细胞梯度力学微环境体外构建的研究
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摘要
细胞微环境与细胞的相互作用日益成为细胞生物学领域研究热点。微环境中物理信号(如基底的力学性能、形貌和牵张力)在控制细胞命运中的作用更不容忽视。其中力学刺激常以不均一的梯度形式参与调节发育、炎症、伤口愈合以及癌症过程中不同细胞的增殖、迁移和分化等行为。水凝胶是模拟细胞外基质(extracellular matrix, ECM)二维/三维组织支架的理想材料。先进的微纳制造技术已被广泛应用于支撑或包裹细胞的仿生水凝胶的合成和微环境的个性化定制研究中。本文阐述了体内细胞力学微环境中刚度和拉压应力刺激的构建方法与表征手段的研究现状,并着重综述了近年来水凝胶在细胞梯度力学微环境体外构建中的应用研究,同时也对未来研究中所面临的挑战提出了新的展望。这些工作对于组织工程及再生医学具有重要意义。
In vivo cells live in a complex microenvironment, which plays a vital role in maintaining cell functions. Many investigations have revealed that in vivo cells respond to various gradient mechanical stimuli, which can regulate cell behavior and guide cell fate. Hydrogels are widely applied to engineering cell microenvironment due to their hydrated environment and tunable properties(e.g., mechanical, chemical and biocompatible), similar to the native extracellular matrix. Herein, the methods of construction, detection and characterization of cell mechanical microenvironment, especially stiffness and tensile/compressive stress, were described. The latest research progress of hydrogels, which are selected as an appropriate matrix for mimicking 2 D and 3 D cell mechanical microenvironment, was introduced. What's more, the new technologies and methods for the construction of gradient mechanical microenvironment and its implications in controlling the development, healing, and homeostasis attainment were highlighted. And, some challenges and the expectations in the application of gradient mechanical microenvironment in tissue remodeling and regeneration medicine were also proposed.
In vivo cells live in a complex microenvironment, which plays a vital role in maintaining cell functions. Many investigations have revealed that in vivo cells respond to various gradient mechanical stimuli, which can regulate cell behavior and guide cell fate. Hydrogels are widely applied to engineering cell microenvironment due to their hydrated environment and tunable properties(e.g., mechanical, chemical and biocompatible), similar to the native extracellular matrix. Herein, the methods of construction, detection and characterization of cell mechanical microenvironment, especially stiffness and tensile/compressive stress, were described. The latest research progress of hydrogels, which are selected as an appropriate matrix for mimicking 2 D and 3 D cell mechanical microenvironment, was introduced. What's more, the new technologies and methods for the construction of gradient mechanical microenvironment and its implications in controlling the development, healing, and homeostasis attainment were highlighted. And, some challenges and the expectations in the application of gradient mechanical microenvironment in tissue remodeling and regeneration medicine were also proposed.
引文
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[30]HAN S J,SNIADECKI N J.Nanotechnology usages for cellular adhesion and traction forces[J].Cellular and Biomolecular Mechanics and Mechanobiology,2010,4:177-200.
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[36]SHARMA R I,SNEDEKER J G.Biochemical and biomechanical gradients for directed bone marrow stromal cell differentia tion toward tendon and bone[J].Biomaterials,2010,31(30):7695-7704.
[37]JEON O,ALT D S,LINDERMAN S W,et al.Biochemical and physical signal gradients in hydrogels to control stem cell behavior[J].Advanced Materials,2013,25(44):6366-6372.
[38]HSIEH H Y,CAMCI UNAL G,HUANG T W,et al.Gradient static-strain stimulation in a microfluidic chip for 3D cellular alignment[J].Lab on a Chip,2014,14(3):482-493.
[39]SOKOLOV I,DOKUKIN M E,GUZ N V.Method for quantitative measurements of the elastic modulus of biological cells in AFM indentation experiments[J].Methods,2013,60(2):202-213.
[40]HENSHAW D R,ATTIA E,BHARGAVA M,et al.Canine A-CL fibroblast integrin expression and cell alignment in response to cyclic tensile strain in three-dimensional collagen gels[J].Journal of Orthopaedic Research,2006,24(3):481-490.
[41]MA Y,LIN M,HUANG G,et al.3D spatiotemporal mechanical microenvironment:a hydrogel-based platform for guiding stem cell fate[J].Advanced Materials,2018,30(49):1705911.
[2]FAN D,TAKAWALE A,LEE J,et al.Cardiac fibroblasts,fibrosis and extracellular matrix remodeling in heart disease[J].Fibrogenesis Tissue Repair,2012,5(1):15-30.
[3]PORTER K E,TURNER N A.Cardiac fibroblasts:at the heart of myocardial remodeling[J].Pharmacology&Therapeutics,2009,123(2):255-278.
[4]WANG L,LI Y,HUANG G,et al.Hydrogel-based methods for engineering cellular microenvironment with spatiotemporal gradients[J].Critical Reviews in Biotechnology,2016,36(3):553-565.
[5]MOVILLA N,BORAU C,VALERO C,et al.Degradation of extracellular matrix regulates osteoblast migration:a microfluidic-based study[J].Bone,2018,107:10-17.
[6]KIM S,KIM H J,JEON N L.Biological applications of microfluidic gradient devices[J].Integrative Biology,2010,2(11-12):584-603.
[7]DISCHER D E,JANMEY P,WANG Y L.Tissue cells feel and respond to the stiffness of their substrate[J].Science,2005,310(5751):1139-1143.
[8]SCHAFFLER M B,BURR D B.Stiffness of compact bone:effects of porosity and density[J].Journal of Biomechanics,1988,21(1):13-16.
[9]Lü H,LI L,SUN M,et al.Mechanism of regulation of stem cell differentiation by matrix stiffness[J].Stem Cell Research&Therapy,2015,6(1):103-114.
[10]NASROLLAHI S,WALTER C,LOZA A J,et al.Past matrix stiffness primes epithelial cells and regulates their future collective migration through a mechanical memory[J].Biomaterials,2017,146:146-155.
[11]LU P,WEAVER V M,WERB Z.The extracellular matrix:a dynamic niche in cancer progression[J].The Journal of Cell Biology,2012,196(4):395-406.
[12]LI C,XU Q.Mechanical stress-initiated signal transductions in vascular smooth muscle cells[J].Cellular Signalling,2000,12(7):435-445.
[13]PELLEGRINELLI V,HEUVINGH J,DU ROURE O,et al.Human adipocyte function is impacted by mechanical cues[J].The Journal of Pathology,2014,233(2):183-195.
[14]HUANG G,LI F,ZHAO X,et al.Functional and biomimetic materials for engineering of the three-dimensional cell microenvironment[J].Chemical Reviews,2017,117(20):12764-12850.
[15]DE SILVA M N,DESAI R,ODDE D J.Micro-patterning of animal cells on PDMS substrates in the presence of serum without use of adhesion inhibitors[J].Biomedical Microdevices,2004,6(3):219-222.
[16]LI B,ZHANG X,LI X,et al.Photo-assisted preparation and patterning of large-area reduced graphene oxide-TiO2conductive thin film[J].Chemical Communications,2010,46(20):3499-3501.
[17]CHEN Z,ZHAO Y,WANG W,et al.Microfluidic patterning of nanoparticle monolayers[J].Microfluidics and Nanofluidics,2009,7(4):585-591.
[18]QING H,JIN G,ZHAO G,et al.Heterostructured silk-nanofiberreduced graphene oxide composite scaffold for SH-SY5Y cell alignment and differentiation[J].American Chemical Society Applied Materials&Interfaces,2018,DOI:10.1021/acsami.8b12562.
[19]BAUER A,GU L,KWEE B,et al.Hydrogel substrate stressrelaxation regulates the spreading and proliferation of mouse myoblasts[J].Acta Biomaterialia,2017,62:82-90.
[20]BLOCK S M,GOLDSTEIN L S,SCHNAPP B J.Bead movement by single kinesin molecules studied with optical tweezers[J].Nature,1990,348:348-352.
[21]GOSSE C,CROQUETTE V.Magnetic tweezers:micromanipulation and force measurement at the molecular level[J].Biophysical Journal,2002,82(6):3314-3329.
[22]INOUE K,TANIKAWA T,ARAI T.Micro-manipulation system with a two-fingered micro-hand and its potential application in bioscience[J].Journal of Biotechnology,2008,133(2):219-224.
[23]DITTRICH P S,MANZ A.Lab-on-a-chip:microfluidics in drug discovery[J].Nature Reviews Drug Discovery,2006,5(3):210-218.
[24]MICHALET X,EKONG R,FOUGEROUSSE F,et al.Dynamic molecular combing:stretching the whole human genome for high-resolution studies[J].Science,1997,277(5331):1518-1523.
[25]SUGIMOTO Y,ABE M,HIRAYAMA S,et al.Atom inlays performed at room temperature using atomic force microscopy[J].Nature Materials,2005,4(2):156-159.
[26]MATHESON L A,FAIRBANK N J,MAKSYM G N,et al.Characterization of the FlexcellTMUniflexTMcyclic strain culture system with U937 macrophage-like cells[J].Biomaterials,2006,27(2):226-233.
[27]LEE C H,SHIN H J,CHO I H,et al.Nanofiber alignment and direction of mechanical strain affect the ECM production of human ACL fibroblast[J].Biomaterials,2005,26(11):1261-1270.
[28]SONG J,RYU H,CHUNG M,et al.Microfluidic platform for single cell analysis under dynamic spatial and temporal stimulation[J].Biosens Bioelectron,2018,104:58-64.
[29]CHENG B,LIN M,HUANG G,et al.Cellular mechanosensing of the biophysical microenvironment:a review of mathematical models of biophysical regulation of cell responses[J].Physics of Life Reviews,2017,22-23:88-119.
[30]HAN S J,SNIADECKI N J.Nanotechnology usages for cellular adhesion and traction forces[J].Cellular and Biomolecular Mechanics and Mechanobiology,2010,4:177-200.
[31]LEGANT W R,CHOI C K,MILLER J S,et al.Multidimensional traction force microscopy reveals out-of-plane rotational moments about focal adhesions[J].Proceedings of the National Academy of Sciences USA,2013,110(3):881-886.
[32]FU J,WANG Y K,YANG M T,et al.Mechanical regulation of cell function with geometrically modulated elastomeric substrates[J].Nature Methods,2010,7(9):733-736.
[33]LEGANT W R,PATHAK A,YANG M T,et al.Microfabricated tissue gauges to measure and manipulate forces from 3Dmicrotissues[J].Proceedings of the National Academy of Sciences USA,2009,106(25):10097-10102.
[34]TAN J L,TIEN J,PIRONE D M,et al.Cells lying on a bed of microneedles:an approach to isolate mechanical force[J].Proceedings of the National Academy of Sciences USA,2003,100(4):1484-1489.
[35]XIA T,LIU W,YANG L.A review of gradient stiffness hydrogels used in tissue engineering and regenerative medicine[J].Journal of Biomedical Materials Research,2017,105(6):1799-1812.
[36]SHARMA R I,SNEDEKER J G.Biochemical and biomechanical gradients for directed bone marrow stromal cell differentia tion toward tendon and bone[J].Biomaterials,2010,31(30):7695-7704.
[37]JEON O,ALT D S,LINDERMAN S W,et al.Biochemical and physical signal gradients in hydrogels to control stem cell behavior[J].Advanced Materials,2013,25(44):6366-6372.
[38]HSIEH H Y,CAMCI UNAL G,HUANG T W,et al.Gradient static-strain stimulation in a microfluidic chip for 3D cellular alignment[J].Lab on a Chip,2014,14(3):482-493.
[39]SOKOLOV I,DOKUKIN M E,GUZ N V.Method for quantitative measurements of the elastic modulus of biological cells in AFM indentation experiments[J].Methods,2013,60(2):202-213.
[40]HENSHAW D R,ATTIA E,BHARGAVA M,et al.Canine A-CL fibroblast integrin expression and cell alignment in response to cyclic tensile strain in three-dimensional collagen gels[J].Journal of Orthopaedic Research,2006,24(3):481-490.
[41]MA Y,LIN M,HUANG G,et al.3D spatiotemporal mechanical microenvironment:a hydrogel-based platform for guiding stem cell fate[J].Advanced Materials,2018,30(49):1705911.