© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 Biotechnol. J. 2012, 7 DOI 10.1002/biot.201200149 www.biotechnology-journal.com 1 Introduction The challenge of realizing the promise of stem cells to pro- vide cell models and therapeutic cell populations for re- generative medicine is creating demand for increasingly accurate cellular environmental control and enhanced ex- perimental data throughput. Concurrently, the systems biology era is catalyzing change in analytical systems to- ward high-content/high-throughput detection, and/or multiplexing of environments to increase experimental parameter space. Both of these developments are driving an evolution of cell culture platforms away from legacy cultureware (multi-well tissue culture plates, tissue cul- ture flasks, petri dishes, etc.) toward miniaturized, highly integrated, “smart” platforms. Indeed, the high-through- put, small sample volume, and massive replication requirements of these new technologies dictate the in- evitability of miniaturization. Utilizing micro- and nano- fabrication strategies developed originally for the semi- conductor industry, increasing numbers of next-genera- tion technologies are now based on enabling microtech- nologies, and are beginning to simplify the way in which complex biological problems are being tackled [1]. These next-generation, miniaturized technologies of- fer leverage of several lengthscale-dependent physical phenomena: laminar fluid flow, diffusion-based fluid mix- ing, fluidic resistance, surface tension, closed culture vol- umes, and large surface-area-to-volume ratios [2]. Such phenomena provide opportunities for the accurate Review Arrayed cellular environments for stem cells and regenerative medicine Drew M. Titmarsh 1 , Huaying Chen 1 , Ernst J. Wolvetang 1 and Justin J. Cooper-White 1,2 1 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, Australia 2 School of Chemical Engineering, The University of Queensland, St. Lucia, Australia The behavior and composition of both multipotent and pluripotent stem cell populations are ex- quisitely controlled by a complex, spatiotemporally variable interplay of physico-chemical, extra- cellular matrix, cell–cell interaction, and soluble factor cues that collectively define the stem cell niche. The push for stem cell-based regenerative medicine models and therapies has fuelled demands for increasingly accurate cellular environmental control and enhanced experimental throughput, driving an evolution of cell culture platforms away from conventional culture formats toward integrated systems. Arrayed cellular environments typically provide a set of discrete exper- imental elements with variation of one or several classes of stimuli across elements of the array. These are based on high-content/high-throughput detection, small sample volumes, and multi- plexing of environments to increase experimental parameter space, and can be used to address a range of biological processes at the cell population, single-cell, or subcellular level. Arrayed cellu- lar environments have the capability to provide an unprecedented understanding of the molecu- lar and cellular events that underlie expansion and specification of stem cell and therapeutic cell populations, and thus generate successful regenerative medicine outcomes. This review focuses on recent key developments of arrayed cellular environments and their contribution and potential in stem cells and regenerative medicine. Keywords: Extracellular matrix · Microarrays · Single cell · Soluble factors · Stem cells Correspondence: Prof. Justin J. Cooper-White, Australian Institute for Bio- engineering and Nanotechnology, Building 75, Corner Cooper and College Roads, The University of Queensland, St. Lucia QLD 4072, Australia E-mail: j.cooperwhite@uq.edu.au Abbreviations: ECM, extracellular matrix; hESC, human embryonic stem cell; mESC, mouse embryonic stem cell; MSC, mesenchymal stem cell; NSC, neural stem cell Received 23 MAY 2012 Revised 02 JUL 2012 Accepted 17 JUL 2012