P. Vertebrate skeletogenesis. Curr Top Dev Biol. 2010, 90, 291-317.  
124. Ni, S.; Ling, Z.; Wang, X.; Cao, Y.; Wu, T.; Deng, R.; Crane, J. L.; Skolasky, R.; Demehri, S.; Zhen, G.; Jain, A.; Wu, P.; Pan, D.; Hu, B.; Lyu, X.; Li, Y.; Chen, H.; Qi, H.; Guan, Y.; Dong, X.; Wan, M.; Zou, X.; Lu, H.; Hu, J.; Cao, X. Sensory innervation in porous endplates by Netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice. Nat Commun. 2019, 10, 5643.  
125. Lacroix, D.; Prendergast, P. J. A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J Biomech. 2002, 35, 1163-1171.  
126. Meza, D.; Musmacker, B.; Steadman, E.; Stransky, T.; Rubenstein, D. A.; Yin, W. Endothelial cell biomechanical responses are dependent on both fluid shear stress and tensile strain. Cell Mol Bioeng. 2019, 12, 311-325.  
127. Gayer, C. P.; Basson, M. D. The effects of mechanical forces on intestinal physiology and pathology. Cell Signal. 2009, 21, 1237-1244.  
128. Madhavan, S.; Anghelina, M.; Rath-Deschner, B.; Wypasek, E.; John, A.; Deschner, J.; Piesco, N.; Agarwal, S. Biomechanical signals exert sustained attenuation of proinflammatory gene induction in articular chondrocytes. Osteoarthritis Cartilage. 2006, 14, 1023-1032.  
129. Sowa, G.; Agarwal, S. Cyclic tensile stress exerts a protective effect on intervertebral disc cells. Am J Phys Med Rehabil. 2008, 87, 537-544.  
130. Branski, R. C.; Perera, P.; Verdolini, K.; Rosen, C. A.; Hebda, P. A.; Agarwal, S. Dynamic biomechanical strain inhibits IL-1beta-induced inflammation in vocal fold fibroblasts. J Voice. 2007, 21, 651-660.  
131. Zhao, R.; Liu, W.; Xia, T.; Yang, L. Disordered mechanical stress and tissue engineering therapies in intervertebral disc degeneration. Polymers (Basel). 2019, 11, 1151.  
132. Pratsinis, H.; Papadopoulou, A.; Neidlinger-Wilke, C.; Brayda-Bruno, M.; Wilke, H. J.; Kletsas, D. Cyclic tensile stress of human annulus fibrosus cells induces MAPK activation: involvement in proinflammatory gene expression. Osteoarthritis Cartilage. 2016, 24, 679-687.  
133. Yurube, T.; Hirata, H.; Kakutani, K.; Maeno, K.; Takada, T.; Zhang, Z.; Takayama, K.; Matsushita, T.; Kuroda, R.; Kurosaka, M.; Nishida, K. Notochordal cell disappearance and modes of apoptotic cell death in a rat tail static compression-induced disc degeneration model. Arthritis Res Ther. 2014, 16, R31.  
134. Chang, S. H.; Mori, D.; Kobayashi, H.; Mori, Y.; Nakamoto, H.; Okada, K.; Taniguchi, Y.; Sugita, S.; Yano, F.; Chung, U. I.; Kim-Kaneyama, J. R.; Yanagita, M.; Economides, A.; Canalis, E.; Chen, D.; Tanaka, S.; Saito, T. Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway. Nat Commun. 2019, 10, 1442.  
135. Yanoshita, M.; Hirose, N.; Okamoto, Y.; Sumi, C.; Takano, M.; Nishiyama, S.; Asakawa-Tanne, Y.; Horie, K.; Onishi, A.; Yamauchi, Y.; Mitsuyoshi, T.; Kunimatsu, R.; Tanimoto, K. Cyclic tensile strain upregulates pro-inflammatory cytokine expression via FAK-MAPK signaling in chondrocytes. Inflammation. 2018, 41, 1621-1630.  
136. Hirose, N.; Okamoto, Y.; Yanoshita, M.; Asakawa, Y.; Sumi, C.; Takano, M.; Nishiyama, S.; Su, S. C.; Mitsuyoshi, T.; Kunimatsu, R.; Tanne, K.; Tanimoto, K. Protective effects of cilengitide on inflammation in chondrocytes under excessive mechanical stress. Cell Biol Int. 2020, 44, 966-974.  
137. Hunt, B. J.; Jurd, K. M. Endothelial cell activation. A central pathophysiological process. BMJ. 1998, 316, 1328-1329.  
138. Chatterjee, S.; Browning, E. A.; Hong, N.; DeBolt, K.; Sorokina, E. M.; Liu, W.; Birnbaum, M. J.; Fisher, A. B. Membrane depolarization is the trigger for PI3K/Akt activation and leads to the generation of ROS. Am J Physiol Heart Circ Physiol. 2012, 302, H105-114.  
139. Hynes, R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992, 69, 11-25.  
140. Guan, J. L. Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer. IUBMB Life. 2010, 62, 268-276.  
141. Bolós, V.; Gasent, J. M.; López-Tarruella, S.; Grande, E. The dual kinase complex FAK-Src as a promising therapeutic target in cancer. Onco Targets Ther. 2010, 3, 83-97.  
142. Liu, C.; Luo, J. W.; Liang, T.; Lin, L. X.; Luo, Z. P.; Zhuang, Y. Q.; Sun, Y. L. Matrix stiffness regulates the differentiation of tendon-derived stem cells through FAK-ERK1/2 activation. Exp Cell Res. 2018, 373, 62-70.  
143. Lee, H. J.; Li, N.; Evans, S. M.; Diaz, M. F.; Wenzel, P. L. Biomechanical force in blood development: extrinsic physical cues drive pro-hematopoietic signaling. Differentiation. 2013, 86, 92-103.  
144. Biggs, M. J.; Richards, R. G.; Gadegaard, N.; Wilkinson, C. D.; Oreffo, R. O.; Dalby, M. J. The use of nanoscale topography to modulate the dynamics of adhesion formation in primary osteoblasts and ERK/MAPK signalling in STRO-1+ enriched skeletal stem cells. Biomaterials. 2009, 30, 5094-5103.  
145. Teo, B. K.; Wong, S. T.; Lim, C. K.; Kung, T. Y.; Yap, C. H.; Ramagopal, Y.; Romer, L. H.; Yim, E. K. Nanotopography modulates mechanotransduction of stem cells and induces differentiation through focal adhesion kinase. ACS Nano. 2013, 7, 4785-4798.  
146. Khatiwala, C. B.; Kim, P. D.; Peyton, S. R.; Putnam, A. J. ECM compliance regulates osteogenesis by influencing MAPK signaling downstream of RhoA and ROCK. J Bone Miner Res. 2009, 24, 886-898.  
147. Halder, G.; Dupont, S.; Piccolo, S. Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat Rev Mol Cell Biol. 2012, 13, 591-600.  
148. Dasgupta, I.; McCollum, D. Control of cellular responses to mechanical cues through YAP/TAZ regulation. J Biol Chem. 2019, 294, 17693-17706.  
149. Du, J.; Chen, X.; Liang, X.; Zhang, G.; Xu, J.; He, L.; Zhan, Q.; Feng, X. Q.; Chien, S.; Yang, C. Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity. Proc Natl Acad Sci U S A. 2011, 108, 9466-9471.  
150. Coste, B.; Mathur, J.; Schmidt, M.; Earley, T. J.; Ranade, S.; Petrus, M. J.; Dubin, A. E.; Patapoutian, A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science. 2010, 330, 55-60.  
151. Pethő, Z.; Najder, K.; Bulk, E.; Schwab, A. Mechanosensitive ion channels push cancer progression. Cell Calcium. 2019, 80, 79-90.  
152. Caliari, S. R.; Vega, S. L.; Kwon, M.; Soulas, E. M.; Burdick, J. A. Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments. Biomaterials. 2016, 103, 314-323.  
153. Cameron, A. R.; Frith, J. E.; Gomez, G. A.; Yap, A. S.; Cooper-White, J. J. The effect of time-dependent deformation of viscoelastic hydrogels on myogenic induction and Rac1 activity in mesenchymal stem cells. Biomaterials. 2014, 35, 1857-1868.  
154. Yim, E. K.; Darling, E. M.; Kulangara, K.; Guilak, F.; Leong, K. W. Nanotopography-induced changes in focal adhesions, cytoskeletal organization, and mechanical properties of human mesenchymal stem cells. Biomaterials. 2010, 31, 1299-1306.  
155. Mascharak, S.; Benitez, P. L.; Proctor, A. C.; Madl, C. M.; Hu, K. H.; Dewi, R. E.; Butte, M. J.; Heilshorn, S. C. YAP-dependent mechanotransduction is required for proliferation and migration on native-like substrate topography. Biomaterials. 2017, 115, 155-166.  
156. Cui, Y.; Hameed, F. M.; Yang, B.; Lee, K.; Pan, C. Q.; Park, S.; Sheetz, M. Cyclic stretching of soft substrates induces spreading and growth. Nat Commun. 2015, 6, 6333.  
157. Wang, L.; Luo, J. Y.; Li, B.; Tian, X. Y.; Chen, L. J.; Huang, Y.; Liu, J.; Deng, D.; Lau, C. W.; Wan, S.; Ai, D.; Mak, K. K.; Tong, K. K.; Kwan, K. M.; Wang, N.; Chiu, J. J.; Zhu, Y.; Huang, Y. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature. 2016, 540, 579-582.  
158. Pathak, M. M.; Nourse, J. L.; Tran, T.; Hwe, J.; Arulmoli, J.; Le, D. T.; Bernardis, E.; Flanagan, L. A.; Tombola, F. Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells. Proc Natl Acad Sci U S A. 2014, 111, 16148-16153.  
159. Niepel, M. S.; Ekambaram, B. K.; Schmelzer, C. E. H.; Groth, T. Polyelectrolyte multilayers of poly (l-lysine) and hyaluronic acid on nanostructured surfaces affect stem cell response. Nanoscale. 2019, 11, 2878-2891.  
160. Yao, S.; Liu, X.; Yu, S.; Wang, X.; Zhang, S.; Wu, Q.; Sun, X.; Mao, H. Co-effects of matrix low elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth. Nanoscale. 2016, 8, 10252-10265.  
161. Frank, V.; Kaufmann, S.; Wright, R.; Horn, P.; Yoshikawa, H. Y.; Wuchter, P.; Madsen, J.; Lewis, A. L.; Armes, S. P.; Ho, A. D.; Tanaka, M. Frequent mechanical stress suppresses proliferation of mesenchymal stem cells from human bone marrow without loss of multipotency. Sci Rep. 2016, 6, 24264.  
162. Tan, S.; Fang, J. Y.; Yang, Z.; Nimni, M. E.; Han, B. The synergetic effect of hydrogel stiffness and growth factor on osteogenic differentiation. Biomaterials. 2014, 35, 5294-5306.  
163. Grinnell, F.; Ho, C. H. The effect of growth factor environment on fibroblast morphological response to substrate stiffness. Biomaterials. 2013, 34, 965-974.  
164. Chen, C.; Xie, J.; Deng, L.; Yang, L. Substrate stiffness together with soluble factors affects chondrocyte mechanoresponses. ACS Appl Mater Interfaces. 2014, 6, 16106-16116.  
165. Chang, H.; Liu, X. Q.; Hu, M.; Zhang, H.; Li, B. C.; Ren, K. F.; Boudou, T.; Albiges-Rizo, C.; Picart, C.; Ji, J. Substrate stiffness combined with hepatocyte growth factor modulates endothelial cell behavior. Biomacromolecules. 2016, 17, 2767-2776.  
166. Wang, J.; Tian, L.; Chen, N.; Ramakrishna, S.; Mo, X. The cellular response of nerve cells on poly-L-lysine coated PLGA-MWCNTs aligned nanofibers under electrical stimulation. Mater Sci Eng C Mater Biol Appl. 2018, 91, 715-726.  
167. Li, Q.; Zhang, B.; Kasoju, N.; Ma, J.; Yang, A.; Cui, Z.; Wang, H.; Ye, H. Differential and interactive effects of substrate topography and chemistry on human mesenchymal stem cell gene expression. Int J Mol Sci. 2018, 19, 2344.  
168. Yamamoto, S.; Okada, K.; Sasaki, N.; Chang, A. C.; Yamaguchi, K.; Nakanishi, J. Photoactivatable hydrogel interfaces for resolving the interplay of chemical, mechanical, and geometrical regulation of collective cell migration. Langmuir. 2019, 35, 7459-7468.  
169. Li, J.; Kwiatkowska, B.; Lu, H.; Voglstätter, M.; Ueda, E.; Grunze, M.; Sleeman, J.; Levkin, P. A.; Nazarenko, I. Collaborative action of surface chemistry and topography in the regulation of mesenchymal and epithelial markers and the shape of cancer cells. ACS Appl Mater Interfaces. 2016, 8, 28554-28565.  

Conflict of interest
The authors declare they have no competing interests.
Share
Back to top