Special Issue: Biomaterials in Mechanobiology

Cells respond to a wide range of cues from their extracellular environment. Often we focus on biochemical signals such as growth factors or adhesion ligands; however, recent research has expanded our understanding of the importance of biophysical signals from the environment, including the mechanics of the surrounding extracellular matrix or extrinsic signals such as fluid flow and mechanical deformation.[1] The field of mechanobiology has emerged to explore the translation of these forces into cellular signaling and responses – behaviors that may be important in cellular homeostasis, during tissue development, in the evolution of disease (e.g., fibrosis, cancer), or as a handle to control cell function and differentiation.[2] Biomaterials are contributing greatly to the field of mechanobiology, as platforms that can be used to probe how cells respond to varied and changing mechanical signals. Specifically, biomaterials with tuned mechanical properties can act as substrates for cell culture, as models of extracellular matrices, or can be processed into microfluidic platforms and as in vitro tissue models (Figure 1). Early studies exploited simple wrinkling substrates or soft hydrogels where differential cell behavior could be observed based on substrate mechanics; however, the complexity of biomaterial systems has evolved as far as organ-on-a-chip models where fluid flow and 3D matrix properties can be tailored to biological questions encompassing multiple cell types, including organoids.[3] Such platforms allow us to better understand cell behavior in the context of physical forces in health and disease, particularly towards the identification of new understanding and therapeutic targets. The goal of this special issue on Biomaterials in Mechanobiology is to review relevant areas within the field, as well as to highlight emerging concepts that explore biomaterials in the context of mechanobiology. The special issue contains 9 review articles and 6 original research articles across a range of topics related to mechanobiology. As a field, there is still much to be learned on how the biochemical and biophysical properties of the surrounding microenvironment influence cells and how new tools can be developed to probe these behaviors. For example, we are still uncovering how material properties, such as viscoelasticity and dynamic properties, influence cells. Salmeron-Sanchez and co-workers review this evolving area, including various mathematical models and viscoelastic platforms that are being used to probe cell mechanosensing in 2D and 3D (see article https://doi.org/10.1002/adhm.201901259). It is also important to measure the forces that cells place on their surroundings to better understand this interface. Sniadecki and colleagues review various techniques that are being developed to measure cellular forces (see article https://doi.org/10.1002/adhm.201901454). These techniques primarily utilize deformable materials (e.g., polydimethylsiloxane elastomers, polyacrylamide hydrogels) and deformable structures (e.g., microposts, cantilevers) for the quantitative determination of cellular tractions. Barker and colleagues review our understanding of the bi-directional interactions between cells and their mechanical environment, particularly related to mechanotransduction platforms and involving focal adhesion complexes (see article https://doi.org/10.1002/adhm.201901445). Cells respond through changes in behaviors including spreading, migration, proliferation, and differentiation and dysregulation of the biophysical environment can lead to aberrant cell behaviors. Looking inside the cells, Mauck and colleagues review our understanding of how changes in physical cues relate to changes in the cell nucleus, including mechanical memory and epigenome alterations (see article https://doi.org/10.1002/adhm.202000030). Biomaterial platforms are of particular interest in disease, as mechanics vary with disease progression and can be used to better evaluate potential therapies. Wells and colleagues review various approaches that have been taken to design materials with spatiotemporally controlled properties that are important during fibrosis (see article https://doi.org/10.1002/adhm.201901682). These materials mimic the changes in mechanical properties observed with increased ECM accumulation during tissue fibrosis and even the resolution of matrix changes with treatment. One area where fibrosis and mechanical changes are observed with disease is in cardiac tissue, where cardiomyocytes reside as a contractile cell within varied mechanical environments. Pruitt and colleagues review assays that have been developed to place cardiomyocytes in varied environments to probe electrophysiology and function, particularly to understand drug cardiotoxicity (see article https://doi.org/10.1002/adhm.201901656). Towards furthering in vitro models to investigate and understand physiological systems, Peyton and colleagues review the development of vascularization strategies that mimic aspects of tumor physiology to probe cancer metastasis (see article https://doi.org/10.1002/adhm.201901459). These systems utilize vasculogenesis or the fabrication of channel structures to support the formation of vessels to explore various parameters involved in tumor cell intravasation and extravasation, including matrix mechanics and fluid flow. Coughlin and Kamm build further into this area and review how microfluidic platforms can be used to specifically investigate cancer cell extravasation (see article https://doi.org/10.1002/adhm.201901410). Microfluidic systems are of particular interest in these studies as various cellular and matrix components can be precisely controlled. Slater and colleagues further review fabrication strategies to introduce vascular networks into materials and their application into multi-cellular microphysiological systems to model organ and tissue pathologies (see article https://doi.org/10.1002/adhm.201901255). Towards original research, this special issue includes several manuscripts where mechanobiology plays a role. In some cases, this involves the seeding of cells atop matrices where mechanical properties can be varied. For example, Engler and colleagues investigated the epithelial-to-mesenchymal transition of mammary epithelial cells on polyacrylamide gels of varied stiffness (see article https://doi.org/10.1002/adhm.201901366). Ras-transformed MCF10AT cells spread on soft matrices, driven by ERK activation and dynamic microtubules, indicating a cell-specific mechanosensing behavior. Phillips and colleagues utilized substrates of uniform and gradient mechanics to understand how neural cells respond to specific gradient levels, towards better understanding how materials can be developed for applications in tissue regeneration (see article https://doi.org/10.1002/adhm.201901036). Biomaterial platforms are also important for culturing cells within 3D environments where cells are surrounded by matrix, such as is found in many tissues and during development. For example, Anseth and colleagues developed hydrogels that soften through photocleaving of crosslinks to explore how the relaxation of surroundings influences intestinal organoid development and crypt formation (see article https://doi.org/10.1002/adhm.201901214). They observed that softening of the matrix influenced crypt formation, size, and number during culture, providing an avenue to better control organoid behavior towards their use in applications like drug screening. Burdick and colleagues explored how the mechanics of fibrous matrices influences the migration of cells into a fibrous matrix, particularly towards the repair of meniscal tissue (see article https://doi.org/10.1002/adhm.201901228). They observed that softer fibers rapidly deformed and densified, resulting in decreased invasion when compared to stiffer fibers that retained their porosity better. Akinsab and colleagues investigated how substrate mechanics influence advential fibroblast behavior, in the context of vascular remodeling and arterial disease (see article https://doi.org/10.1002/adhm.201901593). With engineered poly(ethylene glycol) hydrogels, they observed the influence of hydrogel mechanics on myofibroblast transdifferentiation and matrix production. As a last example of 3D culture, Ma and colleagues developed 3D cardiac microtissues that introduce mechanical non-uniformity through 3D-printing that better mimic the pathology of tissues in diseased environments. (see article https://doi.org/10.1002/adhm.201901373). We hope this special issue will encourage and excite the field of biomaterials in mechanobiology even further. There are many applications that would benefit from further development of biomaterials where mechanics can be controlled to uncover biological mechanism, or to develop and screen new therapeutics. We would like to thank all of the authors that contributed to the special issue, providing their time and expertise in furthering this growing and important field. The work highlighted in the issue is being advanced through many organizations, such as the Center for Engineering MechanoBiology (CEMB), a National Science Foundation supported multi-institutional Science and Technology Center where Burdick is a Principal Investigator, and the Georgia Tech Petit Institute for Bioengineering and Bioscience, where García is the Executive Director. We thank the Wiley-VCH staff, particularly Uta Goebel, for all of the efforts in making this special issue happen. Finally, we remember Robert M. Nerem, a visionary and pioneer in mechanobiology (even before this term was used) as it related to the effects of fluid flow on vascular biology, who inspired and mentored many of us to study these phenomena. Jason A. Burdick is the Robert D. Bent Professor in the Department of Bioengineering at the University of Pennsylvania and a Principal Investigator in the Center for Engineering Mechanobiology. His research is focused on the design of functional and dynamic biomaterials for therapeutic applications and towards fundamental questions related to cellular microenvironments, such as in mechanobiology. Andrés J. Garcia is the Executive Director of the Parker H. Petit Institute for Bioengineering and Bioscience and the George W. Woodruff School of Mechanical Engineering Regents Professor at Georgia Institute of Technology. His research integrates engineering and biological principles in the design of biomaterials to control cell function, particularly in tissue repair and in understanding mechanisms of cell adhesion.