Microvasculature-on-a-Chip: Bridging the interstitial blood-lymph interface via mechanobiological stimuli

Abstract

After decades of simply being referred to as the body's sewage system, the lymphatic system has recently been recognized as a key player in numerous physiological and pathological processes. As an essential site of immune cell interactions, the lymphatic system is a potential target for next-generation drug delivery approaches in treatments for cancer, infections, and inflammatory diseases. However, the lack of cell-based assays capable of recapitulating the required biological complexity combined with unreliable in vivo animal models currently hamper scientific progress in lymph-targeted drug delivery. To gain more in-depth insight into the blood-lymph interface, we established an advanced chip-based microvascular model to study mechanical stimulation's importance on lymphatic sprout formation. Our microvascular model's key feature is the co-cultivation of spatially separated 3D blood and lymphatic vessels under controlled, unidirectional interstitial fluid flow while allowing signaling molecule exchange similar to the in vivo situation. We demonstrate that our microphysiological model recreates biomimetic interstitial fluid flow, mimicking the route of fluid in vivo, where shear stress within blood vessels pushes fluid into the interstitial space, which is subsequently transported to the nearby lymphatic capillaries. Results of our cell culture optimization study clearly show an increased vessel sprouting number, length, and morphological characteristics under dynamic cultivation conditions and physiological relevant mechanobiological stimulation. For the first time, a microvascular on-chip system incorporating microcapillaries of both blood and lymphatic origin in vitro recapitulates the interstitial blood-lymph interface.

Sensor‐integrated brain‐on‐a‐chip platforms: Improving the predictive validity in neurodegenerative research

“…Finally, there has been a growing body of evidence implicating T‐cells in the pathogenesis of NDDs, rendering their consideration essential in the design of in vitro models 43 . However, significant progress has been made in the microphysiological recapitulation of these constituents individually (e.g., engineered networks of the BBB, the lymphatic system, T‐cell perfusion), providing an ideal basis for future NDD models 27,29,44–46 …”

“… 43 However, significant progress has been made in the microphysiological recapitulation of these constituents individually (e.g., engineered networks of the BBB, the lymphatic system, T‐cell perfusion), providing an ideal basis for future NDD models. 27 , 29 , 44 , 45 , 46 …”

“…43 However, significant progress has been made in the microphysiological recapitulation of these constituents individually (e.g., engineered networks of the BBB, the lymphatic system, T-cell perfusion), providing an ideal basis for future NDD models. 27,29,[44][45][46] Furthermore, to meet the need for predictive NDD in vitro models, effective microphysiological system monitoring is paramount. This is of particular importance considering both the increasing complexity and potential variability of microtissue-analogs as well as the occurrence of dynamic changes within NDD-associated phenotypes.…”

Lymph Nodes-On-Chip: Promising Immune Platforms for Pharmacological and Toxicological Applications

“…In the following sections, we describe attempts to recreate aspects of the lymph nodes on-chip and shed the light on future directions associated with lymph node-on-chip design and implementation in drug discovery and development. There are other organ-onchip models that are immune related and that hold promising potential for investigations related to the immune system 2017) (Stachowiak and Irvine, 2008;Jones et al, 2012;Dura et al, 2015;Sun et al, 2019;Fathi et al, 2020;Bachmann et al, 2021) but we will focus on models that mimic the lymph node physiology.…”

“…In addition they represent improved and attractive platforms for various applications in immunology, pathology, pharmacology and toxicology, as we will next describe. Although the review here focuses on models that mimic the lymph node physiology, there are other organon-chip models that are immune related and that hold promising potential for investigations related to the immune system (Stachowiak and Irvine, 2008;Jones et al, 2012;Dura et al, 2015;Sun et al, 2019;Fathi et al, 2020;Bachmann et al, 2021).…”