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1 School of Mechanical Engineering, Purdue University, West Lafayette, Indiana, USA
2 School of Mechanical Engineering, Purdue University, West Lafayette, Indiana, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
3 Department of Mechanical Engineering, University of Alabama, Tuscaloosa, Alabama, USA
4 Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
5 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA; Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
* To whom correspondence should be addressed. E-mail: harbins{at}purdue.edu.
The extracellular matrix (ECM) provides the principal means by which mechanical information is communicated between global (tissue) and local (cellular) levels of function. These mechanical signals play a central role in controlling cell fate and establishing tissue structure-function. However, little is known regarding the mechanisms by which specific structural and mechanical properties of the ECM influence its interaction with cells and communication of mechanical loads, especially within a tissue-like context. This lack of knowledge precludes formulation of biomimetic microenvironments for effective tissue repair and replacement. The present study determined the role of collagen fibril density in regulating local cell-ECM biomechanics and fundamental fibroblast behavior. The model system consisted of fibroblasts seeded within collagen ECMs with controlled microstructure. Confocal microscopy was used to collect multi-dimensional images of both ECM microstructure and specific cellular characteristics. From these images 1) temporal changes in three-dimensional (3D) cell morphology, 2) time- and spatial-dependent changes in the 3D local strain state of a cell and its ECM, and 3) spatial distribution of 
1-integrin were quantified. Results showed that fibroblasts grown within high-fibril-density ECMs had decreased length:height ratios, increased 3D surface areas, and a greater number of cytoplasmic projections. Furthermore, fibroblasts within low-fibril-density ECMs reorganized their surrounding ECM to a greater extent, and it appeared that 1-integrin localization was related to local strain and ECM remodeling events. Finally, fibroblast proliferation was enhanced in low-fibril-density ECMs, indicating that ECM microstructure is a critical determinant of early events associated with cell-ECM interactions as well as cell phenotype and function. Collectively, results of these studies are significant because they provide new insight into how specific physical properties of a cell's ECM microenvironment contribute to tissue remodeling events in vivo and to the design and engineering of functional tissue replacements.
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