软骨组织工程构建中的生物力学

张春秋; 李可; 高丽兰; 张西正

doi:10.6052/1000-0992-17-007

软骨组织工程构建中的生物力学

doi: 10.6052/1000-0992-17-007

天津市先进机电系统设计与智能控制重点实验室,天津理工大学机械工程学院,天津 300384

基金项目: 国家自然科学基金重点项目(11432016), 国家自然科学基金(11672208, 11572222, 11402171, 11402172)资助

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作者简介:
null

作者简介：张春秋, 男, 天津理工大学机械工程学院教授、博士生导师; 2003年获得吉林大学固体力学博士学位, 2006年于解放军军事医学科学院生物学博士后出站, 2009年于北京航空航天大学生物医学工程博士后出站; 2013年在布朗大学做访问学者. 任中国力学学会生物力学专业委员会委员, 天津市力学学会理事, 天津市力学学会生物力学专业委员会副主任委员; 天津市中青年骨干创新人才, 天津市高校学科领军人才.主要从事生物力学、组织工程生物反应器、固体力学数值方法和应用的研究, 研究方向主要为骨、软骨生物力学; 近年来承担国家级、省部级基金和横向课题10余项, 其中主持国家自然科学基金4项; 在国内外刊物发表学术论文100余篇, 其中SCI、EI收录30余篇; 授权发明专利16项; 2014年获中国人民武装警察部队科学技术进步二等奖.

通讯作者:
张春秋

中图分类号: R318.01;
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出版历程
- 收稿日期: 2017-04-01
- 刊出日期: 2018-02-08

Biomechanics in cartilage tissue engineering

Tianjin Key Laboratory of the Design and Intelligent Control of the Advanced Mechatronical System, School of Mechanical Engineering, Tianjin University of Technology, Tianjin 300384, China

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^ɛ E-mail:zhang chunqiu@126.com

Corresponding author: ZHANG Chunqiu

摘要

摘要: 关节软骨是关节表面具有弹性的承重组织, 其结构复杂, 由固体相和液体相组成. 固体相包括胶原纤维、蛋白多糖等, 属纤维增强型复合结构; 液体相包括水、电解质等.关节软骨提供了一个低磨损和低摩擦的光滑界面, 起缓冲振动和传递载荷等支撑作用. 由于膝关节承受的运动量大、应力高, 关节软骨损伤在临床上较为常见. 但软骨内没有血管, 代谢缓慢, 其损伤后难以实现自我修复. 组织工程从理论上建立了一种治疗软骨缺损的理想方法, 但尚未成为临床上常规的治疗选择. 如何获得结构和功能相匹配, 同时适用于临床治疗的工程软骨, 至今仍是亟需解决的问题.在体外构建功能化工程软骨, 关键在于运用生物反应器对组织施加合适的力学载荷: 首先保证工程软骨复合体内信号分子、营养和废物的有效运输; 其次对支架内种子细胞产生特定的力学刺激; 同时促进细胞外基质结构与功能的适应性发展.本文对力学载荷在软骨组织工程构建中的应用进展加以综述: 按照作用于组织层面的力学载荷传递所需的介质属性, 将其分为液体介导、固体介导和其他媒质介导三种类型, 重点关注不同载荷对工程软骨功能化构建的作用和效果; 分析讨论软骨组织工程构建中存在的关键生物力学问题; 总结和展望软骨组织工程未来的发展趋势.软骨组织工程体外培养需要考虑力学载荷和生化刺激的耦合作用; 在合适的生化条件下进行滚动、滑动和压缩复合加载, 将有利于工程软骨的体外功能化构建.
- 关节软骨 /
- 组织工程 /
- 力学载荷 /
- 生物力学 /
- 力学生物学
Abstract: Articular cartilage is one kind of elastic loaded tissues. Its complex structure contains solid and liquid phases. The solid phase consists of collagens and proteoglycans, and the liquid phase consists of water and electrolyte. The microstructure of the solid phase is a type of fiber reinforced composites. Articular cartilage provides a smooth interface with low wear and friction, and plays an important role in buffering shocks, transferring loading and etc. The knee joint is subjected to a large amount of exercise and high stress, which make the articular cartilage injury common in clinic. Since there is no blood supply in cartilage tissues, they are difficult to heal once injury. Tissue engineering provides an ideal method for the treatment of defects in cartilages. Although cartilage tissue engineering has started to be applied in clinic, but the method is not widely employed. How to get the engineered cartilage, and which structure and function are suitable for the clinical use are still remaining problems to be solved. The key to the construction of functional engineered cartilage in vitro is to apply appropriate mechanical conditions in bioreactors. First, the loads ensure the effective transportation of the internal signals, nutrients and wastes; second, it is necessary to apply specific mechanical stimulations on seed cells in scaffolds; third, it needs to promote the development of the structure and function of extracellular matrix. This paper reviews the latest research in cartilage tissue engineering. This review categorizes the mechanical stimuli into three types according to different medias during the process of load transfer: namely, liquid-mediated forces, solid-mediated forces and other forces. This paper analyzes the major biomechanical problems in cartilage tissue engineering and predicts the trend of future developments. At last, this paper suggests that the synergy of mechanical and biochemical stimuli should be taken into account in cartilage tissue construction. In this way, rolling-sliding-compression load accompanied by appropriate biochemical conditions may be beneficial to realize the functional development of engineered cartilage in vitro.
- articular cartilage /
- tissue engineering /
- mechanical stimuli /
- biomechanics /
- mechanobiology

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参考文献(145)

[1]	葛洪玉, 张春秋, 高丽兰, 张西正. 2015. 针对细胞高加速度离心式加载机的研制. 中国组织工程研究, 19: 7350-7355 (Ge H Y, Zhang C Q, Gao L L, Zhang X Z.2015. Design of a centrifuge device for high acceleration loading on cells. Zhongguo Zuzhi Gongcheng Yanjiu, 19: 7350-7355).
[2]	Joseph A B, Thomas A E, Sheldon R S.2001. 骨科基础科学------骨关节肌肉系统生物学和生物力学 (Joseph A B, Thomas A E, Sheldon R S.2001. Orthopedic Basic Science: Biology and Biomechanics of the Musculoskeletal System).
[3]	李殿威, 周强, 郭平, 宋磊, 刘涌. 2010. 压应力对组织工程软骨细胞增殖的影响. 南方医科大学学报, 30: 2530-2532 (Li D W, Zhou Q, Guo P, Song L, Liu Y.2010. Proliferation of tissue-engineered cartilage cells under compressive stress. J. South. Med. Univ.,30: 2530-2532 ).
[4]	李军, 孙明林, 宋光明, 张春秋, 李瑞欣, 张西正, 黄揆, 刘迎节. 2017. 成骨细胞MC3T3-E1对高重力的力学生物学响应. 医用生物力学, 32: 122-129 (Li J, Sun M L, Song G M, Zhang C Q, Li R X, Zhang X Z, Huang K, Liu Y J.2017. The mechanical and biological responses of MC3T3-E1 cells under hypergravity. J. Med. Biomech., 32: 122-129).
[5]	张春秋, 孙明林, 李江, 叶金铎, 刘海英. 2009. 关节软骨体外构建力学环境的研究进展. 医用生物力学, 24: 462-467 (Zhang C Q, Sun M L, Li J, Ye J D, Liu H Y.2009. Advances of mechanical conditions in engineering cartilage tissue. J. Med. Biomech.,24: 462-467 ).
[6]	张春秋, 张兵, 高丽兰, 刘清, 董心. 2016. 一种多位置点循环加载生物反应器. 中国: CN104152351B (Zhang C Q, Zhang B, Gao L L, Liu Q, Dong X.2016. Multi-position cyclic loading bioreactor. China: CN104152351B).
[7]	Afoke N Y, Byers P D, Hutton W C.1987. Contact pressures in the human hip joint. J. Bone Joint Surg. Br., 69: 536-541.
[8]	Albro M B, Nims R J, Durney K M, Cigan A D, Shim J J, Vunjak-Novakovic G, Hung C T, Ateshian G A.2016. Heterogeneous engineered cartilage growth results from gradients of media-supplemented active TGF-(eta) and is ameliorated by the alternative supplementation of latent TGF-β. Biomaterials, 77: 173-185.
[9]	Baker B M, Shah R P, Huang A H, Mauck R L.2011. Dynamic tensile loading improves the functional properties of mesenchymal stem cell-laden nanofiber-based fibrocartilage. Tissue Eng. Part A, 17: 1445-1455.
[10]	Bastiaansen-Jenniskens Y M, de Bart A C W, Koevoet W, Jansen K M B, Verhaar J A N, van Osch G J V M, DeGroot J.2010. Elevated levels of cartilage oligomeric matrix protein during in vitro cartilage matrix generation decrease collagen fibril diameter. Cartilage, 1: 200-210.
[11]	Bernhard J C, Vunjak-Novakovic G.2016. Should we use cells, biomaterials, or tissue engineering for cartilage regeneration? {it Stem Cell Res. Ther.}, 7: 56.
[12]	Bilgen B, Chu D, Stefani R, Aaron R K.2013. Design of a biaxial mechanical loading bioreactor for tissue engineering. J. Vis. Exp., 74: e50387.
[13]	Brady M A, Vaze R, Amin H D, Overby D R, Ethier C R.2014. The design and development of a high-throughput magneto-mechanostimulation device for cartilage tissue engineering. Tissue Eng. Part C Methods, 20: 149-159.
[14]	Bueno E M, Bilgen B, Barabino G A.2009. Hydrodynamic parameters modulate biochemical, histological, and mechanical properties of engineered cartilage. Tissue Eng. Part A, 15: 773-785.
[15]	Caldwell K L, Wang J.2015. Cell-based articular cartilage repair: the link between development and regeneration. Osteoarthritis Cartilage, 23: 351-362.
[16]	Carmona-Moran C A, Wick T M.2015. Transient growth factor stimulation improves chondrogenesis in static culture and under dynamic conditions in a novel shear and perfusion bioreactor. Cell. Mole. Bioeng., 8: 267-277.
[17]	Cashion A T, Caballero M, Halevi A, Pappa A, Dennis R G, van-Aalst J A.2014. Programmable mechanobioreactor for exploration of the effects of periodic vibratory stimulus on mesenchymal stem cell differentiation. Biores. Open Access, 3: 19-28.
[18]	Chen J, Yuan Z, Liu Y, Zheng R, Dai Y, Tao R, Xia H, Liu H, Zhang Z, Zhang W, Liu W, Cao Y, Zhou G.2017. Improvement of in vitro three-dimensional cartilage regeneration by a novel hydrostatic pressure bioreactor. Stem Cells Transl. Med., 6: 982-991.
[19]	Cheng X, Gurkan U A, Dehen C J, Tate M P, Hillhouse H W, Simpson G J, Akkus O.2008. An electrochemical fabrication process for the assembly of anisotropically oriented collagen bundles. Biomaterials, 29: 3278-3288.
[20]	Chung C, Burdick J A.2008. Engineering cartilage tissue. Adv. Drug Deliv. Rev., 60: 243-262.
[21]	Chung C Y, Heebner J, Baskaran H, Welter J F, Mansour J M.2015. Ultrasound elastography for estimation of regional strain of multilayered hydrogels and tissue-engineered cartilage. Ann. Biomed. Eng., 43: 2991-3003.
[22]	Cigan A D, Roach B L, Nims R J, Tan A R, Albro M B, Stoker A M, Cook J L, Vunjak-Novakovic G, Hung C T, Ateshian G A.2016. High seeding density of human chondrocytes in agarose produces tissue-engineered cartilage approaching native mechanical and biochemical properties. J. Biomech., 49: 1909-1917.
[23]	Connelly J T, Vanderploeg E J, Mouw J K, Wilson C G, Levenston M E.2010. Tensile loading modulates bone marrow stromal cell differentiation and the development of engineered fibrocartilage constructs. Tissue Eng. Part A, 16: 1913-1923.
[24]	Correia C, Pereira A L, Duarte A R, Frias A M, Pedro A J, Oliveira J T, Sousa R A, Reis R L.2012. Dynamic culturing of cartilage tissue: the significance of hydrostatic pressure. Tissue Eng. Part A, 18: 1979-1991.
[25]	Correia V, Panadero J A, Ribeiro C, Sencadas V, Rocha J G, Gomez-Ribelles J L, Lanceros-M'{e}ndez S.2016. Design and validation of a biomechanical bioreactor for cartilage tissue culture. Biomech. Model Mechanobiol., 15: 471-478.
[26]	Crowe J J, Grant S C, Logan T M, Ma T.2011. A magnetic resonance-compatible perfusion bioreactor system for three-dimensional human mesenchymal stem cell construct development. Chem. Eng. Sci., 66: 4138-4147.
[27]	Cucchiarini M, Madry H, Guilak F, Saris D B, Stoddart M J, Koon-Wong M, Roughley P.2014. A vision on the future of articular cartilage repair. Eur. Cell. Mater., 27: 12-16.
[28]	Detzel C J, Van-Wie B J.2011. Use of a centrifugal bioreactor for cartilaginous tissue formation from isolated chondrocytes. Biotechnol. Prog., 27: 451-459.
[29]	Di-Federico E, Bader D L, Shelton J C.2014. Design and validation of an in vitro loading system for the combined application of cyclic compression and shear to 3D chondrocytes-seeded agarose constructs. Med. Eng. Phys., 36: 534-540.
[30]	Dumont S, Prakash M.2014. Emergent mechanics of biological structures. Mol. Biol. Cell, 25: 3461-3465.
[31]	D'{e}marteau O, Jakob M, Schäfer D, Heberer M, Martin I.2003. Development and validation of a bioreactor for physical stimulation of engineered cartilage. Biorheology, 40: 331-336.
[32]	Elder B D, Athanasiou K A.2009. Hydrostatic pressure in articular cartilage tissue engineering: From chondrocytes to tissue regeneration. Tissue Eng. Part B Rev., 15: 43-53.
[33]	Emin N, Koc{c} A, Durkut S, Elc{c}in A E, Elc{c}in Y M.2008. Engineering of rat articular cartilage on porous sponges: effects of tgf-beta 1 and microgravity bioreactor culture. Artif. Cells Blood Substit. Immobil. Biotechnol., 36: 123-137.
[34]	Fan Z, Zhang C, Liu H, Xu B, Li J, Gao L.2011. A novel model for the mass transfer of articular cartilage: Rolling depression load device. Commun. Comput. Info. Sci., 135: 580-585.
[35]	Freed L E, Vunjak-Novakovic G.1995. Cultivation of cell-polymer tissue constructs in simulated microgravity. Biotechnol. Bioeng., 46: 306-313.
[36]	Fritton S P, Mcleod K J, Rubin C T.2000. Quantifying the strain history of bone: Spatial uniformity and self-similarity of low-magnitude strains. J. Biomech., 33: 317-325.
[37]	Gao J, Zhang C, Liu H, Gao L, Sun M, Dong X.2011. A roller-loading bioreactor system for researching cartilage mechanobiology. Procedia Environ. Sci., 8: 197-201.
[38]	Gao L L, Zhang C Q, Dong L M, Jia Y W.2012. Description of depth-dependent nonlinear viscoelastic behavior for articular cartilage in unconfined compression. Mater. Sci. Eng. C Mater. Biol. Appl., 32: 119-125.
[39]	Gao L L, Zhang C Q, Yang Y B, Shi J P, Jia Y W.2013. Depth-dependent strain fields of articular cartilage under rolling load by the optimized digital image correlation technique. Mater. Sci. Eng. C Mater. Biol. Appl., 33: 2317-2322.
[40]	Gao L L, Zhang C Q, Gao H, Liu Z D, Xiao P P.2014. Depth and rate dependent mechanical behaviors for articular cartilage: experiments and theoretical predictions. Mater. Sci. Eng. C Mater. Biol. Appl., 38: 244-251.
[41]	Gao L L, Qin X Y, Zhang C Q, Gao H, Ge H Y, Zhang X Z.2015. Ratcheting behavior of articular cartilage under cyclic unconfined compression. Mater. Sci. Eng. C Mater. Biol. Appl., 57: 371-377.
[42]	Gharravi A M, Orazizadeh M, Ansari-Asl K, Banoni S, Izadi S, Hashemitabar M.2012. Design and fabrication of anatomical bioreactor systems containing alginate scaffolds for cartilage tissue engineering. Avicenna J. Med. Biotechnol., 4: 65-74.
[43]	Gharravi A M, Orazizadeh M, Hashemitabar M.2016. Fluid-induced low shear stress improves cartilage like tissue fabrication by encapsulating chondrocytes. Cell Tissue Bank., 17: 117-122.
[44]	Goepfert C, Blume G, Faschian R, Meyer S, Schirmer C, Müller-Wichards W, Müller J, Fischer J, Feyerabend F, Pörtne R.2013. A modular flow-chamber bioreactor concept as a tool for continuous 2D- and 3D-cell culture. BMC Proc., 7: p87.
[45]	Grad S, Eglin D, Alini M, Stoddart M J.2011. Physical stimulation of chondrogenic cells in vitro: A review. Clin. Orthop. Relat. Res., 469: 2764-2772.
[46]	Grad S, Loparic M, Peter R, Stolz M, Aebi U, Alini M.2012. Sliding motion modulates stiffness and friction coefficient at the surface of tissue engineered cartilage. Osteoarthritis Cartilage, 20: 288-295.
[47]	Green J D, Tollemar V, Dougherty M, Yan Z, Yin L, Ye J, Collier Z, Mohammed M K, Haydon R C, Luu H H, Kang R, Lee M J, Ho S H, He T C, Shi L L, Athiviraham A.2015. Multifaceted signaling regulators of chondrogenesis: Implications in cartilage regeneration and tissue engineering. Genes Dis., 2: 307-327.
[48]	Grogan S P, Miyaki S, Asahara H, D'Lima D D, Lotz M K.2009. Mesenchymal progenitor cell markers in human articular cartilage: Normal distribution and changes in osteoarthritis. Arthritis. Res. Ther., 11: R85.
[49]	Guha-Thakurta S, Kraft M, Viljoen H J, Subramanian A.2014. Enhanced depth-independent chondrocyte proliferation and phenotype maintenance in an ultrasound bioreactor and an assessment of ultrasound dampening in the scaffold. Acta Biomater., 10: 4798-4810.
[50]	Guilak F, Butler D L, Goldstein S A, Baaijens F P T.2014. Biomechanics and mechanobiology in functional tissue engineering. J. Biomech., 47: 1933-1940.
[51]	Guo T, Yu L, Lim C G, Goodley A S, Xiao X, Placone J K, Ferlin K M, Nguyen B N, Hsieh A H, Fisher J P.2016. Effect of dynamic culture and periodic compression on humanmesenchymal stem cell proliferation and chondrogenesis. Ann. Biomed. Eng., 44: 2103-2113.
[52]	Hall A C, Urban J P, Gehl K A.1991. The effects of hydrostatic pressure on matrixsynthesis in articular cartilage. J. Orthop. Res. 9: 1-10.
[53]	Heyland J, Wiegandt K, Goepfert C, Nagel-Heyer S, Ilinich E, Schumacher U, Pörtner R.2006. Redifferentiation of chondrocytes and cartilage formation under intermittent hydrostatic pressure. Biotechnol. Lett., 28: 1641-1648.
[54]	Hilz F M, Ahrens P, Grad S, Stoddart M J, Dahmani C, Wilken F L, Sauerschnig M, Niemeyer P, Zwingmann J, Burgkart R, von-Eisenhart-Rothe R, Südkamp N P, Weyh T, Imhoff A B, Alini M, Salzmann G M.2014. Influence of extremely low frequency, low energy electromagnetic fields and combined mechanical stimulation on chondrocytes in 3-D constructs for cartilage tissue engineering. Bioelectromagnetics, 35: 116-128.
[55]	Hoenig E, Leicht U, Winkler T, Mielke G, Beck K, Peters F, Schilling A F, Morlock M M.2013. Mechanical properties of native and tissue-engineered cartilage depend on carrier permeability: A bioreactor study. Tissue Eng. Part A, 19: 1534-1542.
[56]	Hoffmann W, Feliciano S, Martin I, de-Wild M, Wendt D.2015. Novel perfused compression bioreactor system as an in vitro model to investigate fracture healing. Front Bioeng. Biotechnol., 3: 10.
[57]	Hsu S H, Kuo C C, Whu S W, Lin C H, Tsai C L.2006. The effect of ultrasound stimulation versus bioreactors on neocartilage formation in tissue engineering scaffolds seeded with human chondrocytes in vitro. Biomol. Eng., 23: 259-264.
[58]	Huang A H, Baker B M, Ateshian G A, Mauck R L.2012. Sliding contact loading enhances the tensile properties of mesenchymal stem cell-seeded hydrogels. Eur. Cell. Mater., 24: 29-45.
[59]	Huey D J, Hu J C, Athanasiou K A.2012. Unlike bone, cartilage regeneration remains elusive. Science, 338: 917-921.
[60]	Hussein H, Williams D J, Liu Y.2015. Design modification and optimisation of the perfusion system of a tri-axial bioreactor for tissue engineering. Bioprocess Biosyst. Eng., 38: 1423-1429.
[61]	Huynh N P, Anderson B A, Guilak F, McAlinden A.2017. Emerging roles for long noncoding RNAs in skeletal biology and disease. Connect. Tissue Res., 58: 116-141.
[62]	Iannetti L, D'Urso G, Conoscenti G, Cutr`{i} E, Tuan R S, Raimondi M T, Gottardi R, Zunino P.2016. Distributed and lumped parameter models for the characterization of high throughput bioreactors. PLoS One, 11: e0162774.
[63]	Ji Q, He C.2016. Extracorporeal shockwave therapy promotes chondrogenesis in cartilage tissue engineering: A hypothesis based on previous evidence. Med. Hypotheses, 91: 9-15.
[64]	Khan A A, Surrao D C.2012. The importance of bicarbonate and nonbicarbonate buffer systems in batch and continuous flow bioreactors for articular cartilage tissue engineering. Tissue Eng. Part C Methods 18: 358-368.
[65]	Kraft J J, Jeong C, Novotny J E, Seacrist T, Chan G, Domzalski M, Turka C M, Richardson D W, Dodge G R.2011. Effects of hydrostatic loading on a self-aggregating, suspension culture-derived cartilage tissue analog. Cartilage, 2: 254-264.
[66]	Kuo C K, Tuan R S.2008. Mechanoactive tenogenic differentiation of human mesenchymal stem cells. Tissue Eng. Part A, 14: 1615-1627
[67]	Li B, Wang X, Wang Y, Gou W, Yuan X, Peng J, Guo Q, Lu S.2015. Past, present, and future of microcarrier-based tissue engineering. J. Orthop. Translat., 3: 51-57.
[68]	Li S T, Liu Y, Zhou Q, Lue R F, Song L, Dong S W, Guo P, Kopjar B.2014. A novel axial-stress bioreactor system combined with a substance exchanger for tissue engineering of 3D constructs. Tissue Eng. Part C Methods, 20: 205-214.
[69]	Li Z, Yao S, Alini M, Grad S.2007. Different response of articular chondrocyte subpopulations to surface motion. Osteoarthritis Cartilage, 15: 1034-1041.
[70]	Lin H, Lozito T P, Alexander P G, Gottardi R, Tuan R S.2014. Stem cell-based microphysiological osteochondral system to modeltissue response to interleukin-1β. Mol. Pharm., 11: 2203-2212.
[71]	Lin W Y, Chang Y H, Wang H Y, Yang T C, Chiu T K, Huang S B, Wu M H.2014. The study of the frequency effect of dynamic compressive loading on primary articular chondrocyte functions using a microcell culture system. BioMed. Res. Int., 2014: 762570.
[72]	Lujan T J, Wirtz K M, Bahney C S, Madey S M, Johnstone B, Bottlang M.2011. A novel bioreactor for the dynamic stimulation and mechanical evaluation of multiple tissue-engineered constructs. Tissue Eng. Part C Methods, 17: 367-374.
[73]	Luria A, Chu C R.2014. Articular cartilage changes in maturing athletes: New targets for joint rejuvenation. Sports Health, 6: 18-30.
[74]	Mabvuure N, Hindocha S, Khan W S.2012. The role of bioreactors in cartilage tissue engineering. Curr. Stem Cell Res. Ther., 7: 287-292.
[75]	Madeira C, Santhagunam A, Salgueiro J B, Cabral J M.2015. Advanced cell therapies for articular cartilage regeneration. Trends Biotechnol., 33: 35-42.
[76]	Madry H, Kaul G, Zurakowski D, Vunjak-Novakovic G, Cucchiarini M.2013. Cartilage constructs engineered from chondrocytes overexpressing IGF-I improve the repair of osteochondral defects in a rabbit model. Eur. Cell. Mater., 25: 229-247.
[77]	Makris E A, Gomoll A H, Malizos K N, Hu J C, Athanasiou K A.2015. Repair and tissue engineering techniques for articular cartilage. Nat. Rev. Rheumatol., 11: 21-34.
[78]	Mansour J M, Gu D W, Chung C Y, Heebner J, Althans J, Abdalian S, Schluchter M D, Liu Y, Welter J F.2014. Towards the feasibility of using ultrasound to determine mechanical properties of tissues in a bioreactor. Ann. Biomed. Eng., 42: 2190-2202.
[79]	Mizuno S.2011. Novel cell culture model using pure hydrostatic pressure and a semipermeable membrane pouch. Cell Transplant., 20: 767-774.
[80]	Moutos F T, Glass K A, Compton S A, Ross A K, Gersbach C A, Guilak F, Estes B T.2016. Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing. Proc. Natl. Acad. Sci. U. S. A., 113: E4513-E4522.
[81]	Mow V C, Wang C C.1999. Some bioengineering considerations for tissue engineering of articular cartilage. Clin. Orthop. Relat. Res., 367(S): S204-S223.
[82]	Nazempour A, Quisenberry C R, Van-Wie B J, Abu-Lail N I.2016. Nanomechanics of engineered articular cartilage: Synergistic influences of transforming growth factor-β3 and oscillating pressure. J. Nanosci. Nanotechnol., 16: 3136-3145.
[83]	Nebelung S, Gavenis K, Rath B, Tingart M, Ladenburger A, Stoffel M, Zhou B, Mueller-Rath R.2011. Continuous cyclic compressive loading modulates biological and mechanical properties of collagen hydrogels seeded with human chondrocytes. Biorheology, 48: 247-261.
[84]	Ng J, Wei Y, Zhou B, Burapachaisri A, Guo E, Vunjak-Novakovic G.2016. Extracellular matrix components and culture regimen selectively regulate cartilage formation by self-assembling human mesenchymal stem cells in vitro and in vivo. Stem Cell Res. Ther., 7: 183.
[85]	Ng K W, Mauck R L, Wang C C, Kelly T A, Ho M M, Chen F H, Ateshian G A, Hung C T.2009. Duty cycle of deformational loading influences the growth of engineered articular cartilage. Cell Mol. Bioeng., 2: 386-394.
[86]	Nims R J, Cigan A D, Durney K M, Jones B K, O'Neill J D, Law W A, Vunjak-Novakovic G, Hung C T, Ateshian G A.2017. Constrained cage culture improves engineered cartilage functional properties by enhancing collagen network stability. Tissue Eng. Part A, 23: 847-858.
[87]	Nukavarapu S P, Dorcemus D L.2013. Osteochondral tissue engineering: Current strategies and challenges. Biotechnol. Adv., 31: 706-721.
[88]	Omata S, Sonokawa S, Sawae Y, Murakami T.2012. Effects of both vitamin C and mechanical stimulation on improving the mechanical characteristics of regenerated cartilage. Biochem. Biophys. Res. Commun., 424: 724-729.
[89]	Ongaro A, Pellati A, Setti S, Masieri F F, Aquila G, Fini M, Caruso A, De-Mattei M.2015. Electromagnetic fields counteract IL-1β activity during chondrogenesis of bovine mesenchymal stem cells. J. Tissue Eng. Regen. Med., 9: E229-E238.
[90]	Oragui E, Nannaparaju M, Khan W S.2011. The role of bioreactors intissue engineering for musculoskeletal applications. Open Orthop. J., 5: 267-270.
[91]	O'Conor C J, Case N, Guilak F.2013. Mechanical regulation of chondrogenesis. Stem Cell Res. Ther., 4: 61.
[92]	O'Conor C J, Leddy H A, Benefield H C, Liedtke W B, Guilak F.2014. TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc. Natl. Acad. Sci. U. S. A., 111: 1316-1321.
[93]	Parker E, Vessillier S, Pingguan-Murphy B, Abas W, Bader D L, Chowdhury T T.2013. Low oxygen tension increased fibronectin fragment induced catabolic activities-response prevented with biomechanical signals. Arthritis Res. Ther., 15: R163.
[94]	Paten J A, Tilburey G E, Molloy E A, Zareian R, Trainor C V, Ruberti J W.2013. Utility of an optically-based, micromechanical system for printing collagen fibers. Biomaterials, 34: 2577-2587.
[95]	Pei Y, Fan J J, Zhang X Q, Zhang Z Y, Yu M.2014. Repairing the osteochondral defect in goat with the tissue-engineered osteochondral graft preconstructed in a double chamber stirring bioreactor. Biomed. Res. Int., 2014: 219203.
[96]	Petri M, Ufer K, Toma I, Becher C, Liodakis E, Brand S, Haas P, Liu C, Richter B, Haasper C, von-Lewinski G, Jagodzinski M.2012. Effects of perfusion and cyclic compression on in vitro tissue engineered meniscus implants. Knee Surg. Sports Traumatol. Arthrosc., 20: 223-231.
[97]	Pohlig F, Guell F, Lenze U, Lenze F W, Mühlhofer H M L, Schauwecker J, Toepfer A, Mayer-Kuckuk P, von-Eisenhart-Rothe R, Burgkart R, Salzmann G M.2016. Hyaluronic acid suppresses the expression of metalloproteinases in osteoarthritic cartilage stimulated simultaneously by interleukin 1β and mechanical load. PLoS One, 11: e0150020.
[98]	Qiu L, Xuemei M A, Gao L, Men Y, Zhang C.2016. Analysis of the mechanical state of the human knee joint with defect cartilage in standing. J. Mech. Med. Biol., 16: 1640021.
[99]	Raimondi M T, Causin P, Mara A, Nava M, Lagan`{a} M, Sacco R.2011. Breakthroughs in computational modeling of cartilage regeneration in perfused bioreactors. IEEE Trans. Biomed. Eng., 58: 3496-3499.
[100]	Responte D J, Lee J K, Hu J C, Athanasiou K A.2012. Biomechanics-driven chondrogenesis: From embryo to adult. FASEB J., 26: 3614-3624.
[101]	Reyes M L, Hern'{a}ndez M, Holmgren L J, Sanhueza E, Escobar R G.2011. High-frequency, low-intensity vibrations increase bone mass and muscle strength in upper limbs, improving autonomy in disabled children. J. Bone Miner. Res., 26: 1759-1766.
[102]	Roddy K A, Prendergast P J, Murphy P.2011. Mechanical influences on morphogenesis of the knee joint revealed through morphological, molecular and computational analysis of immobilised embryos. PLoS One, 6: e17526.
[103]	Rotherham M, El-Haj A J.2015. Remote activation of the Wnt/β-catenin signalling pathway using functionalised magnetic particles. PLoS One, 10: e0121761.
[104]	Saeidi N, Sander E A, Ruberti J W.2009. Dynamic shear-influenced collagen self-assembly. Biomaterials, 30: 6581-6592
[105]	Saeidi N, Sander E A, Zareian R, Ruberti J W.2011. Production of highly aligned collagen lamellae by combining shear force and thin film confinement. Acta. Biomater., 7: 2437-2447.
[106]	Schon B S, Hooper G J, Woodfield T B.2017. Modular tissue assembly strategies for biofabrication of engineered cartilage. Ann. Biomed. Eng., 45: 100-114.
[107]	Schrobback K, Klein T J, Crawford R, Upton Z, Malda J, Leavesley D I.2012. Effects of oxygen and culture system on in vitro propagation and redifferentiation of osteoarthritic human articular chondrocytes. Cell Tissue Res., 347: 649-663.
[108]	Schröder C, Hölzer A, Zhu G, Woiczinski M, Betz O B, Graf G, Mayer-Wagner S, Müller P E.2016. A closed loop perfusion bioreactor for dynamic hydrostatic pressure loading and cartilage tissue engineering. J. Mech. Med. Bio., 16: 1650025.
[109]	Schätti O, Grad S, Goldhahn J, Salzmann G, Li Z, Alini M, Stoddart M J.2011. A combination of shear and dynamic compression leads to mechanically induced chondrogenesis of human mesenchymal stem cells. Eur. Cell. Mater., 22: 214-225.
[110]	Seidel J O, Pei M, Gray M L, Langer R, Freed L E, Vunjak-Novakovic G.2004. Long-term culture of tissue engineered cartilage in a perfused chamber with mechanical stimulation. Biorheology, 41: 445-458.
[111]	Shafa M, Sjonnesen K, Yamashita A, Liu S, Michalak M, Kallos M S, Rancourt D E.2012. Expansion and long-term maintenance of induced pluripotent stem cells in stirred suspension bioreactors. J. Tissue Eng. Regen. Med., 6: 462-472.
[112]	Soltz M A, Ateshian G A.2000. Interstitial fluid pressurization during confined compression cyclical loading of articular cartilage. Ann. Biomed. Eng., 28: 150-159.
[113]	Spitters T W, Leijten J C, Deus F D, Costa I B, van-Apeldoorn A A, van-Blitterswijk C A, Karperien M.2013. A dual flow bioreactor with controlled mechanical stimulation for cartilage tissue engineering. Tissue Eng. Part C Methods, 19: 774-783.
[114]	Stoddart M J, Ettinger L, Häuselmann H J.2006. Enhanced matrix synthesis in de novo, scaffold free cartilage-like tissue exposed to compression and shear. Biotechnol. Bioeng., 95: 1043-1051.
[115]	Subramanian A, Turner J A, Budhiraja G, Guha-Thakurta S, Whitney N P, Nudurupati S S.2013. Ultrasonic bioreactor as a platform for studying cellular response. Tissue Eng. Part C Methods, 19: 244-255.
[116]	Sun M, Lv D, Zhang C, Zhu L.2010. Culturing functional cartilage tissue under a novel bionic mechanical condition. Med. Hypotheses, 75: 657-659.
[117]	Tan Q, Zhang C, Gao L, Men Y.2016. Research on the platform of combined multi-functional bioreactor loading performance. MATEC Web Conf., 77: 11001 (ICMMR2016).
[118]	Tarng Y W, Huang B F, Su F C.2012. A novel recirculating flow-perfusion bioreactor for periosteal chondrogenesis. Int. Orthop. 36: 863-868.
[119]	Theodoropoulos J S, Decroos A J N, Petrera M, Park S, Kandel R A.2016. Mechanical stimulation enhances integration in an in vitro model of cartilage repair. Knee Surg. Sports Traumatol. Arthrosc., 24: 2055-2064.
[120]	Tonnarelli B, Santoro R, Adelaide-Asnaghi M, Wendt D.2016. Streamlined bioreactor-based production of human cartilage tissues. Eur. Cell. Mater., 31: 382-394.
[121]	Tsai M T, Li W J, Tuan R S, Chang W H.2009. Modulation of osteogenesis in human mesenchymal stem cells by specific pulsed electromagnetic field stimulation. J. Orthop. Res.,27: 1169-1174.
[122]	Tuan R S, Chen A F, Klatt B A.2013. Cartilage regeneration. J. Am. Acad. Orthop. Surg., 21: 303-311.
[123]	Villanueva I, Klement B J, von Deutsch D, Bryant S J.2009. Cross-linking density alters early metabolic activities in chondrocytes encapsulated in poly (ethylene glycol) hydrogels and cultured in the rotating wall vessel.~{it Biotechnol. Bioeng}.,~102: 1242-1250.
[124]	von Eisenhart R, Adam C, Steinlechner M, Müller-Gerbl M, Eckstein F.1999. Quantitative determination of joint incongruity andpressure distribution during simulated gait and cartilage thickness in the human hip joint. J. Orthop. Res., 17: 532-539.
[125]	Vonk L A, de Windt T S, Slaper-Cortenbach I C, Saris D B.2015. Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why: A concise review. Stem Cell Res. Ther., 6: 94.
[126]	Vunjak-Novakovic G, Martin I, Obradovic B, Treppo S, Grodzinsky A J, Langer R, Freed L E.1999. Bioreactor cultivation conditions modulate the composition and mechanical properties of tissue-engineered cartilage. J. Orthop. Res., 17: 130-138
[127]	Vunjak-Novakovic G, Scadden D T.2011. Biomimetic platforms for human stem cell research. Cell Stem Cell, 8: 252-261.
[128]	Waldman S D, Spiteri C G, Grynpas M D, Pilliar R M, Kandel R A.2003. Long-term intermittent shear deformation improves the quality of cartilaginous tissue formed in vitro. J. Orthop. Res., 21: 590-596.
[129]	Wang D S, Men Y T, Gao L L, Dong X, Lu J, Zhang C Q.2013. A new multifunctional bioreactor based on linear motor. Appl. Mech. Mater., 391: 242-245.
[130]	Wang J, Tang N, Xiao Q, Zhao L, Li Y, Li J, Wang J, Zhao Z, Tan L.2016. The potential application of pulsed ultrasound on bone defect repair via developmental engineering: An in vitro study. Artif. Organs, 40: 505-513.
[131]	Wang N, Grad S, Stoddart M J, Niemeyer P, Südkamp N P, Pestka J, Alini M, Chen J, Salzmann G M.2013. Bioreactor-induced chondrocyte maturation is dependent on cell passage and onset of loading. Cartilage, 4: 165-176.
[132]	Wang N, Grad S, Stoddart M J, Niemeyer P, Reising K, Schmal H, Südkamp N P, Alini M, Salzmann G M.2014. Particulate cartilage under bioreactor-induced compression and shear. Int. Orthop., 38: 1105-1111.
[133]	Wernike E, Li Z, Alini M, Grad S.2008. Effect of reduced oxygen tension and long-term mechanical stimulation on chondrocyte-polymer construct. Cell Tissue Res., 331: 473-483.
[134]	Wong M, Carter D R.2003. Articular cartilage functional histomorphology and mechanobiology: A research perspective. Bone, 33: 1-13.
[135]	Wu M H, Wang H Y, Liu H L, Wang S S, Liu Y T, Chen Y M, Tsai S W, Lin C L.2011. Development of high-throughput perfusion-based microbioreactor platform capable of providing tunable dynamic tensile loading to cells and its application for the study of bovine articular chondrocytes. Biomed. Microdevices, 13: 789-798.
[136]	Xie L, Jacobson J M, Choi E S, Busa B, Donahue L R, Miller L M, Rubin C T, Judex S.2006. Low-level mechanical vibrations can influence bone resorption and bone formation in the growing skeleton. Bone, 39: 1059-1066.
[137]	Xu P, Men Y T, Xu B S, Yang Q, Lu J, Zhang C Q.2013. A new loading device driven by voice coil motor. Appl. Mech. Mater., 391: 250-253.
[138]	Xu P, Liu H Y, Men Y T, Xu B S, Lu J, Zhang C Q.2014. A new type fatigue machine design with high frequency large stroke. Appl. Mech. Mater., 496-500: 1522-1525.
[139]	Yusoff N, Abu Osman N A, Pingguan-Murphy B.2011. Design and validation of a bi-axial loading bioreactor for mechanical stimulation of engineered cartilage. Med. Eng. Phys., 33: 782-788.
[140]	Zhang C, Qiu L, Gao L, Guan Y, Xu Q, Zhang X, Chen Q.2016. A novel dual-frequency loading system for studying mechanobiology of load-bearing tissue. Mater. Sci. Eng. C Mater. Biol. Appl., 69: 262-267.
[141]	Zhang C Q, Gao L L, Dong L M, Liu H Y.2012. Depth-dependent normal strain of articular cartilage under sliding load by the optimized digital image correlation technique. Mater. Sci. Eng. C Mater. Biol. Appl., 32: 2390-2395.
[142]	Zhang Q, Gao L, Xiao P, Zhang C, Ye J.2014. Finite element analysis on the mechanical behavior of articular cartilage under rolling load. 2014 IEEE Int. Conf. Mechatronics Autom., 2014 (ICMA2014): 936-940.
[143]	Zhao J, Griffin M, Cai J, Li S, Bulter P E M, Kalaskar D M.2016. Bioreactors for tissue engineering: An update. Biochem. Eng. J., 109: 268-281.
[144]	Zhu G, Mayer-Wagner S, Schröder C, Woiczinski M, Blum H, Lavagi I, Krebs S, Redeker J I, Hölzer A, Jansson V, Betz O, Müller P E.2015. Comparing effects of perfusion and hydrostatic pressure on gene profiles of human chondrocyte. J. Biotechnol., 210: 59-65.
[145]	Zhu Y, Song K, Jiang S, Chen J, Tang L, Li S, Fan J, Wang Y, Zhao J, Liu T.2017. Numerical simulation of mass transfer and three-dimensional fabrication of tissue-engineered cartilages based on chitosan/gelatin hybrid hydrogel scaffold in a rotating bioreactor. Appl. Biochem. Biotechnol., 181: 250-266.