MatriFlux

Bioprinted Perfusion Bioreactor

Motivation

The traditional in vitro models, predominantly two-dimensional cell systems, have been instrumental in providing insights into cellular functions, signaling pathways, and nuclear activities. Despite their utility, these models fall short of replicating the complexity and heterogeneity of in vivo systems, often necessitating the use of animals in experimental research. Annually, nearly 10 million animals are used in the EU for research, regulatory, and production purposes, with an additional 12 million bred and euthanized without being used in experiments. This extensive use of animals raises significant ethical concerns and is further complicated by the inefficiency of animal testing in predicting clinical outcomes, evidenced by the high 90% failure rate in clinical drug development. (Zushin et al. 2023) These issues highlight the urgent need for developing alternative methods that can offer more ethical approaches and have greater translational relevance to human medicine.

Purpose

MatriFlux is a bioprinted microfluidic perfusion bioreactor designed to cultivate 3D tissue constructs within a precisely controlled environment—regulating temperature, humidity, and CO2 levels. Its primary purpose is to replicate the physiological conditions of living organisms by matching tissue-specific flow rates and shear stresses that vascular cells experience. This bioreactor provides a more reliable in vitro platform for studying disease mechanisms, tissue development, and drug responses, thereby bridging the gap between experimental research and clinical applications.

Design

At the heart of this bioreactor is a bioprinted scaffold with intricate microfluidic channels. The microfluidic channels, which can range from a few hundred microns to several millimeters in width, facilitate the even distribution of nutrients, gases, and growth factors, closely replicating the natural microcirculation found in living tissues. The channel design can vary from planar configurations to more complex 3D structures that biomimetically fill up space, enhancing the bioreactor’s capability to mimic various tissue environments.

The bioreactor supports both "intravenous" and topical drug administration, allowing substances to be applied directly on top of the tissue model or introduced into the microfluidic system, mimicking how drugs are delivered within the body. Designed for versatility, the bioreactor facilitates the cultivation of diverse tissue types, from simple epithelial layers to complex vascularized organ tissues. These can be cultured both in isolation and interconnected setups, modeling systemic physiological interactions. Notably, the bioreactor can simulate both venous and arterial flows within a single tissue model, enhancing its applicability for advanced cardiovascular studies.

The bioreactor's modular design allows for customization to specific research needs, accommodating different sizes and shapes of tissue constructs. It incorporates monitoring capabilities, including real-time microscopy for detailed observation of the tissue model, ensuring precise tracking of cellular behavior. Additionally, real-time spectroscopic analysis of the perfused culture medium enables continuous monitoring of the cellular biochemical environment. Furthermore, the culture medium can be sampled or completely replaced remotely, ensuring minimal disruption to the tissue and ongoing experiments.

Impact

Biomedical Research

The bioreactor presents a tool for understanding complex biological processes. It enables the study of cellular behaviors and tissue responses in a more physiologically relevant setting, bridging the gap between traditional 2D cell cultures and in vivo studies.

Disease Modeling

The bioreactor can replicate human organ functions and disease states, allowing researchers to study diseases in human-relevant models. This can lead to a better understanding of disease mechanisms, identification of potential therapeutic targets, and testing of interventions in various conditions including cardiovascular, pulmonary, and neurodegenerative diseases.

Personalized (Precision) Medicine

By using cells derived from specific patients, the bioreactor can model individual responses to treatments, aiding in the customization of therapies optimized for each patient’s unique biological makeup.

Drug Testing and Development

The bioreactor offers a more accurate drug screening and toxicity testing platform. Enabling the cultivation of human tissues provides a more relevant model for human physiology, which can lead to more effective and safer drugs. This will significantly reduce the time and cost associated with drug development and decrease reliance on animal testing.

PK-PD Studies

The bioreactor’s ability to accurately simulate human physiology extends its utility to Pharmacokinetics-Pharmacodynamics (PK-PD) studies. These studies assess how a drug moves through and affects the body, crucial for understanding dosing requirements and therapeutic effects. By using the bioreactor for PK-PD modeling, researchers can predict how different dosages are metabolized and lead to specific outcomes, enhancing drug formulation and therapeutic strategies. This capability ensures that drug development is not only safer and more effective but also more efficient, minimizing the need for extensive clinical trials.

Safety Testing

The bioreactor offers a promising avenue for assessing the safety of chemicals and potential pharmaceuticals more effectively than conventional cell culture and animal testing, by mimicking the human response to these substances in a controlled environment.

ADME-Tox Studies

In addition to its other applications, the bioreactor is particularly valuable for ADME-Tox (Absorption, Distribution, Metabolism, Excretion, and Toxicology) studies. By simulating human metabolic processes more accurately than conventional models, the bioreactor can provide critical data on how drugs are metabolized and excreted in the human body, essential for predicting drug behavior and interactions before clinical trials.

References

Zushin, Peter-James H., Mukherjee, Souhrid, Wu, Joseph C., J. Clin. Invest. 133, 10–14 (2023)