Modeling collagen remodeling Frank Baaijens à , Carlijn Bouten, Niels Driessen Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands article info Article history: Accepted 21 August 2009 Keywords: Collagen Remodeling Cardiovascular Tissue engineering Computational abstract Collagen is the main load bearing protein in many soft tissues, and in cardiovascular tissues in particular. In many tissues collagen has a specific architecture that is crucial for the biomechanical function of the tissue. Typical examples are the hammock-shaped collagen architecture in heart valves and a helical pattern in arteries. One of the objectives in cardiovascular tissue engineering is the reconstitution of this architecture. It is hypothesized that the architecture is mediated by mechanical stimulation. Computational models were developed to predict the mechanoregulation of the collagen architecture. This review recapitulates the key modeling assumptions and results achieved to date. & 2009 Elsevier Ltd. All rights reserved. 1. Introduction Cardiovascular tissues have, like other tissue types, the ability to adapt to changes in the applied load, according to Wolff’s (1892) law. The cells are the key modulators of mechanically induced tissue formation and remodeling. The cells can remodel the extracellular matrix by producing matrix components, such as collagen and elastin, by secreting matrix enhancing or degrading products and their inhibitors, and by applying (traction) forces to the deposited fibers. To date it is not exactly known how the cells sense and affect their environment, but several cellular mechan- osensors and mechanotransduction pathways have been proposed (Streuli, 1999; Chiquet, 1999). It is generally accepted that collagen synthesis, accumulation and organization are affected by mechanical stimuli, thereby modulating the mechanical properties of the tissue. Cyclic strain increases the production of collagen in engineered smooth muscle tissue (Kim et al., 1999; Boerboom et al., 2008; Rubbens et al., 2009a) and in mechanically stimulated in vitro pulmonary arteries (Kolpakov et al., 1995). Studies on tissue-engineered heart valves also revealed changes in collagen content, both after in vitro and in vivo remodeling (Hoerstrup et al., 2000; Sutherland et al., 2005). However, little information is available about the concomitant changes in collagen architecture in these (engineered) tissues. A variety of experiments demonstrated that expression and synthesis of elastin was regulated by mechanical strain, including those of Kolpakov et al. (1995), Kim et al. (1999) and Jackson et al. (2002). Studies on tissue engineered heart valves revealed that elastin was not detectable after in vitro conditioning. In order to overcome this shortcoming, Shi et al. (2002) developed elastin sheets and tubes by culturing neonatal rat aortic smooth muscle cells. Besides the synthesis and secretion of extracellular matrix proteins, the regulation of matrix metallo- proteinases (MMPs) and their inhibitors (tissue inhibitor of metalloproteinases, TIMPs) plays an important role in cardiovas- cular tissue remodeling (Birkedal-Hansen, 1995). MMPs are able to degrade matrix components and are expressed at low levels in normal adult tissue, but are upregulated by the cells during pathological conditions and remodeling processes. The expres- sion, secretion and activation of MMPs is affected by mechanical stimuli, but results are controversial. Meng et al. (1999) and Jackson et al. (2002) showed an upregulation of MMP-2 and MMP-9 in longitudinally stretched blood vessels. Yang et al. (1998), on the other hand, showed that mechanical strain suppressed the expression of MMP-1 in human vascular smooth muscle cells. Rabkin et al. (2002) reported on the evolution of MMP-13 (collagenase 3) in tissue-engineered heart valves. Initially the expression of MMP-13 was upregulated, but only few cells were still positive for this enzyme in explants at 16-20 weeks, possibly indicative of mature stable tissue. To understand the mechanoregulation of the collagen archi- tecture (computational) models were developed. On the basis of collagen synthesis and degradation Humphrey (1999b) investi- gated collagen remodeling in statically loaded soft connective tissues, but investigated homogeneous loaded tissues only. Barocas and Tranquillo (1997a, b) formulated a theory to study traction induced deformation and reorganization of the extra- cellular matrix that accounts for contact guidance and the coupling of cell traction forces to the mechanical state of the matrix, and collagen alignment with the principal strain direction is assumed. They successfully predicted cellular alignment in mandril compacted tissue equivalents (Barocas et al., 1998). Boerboom et al. (2003) and Driessen et al. (2003a, b) assumed that the collagen fibers align with the principal strain directions, ARTICLE IN PRESS Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/jbiomech www.JBiomech.com Journal of Biomechanics 0021-9290/$ - see front matter & 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jbiomech.2009.09.022 à Corresponding author. E-mail address: F.P.T.Baaijens@tue.nl (F. Baaijens). Journal of Biomechanics 43 (2010) 166–175