Microfluidic device to control interstitial flow-mediated homotypic and heterotypic cellular communication

Abstract

Tissue engineering can potentially recreate in vivo cellular microenvironments in vitro for an array of applications such as biological inquiry and drug discovery. However, the majority of current in vitro systems still neglect many biological, chemical, and mechanical cues that are known to impact cellular fucntions such as proliferation, migration, and differentiation. To address this gap, we have developed a novel microfluidic device that precisely controls the spatial and temporal interactions between adjacent three-dimensional cellular environments. The device consists of four interconnected microtissue compartments (~0.1 mm3) arranged in a square. The top and bottom pairs of compartments can be sequentially loaded with discreate cellularized hydrogels creating the opportunity to investigate homotypic (left to right or x-direction) and heterotypic (top to bottom or y-direction) cell-cell communication. A controlled hydrostatic pressure difference across the tissue compartments in both x and y direction induces interstitial flow and modulates communication via soluble factors. To validate the biological significance of this novel platform, we examined the role of stromal cells in the process of vasculogenesis. Our device confirms previous observations that soluble mediators derived from normal human lung fibroblasts (NHLFs) are necessary to form a vascular network derived from endothelial colony forming cell-derived endothelial cells (ECFC-ECs). We conclude that this platfrom could be used to study important physiological and pathological processes that rely on homotypic and heterotypic cell-cell communication.

Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N -cadherin balance in mural cell–endothelial cell-regulated barrier function

“…A deeper understanding of human pathophysiology requires the development of robust on-chip systems that can recapitulate the structures, mechanics, and complex cell-cell interactions that occur in vivo (76)(77)(78)(79)(80)). Whereas we demonstrate herein the feasibility to capture these interactions in on-chip systems, a challenge in the future is to establish tissue-specific features of vascular beds such as low permeable brain vasculature (blood brain barrier) or high permeable liver sinusoids consisting of endothelial cells with fenestrae.…”

An on-chip microfluidic pressure regulator that facilitates reproducible loading of cells and hydrogels into microphysiological system platforms

“…interstitial flow velocity or profile, etc.) inside the tissue chamber [23]. In order to maintain uniform and well-controlled perfusion it might be beneficial to separate the fluidic channel and multi-tissue co-culture chambers into different layers.…”

Biomimetic on-a-chip platforms for studying cancer metastasis

“…Proliferating ECs in the surrounding matrix form new sprouts, and these sprouts make loops to become a vascular lumen [23]. There have been on-a-chip models that recapitulate hallmarks of the angiogenesis, such as vascular sprouting [18 •• ,24], network formation [20,21], perfused lumen formation [18 •• ,19,21], and maturation [25,26]. For example, Nguyen et al .…”

“…Three dimensional vascular network formation was demonstrated in an in vitro vasculogenesis model by Alonzo et al . (Figure 2ii) [21]. They reported perfused human capillary networks, and claimed that soluble factors derived from normal human lung fibroblasts (NHLFs) are necessary to form a vascular network derived from endothelial colony forming cell-derived endothelial cells (ECFC-ECs) [21].…”