**1. Introduction**

**Cell-ECM interactions** Fundamental to the success of using biomaterials in medical and health care applications, is the understanding of their interactions with biological tissues and systems. First step towards this end is the elucidation of cell-ECM interactions, which has attracted considerable interest in recent decade. Cellular decision-making process is driven by the internal genetic program and external factors comprising primarily other cells and extracellular matrix (ECM) via soluble factors and direct physical connections such as focal adhesion [1, 2]. Three key features of ECM have been identified of great significance in affecting cells, namely, chemical and biological composition, dimensionality (two- vs. threedimensional), and physical properties [3-6]. These features can be sensed by cells via cell-ECM linkages, and the resulting signals subsequently follow intracellular pathways and trigger a cascade of events leading to alterations in gene expression and manifestation in phenotype. In contrast to the long recognized chemical composition and adhesive character‐ istics of the ECM, physical cues including topography, pore size, geometric patterns, and mechanical stiffness and their significance has just started being appreciated [7-10]. Whilst characteristics of ECM have profound effect on cells, cells may also actively exert impact on ECM by secretion of soluble factors or modify properties of ECM, or contribute to maintain‐ ing integrity or properties of ECM. At a larger scale, biological systems may actively interact with biomaterials to maintain or re-establish homeostasis.

**Dynamic aspect of ECM** To date, the majority of the substrates employed in cellular studies and other biological investigations have been of fixed mechanical stiffness and/or adhesive properties throughout cell culture. There is an increasing realization that a cell's microenvir‐ onment is dynamic and changing with time [11-13]. It is the case in both pathologic and nor‐ mal tissues, at the tissue-implant interfaces, and during development and aging [14],

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especially for load-bearing and mechanically active tissues (e.g., heart, cartilage, lung) [15]. Not only do these changes naturally occur, but there are also benefits associated with them from a tissue engineering viewpoint, as highlighted in the series of discussions in the March 2005 issue of MRS (Materials Research Society) Bulletin [16, 17] and later studies. Whitesides [18] and Mrksich [19] and their coworkers among a number of investigators pioneered the work on engineering cell growth by using dynamic substrates. Their work and later reports on differential cell responses to materials with different properties suggest that it is benefi‐ cial for biomaterials to have controlled changing properties [20]. These facts make it very de‐ sirable for the bio-mimetic materials to have the capability of undergoing controlled remodeling with respect to time. They also raised caution in interpretation of the observa‐ tions made from the majority of the biological studies, where properties of the substrates (e.g., culture flask, Petri dish, and hydrogels) remain unchanged throughout the process.

**The scope of this work** A significant number of reviews are available on the changes in soluble factors of ECM that may affect cellular behavior (e.g., [21]) and particularly on the changing environment in bioreactors [22] (e.g., nutrients concentration, oxygen level, tem‐ perature). Thus, they are not covered in this review. Moreover, flow conditions and the re‐ sulting traction forces, and their effect on certain cell types including blood cells (i.e., endothelial cells and red blood cells) have also been intensively reviewed and hence are not discussed here. This is also the case for mechanical forces, strain and stress applied directly to the cells (e.g., [23, 24]) in load-bearing tissues such as bone, cartilage and lung (for refer‐ ence, see, e.g., [25-27] ).

Therefore, this review is focused on the latest studies and current knowledge of two- or three- dimensional substrates with changing or dynamic mechanical and adhesive proper‐ ties, design and conditions to trigger and achieve designed dynamics, and the impact of insitu change of these properties on cell behavior, which provides guideline for design of biomaterials for their applications in medical and healthcare applications. Note that me‐ chanical stiffness and elastic modulus were used interchangeably in this work.
