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Integrated Micro/Nanoengineered Functional Biomaterials for Cell Mechanics and Mechanobiology: REVIEW a Materials Perspective

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Integrated Micro/Nanoengineered Functional Biomaterials for Cell Mechanics and Mechanobiology: REVIEW a Materials Perspective www.advmat.de www.MaterialsViews.com Integrated Micro/Nanoengineered Functional Biomaterials for Cell Mechanics and Mechanobiology: REVIEW A Materials Perspective Yue Shao and Jianping Fu * which actively signals to cells to regulate The rapid development of micro/nanoengineered functional biomaterials in their fate and function. The microenviron- the last two decades has empowered materials scientists and bioengineers mental factors, including cell-cell inter- to precisely control different aspects of the in vitro cell microenvironment. actions, soluble factors such as oxygen tension and growth factors, and adhesive Following a philosophy of reductionism, many studies using synthetic and biophysical interactions between functional biomaterials have revealed instructive roles of individual extra- cells and extracellular matrix (ECM), are cellular biophysical and biochemical cues in regulating cellular behaviors. all important for regulation of cellular Development of integrated micro/nanoengineered functional biomaterials behaviors. Cells and the surrounding to study complex and emergent biological phenomena has also thrived microenvironment can also dynamically infl uence each other during normal devel- rapidly in recent years, revealing adaptive and integrated cellular behaviors opment, tissue homeostasis and repair, closely relevant to human physiological and pathological conditions. Working and progression of diseases through their at the interface between materials science and engineering, biology, and reciprocal biochemical and biophysical medicine, we are now at the beginning of a great exploration using micro/ interactions. [ 1–6 ] Thus, a detailed appre- nanoengineered functional biomaterials for both fundamental biology study hension and understanding of cell-micro- and clinical and biomedical applications such as regenerative medicine and environment interactions is critical for both advancing basic biology knowledge drug screening. In this review, an overview of state of the art micro/nanoengi- and improving human health through neered functional biomaterials that can control precisely individual aspects of regenerative medicine, developing in vitro cell-microenvironment interactions is presented and they are highlighted as human disease models and other thera- well-controlled platforms for mechanistic studies of mechano-sensitive and peutic and diagnostic research. -responsive cellular behaviors and integrative biology research. The recent A critical component for studying cell-microenvironment interactions is exciting trend where micro/nanoengineered biomaterials are integrated into to create, characterize and manipulate miniaturized biological and biomimetic systems for dynamic multiparametric dynamic microenvironmental cues in vitro microenvironmental control of emergent and integrated cellular behaviors is down to a cellular (micrometer) and sub- also discussed. The impact of integrated micro/nanoengineered functional cellular (nanometer) length scale. Over the biomaterials for future in vitro studies of regenerative medicine, cell biology, last two decades, different micro/nanoen- as well as human development and disease models are discussed. gineering tools and synthesis methods for functional biomaterials have been success- fully developed and applied for biological and biomedical research, establishing a 1 . Introduction rich toolbox of diverse micro/nanoengineered functional bio- materials for dynamic generation, modulation, stimulation of Cell populations within the human body are established, main- various extracellular biochemical and biophysical signals at tained and regulated within the adjacent microenvironment, a subcellular resolution to in vitro cultured cells. [ 7–12 ] These micro/nanoengineered functional biomaterials have particu- larly helped reveal independent effects of individual biophysical Y. Shao, Prof. J. Fu signals of cell microenvironment, such as cell shape and geom- Integrated Biosystems and Biomechanics Laboratory Department of Mechanical Engineering etry, ECM rigidity and topography, extracellular forces, and University of Michigan , Ann Arbor , 48109 , USA spatial organization of adhesive proteins, in regulating cellular E-mail: [email protected] behaviors such as cell migration, proliferation and survival, and Prof. J. Fu differentiation. [ 13–23 ] The rapid development of micro/nanoen- Department of Biomedical Engineering gineered functional biomaterials coupled with high-throughput University of Michigan Ann Arbor , 48109 , USA screening tools and the concomitant discoveries of cellular mechano-sensitive and -responsive behaviors have culminated DOI: 10.1002/adma.201304431 in recent excitements in mechanobiology, [ 9,20,24,25 ] regenerative 1494 wileyonlinelibrary.com © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2014, 26, 1494–1533 www.advmat.de www.MaterialsViews.com REVIEW medicine, [ 14,26,27 ] physical oncology, [ 17,18 ] and cellular heteroge- neity at the single-cell level. [ 28–32 ] Yue Shao is a PhD candi- So far, many micro/nanoengineered functional biomaterials date in the Department of have been demonstrated useful for studying how individual Mechanical Engineering at biophysical signals of cell microenvironment can regulate cel- the University of Michigan, lular behaviors in vitro. However, to fully understand the func- Ann Arbor. He received his tional role of cell-microenvironment interactions in regulating B.E. and M.E. degrees from cell function, it is important to take into account the three- Tsinghua University, China, in dimensional (3D), multiparametric nature of in vivo cell micro- 2008 and 2011, respectively. environment. [ 33–37 ] The recent exciting trend of developing His current research inter- integrated miniaturized biological and biomimetic systems for ests include biomechanics dynamic multiparametric microenvironmental control to regu- of cellular mechanosensing late emergent and integrated cellular behaviors has started to and mechanotransduction of illustrate the impact of integrated micro/nanoengineered func- extracellular physical cues, stem cell mechanobiology, and tional biomaterials for future research on regenerative medi- micro/nanoengineering ex vivo cell microenvironment for cine, cell biology, human normal development and diseases, as regenerative medicine. well as drug development. In this review, we fi rst present an overview of state of the Dr. Jianping Fu has been art micro/nanoengineered functional biomaterials developed an assistant professor of in the last two decades, which can be utilized to control and Mechanical and Biomedical modulate various biophysical aspects of local cell microenvi- Engineering at the University ronment in vitro. In addition to their technical improvements, of Michigan, Ann Arbor these micro/nanoengineered functional biomaterials have also since 2009. Dr. Fu received been utilized for studying mechano-sensitive and -responsive his Ph. D. degree from the cellular behaviors and underlying mechanotransduction mech- Massachusetts Institute anisms. We will then focus on reviewing the recent progress of Technology in 2007. He in integrating micro/nanoengineered functional biomaterials was an American Heart to develop miniaturized biological and biomimetic systems for Association Postdoctoral dynamic multiparametric microenvironmental control of emer- Fellow at the University of gent and integrated cellular behaviors. We will conclude with Pennsylvania from 2007 to 2009. Dr. Fu’s research focuses remarks and future outlook. There are other recent informative on mechanobiology, stem cell biology, and applying reviews published elsewhere that provide detailed discussions microfabrication technology to elucidate biosystems at specifi cally on micro/nanofabrication techniques for biomed- molecular and cellular levels. ical engineering, [ 8,38–43 ] synthetic biomaterials as instructive extracellular microenvironments for tissue engineering and [26,44–47] regenerative medicine, engineering 3D microenviron- [33,34,39,48] ments for studying tissue physiology in vitro, and and technologies and explain critical steps or technical infor- mechanotransduction mechanisms in development and dis- [2–5,18,20,24,49–53] mation associated with them. We will summarize and discuss eases. Readers interested in discussions in these their applications in studying mechano-sensitive and -respon- specifi c topics are referred to these excellent reviews. sive cellular properties. 2 . Toolbox of Micro/Nanoengineered Functional 2.1 . Micro/Nanoengineered Synthetic Substrates Biomaterials with Tunable Properties In this section, we will present a review of state of the art 2.1.1 . Engineering Micro/Nanoscale Surface Topography micro/nanoengineered functional biomaterials developed in the last two decades that have allowed researchers to probe In vivo, cells reside in the ECM with complex 3D architectures and characterize cell-microenvironment interactions as well ranging from highly discrete and porous fi brous networks to as to obtain insights on mechano-sensitive and -responsive continuous basement membranes, representing a vast topo- cellular properties in response to individual extracellular bio- graphical diversity of the local cell microenvironment. The physical cues, including cell shape and geometry, ECM rigidity characteristic size dimension of topographical features at the and topography, extracellular forces, and spatial organization cell-ECM interface can range from tens (such as fi brillar col- of adhesive proteins.
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