Experimental models of physiological processes enable investiga-tions of complex cellular dynamics in controlled conditions. Dynamic mechanical forces that result from tissue deformation or fluid flow are key factors influencing cellular fate in living tissues. In this chapter, we review recent efforts in our research group to apply dynamic mechanical forces to cultured cells and tissue constructs. We describe microfabricated platforms for cell stretching, biomaterial compression, and cell co-culture under fluid flow conditions. We discuss the benefits of arrayed and microfabricated platforms and demonstrate their utility for experimental mechanobiology. These physiologically relevant cell culture strategies enable investigations of processes for which in vivo access is limited. Their arrayed and scalable formats increase
experimental throughput and show promise for drug screening that is predictive of in vivo results. 13.1 IntroductionDynamic mechanical forces are ubiquitous physiological and pathological regulators of cell behavior but they are not recapitulated in traditional static cell culture platforms. Although traditional culture platforms lack mechanically dynamic aspects of in vivo environments, they often include arrayed formats in which many independent culture conditions are varied systematically (Fig. 13.1a). These platforms enable high-throughput screening (HTS) of cell responses to soluble factors that are added to the culture media . HTS has become a central part of the drug discovery process, but the fraction of seemingly promising HTS leads that result in clinically effective therapeutics is notoriously low . For this reason, emphasis is shifting from developing higher screening throughput capabilities toward improving the content and quality of such biological test systems [2,3]. Improved in vitro models are sought to ensure that HTS assays are relevant and predictive of in vivo results [2,4]. These will include applicationspecific co-culture of multiple cell types, fluid flow, and a variety of dynamic mechanical forces that are found in the body.In contrast to array-based static culture platforms, customized “mechano-culture” systems that apply fluid flow and dynamic mechanical forces to cells and tissues have relatively low experi-mental throughput . Hence, these technologies typically enable researchers to replicate dynamic aspects of physiological or pathological processes while sacrificing the advantages associated with high-throughput experimental platforms. This limitation is significant because combinatorial experiments are required to examine the effects of mechanical loading parameters and their modulation of other (e.g., soluble) factors. Although conventional macroscale techniques require a large number of cells per set of environmental conditions, emerging array-based mechano-culture platforms (Fig. 13.1b) are well suited to study the response of rare cell types to combinatorially manipulated mechanobiological cues. As outlined in Fig. 13.1c, cells and tissues are subjected to a variety of mechanical forces that include hydrostatic pressure, fluid shear, and mechanical strain in shear, tension, and compression. Emerging
mechanically active culture platforms apply these forces to cells and tissues to improve the physiological relevance of such culture systems, with the potential for high experimental throughput .