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A Tumor-on-a-Chip System with Bioprinted Blood and Lymphatic Vessel Pair

ABSTRACT: Current in vitro anti-tumor drug screening strategies are insufficiently portrayed lacking true perfusion and draining microcirculation systems, which may post significant limitation in reproducing the transport kinetics of cancer therapeutics explicitly. Herein, we report the fabrication of an improved tumor model consisting of bioprinted hollow blood vessel and lymphatic vessel pair, hosted in a three-dimensional (3D) tumor microenvironment-mimetic hydrogel matrix, termed as the tumor-on-a-chip with bioprinted blood and lymphatic vessel pair (TOC-BBL). The bioprinted blood vessel was perfusable channel with opening on both ends while the bioprinted lymphatic vessel was blinded on one end, both of which were embedded in a hydrogel tumor mass, with vessel permeability individually tunable through optimization of the composition of the bioinks. We demonstrated that systems with different combinations of these bioprinted blood/lymphatic vessels exhibited varying levels of diffusion profiles for biomolecules and anti-cancer drugs. Our TOC-BBL platform mimicking the natural pathway of drug-tumor interactions would have the drug introduced through the perfusable blood vessel, cross the vascular wall into the tumor tissue via diffusion, and eventually drained into the lymphatic vessel along with the carrier flow. Our results suggested that this unique in vitro tumor model containing the bioprinted blood/lymphatic vessel pair may have the capacity of simulating the complex transport mechanisms of certain pharmaceutical compounds inside the tumor microenvironment, potentially providing improved accuracy in future cancer drug screening. Graphical Abstract

SUBMITTER: Cao X

PROVIDER: S-EPMC7546431 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Project description:IntroductionLymphatic vessels (LVs) maintain fluid homeostasis by draining excess interstitial fluid, which is accomplished by two distinct LVs: initial LVs and collecting LVs. The interstitial fluid is first drained into the initial LVs through permeable "button-like" lymphatic endothelial cell (LEC) junctions. Next, the drained fluid ("lymph") transports to lymph nodes through the collecting LVs with less permeable "zipper-like" junctions that minimize loss of lymph. Despite the significance of LEC junctions in lymphatic drainage and transport, it remains unclear how luminal or interstitial flow affects LEC junctions in vascular endothelial growth factors A and C (VEGF-A and VEGF-C) conditions. Moreover, it remains unclear how these flow and growth factor conditions impact lymphatic sprouting.MethodsWe developed a 3D human lymphatic vessel-on-chip that can generate four different flow conditions (no flow, luminal flow, interstitial flow, both luminal and interstitial flow) to allow an engineered, rudimentary LV to experience those flows and respond to them in VEGF-A/C.ResultsWe examined LEC junction discontinuities, lymphatic sprouting, LEC junction thicknesses, and cell contractility-dependent vessel diameters in the four different flow conditions in VEGF-A/C. We discovered that interstitial flow in VEGF-C generates discontinuous LEC junctions that may be similar to the button-like junctions with no lymphatic sprouting. However, interstitial flow or both luminal and interstitial flow stimulated lymphatic sprouting in VEGF-A, maintaining zipper-like LEC junctions. LEC junction thickness and cell contractility-dependent vessel diameters were not changed by those conditions.ConclusionsIn this study, we provide an engineered lymphatic vessel platform that can generate four different flow regimes and reveal the roles of interstitial flow and VEGF-A/C for lymphatic sprouting and discontinuous junction formation.Supplementary informationThe online version contains supplementary material available at 10.1007/s12195-023-00780-0.

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A Tumor-on-a-Chip System with Bioprinted Blood and Lymphatic Vessel Pair

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