A Comparative Study of Collagen Matrix Density Effect on Endothelial Sprout Formation Using Experimental and Computational Approaches.

A thorough understanding of determining factors in angiogenesis is a necessary step to control the development of new blood vessels. Extracellular matrix density is known to have a significant influence on cellular behaviors and consequently can regulate vessel formation. The utilization of experimental platforms in combination with numerical models can be a powerful method to explore the mechanisms of new capillary sprout formation. In this study, using an integrative method, the interplay between the matrix density and angiogenesis was investigated. Owing the fact that the extracellular matrix density is a global parameter that can affect other parameters such as pore size, stiffness, cell-matrix adhesion and cross-linking, deeper understanding of the most important biomechanical or biochemical properties of the ECM causing changes in sprout morphogenesis is crucial. Here, we implemented both computational and experimental methods to analyze the mechanisms responsible for the influence of ECM density on the sprout formation that is difficult to be investigated comprehensively using each of these single methods. For this purpose, we first utilized an innovative approach to quantify the correspondence of the simulated collagen fibril density to the collagen density in the experimental part. Comparing the results of the experimental study and computational model led to some considerable achievements. First, we verified the results of the computational model using the experimental results. Then, we reported parameters such as the ratio of proliferating cells to migrating cells that was difficult to obtain from experimental study. Finally, this integrative system led to gain an understanding of the possible mechanisms responsible for the effect of ECM density on angiogenesis. The results showed that stable and long sprouts were observed at an intermediate collagen matrix density of 1.2 and 1.9 mg/ml due to a balance between the number of migrating and proliferating cells. As a result of weaker connections between the cells and matrix, a lower collagen matrix density (0.7 mg/ml) led to unstable and broken sprouts. However, higher matrix density (2.7 mg/ml) suppressed sprout formation due to the high level of matrix entanglement, which inhibited cell migration. This study also showed that extracellular matrix density can influence sprout branching. Our experimental results support this finding.

Integrative Utilization of Microenvironments, Biomaterials and Computational Techniques for Advanced Tissue Engineering.

This review aims to propose the integrative implementation of microfluidic devices, biomaterials, and computational methods that can lead to a significant progress in tissue engineering and regenerative medicine researches. Simultaneous implementation of multiple techniques can be very helpful in addressing biological processes. Providing controllable biochemical and biomechanical cues within artificial extracellular matrix similar to in vivo conditions is crucial in tissue engineering and regenerative medicine researches. Microfluidic devices provide precise spatial and temporal control over cell microenvironment. Moreover, generation of accurate and controllable spatial and temporal gradients of biochemical factors is attainable inside microdevices. Since biomaterials with tunable properties are a worthwhile option to construct artificial extracellular matrix, in vitro platforms that simultaneously utilize natural, synthetic, or engineered biomaterials inside microfluidic devices are phenomenally advantageous to experimental studies in the field of tissue engineering. Additionally, collaboration between experimental and computational methods is a useful way to predict and understand mechanisms responsible for complex biological phenomena. Computational results can be verified by using experimental platforms. Computational methods can also broaden the understanding of the mechanisms behind the biological phenomena observed during experiments. Furthermore, computational methods are powerful tools to optimize the fabrication of microfluidic devices and biomaterials with specific features. Here we present a succinct review of the benefits of microfluidic devices, biomaterial, and computational methods in the case of tissue engineering and regeneration medicine. Furthermore, some breakthroughs in biological phenomena including the neuronal axon development, cancerous cell migration and blood vessel formation via angiogenesis by virtue of the aforementioned approaches are discussed.