Simple SummaryThere is a dearth of in vitro tissue culture tools to study the complex biology of the skin bite site created by blood-feeding arthropods such as mosquitoes. To address this shortage, we engineered model human dermal microvascular bed tissue that included blood using capillary alginate gel (Capgel) biomaterial scaffolds and human cells. In a set of proof-of-concept experiments presented here, femaleAedes aegyptibit into, probed, and blood-fed from these engineered dermal microvessel beds, similarly to how these mosquitoes would acquire blood meals from human hosts. Further, these tissue constructs remained intact and could be cleanly cultured for days after such blood meal acquisitions. Overall, the present study demonstrates this innovative new platform—termed a Biologic Interfacial Tissue-Engineered System (BITES)—with mosquitoes and signals its potential to break new ground in arthropod bite-site biology investigations.AbstractVector-borne diseases transmitted through the bites of hematophagous arthropods, such as mosquitoes, continue to be a significant threat to human health globally. Transmission of disease by biting arthropod vectors includes interactions between (1) saliva expectorated by a vector during blood meal acquisition from a human host, (2) the transmitted vector-borne pathogens, and (3) host cells present at the skin bite site. Currently, the investigation of bite-site biology is challenged by the lack of model 3D human skin tissues for in vitro analyses. To help fill this gap, we have used a tissue engineering approach to develop new stylized human dermal microvascular bed tissue approximates—complete with warm blood—built with 3D capillary alginate gel (Capgel) biomaterial scaffolds. These engineered tissues, termed a Biologic Interfacial Tissue-Engineered System (BITES), were cellularized with either human dermal fibroblasts (HDFs) or human umbilical vein endothelial cells (HUVECs). Both cell types formed tubular microvessel-like tissue structures of oriented cells (82% and 54% for HDFs and HUVECs, respectively) lining the unique Capgel parallel capillary microstructures. FemaleAedes(Ae.)aegyptimosquitoes, a prototypic hematophagous biting vector arthropod, swarmed, bit, and probed blood-loaded HDF BITES microvessel bed tissues that were warmed (34–37 °C), acquiring blood meals in 151 ± 46 s on average, with some ingesting ≳4 µL or more of blood. Further, these tissue-engineered constructs could be cultured for at least three (3) days following blood meal acquisitions. Altogether, these studies serve as a powerful proof-of-concept demonstration of the innovative BITES platform and indicate its potential for the future investigation of arthropod bite-site cellular and molecular biology.