Anderson Eric J, Knothe Tate Melissa L
Department of Mechanical and Aerospace Engineering, Case School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
Tissue Eng. 2007 Oct;13(10):2525-38. doi: 10.1089/ten.2006.0443.
New approaches to tissue engineering aim to exploit endogenous strategies such as those occurring in prenatal development and recapitulated during postnatal healing. Defining tissue template specifications to mimic the environment of the condensed mesenchyme during development allows for exploitation of tissue scaffolds as delivery devices for extrinsic cues, including biochemical and mechanical signals, to drive the fate of mesenchymal stem cells seeded within. Although a variety of biochemical signals that modulate stem cell fate have been identified, the mechanical signals conducive to guiding pluripotent cells toward specific lineages are less well characterized. Furthermore, not only is spatial and temporal control of mechanical stimuli to cells challenging, but also tissue template geometries vary with time due to tissue ingrowth and/or scaffold degradation. Hence, a case study was carried out to analyze flow regimes in a testbed scaffold as a first step toward optimizing scaffold architecture. A pressure gradient was applied to produce local (nm-micron) flow fields conducive to migration, adhesion, proliferation, and differentiation of cells seeded within, as well as global flow parameters (micron-mm), including flow velocity and permeability, to enhance directed cell infiltration and augment mass transport. Iterative occlusion of flow channel dimensions was carried out to predict virtually the effect of temporal geometric variation (e.g., due to tissue development and growth) on delivery of local and global mechanical signals. Thereafter, insights from the case study were generalized to present an optimization scheme for future development of scaffolds to be implemented in vitro or in vivo. Although it is likely that manufacture and testing will be required to finalize design specifications, it is expected that the use of the rational design optimization will reduce the number of iterations required to determine final prototype geometries and flow conditions. As the range of mechanical signals conducive to guiding cell fate in situ is further elucidated, these refined design criteria can be integrated into the general optimization rubric, providing a technological platform to exploit nature's endogenous tissue engineering strategies for targeted tissue generation in the lab or the clinic.
组织工程的新方法旨在利用内源性策略，例如那些在产前发育过程中出现并在产后愈合过程中重现的策略。定义组织模板规格以模拟发育过程中致密间充质的环境，能够将组织支架用作传递外部信号（包括生化和机械信号）的载体，从而驱动接种在其中的间充质干细胞的命运。尽管已经确定了多种调节干细胞命运的生化信号，但有利于引导多能细胞向特定谱系分化的机械信号的特征却不太明确。此外，对细胞施加机械刺激的时空控制不仅具有挑战性，而且由于组织向内生长和/或支架降解，组织模板的几何形状会随时间变化。因此，开展了一项案例研究，以分析试验台支架中的流动状态，作为优化支架结构的第一步。施加压力梯度以产生有利于接种在其中的细胞迁移、黏附、增殖和分化的局部（纳米 - 微米）流场，以及包括流速和渗透率在内的全局流动参数（微米 - 毫米），以增强细胞的定向浸润并促进物质运输。对流动通道尺寸进行迭代封堵，以虚拟预测时间几何变化（例如由于组织发育和生长）对局部和全局机械信号传递的影响。此后，将案例研究的见解进行归纳，以提出一种优化方案，用于未来体外或体内使用的支架的开发。尽管可能需要进行制造和测试来确定最终的设计规格，但预计使用合理的设计优化将减少确定最终原型几何形状和流动条件所需的迭代次数。随着有利于原位引导细胞命运的机械信号范围得到进一步阐明，这些精细的设计标准可以整合到一般的优化准则中，提供一个技术平台，以利用自然的内源性组织工程策略在实验室或临床中实现靶向组织生成。
