The knowledge of the blood microvasculature and its functional role in health and disease has grown significantly attributable to decades of research and numerous advances in cell biology and tissue engineering; however, the lymphatics (the secondary vascular system) has not garnered similar attention, in part due to a lack of relevant in vitro models that mimic its pathophysiological functions. Here, a microfluidic‐based approach is adopted to achieve precise control over the biological transport of growth factors and interstitial flow that drive the in vivo growth of lymphatic capillaries (lymphangiogenesis). The engineered on‐chip lymphatics with in vivo‐like morphology exhibit tissue‐scale functionality with drainage rates of interstitial proteins and molecules comparable to in vivo standards. Computational and scaling analyses of the underlying transport phenomena elucidate the critical role of the three‐dimensional geometry and lymphatic endothelium in recapitulating physiological drainage. Finally, the engineered on‐chip lymphatics enabled studies of lymphatic‐immune interactions that revealed inflammation‐driven responses by the lymphatics to recruit immune cells via chemotactic signals similar to in vivo, pathological events. This on‐chip lymphatics platform permits the interrogation of various lymphatic biological functions, as well as screening of lymphatic‐based therapies such as interstitial absorption of protein therapeutics and lymphatic immunomodulation for cancer therapy.
Efficient delivery of oxygen and nutrients to tissues requires an intricate balance of blood, lymphatic, and interstitial fluid pressures (IFPs), and gradients in fluid pressure drive the flow of blood, lymph, and interstitial fluid through tissues. While specific fluid mechanical stimuli, such as wall shear stress, have been shown to modulate cellular signaling pathways along with gene and protein expression patterns, an understanding of the key signals imparted by flowing fluid and how these signals are integrated across multiple cells and cell types in native tissues is incomplete due to limitations with current assays. Here, we introduce a multi-layer microfluidic platform (MμLTI-Flow) that enables the culture of engineered blood and lymphatic microvessels and independent control of blood, lymphatic, and IFPs. Using optical microscopy methods to measure fluid velocity for applied input pressures, we demonstrate varying rates of interstitial fluid flow as a function of blood, lymphatic, and interstitial pressure, consistent with computational fluid dynamics (CFD) models. The resulting microfluidic and computational platforms will provide for analysis of key fluid mechanical parameters and cellular mechanisms that contribute to diseases in which fluid imbalances play a role in progression, including lymphedema and solid cancer.
more » « less- NSF-PAR ID:
- 10362099
- Publisher / Repository:
- IOP Publishing
- Date Published:
- Journal Name:
- Biofabrication
- Volume:
- 14
- Issue:
- 2
- ISSN:
- 1758-5082
- Page Range / eLocation ID:
- Article No. 025007
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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