(CCE) SMCs co-encapsulated with gelatin coated dextran (Cytodex-3) microcarriers in HA capsules. be further tuned by blending collagen with PIAS1 or suspending microcarriers in the GAG answer These capsule modules were seeded externally with vascular endothelial cells (VEC), and subsequently fused into tissue constructs possessing VEC-lined, inter-capsule channels. The microcapsules supported high density growth achieving clinically significant cell densities. Fusion of the endothelialized, capsules generated three dimensional constructs with an embedded network of interconnected channels that enabled long-term perfusion culture of the construct. A prototype, designed liver tissue, formed by fusion of hepatocyte-containing capsules exhibited urea synthesis rates and albumin synthesis rates comparable to standard collagen sandwich hepatocyte cultures. The Azelnidipine capsule based, modular approach described here has the potential to allow rapid assembly of tissue constructs with clinically significant cell densities, uniform cell distribution, and endothelialized, perfusable channels. Introduction Fabrication of 3D constructs that promote cell-cell conversation, extra cellular matrix (ECM) deposition and tissue level business is usually a primary goal of tissue engineering [1]. Accomplishing these prerequisites with the currently available conventional scaffolds and fabrication techniques still remains a challenge. Some of the tissue types that have been successfully designed include skin [2], bone [3]C[5] and cartilage [4], [6], [7]. Significant success has also been achieved in nerve regeneration [8], corneal construction [9]C[11] and vascular tissue engineering [12]; However, the success rate has been relatively low in engineering complex tissue types such as liver, lung, and kidney due to their complex architectures and metabolic activities. In conventional preformed scaffolds, the cell viability depends on diffusion of oxygen, nutrients and growth factors from the surrounding host tissues, and it is limited to 100C200 microns thickness at cell densities comparable to that of normal tissues [13]. Hence in constructs with larger dimensions, efficient mass transfer and subsequent cell survival can Azelnidipine be achieved only by significantly reducing cell densities or by tolerating Azelnidipine hypoxic conditions. Moreover, in a porous scaffold, uniform distribution throughout the construct is difficult to achieve, and the seeded cells will stay around the peripheral surface of the construct forming a thin peripheral layer. In addition, these scaffolds cannot facilitate incorporation of multiple cell types in a controlled manner. Hence the slow vascularization, mass transfer limitation, low cell density and non-uniform cell distribution limits Azelnidipine conventional methods from engineering large and more complex organs. Therefore, an innate structure that supports functional vascularization is imperative for engineering large tissues grafts. Many strategies have been proposed to incorporate vascular structure that includes creating endothelial microchannels inside scaffolds [14], [15], surface modification and/or controlled releasing of pro-vasculogenic growth factor and cytokines [16]C[18], coculturing vascular cell types for microvessel formation [19] etc. Despite their limited success, none of these approaches is able to incorporate an extensive vasculature as seen in natural organs. The bioinspired modular tissue engineering approach has emerged in recent years as a promising fabrication strategy to address the common shortcomings of a preformed scaffold by assembling tissue constructs from the bottom up [20], [21]. Using this theory, complex tissues and organs can be designed efficiently from microscale modules as opposed to the top down approach of conventional scaffolds [21]. This approach is increasingly becoming a promising tool to study and recreate vascular physiology in tissue engineering applications [22], [23]. Some of the proposed modular TE strategies include 3D tissue printing [24]C[26], cell linens technology [27] and assembly of cell laden hydrogels [20], [28] (Physique 1). Open in a separate window Physique 1 Bottom-up vs. top-down approaches in tissue engineering.The traditional, top-down approach (right) involves seeding cells into full sized porous scaffolds to form tissue constructs. This approach poses many limitations such as slow vascularization, diffusion limitations, low cell.