Anaerobic Gut-On-A-Chip with Oxygen Gradient Membrane

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Solution Overview

Problem

Current in vitro models fail to sustain complex populations of human aerobic and anaerobic microbiota in direct contact with living human tissues, limiting the analysis of dynamic and physiologically relevant host-microbiome interactions.

Innovation Solution

A microfluidic device with a membrane allowing oxygen flow between two channels, one containing human intestinal epithelium and the other vascular endothelium, creates a physiologically relevant oxygen gradient, enabling stable co-culture of complex microbial communities with real-time oxygen monitoring using embedded microscale oxygen sensors.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If aerobic co-culture conditions are used, then oxygen levels are sufficient for human intestinal cells, but microbial diversity decreases and obligate anaerobes cannot survive

Engineering Contradiction:

Improvehuman intestinal cell viabilityVSAvoidmicrobial diversity

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The device divides the culture system into two separate channels: an apical channel for human intestinal epithelium and a basolateral channel for microbiota. This segmentation allows each channel to have optimized oxygen conditions - the apical channel receives oxygenated medium for cell viability while the basolateral channel maintains lower oxygen levels for anaerobic bacteria survival

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Different oxygen concentrations are applied to different regions of the device. The apical channel is supplied with oxygenated medium (5% CO2, 95% air) to support human cell metabolism, while the basolateral channel receives less oxygenated medium to create anaerobic conditions suitable for obligate anaerobes like Bacteroides and Clostridium species

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If direct contact between human intestinal cells and complex microbiota is established, then physiologically relevant interactions are enabled, but bacterial overgrowth leads to cell injury and death within hours

Engineering Contradiction:

Improvehost-microbiome interaction capabilityVSAvoidco-culture stability

Core Design Contradiction:

Adaptability or versatilityVSDuration of action of stationary object

Solution Approach 1:

A porous polycarbonate membrane serves as an intermediary between the apical and basolateral channels. This membrane allows selective passage of nutrients, waste products, and signaling molecules while providing mechanical support and preventing direct bacterial contact with epithelial cells, thus avoiding cell injury from bacterial overgrowth

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The device uses controlled fluid flow through microchannels to deliver nutrients and maintain waste removal. Peristalsis-like mechanical deformations are applied to the membrane to enhance mixing and simulate physiological conditions, enabling stable co-culture for weeks rather than hours

Inventive Principle:

Principle #29Pneumatics and hydraulics

3Ease of operation

If existing in vitro models are used, then human host-microbe interactions can be studied, but they cannot maintain stable complex microbial communities in direct contact with intestinal epithelium

Engineering Contradiction:

Improvemodel accessibilityVSAvoidmicrobial community stability

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The system transitions from static culture conditions to dynamic flow conditions with peristalsis-like mechanical deformations. This dynamic environment better mimics physiological conditions in the human intestine, enabling stable maintenance of complex microbial communities while remaining operationally accessible through standardized microfluidic techniques

Inventive Principle:

Principle #15Dynamics

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This setup supports the growth of diverse microbial communities similar to those found in the human intestine, enhancing intestinal barrier function and allowing for extended co-culture of living human intestinal epithelium with complex gut microbiota, facilitating the study of host-microbiome interactions and potential therapeutic developments.

Implementation Method 1

a membrane located at an interface region between the first microchannel and the second microchannel, the membrane being composed of an oxygen-permeable material or further having pores via which oxygen flows between the first microchannel and the second microchannel

Methodology Applied

Scientific EffectOxygen flow through membrane: Permeation

Data Source

PatentUS20240002808A1Complex Human Gut Microbiome Cultured In An Anaerobic Human Gut-On-A-Chip

Publication Date: 2024.01.04 PRESIDENT & FELLOWS OF HARVARD COLLEGE

AI summary

A microfluidic device is directed to sustaining a complex microbial community in direct and indirect contact with living human intestinal cells in vitro. The device includes a first microchannel having cultured cells of a human intestinal epithelium and microbiota, the first microchannel further having a first level of oxygen. The device further includes a second microchannel having cultured cells of a vascular endothelium, the second microchannel further having a second level of oxygen. The device also includes a membrane located at an interface region between the first microchannel and the second microchannel, the membrane being composed of an oxygen-permeable material or further having pores via which oxygen flows between the first microchannel and the second microchannel to form a physiologically-relevant oxygen gradient.