Plug-and-play organ-on-a-chip can be customized to the patient

Date:
April 27, 2022
Source:
Columbia University School of Engineering and Applied Science
Summary:
Researchers have developed a model of human physiology in the form
of a multi-organ chip consisting of engineered human heart, bone,
liver, and skin that are linked by vascular flow with circulating
immune cells, to allow recapitulation of interdependent organ
functions. The researchers have essentially created a plug-and-play
multi-organ chip, which is the size of a microscope slide, that
can be customized to the patient.



FULL STORY ========================================================================== Engineered tissues have become a critical component for modeling
diseases and testing the efficacy and safety of drugs in a human
context. A major challenge for researchers has been how to model body
functions and systemic diseases with multiple engineered tissues that can physiologically communicate -- just like they do in the body. However, it
is essential to provide each engineered tissue with its own environment so
that the specific tissue phenotypes can be maintained for weeks to months,
as required for biological and biomedical studies. Making the challenge
even more complex is the necessity of linking the tissue modules together
to facilitate their physiological communication, which is required for
modeling conditions that involve more than one organ system, without sacrificing the individual engineered tissue environments.


========================================================================== Novel plug-and-play multi-organ chip, customized to the patient Up to now,
no one has been able to meet both conditions. Today, a team of researchers
from Columbia Engineering and Columbia University Irving Medical Center
reports that they have developed a model of human physiology in the
form of a multi-organ chip consisting of engineered human heart, bone,
liver, and skin that are linked by vascular flow with circulating immune
cells, to allow recapitulation of interdependent organ functions. The researchers have essentially created a plug-and-play multi-organ chip,
which is the size of a microscope slide, that can be customized to the
patient. Because disease progression and responses to treatment vary
greatly from one person to another, such a chip will eventually enable personalized optimization of therapy for each patient. The study is the
cover story of the April 2022 issue of Nature Biomedical Engineering.

"This is a huge achievement for us -- we've spent ten years running
hundreds of experiments, exploring innumerable great ideas, and building
many prototypes, and now at last we've developed this platform that successfully captures the biology of organ interactions in the body,"
said the project leader Gordana Vunjak-Novakovic, University Professor
and the Mikati Foundation Professor of Biomedical Engineering, Medical Sciences, and Dental Medicine.

Inspired by the human body Taking inspiration from how the human
body works, the team has built a human tissue-chip system in which
they linked matured heart, liver, bone, and skin tissue modules by recirculating vascular flow, allowing for interdependent organs to
communicate just as they do in the human body. The researchers chose
these tissues because they have distinctly different embryonic origins, structural and functional properties, and are adversely affected by cancer treatment drugs, presenting a rigorous test of the proposed approach.



========================================================================== "Providing communication between tissues while preserving their
individual phenotypes has been a major challenge," said Kacey Ronaldson-Bouchard, the study's lead author and an associate research
scientist in Vunjak-Novakovic's Laboratory for Stem Cells and Tissue Engineering. "Because we focus on using patient-derived tissue models
we must individually mature each tissue so that it functions in a way
that mimics responses you would see in the patient, and we don't want to sacrifice this advanced functionality when connecting multiple tissues. In
the body, each organ maintains its own environment, while interacting with other organs by vascular flow carrying circulating cells and bioactive
factors. So we chose to connect the tissues by vascular circulation,
while preserving each individual tissue niche that is necessary to
maintain its biological fidelity, mimicking the way that our organs are connected within the body. " Optimized tissue modules can be maintained
for more than a month The group created tissue modules, each within its optimized environment and separated them from the common vascular flow
by a selectively permeable endothelial barrier. The individual tissue environments were able to communicate across the endothelial barriers
and via vascular circulation. The researchers also introduced into the
vascular circulation the monocytes giving rise to macrophages, because of
their important roles in directing tissue responses to injury, disease,
and therapeutic outcomes.

All tissues were derived from the same line of human induced pluripotent
stem cells (iPSC), obtained from a small sample of blood, in order to demonstrate the ability for individualized, patient-specific studies. And,
to prove the model can be used for long-term studies, the team maintained
the tissues, which had already been grown and matured for four to six
weeks, for an additional four weeks, after they were linked by vascular perfusion.

Using the model to study anticancer drugs The researchers also wanted
to demonstrate how the model could be used for studies of an important
systemic condition in a human context and chose to examine the adverse
effects of anticancer drugs. They investigated the effects of doxorubicin
-- a broadly used anticancer drug -- on heart, liver, bone, skin, and vasculature. They showed that the measured effects recapitulated those
reported from clinical studies of cancer therapy using the same drug.



==========================================================================
The team developed in parallel a novel computational model of the
multi-organ chip for mathematical simulations of drug's absorption, distribution, metabolism, and secretion. This model correctly predicted doxorubicin's metabolism into doxorubicinol and its diffusion into
the chip. The combination of the multi-organ chip with computational methodology in future studies of pharmacokinetics and pharmacodynamics
of other drugs provides an improved basis for preclinical to clinical extrapolation, with improvements in the drug development pipeline.

"While doing that, we were also able to identify some early molecular
markers of cardiotoxicity, the main side-effect that limits the broad
use of the drug.Most notably, the multi-organ chip predicted precisely
the cardiotoxicity and cardiomyopathy that often require clinicians to
decrease therapeutic dosages of doxorubicin or even to stop the therapy,"
said Vunjak-Novakovic.

Collaborations across the university The development of the
multi-organ chip began from a platform with the heart, liver,
and vasculature, nicknamed the HeLiVa platform. As is always the
case with Vunjak-Novakovic's biomedical research, collaborations
were critical for completing the work. These include the collective
talent of her laboratory, Andrea Califano and his systems biology team (Columbia University), Christopher S. Chen (Boston University) and Karen
K. Hirschi (University of Virginia) with their expertise in vascular
biology and engineering, Angela M. Christiano and her skin research team (Columbia University), Rajesh K. Soni of the Proteomics Core at Columbia University, and the computational modeling support of the team at CFD
Research Corporation.

A multitude of applications, allin individualized patient-specific
contexts The research team is currently using variations of this chip
to study, all in individualized patient-specific contexts: breast cancer metastasis; prostate cancer metastasis; leukemia; effects of radiation on
human tissues; the effects of SARS-CoV-2 on heart, lung, and vasculature;
the effects of ischemia on the heart and brain; and the safety and effectiveness of drugs. The group is also developing a user-friendly standardized chip for both academic and clinical laboratories, to help
utilize its full potential for advancing biological and medical studies.

Vunjak-Novakovic added, "After ten years of research on organs-on-chips,
we still find it amazing that we can model a patient's physiology by
connecting millimeter sized tissues -- the beating heart muscle, the metabolizing liver, and the functioning skin and bone that are grown
from the patient's cells. We are excited about the potential of this
approach. It's uniquely designed for studies of systemic conditions
associated with injury or disease, and will enable us to maintain the biological properties of engineered human tissues along with their communication. One patient at a time, from inflammation to cancer!"

========================================================================== Story Source: Materials provided by Columbia_University_School_of_Engineering_and_Applied Science. Original
written by Holly Evarts. Note: Content may be edited for style and length.


========================================================================== Related Multimedia:
* The_new_multi-organ_chip ========================================================================== Journal Reference:
1. Kacey Ronaldson-Bouchard, Diogo Teles, Keith Yeager, Daniel Naveed
Tavakol, Yimu Zhao, Alan Chramiec, Somnath Tagore, Max Summers,
Sophia Stylianos, Manuel Tamargo, Busub Marcus Lee, Susan
P. Halligan, Erbil Hasan Abaci, Zongyou Guo, Joanna Jacko'w,
Alberto Pappalardo, Jerry Shih, Rajesh K. Soni, Shivam Sonar,
Carrie German, Angela M. Christiano, Andrea Califano, Karen
K. Hirschi, Christopher S. Chen, Andrzej Przekwas, Gordana
Vunjak-Novakovic. A multi-organ chip with matured tissue niches
linked by vascular flow. Nature Biomedical Engineering, 2022; 6
(4): 351 DOI: 10.1038/s41551-022-00882-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220427115732.htm

--- up 8 weeks, 2 days, 10 hours, 51 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)