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May 18, 2021

Biofabricated thick, functional, vascularized liver tissue; MVP liver™

Updated: Nov 14, 2022

 

In vitro models of human liver tissue and function are proving invaluable in liver disease modelling, hepatotoxicity screening for drugs, predictive drug targeting, and more. Models that recapitulate more of the native liver tissue environment would improve discovery efforts and enable investigations into liver health and disease that is currently challenging to perform with other, less complex models, such as tumor-liver tissue dynamics and parasite infections. This includes the presence of native microvasculature, including the variety of vascular and perivascular niche cells intrinsic to the native microvessel.

Figure 1: MVP- liver tissue modules. A) MVP-liver tissue in a 12 well plate. B, C) Maximum intensity projections of low and high magnification confocal image stacks of biofabricated liver tissue. D) Confocal image of a histology slice of MVP-liver tissue. E) Gross images of MVP-liver tissues exposed to differing doses of acetaminophen in a 96 well plate.
Figure 1: MVP- liver tissue modules. A) MVP-liver tissue in a 12 well plate. B, C) Maximum intensity projections of low and high magnification confocal image stacks of biofabricated liver tissue. D) Confocal image of a histology slice of MVP-liver tissue. E) Gross images of MVP-liver tissues exposed to differing doses of acetaminophen in a 96 well plate.

To this end, ASLS has developed a vascularized liver tissue called MVP liver™ tissue modules. The MVP liver™ tissues are built using the BioAssembly™ biofabrication platform and uses Angiomics® human adipose-derived, intact microvessels (haMVs) as the means to vascularize the liver tissue bed.


In fabricating the MVP liver™ tissue modules, primary hepatocytes, primary non-parenchymal cells, and Angiomics® haMVs were combined around a printed tissue frame within wells of a multi-well plate. This forms a structured, thick (~ 1 cm), liver tissue containing healthy hepatocytes and native microvessels (Figure 1). The tissue architecture that is established eliminates necrotic tissue zones, even with large tissue volumes (Figure 1). Furthermore, the biofabrication strategy employed is such that MVP liver™ tissues can be configured in a variety of formats and platforms (including perfusion).

Figure 2: Functional assessments of MVP-liver tissues comparing the presence and absence of Angiomics® haMV microvessels.
Figure 2: Functional assessments of MVP-liver tissues comparing the presence and absence of Angiomics® haMV microvessels.

MVP™-liver tissues are stable, as measured by LDH release, for 2 or more weeks and produce urea constitutively over the entire culture period (Figure 2). Additionally, the presence of haMVs in the tissue promoted expression of the MRP2 drug transporter and P450 responses, measured as increased expression of the Cyp3A4 gene, to the drug irritant rifampicin (Figure 2). Furthermore, albumin expression was upregulated, and stellate cell (a-actin positive cells) and macrophage (CD45+ cells) numbers were elevated when haMVs were included (data not shown).


Via ASLS’ BioApp™ program, a workflow software management system, and the robotic BioAssembly™ Platform, MVP liver™ tissues were automatically biofabricated (Figure 3). The BioAssembly™ Platform consists of a 6-axis robotic arm, capable of multiple automatic tool exchanges, a modular tissue culture incubator called the BioStorageBot™, and a confocal high content analysis scanner all uniquely integrated for automated of tissue and organ manufacturing. In automatically fabricating the MVP liver™ tissue modules, the operator loaded the BioAssembly™ Platform with all required components, calls up the liver tissue BioApp™ and presses “go”. The Platform automatically executed the tissue fabrication, which occurred over 5 days without human intervention, in an enclosed, clean environment. MVP liver™ tissues fabricated with the automated workflow exhibited functional readouts equivalent to liver tissue modules fabricated by hand, including urea production and select gene expression (data not shown).


Figure 3. Still images from a video of the entire automated MVP-liver tissue biofabrication highlighting keep steps (circled in red) including plate movement and lidding, printing tissue forms, pipetting primary cells and media, moving plates of tissues to and from the BioStorageBot™ incubator and HCA scanner.
Figure 3. Still images from a video of the entire automated MVP-liver tissue biofabrication highlighting keep steps (circled in red) including plate movement and lidding, printing tissue forms, pipetting primary cells and media, moving plates of tissues to and from the BioStorageBot™ incubator and HCA scanner.

ASLS has developed a human vascularized, thick liver tissue, called MVP liver™ tissue modules, to model liver tissue biology in vitro using a simple, robust, and automated approach. Importantly, the tissue includes isolated, native microvessel fragments (haMVs) that promote liver tissue functionality in the model including enhanced gene expression and drug responses. The modules are readily re-formatted for specific application and study needs. The liver tissue environment is such that the dynamics of focal disease elements, for example tumors or parasite forms, can be examined in the context of healthy liver tissue cells and stroma enabling a breadth of studies and discoveries.


 

Angiomics Human Adipose Microvessels are available for purchase at: https://www.advancedsolutions.com/microvessels


BioApps™ and MVPliver™tissue kits are available for purchase at https://www.advancedsolutions.com/bioapps


The BioAssembly™ Platform is available at https://www.advancedsolutions.com/

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