Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3335-9. doi: 10.1073/pnas.0907813106. Epub 2009 Dec 1.
Many investigators have engineered diverse connective tissues having good mechanical properties, yet few tools enable a global understanding of the associated formation of collagen fibers, the primary determinant of connective tissue stiffness. Toward this end, we developed a biomechanical model for collagenous tissues grown on polymer scaffolds that accounts for the kinetics of polymer degradation as well as the synthesis and degradation of multiple families of collagen fibers in response to cyclic strains imparted in a bioreactor. The model predicted well both overall thickness and stress-stretch relationships for tubular engineered vessels cultured for 8 weeks, and suggested that a steady state had not yet been reached. To facilitate future refinements of the model, we also developed bioreactors that enable intravital nonlinear optical microscopic imaging. Using these tools, we found that collagen fiber alignment was driven strongly by nondegraded polymer fibers at early times during culture, with subsequent mechano-stimulated dispersal of fiber orientations as polymer fibers degraded. In summary, mathematical models of growth and remodeling of engineered tissues cultured on polymeric scaffolds can predict evolving tissue morphology and mechanics after long periods of culture, and related empirical observations promise to further our understanding of collagen matrix development in vitro.
许多研究人员已经设计出具有良好机械性能的多种结缔组织，但很少有工具能够全面了解胶原纤维的相关形成，胶原纤维是结缔组织硬度的主要决定因素。为此，我们开发了一种用于在聚合物支架上生长的胶原组织的生物力学模型，该模型考虑了聚合物降解的动力学以及在生物反应器中施加的循环应变下多种胶原纤维家族的合成和降解。该模型很好地预测了培养 8 周的管状工程血管的整体厚度和应力-应变关系，并表明尚未达到稳定状态。为了促进模型的进一步改进，我们还开发了能够进行活体非线性光学显微镜成像的生物反应器。使用这些工具，我们发现胶原纤维的取向在培养早期主要受到未降解的聚合物纤维的驱动，随着聚合物纤维的降解，纤维取向随后会受到机械刺激而分散。总之，在聚合物支架上培养的工程组织的生长和重塑的数学模型可以预测经过长时间培养后的组织形态和力学变化，相关的经验观察有望进一步加深我们对体外胶原基质发育的理解。
