Convergence of Highly Resolved and Rapid Screening Platforms with Dynamically Engineered, Cell Phenotype-Prescriptive Biomaterials

Curr Pharmacol Rep (2016) 2:142–151 DOI 10.1007/s40495-016-0057-y DRUG DELIVERY (A HATEFI, SECTION EDITOR) Convergence of Highly Resolved and Rapid Screening Platforms with Dynamically Engineered, Cell Phenotype-Prescriptive Biomaterials Neal K. Bennett 1 & Anandika Dhaliwal 1 & Prabhas V. Moghe 1,2 Published online: 18 March 2016 # Springer International Publishing AG 2016 Abstract Biophysical and biochemical cues from the cellular microenvironment initiate intracellular signaling through cellular membrane receptors and trigger specific cell developmental programs. Extracellular substrates and matrix scaffolds engineered to mimic cell’s native physiological environment must incorporate the multifactorial parameters (composition, micro and nanoscale organization, and topography) of the extracellular matrix as well as the dynamic nature of the matrix. The design of such engineered biomaterials is challenged by the inherent complexity and dynamic nature of the cellextracellular matrix reciprocity, while the validation of robust microenvironments requires a deeper, higher content phenotypic resolution of cell-matrix interactions alongside a rapid screening capability. To this end, high-throughput platforms are integral to facilitating the screening and optimization of complex engineered microenvironments for directing desired cell developmental pathway. This review highlights the recent advances in biomaterial platforms that present dynamic cues and enable high throughput screening of cell’s response to a combination of micro-environmental factors. We also address some newer techniques involving high-content image informatics to elucidate emergent cellular behaviors with a focus on stem cell regenerative endpoints. This article is part of the Topical Collection on Drug Delivery Neal K. Bennett and Anandika Dhaliwal contributed equally to this work. * Prabhas V. Moghe 1 Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 088534, USA 2 Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, USA Keywords High throughput screening . High-content imaging . Extracellular matrix . Dynamic scaffolds Introduction The primary goal of regenerative medicine is to recreate human tissues, either to increase understanding of human physiology or pathophysiology, to screen for effective therapeutics, or to replace lost tissue. Key to tissue regeneration or replacement is the effective combination of relevant lineage-specific cells and a supportive biomaterial. Biomaterials used in tissue engineering approaches play a major role of influencing a wide range of cell behavior, including cell viability, differentiation, motility, and apoptosis. These changes in cell behavior are often sensitively modulated by changes in the biomaterial’s properties like topography, stiffness, and material chemistry. Most studies to date have examined cellular response to alterations in specific individual biomaterial parameters [1, 2]. Given the multi-factorial nature of physiologic extracellular matrices, several recent reports indicate that the most favorable cell-niche incorporates a combination of biologically active, microenvironmental cues [3–5]. Further, prevalent studies tend to focus on studying the influence of static topographical, chemical, or mechanical cues on cell behavior. However, dynamic matrix changes are important to a number of biological processes including tissue formation, regeneration, and pathophysiological processes such as tumor growth [6–8]. Therefore, there exists a need to develop biomaterial platforms that can address the limitations in previously developed biomaterials by firstly allowing evaluation of dynamic cues, and secondly by facilitating screening of a combination of cues. Recent advances in stimuli-responsive materials [9–11], as well as the increased recognition of the need to combine programmable cues with dynamic cell behaviors, have led to the Curr Pharmacol Rep (2016) 2:142–151 development of a number of highly innovative biomaterial configurations. Additionally, technological developments such as advances in nanoscale and microsystem technologies have also enabled the fabrication of novel high-throughput platforms to screen varied topographies and geometries [12–14], or to identify an optimal combination of bioactive cues [15, 16]. These high-throughput biomaterial platforms specifically seek to accelerate the development of materials for cell-based applications by designing materials that elicit desired cell behavior, through rapid and parallel screening of cell behaviors in response to a wide range of potentially relevant microenvironmental cues and substrate characteristics. Such platforms have many salient features that include reproducibility, suitability to automation, usage of lesser cells and reagents for screening, and cost effectiveness. Here, we review a newer generation of biomaterials, which leverage the influence of topography, stiffness, and chemistry on cell behavior in innovative ways, particularly focusing on dynamic and high-throughput platforms, as well as highcontent analysis approaches to study cells on these platforms (Fig. 1). Dynamic Platforms to Model-Changing Cell Environments Functional tissue engineering requires a precise control over the spatio-temporal single-cell and multicellular organization and lineage-specific behavior through biomaterial-induced cues. This precise control requires the use of materials that combine desirable mechanical, topographical, and chemical cues, and allow for manipulation of these attributes to mimic the dynamic cell environment. Much of this work has been accomplished through developments with stimuli responsive materials, which change form in response to an external stimuli, such as mechanical strain, light, or change in temperature or pH [17, 18]. Previous studies have used these materials to investigate the effects of changing topography on cell shape, which is mediated by integrin receptor redistribution and cytoskeletal remodeling and ultimately governs cell functions including proliferation, differentiation, or death [19, 20]. However, only in recent studies have efforts been made to decouple effects of dynamic strain and deformation on cellular shape. For example, Pholpabu et al. [21] used a pre-strained elastomeric substrate, SiO2-coated polydimethylsiloxane (PDMS), to produce a substrate capable of alternating between three distinct topographies [21]. The alternation between flat, parallel wavy, or perpendicular wavy grooves was induced in less than 3 s, and by mechanical strain values lower than 3.5 %, which is the threshold strain detected to date by mammalian cells.. The authors observed rapid and robust changes in fibroblast morphology when cultured on substrates switched from flat to wavy features, but no significant changes 143 to gross steady-state morphology on substrates switched from flat to wavy (...truncated)