基于先进生物材料的心肌细胞力--电微环境体外构建

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doi:10.6052/1000-0992-17-014

徐峰^1,2,
张晓慧^1,2,ɛ,,,
鲍雪娇^1,2,
赵国旭^1,2,
刘付生^2,3,
黄国友^1,2,
李昱辉^1,2,
卢天健⁴

1 西安交通大学生命科学与技术学院, 生物信息工程教育部重点实验室, 西安 710049
2 西安交通大学仿生工程与生物力学中心, 西安 710049
3 西安交通大学航空航天学院, 振动与强度国家重点实验室, 西安710049
4 西安交通大学多功能材料与结构教育部重点实验室, 西安 710049

基金项目:国家自然科学基金(81401270, 11372243, 11522219, 11532009)、陕西省自然科学基础研究计划(2015JM3108)、徐峰和张晓慧的青年千人计划项目资助

详细信息

作者简介:
null

作者简介：
徐峰, 2008年取得剑桥大学工程学博士学位, 2008---2011年在哈佛医学院/哈佛大学--麻省理工学院健康科学与技术研究中心任博士后.2011年回国, 现任西安交通大学教授、生命学院副院长, 同卢天健教授共同建立 "仿生工程与生物力学研究中心", 并担任主任.在课题开展中遵循"力学基础理论--生物技术研发--应用推广"的学术思路, 通过理解和探索人体组织/细胞的力学行为和力学环境, 将固体力学和流体力学与工程学、生物医学等领域进行交叉融合, 开展了生物组织热--力--电耦合学、细胞热--力--电微环境工程、基于生物微流体力学的即时诊断技术的研究.科研成果包括中英文专著和教材5本; 作为第一／通讯作者发表150余篇论文; 发明专利20余项; 在生物热--力耦合学方面的工作获得国家自然科学奖二等奖(第二完成人)、教育部科学技术奖一等奖(第二完成人).
张晓慧, 2009年获得美国塔夫茨大学生物技术博士学位, 2009---2013年在哈佛医学院/哈佛大学--麻省理工学院健康科学与技术研究中心任博士后, 2013年全职回国, 现任西安交通大学教授.致力于新型生物材料的开发与应用、工程化组织器官及疾病模型的体外构建、生殖医学工程以及细胞冷冻保存等生物医学领域中的应用研究.2013年入选中组部"青年千人计划". 迄今已在 Advanced Functional Materials. Biomaterials等国际知名学术期刊发表SCI 论文40 余篇, 总引用次数超过 2200 次, H 因子24. 另申报发明专利7 项 (国际 2 项, 美国 2 项, 欧洲 1 项, 日本 1 项, 中国 1 项), 其中5 项为第一发明人. 担任SCI 期刊 Nanobiomedicine 的编委, 应邀担任期刊{\it ASME Journal of Nanotechnology in Engineering and Medicine 专刊副主编, 2014年国际组织工程与再生医学学会亚太年会(TERMIS-AP 2014) 的分会主席.

通讯作者:
张晓慧

中图分类号:Q27,R329,2⁺7;
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出版历程
- 收稿日期:2017-07-04
- 刊出日期:2018-02-08

Engineering mechanical-electrical cell microenvironment in myocardium using advanced biomaterials

XU Feng^1,2,
ZHANG Xiaohui^1,2,ɛ,,,
BAO Xuejiao^1,2,
ZHAO Guoxu^1,2,
LIU Fusheng^2,3,
HUANG Guoyou^1,2,
LI Yuhui^1,2,
LU Tianjian⁴

1 The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
2 Bioinspired Engineering and Biomechanics Center (BEBC),Xi'an Jiaotong University, Xi'an 710049, China
3 State Key Laboratory for Strength and Vibration of Mechanical Structures School of Aerospace, Xi'an Jiaotong University, Xi'an 710049, China
4 Moe Key Laboratory for Multifunction Materials and Structure,Xi'an Jiaotong University, Xi'an 710049, China;

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Author Bio:
^ɛE-mail:xiaohuizhang@mail.xjtu.edu.cn

Corresponding author:ZHANG Xiaohui

摘要

摘要:心血管疾病是当前全球范围内导致人类死亡的首要原因, 心肌组织工程的发展为心血管疾病的治疗, 尤其是心肌组织再生修复提供了最有潜力的解决方案.心血管疾病的发生发展与细胞力--电微环境的变化密切相关. 近十几年, 随着先进生物材料和微纳生物制造技术的发展, 越来越多的研究表明, 细胞力--电微环境的调控对工程化心肌组织的成熟和功能化以及心肌组织再生修复具有重要意义. 本文首先阐明了在体心肌细胞所处力学微环境的生物学基础以及电信号的传导过程, 包括正常和疾病状态下心肌细胞所处的力--电微环境.其次调研了用于心肌组织工程的先进生物材料的研究现状.最后总结用于基底硬度与应力应变细胞微环境以及细胞电学微环境的构建和调控, 以及细胞对力--电微环境的生物学响应.%
- 细胞力学微环境/
- 细胞电学微环境/
- 心肌组织工程/
- 生物材料
Abstract:Cardiovascular diseases remain the leading cause of human death worldwide. The development of cardiac tissue engineering has provided a most potential strategy for the treatment of cardiovascular disease through regenerating functional cardiac tissues and restoring dysfunctional myocardium. The occurrence and progress of cardiovascular diseases are closely related to the changes of mechanical and electrical cell microenvironment in native myocardium. In the last decades, with the advances in biomaterials and micro- and nano-fabrication techniques, increasing evidence has demonstrated that the biomimicking of mechanical-electrical cell microenvironment is important for the maturation and functionalization of engineered cardiac tissues for the purpose of myocardium restoration. In this review, we firstly elucidated the biological basis of mechanical properties and electrical signal transmission in native myocardium, including the mechanical and electrical microenvironment in physiological and pathological conditions. Then, we reviewed the current research progress of advanced biomaterials for cardiac tissue engineering applications. Finally, we summarized the development and manipulation of mechanical and electrical microenvironment using advanced biomaterials, and the biological responses of cardiomyocytes and cardiac tissues to the biomimicking mechanical-electrical microenvironment.
- mechanical microenvironment/
- electrical microenvironment/
- cardiac tissue engineering/
- biomaterial

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参考文献 (237)

[1]	陈新. 2009. 临床心律失常学. 北京: 人民卫生出版社 (Chen X.2009. Clinical Arrhythmology. Beijing: People's Medical Publishing House).
[2]	陈焱. 2015. 静电纺丝纳米纤维支架诱导iPS细胞心肌分化及机制研究. 西安: 第四军医大学 (Chen Y.2015. Electrospun Nanofibrous Scaffold Induces Cardiomyocyte Differentiation of iPS Cell and Its Mechanism. Xi'an: Fourth Military Medical University).
[3]	戴辰程, 李文秀, 肖燕燕, 金梅, 韩玲. 2014. 心室预激性扩张型心肌病临床特点分析. 中华实用儿科临床杂志, 29: 683-686 (Dai C C, Li W X, Xiao Y Y, Jin M, Han L.2014. Clinical characteristics of ventricular preexcitation dilated cardiomyopathy induced by accessory pathway. Journal of Applied Clinical Pediatrics, 29: 683-686 ).
[4]	段翠密, 常海霞, 郭希民, 赵云山, 何文俊, 江红, 王常勇. 2006. 力学刺激在工程化心肌组织结构和功能改建中的作用研究. 组织工程与重建外科杂志, 2: 12-15 (Duan C M, Chang H X, Guo X M, Zhao Y S, He W J, Jiang H, Wang C Y.Effects of mechanical stimulation on the structural and functional remodeling of engineered cardiac muscle. Journal of Tissue Engineering and Reconstructive Surgery,2: 12-15 ).
[5]	郭继鸿. 2003. 缝隙连接与心脏的传导. 临床心电学杂志, 12: 194-199 (Guo J H.2003. Gap junction and electrical trasmmision in heart. Journal of Clinical Electrocardiology,12: 194-199 ).
[6]	郝嘉, 游凯, 肖颖彬. 2011. 心肌成纤维细胞的特性和调节. 心血管病学进展, 32: 405-408 (He J, You K, Xiao Y B.2011. Characteristics and regulation of cardiac fibroblasts. Advances in Cardiovascular Diseases, 32: 405-408).
[7]	贾欣华, 冯建涛, 敖卓, 孙全梅, 韩东, 刘元生. 2014. 高血压心肌肥厚状态下心肌细胞微尺度刚度变化的实验研究. 电子显微学报, 33: 264-270 (Jia X H, Feng J T, Ao Z, Sun Q M, Han D, Liu Y S.2014. Stiffness study on myocardium from hypertension-associated hypertrophy at micro scales. Journal of Chinese Electron Microscopy Society33: 264-270, ).
[8]	况薇, 唐敏, 何学令, 吴文超, 刘小菁, 李良. 2014. 周期性拉伸应变对大鼠骨髓间充质干细胞向心肌样细胞分化的影响. 生物医学工程学杂志, 31: 596-600 (Kuang W, Tang M, He X L, Wu W C, Liu X J, Li L.2014. Differentiation of rat bone marrow-derived mesenchymal stem cell into cardiomyocyte-like cells induced by cyclic stretching strain. Journal of Biomedical Engineering,31: 596-600 ).
[9]	荣仔萍, 董十月, 沈贵林, 张永乐. 2014. 中西医结合治疗急性冠脉综合征 (热结血瘀证) 临床观察. 中国中医急症, 23: 2313-2315 (Rong Z P, Dong S Y, Shen G L, Zhang Y L.2014. Clinical study on integrative medicine treatment for acute coronary syndrome. Journal of Emergency in Traditional Chinese Medicine,23: 2313-2315).
[10]	王佳南, 张晓刚, 郑丽娜, 汤为学. 2009. 仿生电刺激在离体心肌诱导骨髓间充质干细胞向心肌样细胞分化中的作用. 解放军医学杂志, 34: 537-540 (Wang J N, Zhang X G, Zheng L N, Tang W X.2009. Effects of biomimetic electrical stimulation on inducing differentiation of rat bone marrow mesenchymal stem cells into cardiomyocyte-like cells in isolated myocardium. Medical Journal of Chinese People's Liberation Army,34: 537-540 ).
[11]	魏严, 张西正, 郭勇, 李瑞欣, 吴金辉, 闫玉仙, 张永红. 2009. 体外培养心肌细胞代谢和微管蛋白对拉伸应变的响应. 中国生物医学工程学报, 28: 421-427, 438 (Wei Y, Zhang X Z, Guo Y, Li R X, Wu J H, Yan Y X, Zhang Y H.2009. The response of metabolism and tubulin of cardiac myocytes in vitro to mechanical stretch. Chinese Journal of Biomedical Engineering, 28: 421-427, 438).
[12]	徐正平, 周睿. 2014. 依折麦布联合阿托伐他汀治疗急性冠脉综合征的临床疗效. 实用临床医药杂志, 18: 110-111 (Xu Z P, Zhou R.2014. The clinical effect of Ezetimibe combining atorvastatin for the treatment of acute coronary syndrome. Journal of Clinical Medicine in Practice,18: 110-111 ).
[13]	薛梅, 梁涛, 邱建丽, 刘波. 2014. 心脏移植受者生存质量现状的研究. 中华护理杂志, 49: 924-927 (Xue M, Liang T, Qiu J L, Liu B.2014. Quality of life in heart transplantation recipients. Chinese Journal of Nursing,49: 924-927 ).
[14]	杨作成. 2014. 儿童扩张型心肌病合并心律失常诊治. 中国实用儿科杂志, 29: 654-658 (Yang Z C.2014. Diagnosis and treatment of dilated cardiomyopathy combined with arrhythmia in children. Cardiovascular Disease Journal of Integrated Traditional Chinese and Western Medicine, 29: 654-658).
[15]	余承高. 1985. 心肌细胞间的连接和信息交通. 生理科学进展, 70-73 (Yu C G.1985. Gap junction and communication between cardiomycytes. Progress in Physiological Sciences, 70-73).
[16]	张倞, 王永武. 2007. 心肌组织工程研究进展. 心脏杂志, 19: 230-231 (Zhang L, Wang Y W.2007. Research progress in cardiac tissue engineering. Chinese Heart Journal,19: 230-231 ).
[17]	张颖, 郑燕倩, 王红卫, 杨智昉, 刘远谋, 李慈珍. 2007. 新生大鼠心肌细胞培养及电生理特性观察. 上海交通大学学报(医学版), 27: 398-400 (Zhang Y, Zheng Y, Wang H, Yang Z, Liu Y, Li C.2007. Method for culturing neonatal rat cardiac myocytes and observation of its electrophysiological properties. Journal of Shanghai Jiaotong University ( Medical Science), 27: 398-400).
[18]	Abbott A.2003. Cell culture: Biology's new dimension. Nature, 424: 870-872.
[19]	Abraham W T, Fisher W G, Smith A L, Delurgio D B, Leon A R, Loh E, Kocovic D Z, Packer M, Clavell A L, Hayes D L, Ellestad M, Trupp R J, Underwood J, Pickering F, Truex C, McAtee P, Messenger J.2002. Cardiac resynchronization in chronic heart failure. N Engl J Med, 346:1845-1853.
[20]	Agarwal A, Goss J A, Cho A, McCain M L, Parker K K.2013. Microfluidic heart on a chip for higher throughput pharmacological studies. Lab on a Chip, 13: 3599-3608.
[21]	Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Zhu W, Kadowaki T, Yazaki Y.1999. Rho family small G proteins play critical roles in mechanical stress--induced hypertrophic responses in cardiac myocytes. Circ Res, 84: 458-466.
[22]	Annabi N, Shin S R, Tamayol A, Miscuglio M, Bakooshli M A, Assmann A, Mostafalu P, Sun J Y, Mithieux S, Cheung L, Tang X S, Weiss A S, Khademhosseini A.2015. Highly elastic and conductive human-based protein hybrid hydrogels. Advanced Materials, 28: 40.
[23]	Arrenberg A B, Stainier D Y, Baier H, Huisken J.2010. Optogenetic control of cardiac function. Science, 330: 971-974.
[24]	Bajaj P, Tang X, Saif T A, Bashir R.2010. Stiffness of the substrate influences the phenotype of embryonic chicken cardiac myocytes. J Biomed Mater Res A, 95: 1261-1269.
[25]	Baker E L, Zaman M H.2010. The biomechanical integrin. J Biomech, 43: 38-44.
[26]	Banerjee I, Fuseler J W, Price R L, Borg T K, Baudino T A.2007. Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse. Am J Physiol Heart Circ Physiol, 293: H1883-1891
[27]	Barash Y, Dvir T, Tandeitnik P, Ruvinov E, Guterman H, Cohen S.2010. Electric field stimulation integrated into perfusion bioreactor for cardiac tissue engineering. Tissue Engineering Part C: Methods, 16: 1417-1426.
[28]	Baumgartner S, Halbach M, Krausgrill B, Maass M, Srinivasan S P, Sahito R G.2015. Electrophysiological and morphological maturation of murine fetal cardiomyocytes during electrical stimulation in vitro. J Cardiovasc Pharmacol Ther, 20: 104-112.
[29]	Beauchamp P, Desplantez T, McCain M L, Li W, Asimaki A, Rigoli G, Parker K K, Saffitz J E, Kleber A G.2012. Electrical coupling and propagation in engineered ventricular myocardium with heterogeneous expression of connexin43. Circ Res, 110: 1445-1453.
[30]	Bernardo B C, Weeks K L, Pretorius L, McMullen J R.2010. Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies. Pharmacology & Therapeutics, 128: 191-227.
[31]	Bett G C, Sachs F.1997. Cardiac mechanosensitivity and stretch-activated ion channels. Trends in Cardiovascular Medicine, 7: 4.
[32]	Bhana B, Iyer R K, Chen W L, Zhao R, Sider K L, Likhitpanichkul M, Simmons C A, Radisic M.2010. Influence of substrate stiffness on the phenotype of heart cells. Biotechnol Bioeng, 105: 1148-1160.
[33]	Bhandari J, Mishra H, Mishra P K, Wimmer R W, Ahmad F J, Talegaonkar S.2017. Cellulose nanofiber aerogel as a promising biomaterial for customized oral drug delivery. International Journal of Nanomedicine, 12: 2021-2031.
[34]	Bhatia S N, Ingber D E.2014. Microfluidic organs-on-chips. Nature biotechnology, 32: 760-772.
[35]	Bierhuizen M F, Boulaksil M, van Stuijvenberg L, van der Nagel R, Jansen A T, Mutsaers N A M, Yildirim {C}, {van Veen} T A B, {de Windt }L J.2008. In calcineurin-induced cardiac hypertrophy expression of Na V 1.5, Cx40 and Cx43 is reduced by different mechanisms. J Mol Cell Cardiol, 45: 373-384.
[36]	Birla R K, Huang Y C, Dennis R G.2007. Development of a novel bioreactor for the mechanical loading of tissue-engineered heart muscle. Tissue Eng, 13: 2239-2248.
[37]	Black L D 3rd, Meyers J D, Weinbaum J S, Shvelidze Y A, Tranquillo R T.2009. Cell-induced alignment augments twitch force in fibrin gel-based engineered myocardium via gap junction modification. Tissue Engineering Part A, 15: 3099-3108.
[38]	Black L D 3rd, Meyers J D, Weinbaum J S, Shvelidze Y A, Tranquillo R T.2009. Cell-induced alignment augments twitch force in fibrin gel-based engineered myocardium via gap junction modification. Tissue Eng Part A, 15: 3099-3108.
[39]	Boudou T, Legant W R, Mu A, Borochin M A, Thavandiran N, Radisic M, Zandstra P W, Epstein J A, Margulies K B, Chen C S.2012. A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues. Tissue Eng Part A, 18: 910-919.
[40]	Brevet A, Pinto E, Peacock J, Stockdale F E.1976. Myosin synthesis increased by electrical stimulation of skeletal muscle cell cultures. Science, 193: 1152-1154.
[41]	Brown M A, Iyer R K, Radisic M.2008. Pulsatile perfusion bioreactor for cardiac tissue engineering. Biotechnol Prog, 24: 907-920.
[42]	Cao N, Liang H, Huang J J, Wang J, Chen Y X, Chen Z Y, Yang H T.2013. Highly efficient induction and long-term maintenance of multipotent cardiovascular progenitors from human pluripotent stem cells under defined conditions. Cell Research, 23: 1119-1132.
[43]	Cha J M, Park S N, Noh S H, Suh H.2006. Time-dependent modulation of alignment and differentiation of smooth muscle cells seeded on a porous substrate undergoing cyclic mechanical strain. Artif Organs, 30: 250-258.
[44]	Chan C Y, Huang P-H, Guo F, Ding X, Kapur V, Mai J D, Yuen {P K}, {Huang }T J.2013. Accelerating drug discovery via organs-on-chips. Lab on a Chip, 13: 4697-4710.
[45]	Chaudhuri O, Mooney D J.2012. Stem-cell differentiation: Anchoring cell-fate cues. Nat Mater, 11: 568-569.
[46]	Chen Q-Z, Harding S E, Ali N N, Lyon A R, Boccaccini A R.2008. Biomaterials in cardiac tissue engineering: Ten years of research survey. Materials Science and Engineering: R: Reports, 59: 1-37.
[47]	Chi N C, Bussen M, Brand-Arzamendi K, Ding C, Olgin J E, Shaw R M, Martin G R, Stainier D Y.2010. Cardiac conduction is required to preserve cardiac chamber morphology. Proceedings of the National Academy of Sciences, 107: 14662-14667.
[48]	Chi N C, Shaw R M, Jungblut B, Huisken J, Ferrer T, Arnaout R, Scott I, Beis D, Xiao T, Baier H, Jan L Y, Tristani-Firouzi M, Stainier D Y.2008. Genetic and physiologic dissection of the vertebrate cardiac conduction system. PLoS Biol, 6: e109.
[49]	Chiu L, Iyer R K, Reis L A, Nunes S S, Radisic M.2011. Cardiac tissue engineering: current state and perspectives. Frontiers in Bioscience( Landmark edition), 17: 1533-1550.
[50]	Conti C R.2006. Cardiac resynchronization therapy for chronic heart failure: why does it not always work? Clin Cardiol, 29: 335-336.
[51]	Control C F D, Prevention.2014. National diabetes statistics report: Estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: US Department of Health and Human Services.
[52]	Corona B T, Ward C L, Baker H B, Walters T J, Christ G J.2013. Implantation of in vitro tissue engineered muscle repair constructs and bladder acellular matrices partially restore in vivo skeletal muscle function in a rat model of volumetric muscle loss injury. Tissue Engineering Part A, 20: 705-715.
[53]	Crespo L M, Grantham C J, Cannell M B.1990. Kinetics, stoichiometry and role of the Na-Ca exchange mechanism in isolated cardiac myocytes. Nature, 345: 618-621.
[54]	Crosara-Alberto D P, Inoue R Y, Costa C R C.2009. FAK signalling mediates NF-$kappa $B activation by mechanical stress in cardiac myocytes. Clinica Chimica Acta, 403: 81-86.
[55]	Curran M E, Splawski I, Timothy K W, Vincen G M, Green E D, Keating M T.1995. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell, 80: 795-803.
[56]	Cysarz D, Lange S, Matthiessen P F, Van Leeuwen P.2007. Regular heartbeat dynamics are associated with cardiac health. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 292: R368-R372.
[57]	Czarnecka D, Kusiak A, Wilinski J, Styczkiewicz K, Wojciechowska W, Bacior B.2010. Effects of cardiac resynchronization therapy on sleep apnea, quality of sleep and daytime sleepiness in patients with chronic heart failure. Przegl Lek, 67: 1249-1252.
[58]	Dawson E, Mapili G, Erickson K, Taqvi S, Roy K.2008. Biomaterials for stem cell differentiation. Adv Drug Deliv Rev, 60: 215-228.
[59]	DeBosch B, Treskov I, Lupu T S, Weinheimer C, Kovacs A, Courtois M, Muslin A J.2006. Akt1 is required for physiological cardiac growth. Circulation, 113: 2097-2104.
[60]	Dhein S, Schreiber A, Steinbach S, Apel D, Salameh A, Schlegel F, Kostelka M, Dohmen P M, Mohr F W.2014. Mechanical control of cell biology. Effects of cyclic mechanical stretch on cardiomyocyte cellular organization. Prog Biophys Mol Biol, 115: 93-102.
[61]	DiFrancesco D, Tortora P.1991. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature, 351: 145-147.
[62]	Dorn T, Goedel A, Lam J T, Haas J, Tian Q, Herrmann F, Bundschu K, Dobreva G, Schiemann M, Dirschinger R, Guo Y, Kühl S J, Sinnecker D, Lipp P, Laugwitz K L, Kühl M, Moretti A.2015. Direct nkx2-5 transcriptional repression of isl1 controls cardiomyocyte subtype identity. Stem Cells, 33: 1113-1129.
[63]	Dvir T, Timko B P, Brigham M D, Naik S R, Karajanagi S S, Levy O, Jin H, Parker K K, Langer R, Kohane D S.2011. Nanowired three-dimensional cardiac patches. Nature Nanotechnology, 6: 720-725.
[64]	Eghbali M, Deva R, Alioua A, Minosyan T Y, Ruan H, Wang Y, Toro L, Stefani E.2005. Molecular and functional signature of heart hypertrophy during pregnancy. Circ Res, 96: 1208-1216.
[65]	Endo M.1977. Calcium release from the sarcoplasmic reticulum. Physiological Reviews, 57: 71-108.
[66]	Engler A J, Carag-Krieger C, Johnson C P, Raab M, Tang H Y, Speicher D W, Sanger J W, Sanger J M, Discher D E.2008. Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: Scar-like rigidity inhibits beating. J Cell Sci, 121: 3794-3802.
[67]	Engler A J, Griffin M A, Sen S, Bonnemann C G, Sweeney H L, Discher D E.2004. Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments. J Cell Biol, 166: 877-887.
[68]	Engler A J, Sen S, Sweeney H L, Discher D E.2006. Matrix elasticity directs stem cell lineage specification. Cell, 126: 677-689.
[69]	Esch M B, Smith A S, Prot J-M, Oleaga C, Hickman J J, Shuler M L.2014. How multi-organ microdevices can help foster drug development. Adv Drug Deliv Rev, 69: 158-169.
[70]	Fabiato A.1983. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. American Journal of Physiology, 245: C1.
[71]	Fahrenbach J P, Mejia-Alvarez R, Banach K.2007. The relevance of non-excitable cells for cardiac pacemaker function. J Physiol, 585: 565-578.
[72]	Fallacara A, Manfredini S, Durini E, Vertuani S.2017. Hyaluronic Acid Fillers in Soft Tissue Regeneration. Facial Plastic Surgery, 33: 087-096.
[73]	Farouz Y, Chen,Y, Terzic A, Menasch'{e} P.2015. Concise review: Growing hearts in the right place: On the design of biomimetic materials for cardiac stem cell differentiation. Stem Cells, 33: 1021-1035.
[74]	Feng Z, Matsumoto T, Nomura Y, Nakamura T.2005. An electro-tensile bioreactor for 3-D culturing of cardiomyocytes. Engineering in Medicine and Biology Magazine, IEEE, 24: 73-79.
[75]	Feric N T, Radisic M.2016. Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv Drug Deliv Rev, 96: 110-134.
[76]	Ferrarini M, Arsic N, Recchia F A, Zentilin L, Zacchigna S, Xu X, et al.2006. Adeno-associated virus-mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs. Circ Res, 98: 954-961.
[77]	Fink C, Ergün S, Kralisch D, Remmers U, Weil J, Eschenhagen T.2000. Chronic stretch of engineered heart tissue induces hypertrophy and functional improvement. The FASEB Journal, 14: 669-679.
[78]	Forte G, Pagliari S, Ebara M, Uto K, Tam J K, Romanazzo S, Escobedo-Lucea C, Romano E, Di Nardo P, Traversa E, Aoyagi T.2012. Substrate stiffness modulates gene expression and phenotype in neonatal cardiomyocytes in vitro. Tissue Eng Part A, 18: 1837-1848.
[79]	Fujio Y, Nguyen T, Wencker D, Kitsis R N, Walsh K.2000. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation, 101: 660-667.
[80]	Galie P A, Byfield F J, Chen C S, Kresh J Y, Janmey P A.2015. Mechanically stimulated contraction of engineered cardiac constructs using a microcantilever. Biomedical Engineering, IEEE Transactions on, 62: 438-442.
[81]	Galie P A, Khalid N, Carnahan K E, Westfall M V, Stegemann J P.2013. Substrate stiffness affects sarcomere and costamere structure and electrophysiological function of isolated adult cardiomyocytes. Cardiovasc Pathol, 22: 219-227
[82]	Galie P A, Stegemann J P.2011. Simultaneous application of interstitial flow and cyclic mechanical strain to a three-dimensional cell-seeded hydrogel. Tissue Eng Part C Methods, 17: 527-536.
[83]	Gattazzo F, Urciuolo A, Bonaldo P.2014. Extracellular matrix: A dynamic microenvironment for stem cell niche. Biochimica et Biophysica Acta (BBA)-General Subjects, 1840: 2506-2519.
[84]	Gershlak J R, Resnikoff J I, Sullivan K E, Williams C, Wang R M, Black L D.2013. Mesenchymal stem cells ability to generate traction stress in response to substrate stiffness is modulated by the changing extracellular matrix composition of the heart during development. Biochemical and Biophysical Research Communications, 439:161-166.
[85]	Ghafar-Zadeh E, Waldeisen J R, Lee L P.2011. Engineered approaches to the stem cell microenvironment for cardiac tissue regeneration. Lab Chip, 11: 3031-3048.
[86]	Griffin M A, Engler A J, Barber T A, Healy K E, Sweeney H L, Discher D E.2004. Patterning, prestress, and peeling dynamics of myocytes. Biophys J, 86: 1209-1222.
[87]	Gros D, Th'{e}veniau-Ruissy M, Bernard M, Calmels T, Kober F, Söhl G, Willecke K, Nargeot J, Jongsma H J, Mangoni M E.2010. Connexin 30 is expressed in the mouse sino-atrial node and modulates heart rate. Cardiovasc Res, 85: 45-55.
[88]	Haggart C R, Ames E G, Lee J K, Holmes J W.2014. Effects of stretch and shortening on gene expression in intact myocardium. Physiol Genomics, 46: 57-65.
[89]	Hazeltine L B, Simmons C S, Salick M R, Lian X, Badur M G, Han W, Delgado S M, Wakatsuki T, Crone W C, Pruitt B L, Palecek S P.2012. Effects of substrate mechanics on contractility of cardiomyocytes generated from human pluripotent stem cells. Int J Cell Biol, 2012: 508294.
[90]	Hench L L, Polak J M.2002. Third-generation biomedical materials. Science, 295: 1014-1017.
[91]	Hidalgo C, Hudson B, Bogomolovas J, Zhu Y, Anderson B, Greaser M, Labeit S, Granzier H.2009. PKC phosphorylation of titin's PEVK element: a novel and conserved pathway for modulating myocardial stiffness. Circ Res, 105: 631-638.
[92]	Hoh J F, McGrath P A, Hale P T.1978. Electrophoretic analysis of multiple forms of rat cardiac myosin: effects of hypophysectomy and thyroxine replacement. J Mol Cell Cardiol, 10: 1053-1076.
[93]	Holle A W, Engler A J.2011. More than a feeling: Discovering, understanding, and influencing mechanosensing pathways. Current Opinion in Biotechnology, 22: 648-654.
[94]	Hsiao C W, Bai M Y, Chang Y, Chung M F, Lee T Y, Wu C T, Maiti B, Liao Z X, Li R K, Sung H W.2013. Electrical coupling of isolated cardiomyocyte clusters grown on aligned conductive nanofibrous meshes for their synchronized beating. Biomaterials, 34: 1063-1072.
[95]	Huebsch N, Arany P R, Mao A S, Shvartsman D, Ali O A, Bencherif S A, Rivera-Feliciano J, Mooney D J.2010. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat Mater, 9: 518-526.
[96]	Huynh K, McMullen J R, Julius T L, Tan J W, Love J E, Cemerlang N, et al.2010. Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy. Diabetes, 59: 1512-1520.
[97]	Isenberg B C, Tranquillo R T.2003. Long-term cyclic distention enhances the mechanical properties of collagen-based media-equivalents. Ann Biomed Eng, 31: 937-949.
[98]	Ivashchenko C Y, Pipes G C, Lozinskaya I M, Lin Z, Xiaoping, X, Needle S, Grygielko E T, Hu E, Toomey J R, Lepore J J, Willette R N.2013. Human-induced pluripotent stem cell-derived cardiomyocytes exhibit temporal changes in phenotype. Am J Physiol Heart Circ Physiol, 305: H913-922.
[99]	Jaalouk D E, Lammerding J.2009. Mechanotransduction gone awry. Nature Reviews. Molecular Cell Biology, 10: 63.
[100]	Jacot J G, Martin J C, Hunt D L.2010. Mechanobiology of cardiomyocyte development. J Biomech, 43: 93-98.
[101]	Jacot J G, McCulloch A D, Omens J H.2008. Substrate stiffness affects the functional maturation of neonatal rat ventricular myocytes. Biophys J, 95: 3479-3487.
[102]	Johnson P, Maxwell D, Tynan M, Allan L.2000. Intracardiac pressures in the human fetus. Heart, 84: 59-63.
[103]	Kajstura J, Fiordaliso F, Andreoli A M, Li B, Chimenti S, Medow M S, Limana F, Nadal-Ginard B, Leri A, Anversa P.2001. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II--mediated oxidative stress. Diabetes, 50: 1414-1424.
[104]	Kapur N K.2011. A clinical commentary on the articles "strategies for tissue engineering cardiac constructs to affect functional repair following myocardial infarction" and "stem cell-based cardiac tissue engineering": repairing, reprogramming, and renewing: the promise of myocardial cytotherapeutics. J Cardiovasc Transl Res, 4: 603-604.
[105]	Khetan S, Katz J S, Burdick J A.2009. Sequential crosslinking to control cellular spreading in 3-dimensional hydrogels. Soft Matter, 5: 1601-1606.
[106]	Kim D H, Lipke E A, Kim P, Cheong R, Thompson S, Delannoy M, Suh K Y, Tung L, Levchenko A.2009. Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Proceedings of the National Academy of Sciences, 107: 565-570.
[107]	Kirchhoff S, Nelles E, Hagendorff A, Kruger O, Traub O, Willecke K.1998. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice. Curr Biol, 8: 299-302.
[108]	Kluge J A, Leisk G G, Cardwell R D, Fernandes A P, House M, Ward A, et al.2011. Bioreactor system using noninvasive imaging and mechanical stretch for biomaterial screening. Annals of Biomedical Engineering, 39: 1390-1402.
[109]	Knollmann B C, Knollmann-Ritschel B E, Weissman N J, Jones L R, Morad M.2000. Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin. J Physiol, 525: 483-498.
[110]	Koizumi R, Azuma K, Izawa H, Morimoto M, Ochi K, Tsuka T, et al.2017. Oral administration of surface-deacetylated chitin nanofibers and chitosan inhibit 5-fluorouracil-induced intestinal mucositis in mice. International Journal of Molecular Sciences, 18: 279.
[111]	Komuro I, Kudo S, Yamazaki T, Zou Y, Shiojima I, Yazaki Y.1996. Mechanical stretch activates the stress-activated protein kinases in cardiac myocytes. The FASEB Journal, 10: 631-636.
[112]	Kreuzberg M M, Sohl G, Kim J S, Verselis V K, Willecke K, Bukauskas F F.2005. Functional properties of mouse connexin30.2 expressed in the conduction system of the heart. Circ Res, 96: 1169-1177.
[113]	Kruger M, Kotter S, Grutzner A, Lang P, Andresen C, Redfield M M, Butt E, dos Remedios C G, Linke W A.2009. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res, 104: 87-94.
[114]	Kumai M, Nishii K, Nakamura K, Takeda N, Suzuki M, Shibata Y.2000. Loss of connexin45 causes a cushion defect in early cardiogenesis. Development, 127: 3501-3512.
[115]	Laflamme M A, Murry C E.2011. Heart regeneration. Nature, 473: 326-335.
[116]	Lammerding J, Kamm R D, Lee R T.2004. Mechanotransduction in cardiac myocytes. Annals of the New York Academy of Sciences, 1015: 53-70.
[117]	Legant W R, Pathak A, Yang M T, Deshpande V S, McMeeking R M, Chen C S.2009. Microfabricated tissue gauges to measure and manipulate forces from 3D microtissues. Proc Natl Acad Sci U S A, 106: 10097-10102.
[118]	LeGrice I J, Smaill B, Chai L, Edgar S, Gavin J, Hunter P J.1995. Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog. American Journal of Physiology-Heart and Circulatory Physiology, 269: H571-H582.
[119]	Leychenko A, Konorev E, Jijiwa M, Matter M L.2011. Stretch-induced hypertrophy activates NFkB-mediated VEGF secretion in adult cardiomyocytes. PLoS One, 6: e29055.
[120]	Li Z, Gong Y, Sun S, Du Y, Lu D, Liu X, Long M.2013. Differential regulation of stiffness, topography, and dimension of substrates in rat mesenchymal stem cells. Biomaterials, 34: 7616-7625.
[121]	Lian X, Zhang J, Azarin S M, Zhu K, Hazeltine L B, Bao X, Hsiao C, Kamp T J, Palecek S P.2012. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/$eta $-catenin signaling under fully defined conditions. Nature Protocols, 8: 162-175.
[122]	Lieu D K, Fu J D, Chiamvimonvat N, Tung K C, McNerney G P, Huser T, Keller G, Kong C W, Li R A.2013. Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol, 6: 191-201.
[123]	Liu M, Montazeri S, Jedlovsky T, Van Wert R, Zhang J, Li R K, et al.1999. Bio-stretch, a computerized cell strain apparatus for three-dimensional organotypic cultures. In Vitro Cell Dev Biol Anim, 35: 87-93.
[124]	Lu D, Luo C, Zhang C, Li Z, Long M.2014. Differential regulation of morphology and stemness of mouse embryonic stem cells by substrate stiffness and topography. Biomaterials, 35: 3945-3955.
[125]	Lu L, Mende M, Yang X, Korber H F, Schnittler H J, Weinert S, et al.2013. Design and validation of a bioreactor for simulating the cardiac niche: A system incorporating cyclic stretch, electrical stimulation, and constant perfusion. Tissue Eng Part A, 19: 403-414.
[126]	Ma Y, Ji Y, Huang G, Ling K, Zhang X, Xu F.2015. Bioprinting 3D cell-laden hydrogel microarray for screening human periodontal ligament stem cell response to extracellular matrix. Biofabrication, 7: 044105.
[127]	Macr'{i}-Pellizzeri L, Pelacho B, Sancho A, Iglesias-Garc'{i}a O, Sim'{o}n-Yarza A M, Soriano-Navarro M, Gonz'{a}lez-Granero S, Garc'{i}a-Verdugo J M, De-Juan-Pardo E M, Prosper F.2015. Substrate stiffness and composition specifically direct differentiation of induced pluripotent stem cells. Tissue Engineering Part A, 21: 1633-1641.
[128]	Maidhof R, Tandon N, Lee E J, Luo J, Duan Y, Yeager K, Konofagou, Konofagou E, Vunjak-Novakovic G.2012. Biomimetic perfusion and electrical stimulation applied in concert improved the assembly of engineered cardiac tissue. Journal of Tissue Engineering and Regenerative Medicine, 6: e12-e23.
[129]	Malhotra R, D'Souza K M, Staron M L, Birukov K G, Bodi I, Akhter S A.2010. G$alpha $q-mediated activation of GRK2 by mechanical stretch in cardiac myocytes the role of protein kinase C. Journal of Biological Chemistry, 285: 13748-13760.
[130]	Mangoni M E, Couette B, Bourinet E, Platzer J, Reimer D, Striessnig J, Nargeot J.2003. Functional role of L-type Cav1.3 Ca$^{2 + }$ channels in cardiac pacemaker activity. Proc Natl Acad Sci U S A, 100: 5543-5548.
[131]	Martins A, Ara'{u}jo J V, Reis R L, Neves N M.2017. Electrospun nanostructured scaffolds for tissue engineering applications. Nanomedicine, 2: 929.
[132]	Martins A M, Eng G, Caridade S G, Mano J O F, Reis R L, Vunjak-Novakovic G.2014. Electrically conductive chitosan/carbon scaffolds for cardiac tissue engineering. Biomacromolecules, 15: 635-643.
[133]	Massai D, Cerino G, Gallo D, Pennella F, Deriu M, Rodriguez A, Montevecchi F M, Bignardi C, Audenino A, Morbiducci U.2013. Bioreactors as engineering support to treat cardiac muscle and vascular disease. Journal of Healthcare Engineering, 4: 329-370.
[134]	McDonough P M, Glembotski C C.1992. Induction of atrial natriuretic factor and myosin light chain-2 gene expression in cultured ventricular myocytes by electrical stimulation of contraction. J Biol Chem, 267: 11665-11668.
[135]	McKinsey T A, Olson E N.1999. Cardiac hypertrophy: sorting out the circuitry. Curr Opin Genet Dev, 9: 267-274.
[136]	Mehrhof F B, Müller F U, Bergmann M W, Li P, Wang Y, Schmitz W, Dietz R, von Harsdorf R.2001. In cardiomyocyte hypoxia, insulin-like growth factor-I-induced antiapoptotic signaling requires phosphatidylinositol-3-OH- kinase- dependent and mitogen-activated protein kinase-dependent activation of the transcription factor cAMP response element-binding protein. Circulation, 104: 2088-2094.
[137]	Mesirca P, Torrente A G, Mangoni M E.2015. Functional role of voltage gated Ca(2+) channels in heart automaticity. Front Physiol, 6: 19.
[138]	Mihic A, Cui Z, Wu J, Vlacic G, Miyagi Y, Li S H, Lu S, Sung H W, Weisel R D, Li R K.2015. A conductive polymer hydrogel supports cell electrical signaling and improves cardiac function after implantation into myocardial infarct. Circulation, 132: 772.
[139]	Mihic A, Li J, Miyagi Y, Gagliardi M, Li S H, Zu J, Weisel R D, Keller G, Li R K.2014. The effect of cyclic stretch on maturation and 3D tissue formation of human embryonic stem cell-derived cardiomyocytes. Biomaterials, 35: 2798-2808.
[140]	Miklas J W, Nunes S S, Sofla A, Reis L A, Pahnke A, Xiao Y, Laschinger C, Radisic M.2014. Bioreactor for modulation of cardiac microtissue phenotype by combined static stretch and electrical stimulation. Biofabrication, 6: 024113.
[141]	Momtahan N, Sukavaneshvar S, Roeder B L, Cook A D.2015. Strategies and processes to decellularize and recellularize hearts to generate functional organs and reduce the risk of thrombosis. Tissue Eng Part B Rev, 21: 115-132.
[142]	Morgan K Y, Black L D 3rd.2014. It's all in the timing: Modeling isovolumic contraction through development and disease with a dynamic dual electromechanical bioreactor system. Organogenesis, 10: 317-322.
[143]	Morgan K Y, Black L D 3rd.2014. Mimicking isovolumic contraction with combined electromechanical stimulation improves the development of engineered cardiac constructs. Tissue Eng Part A, 20: 1654-1667.
[144]	Mozaffarian D, Benjamin E J, Go A S, Arnett D K, Blaha M J, Cushman M, de Ferranti S, Despr'{e}s J P, Fullerton H J, Howard V J, Huffman M D, Judd S E, Kissela B M, Lackland D T, Lichtman J H, Lisabeth L D, Liu S, Mackey R H, Matchar D B, McGuire D K, Mohler E R 3rd, Moy C S, Muntner P, Mussolino M E, Nasir K, Neumar R W, Nichol G, Palaniappan L, Pandey D K, Reeves M J, Rodriguez C J, Sorlie P D, Stein J, Towfighi A, Turan T N, Virani S S, Willey J Z, Woo D, Yeh R W, Turner M B.2015. Heart disease and stroke statistics--2015 update: A report from the American Heart Association. Circulation, 131: e29-322.
[145]	Mozaffarian D, Benjamin E J, Go A S, Arnett D K, Blaha M J, Cushman M, Das S R, de Ferranti S, Despr'{e}s J P, Fullerton H J, Howard V J, Huffman M D, Isasi C R, Jim'{e}nez M C, Judd S E, Kissela B M, Lichtman J H, Lisabeth L D, Liu S, Mackey R H, Magid D J, McGuire D K, Mohler E R 3rd, Moy C S, Muntner P, Mussolino M E, Nasir K, Neumar R W, Nichol G, Palaniappan L, Pandey D K, Reeves M J, Rodriguez C J, Rosamond W, Sorlie P D, Stein J, Towfighi A, Turan T N, Virani S S, Woo D, Yeh R W, Turner M B.2006. Heart disease and stroke statistics---2006 update a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 113: e85-e151.
[146]	Mummery C L, Zhang J, Ng E S, Elliott D A, Elefanty A G, Kamp T J.2012. Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. Circ Res, 111: 344-358.
[147]	Musialik-Lydka A, Sredniawa B, Pasyk S.2003. Heart rate variability in heart failure. Kardiol Pol, 58: 10-16.
[148]	Nadal-Ginard B, Mahdavi V.1989. Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. Journal of Clinical Investigation, 84: 1693.
[149]	Nava M M, Raimondi M T, Pietrabissa R.2012. Controlling self-renewal and differentiation of stem cells via mechanical cues. BioMed Research International, 2012: 797410.
[150]	Nune S K, Rama K S, Dirisala V R, Chavali M Y.2017. Chapter 11-Electrospinning of collagen nanofiber scaffolds for tissue repair and regeneration. Nanostructures for Novel Therapy, 281-311.
[151]	Nunes S S, Miklas J W, Liu J, Aschar-Sobbi R, Xiao Y, Zhang B, Jiang J, Mass'{e} S, Gagliardi M, Hsieh A, Thavandiran N, Laflamme M A, Nanthakumar K, Gross G J, Backx P H, Keller G, Radisic M.2013. Biowire: A platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat Methods, 10: 781-787.
[152]	Ott H C, Matthiesen T S, Goh S K, Black L D, Kren S M, Netoff T I, Taylor D A.2008. Perfusion-decellularized matrix: Using nature's platform to engineer a bioartificial heart. Nature Medicine, 14: 213-221.
[153]	Park H, Larson B L, Kolewe M E, Vunjak-Novakovic G, Freed L E.2014. Biomimetic scaffold combined with electrical stimulation and growth factor promotes tissue engineered cardiac development. Experimental Cell Research, 321: 297-306.
[154]	Passier R, Zeng H, Frey N, Naya F J, Nicol R L, McKinsey T A, Overbeek P,Richardson J A, Grant S R, Olson1 E N.2000. CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest, 105: 1395-1406.
[155]	Pietronave S, Zamperone A, Oltolina F, Colangelo D, Follenzi A, Novelli E, Diena M, Pavesi A, Consolo F, Fiore G B, Soncini M, Prat M.2013. Monophasic and biphasic electrical stimulation induces a precardiac differentiation in progenitor cells isolated from human heart. Stem Cells Dev, 23: 888-898.
[156]	Porter K E, Turner N A.2009. Cardiac fibroblasts: At the heart of myocardial remodeling. Pharmacology & Therapeutics, 123: 255-278.
[157]	Radisic M, Euloth M, Yang L, Langer R, Freed L E, Vunjak-Novakovic G.2003. High-density seeding of myocyte cells for cardiac tissue engineering. Biotechnol Bioeng, 82: 403-414.
[158]	Radisic M, Marsano A, Maidhof R, Wang Y, Vunjak-Novakovic G.2008. Cardiac tissue engineering using perfusion bioreactor systems. Nature Protocols, 3: 719-738.
[159]	Radisic M, Park H, Gerecht S, Cannizzaro C, Langer R, Vunjak-Novakovic G.2007. Biomimetic approach to cardiac tissue engineering. Philos Trans R Soc Lond B Biol Sci, 362: 1357-1368.
[160]	Radisic M, Yang L, Boublik J, Cohen R J, Langer R, Freed L E, et al.2004. Medium perfusion enables engineering of compact and contractile cardiac tissue. Am J Physiol Heart Circ Physiol, 286: H507-516.
[161]	Rangarajan S, Madden L, Bursac N.2014. Use of flow, electrical, and mechanical stimulation to promote engineering of striated muscles. Annals of Biomedical Engineering, 42: 1391-1405.
[162]	Reaume A G, de Sousa P A, Kulkarni S, Langille B L, Zhu D, Davies T C, Juneja S C, Kidder G M, Rossant J.1995. Cardiac malformation in neonatal mice lacking connexin43. Science, 267: 1831-1834.
[163]	Rockwood D N, Akins R E, Jr Parrag I C, Woodhouse K A, Rabolt J F.2008. Culture on electrospun polyurethane scaffolds decreases atrial natriuretic peptide expression by cardiomyocytes in vitro. Biomaterials, 29: 4783-4791.
[164]	Rodriguez A G, Han S J, Regnier M, Sniadecki N J.2011. Substrate stiffness increases twitch power of neonatal cardiomyocytes in correlation with changes in myofibril structure and intracellular calcium. Biophys J, 101, 2455-2464.
[165]	Roy M, Kusurkar T S, Maurya S K, Meena S K, Singh S K, Sethy N, et al.2013. Graphene oxide from silk cocoon: A novel magnetic fluorophore for multi-photon imaging. Biotech, 4: 67-75.
[166]	Sadoshima J, Jahn L, Takahashi T, Kulik T J, Izumo S.1992. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J Biol Chem, 267: 10551-10560.
[167]	Sadoshima J, Xu Y, Slayter H S, Izumo S.1993. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell, 75: 977-984.
[168]	Salameh A, Karl S, Djilali H, Dhein S, Janousek J, Daehnert I.2010a. Opposing and synergistic effects of cyclic mechanical stretch and alpha- or beta-adrenergic stimulation on the cardiac gap junction protein Cx43. Pharmacol Res, 62: 506-513.
[169]	Salameh A, Wustmann A, Karl S, Blanke K, Apel D, Rojas-Gomez D, Franke H, Mohr F W, Janousek J, Dhein S.2010b. Cyclic mechanical stretch induces cardiomyocyte orientation and polarization of the gap junction protein connexin43. Circ Res, 106: 1592-1602.
[170]	Sandow A.1952. Excitation-contraction coupling in muscular response. Yale J Biol Med, 25: 176-201.
[171]	Sano M, Fukuda K, Sato T, Kawaguchi H, Suematsu M, Matsuda S, Koyasu S, Matsui H, Yamauchi-Takihara K, Harada M, Saito Y, Ogawa S.2001. ERK and p38 MAPK, but not NF-kappaB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. Circ Res, 89: 661-669.
[172]	Sapir Y, Polyak B, Cohen S.2014. Cardiac tissue engineering in magnetically actuated scaffolds. Nanotechnology, 25: 014009.
[173]	Schaub M, Hefti M A, Harder B A, Eppenberger H M.1997. Various hypertrophic stimuli induce distinct phenotypes in cardiomyocytes. Journal of Molecular Medicine, 75: 901-920.
[174]	Sedmera, D, Reckova, M, deAlmeida, A, Sedmerova, M, Biermann, M, Volejnik, J, et al.2003. Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts. Am J Physiol Heart Circ Physiol, 284: H1152-1160.
[175]	Seki A, Nishii K, Hagiwara N.2015. Gap junctional regulation of pressure, fluid force, and electrical fields in the epigenetics of cardiac morphogenesis and remodeling. Life Sci, 129: 27-34.
[176]	Shachar, M, Benishti, N, Cohen, S.2012. Effects of mechanical stimulation induced by compression and medium perfusion on cardiac tissue engineering. Biotechnol Prog, 28: 1551-1559.
[177]	Shapira-Schweitzer K, Seliktar D.2007. Matrix stiffness affects spontaneous contraction of cardiomyocytes cultured within a PEGylated fibrinogen biomaterial. Acta Biomater, 3: 33-41.
[178]	Sharp W W, Simpson D G, Borg T K, Samarel A M, Terracio L.1997. Mechanical forces regulate focal adhesion and costamere assembly in cardiac myocytes. Am J Physiol, 273: H546-556.
[179]	Shimizu T, Yamato M, Akutsu T, Shibata T, Isoi Y, Kikuchi A, et al.2002. Electrically communicating three-dimensional cardiac tissue mimic fabricated by layered cultured cardiomyocyte sheets. Journal of Biomedical Materials Research, 60: 110-117.
[180]	Shin S R, Jung S M, Zalabany M, Kim K, Zorlutuna P, Kim S B, Nikkhah M, Khabiry M, Azize M, Kong J, Wan KT, Palacios T, Dokmeci MR, Bae H, Tang XS, Khademhosseini A.2013. Carbon-Nanotube-Embedded Hydrogel Sheets for Engineering Cardiac Constructs and Bioactuators. ACS Nano, 7: 2369-2380.
[181]	Shiojima I, Yefremashvili M, Luo Z, Kureishi Y, Takahashi A, Tao J, Rosenzweig A, Kahn C R, Abel E D, Walsh K.2002. Akt signaling mediates postnatal heart growth in response to insulin and nutritional status. Journal of Biological Chemistry, 277: 37670-37677.
[182]	Shyu K G, Wang B W, Lin C M, Chang H.2010. Cyclic stretch enhances the expression of toll-like receptor 4 gene in cultured cardiomyocytes via p38 MAP kinase and NF-kappaB pathway. J Biomed Sci, 17: 15.
[183]	Sigurdson W, Ruknudin A, Sachs F.1992. Calcium imaging of mechanically induced fluxes in tissue-cultured chick heart: role of stretch-activated ion channels. Am J Physiol, 262: H1110-1115.
[184]	Simmons C S, Petzold B C, Pruitt B L.2012. Microsystems for biomimetic stimulation of cardiac cells. Lab on a Chip, 12: 3235-3248.
[185]	Simpson D G, Sharp W W, Borg T K, Price R L, Samarel A M, Terracio L.1995. Mechanical regulation of cardiac myofibrillar structure. Ann N Y Acad Sci, 752: 131-140.
[186]	Simpson D G, Sharp W W, Borg T K, Price R L, Terracio L, Samarel A M.1996. Mechanical regulation of cardiac myocyte protein turnover and myofibrillar structure. Am J Physiol, 270: C1075-1087.
[187]	Smart S K, Cassady A I, Lu G Q, Martin D J.2006. The biocompatibility of carbon nanotubes. Carbon, 44: 1034-1047.
[188]	Solon J, Levental I, Sengupta K, Georges P C, Janmey P A.2007. Fibroblast adaptation and stiffness matching to soft elastic substrates. Biophys J, 93: 4453-4461.
[189]	Souders C A, Bowers S L, Baudino T A.2009. Cardiac fibroblast: the renaissance cell. Circ Res, 105: 1164-1176.
[190]	Stoppel W L, Hu D, Domian I J, Kaplan D L, Black L D 3rd.2015. Anisotropic silk biomaterials containing cardiac extracellular matrix for cardiac tissue engineering. Biomed Mater, 10: 034105.
[191]	Storm C.2005. Nonlinear Elasticity in Biological Gels. Nature, 435: 191-194.
[192]	Storm C, Pastore J J, MacKintosh F C, Lubensky T C, Janmey P A.2005. Nonlinear elasticity in biological gels. Nature, 435: 191-194.
[193]	Shin S R, Jung S M, Zalabany M, Kim K, Zorlutuna P, Kim S B, Nikkhah M, Khabiry M, Azize M, Kong J, Wan K T, Palacios T, Dokmeci M R, Bae H, Tang X S, Khademhosseini A.2013. Carbon-nanotube-embedded hydrogel sheets for engineering cardiac constructs and bioactuators. ACS Nano, 7: 2369-2380.
[194]	Sullivan K E, Black L D.2013. The role of cardiac fibroblasts in extracellular matrix-mediated signaling during normal and pathological cardiac development. J Biomech Eng, 135: 71001.
[195]	Sutton M G S J, Sharpe N.2000. Left ventricular remodeling after myocardial infarction. Circulation, 101: 2981-2988.
[196]	Takahashi N, Seko Y, Noiri E, Tobe K, Kadowaki T, Sabe H, et al.1999. Vascular endothelial growth factor induces activation and subcellular translocation of focal adhesion kinase (p125FAK) in cultured rat cardiac myocytes. Circ Res, 84: 1194-1202.
[197]	Tallawi M, Rai R, Boccaccini A R, Aifantis K E.2015. Effect of substrate mechanics on cardiomyocyte maturation and growth. Tissue Eng Part B Rev, 21: 157-165.
[198]	Tandon N, Cannizzaro C, Chao P H, Maidhof R, Marsano A, Au H T, Radisic M, Vunjak-Novakovic G.2009. Electrical stimulation systems for cardiac tissue engineering. Nat Protoc, 4: 155-173.
[199]	Tandon N, Marsano A, Maidhof R, Wan L, Park H, Vunjak-Novakovic G.2011. Optimization of electrical stimulation parameters for cardiac tissue engineering. J Tissue Eng Regen Med, 5: e115-125.
[200]	Tang Y, Hong Y Z, Bai H J, Wu Q, Chen C D, Lang J Y, Oheler K R B, Yang H T.2016. Plant homeo domain finger protein 8 regulates mesodermal and cardiac differentiation of embryonic stem cells through mediating the histone demethylation of pmaip1. Stem Cells, 34: 1527-1540.
[201]	Toh W S, Lim T C, Kurisawa M, Spector M.2012. Modulation of mesenchymal stem cell chondrogenesis in a tunable hyaluronic acid hydrogel microenvironment. Biomaterials, 33: 3835-3845.
[202]	Trappmann B, Gautrot J E, Connelly J T, Strange D G, Li Y, Oyen M L, Stuart M A C, Boehm H, Li B J, Vogel V, Spatz J P, Watt F M, Huck W T S.2012. Extracellular-matrix tethering regulates stem-cell fate. Nature Materials, 11: 642-649.
[203]	Tse J R, Engler A J.2010. Preparation of hydrogel substrates with tunable mechanical properties. Curr Protoc Cell Biol, Chapter 10, Unit 10.16, doi:10.1002/0471143030.cb1016s47.
[204]	Tse J R, Engler A J.2011. Stiffness gradients mimicking in vivo tissue variation regulate mesenchymal stem cell fate. PLoS One, 6: e15978.
[205]	Tu S, Chi N C.2012. Zebrafish models in cardiac development and congenital heart birth defects. Differentiation, 84: 4-16.
[206]	Tung L, Parikh S S.1991. Cardiac mechanics at the cellular level. J Biomech Eng, 113: 492-495.
[207]	Van Wamel J, Ruwhof C, Van der Valk-Kokshoorn E, Schrier P, Van der Laarse A.2000. Rapid gene transcription induced by stretch in cardiac myocytes and fibroblasts and their paracrine influence on stationary myocytes and fibroblasts. Pfl"{ugers Archiv}, 439: 781-788.
[208]	Vandenburgh H H, Solerssi R, Shansky J, Adams J W, Henderson S A.1996. Mechanical stimulation of organogenic cardiomyocyte growth in vitro. American Journal of Physiology-Cell Physiology, 270: C1284-C1292.
[209]	Vanichapol, T, Leelawat, K, Hongeng, S.2015. Hypoxia enhances cholangiocarcinoma invasion through activation of hepatocyte growth factor receptor and the extracellular signalregulated kinase signaling pathway. Mol Med Rep, 12: 3265-3272.
[210]	Veerman C C, Kosmidis G, Mummery C L, Casini S, Verkerk A O, Bellin M.2015. Immaturity of human stem-cell-derived cardiomyocytes in culture: fatal flaw or soluble problem? Stem Cells Dev, 24: 1035-1052.
[211]	Vincent L G, Engler A J.2013. Stem cell differentiation: Post-degradation forces kick in. Nat Mater, 12: 384-386.
[212]	Volberg W A, Koci B J, Su W, Lin J, Zhou J.2002. Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. J Pharmacol Exp Ther, 302: 320-327.
[213]	Vunjak-Novakovic G, Tandon N, Godier A, Maidhof R, Marsano A, Martens T P, Radisic M.2010. Challenges in cardiac tissue engineering. Tissue Eng Part B Rev, 16: 169-187.
[214]	Walker L A, Medway A M, Walker J S, Cleveland J C, Jr Buttrick P M.2011. Tissue procurement strategies affect the protein biochemistry of human heart samples. J Muscle Res Cell Motil, 31: 309-314.
[215]	Wang B, Wang G, To F, Butler J R, Claude A, McLaughlin R M, Williams L N, de Jongh Curry A L, Liao J.2013. Myocardial scaffold-based cardiac tissue engineering: application of coordinated mechanical and electrical stimulations. Langmuir, 29: 11109-11117.
[216]	Wang G, McCain M L, Yang L, He A, Pasqualini F S, Agarwal A,Yuan H, Jiang D, Zhang D, Zangi L, Geva J, Roberts A E, Ma Q, Ding J, Chen J, Wang D Z, Li K, Wang J, Wanders R J, Kulik W, Vaz F M, Laflamme M A, Murry C E, Chien K R, Kelley R I, Church G M, Parker K K, Pu W T.2014. Modeling the mitochondrial cardiomyopathy of Barth syndrome with iPSC and heart-on-chip technologies. Nature Medicine, 20: 616.
[217]	Wang Q, Jian M, Wang C, Zhang Y.2017. Carbonized silk nanofiber membrane for transparent and Sensitive electronic skin. Advanced Functional Materials, 27: 1605657.
[218]	Wen Q, Janmey P A.2013. Effects of non-linearity on cell-ECM interactions. Experimental Cell Research, 319: 2481-2489.
[219]	Xia Y, Buja L M, McMillin J B.1998. Activation of the cytochrome c gene by electrical stimulation in neonatal rat cardiac myocytes. Role of NRF-1 and c-Jun. J Biol Chem, 273: 12593-12598.
[220]	Xia Y, McMillin J B, Lewis A, Moore M, Zhu W G, Williams R S, Kellems R E.2000. Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene. J Biol Chem, 275: 1855-1863.
[221]	Xiao Y, Zhang B, Liu H, Miklas J W, Gagliardi M, Pahnke A, Thavandiran N, Sun Y, Simmons C, Keller G, Radisic M.2014. Microfabricated perfusable cardiac biowire: A platform that mimics native cardiac bundle. Lab on a Chip, 14: 869-882.
[222]	Xiong Q M, Cao Q, Zhou Q Q, Xie J Y, Shen Y, Wan R, Yu J H, Yan S J, Marian AliJ, Hong K.2015. Arrhythmogenic cardiomyopathy in a patient with a rare loss-of-function KCNQ1 mutation. J Am Heart Assoc, 4: e001526.
[223]	Yanazume T, Hasegawa K, Wada H, Morimoto T, Abe M, Kawamura T, Sasayama S.2002. Rho/ROCK pathway contributes to the activation of extracellular signal-regulated kinase/GATA-4 during myocardial cell hypertrophy. J Biol Chem, 277: 8618-8625.
[224]	Ye F, Yuan F, Li X, Cooper N, Tinney J P, Keller B B.2013. Gene expression profiles in engineered cardiac tissues respond to mechanical loading and inhibition of tyrosine kinases. Physiol Rep, 1: e00078.
[225]	Ye K Y, Black L D 3rd.2011. Strategies for tissue engineering cardiac constructs to affect functional repair following myocardial infarction. J Cardiovasc Transl Res, 4: 575-591.
[226]	You J O, Rafat M, Ye G J, Auguste D T.2011. Nanoengineering the heart: Conductive scaffolds enhance connexin 43 expression. Nano Letters, 11: 3643-3648.
[227]	Young J, Tuler J, Braden R, Shup-Magoffin P, Christman K, Engler A.2012. Dynamic hyaluronic acid hydrogels for cardiac therapy are biocompatible and degradable. Journal of Tissue Engineering and Regenerative Medicine}, 6: 192-192
[228]	Young J L, Engler A J.2011. Hydrogels with time-dependent material properties enhance cardiomyocyte differentiation in vitro. Biomaterials, 32: 1002-1009.
[229]	Zeidan A, Javadov S, Karmazyn M.2006. Essential role of Rho/ROCK-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes. Cardiovasc Res, 72: 101-111.
[230]	Zentilin L, Puligadda U, Lionetti V, Zacchigna S, Collesi C, Pattarini L, Ruozi G, Camporesi S, Sinagra G, Pepe M, Recchia F A, Giacca M.2010. Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction. FASEB J, 24: 1467-1478.
[231]	Zhang S J, Truskey G A, Kraus W E.2007. Effect of cyclic stretch on $eta $1D-integrin expression and activation of FAK and RhoA. American Journal of Physiology-Cell Physiology, 292: C2057-C2069.
[232]	Zhao H, Yu Y, Wu X, Liu S, Liu B, Du J, Li B, Jiang L H, Feng X Q.2017. A role of BK channel in regulation of Ca$^{2 + }$ channel in ventricular myocytes by substrate stiffness. Biophysical Journal, 112: 1406-1416.
[233]	Zhao S, Xu Z, Wang H, Reese B E, Gushchina L V, Jiang M, Agarwal P, Xu J S, Zhang M J, Shen R L, Liu Z G, Weisleder N, He X M.2016. Bioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction. Nat Commun, 7: 13306.
[234]	Zhao Y W, Zhu T, Zhang X Y, Wang Q Y, Zhang J Y, Ji W B, Ma Y F.2015. Splicing factor 2/alternative splicing factor contributes to extracellular signalregulated kinase activation in hepatocellular carcinoma cells. Mol Med Rep, 12: 3890-3894.
[235]	Zhou J, Chen J, Sun H, Qiu X, Mou Y, Liu Z, Zhao Y, Li X, Han Y, Duan C, Tang R, Wang C, Zhong W, Liu J, Luo Y, Mengqiu Xing M, Wang C.2014. Engineering the heart: Evaluation of conductive nanomaterials for improving implant integration and cardiac function. Scientific Reports, 4.
[236]	Zimmermann W H, Fink C, Kralisch D, Remmers U, Wei J, Eschenhagen T.2000. Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes. Biotechnol Bioeng, 68: 106-114.
[237]	Zimmermann W H, Schneiderbanger K, Schubert P, Didie M, Munzel F, Heubach J F, Kostin S, Neuhuber W L, Eschenhagen T.2002. Tissue engineering of a differentiated cardiac muscle construct. Circ Res, 90: 223-230.