High-throughput 3D microvessel-on-a-chip model to study defective angiogenesis in systemic sclerosis

Abstract

In early systemic sclerosis (Scleroderma, SSc), the vasculature is impaired. Although the exact etiology of endothelial cell damage in SSc remains unclear, it is hypothesized that endothelial to mesenchymal transition (EndoMT) plays a key role. To perform physiologically relevant angiogenic studies, we set out to develop an angiogenesis-on-a-chip platform that is suitable for assessing disease parameters that are relevant to SSc and other vasculopathies. In the model, we substituted Fetal Bovine Serum (FBS) with Human Serum without impairing the stability of the culture. We showed that 3D microvessels and angiogenic factor-induced sprouts exposed to key pro-inflammatory and pro-fibrotic cytokines (TNFα and TGFβ) undergo structural alterations consisting of destructive vasculopathy (loss of small vessels). We also showed that these detrimental effects can be prevented by compound-mediated inhibition of TGFβ-ALK5 signaling or addition of a TNFα neutralizing antibody to the 3D cultures. This demonstrates that our in vitro model is suitable for compound testing and identification of new drugs that can protect from microvascular destabilization or regression in disease-mimicking conditions. To support this, we demonstrated that sera obtained from SSc patients can exert an anti-angiogenic effect on the 3D vessel model, opening the doors to screening for potential SSc drugs, enabling direct patient translatability and personalization of drug treatment.

Fibroblasts and Endothelial Cells in Three-Dimensional Models: A New Tool for Addressing the Pathogenesis of Systemic Sclerosis as a Prototype of Fibrotic Vasculopathies

“…3D scaffold-free and scaffold-based models of SSc have been implemented, mainly for drug development and screening [ 49 , 50 ]. Defective angiogenesis in SSc has recently been studied, employing a 3D microvessel-on-a-chip model [ 51 ]. The overall results indicate the IVTech dynamic multi-compartmental system as an evolution of the traditional 2D cultures and a valuable in vitro alternative to animal employment.…”

The Edifice of Vasculature-On-Chips: A Focused Review on the Key Elements and Assembly of Angiogenesis Models

“…In this system, a distinctive phaseguide design is utilized to generate a boundary-less surface for the ECs to adhere to the hydrogel and sprout toward the center. Similar to previous iterations of the Ogranoplate Graft, its phaseguide technology patterns the hydrogel in the central lane through meniscus pinning, leading to a curved shape contact line . Ultimately, the intention of high-throughput systems is to accelerate the discovery and development of new therapeutics by enabling massive parallel experimentation …”

An Overview of Advancements and Technologies in Vascularization Strategies for Tumor‐On‐A‐Chip Models

“…Injectable hydrogel pre-polymers flow without leaking, forming multicompartment devices. [35,[57][58][59][60][61][62][63][64][65][66][67][68][69] Angiogenesis chips employ various endothelial cell sources, such as HUVECs, human aortic endothelial cells (HAECs), and HMVECs, [30,35,55,56,[70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85] along with sprouting cells with growth factors like endothelial growth factor, VEGF, [13,75,[86][87][88][89][90] TGF-𝛽, PDGF, bone morphogenetic protein (BMP), S1P, PMA, HGF, monocyte chemotactic protein-1 (MCP-1), fibroblast growth factor (bFGF), the addition of ANG-1 with using ECM biomaterials (collagen/matrigel/alginate and fibrin,) according to the study-specific models. [19,32,42,43,56,…”