Continued advancement of diagnostics and therapeutics is critically dependent on our understanding of the underlying mechanisms of disease processes. Tools that enhance disease modeling enable researchers to not only dissect contributing factors in a pathology of interest, but also facilitate testing for novel treatments in systems that mimic complex human biological systems.
Newly developed “organ-on-a-chip” systems use the controlled differentiation of pluripotent stem cells into target cell types, and further integrate engineered microfluidic systems, membranes, and compartments to functionally and physiologically model human organs.
Moreover, the latest iterations of the technology include multiple integrated organs on a single chip, which substantially improves modeling of multi-organ systems and overall translatability to patients. These dynamic systems provide an exciting new avenue for studying underlying disease mechanisms, therapeutic testing, and support the advancement of highly personalized medicine.
Broad applications for disease modeling
Despite the availability of existing culture systems that display some normal cellular function, organ chips provide the distinct advantage of integrated fluid dynamics, allowing the system to more closely replicate human structure and physiology. These attributes suggest that organ chips are a promising foundation for modeling a variety of biological systems and diseases.
As a primary example, Bein et al. of Harvard University recently created an intestinal organ chip to study the dynamics of intestinal coronavirus infection, and to further test the efficacy of approved therapeutics against viral infection. The group used patient-derived intestinal epithelial cells and immune cells to create a functioning intestinal chip with peristaltic activity, which they used to characterize immune responses to viral infection. Bein and colleagues also found that the protease inhibitor drug Nafamostat inhibited viral entry and reduced overall viral load in the system.
Though coronavirus presents a clear use for organ chips in the current health care climate, scientists are already applying these tools to a broad range of health conditions.
Neurological diseases are often mediated by reduced integrity of the blood-brain barrier (BBB), a complex physiological structure that’s extremely difficult to replicate with traditional in vitro tools.
Vatine et al. of Cedars-Sinai Medical Center successfully recapitulated the BBB on a chip using stem cell-derived endothelial cells, neurons, and astrocytes. Vatine and colleagues isolated pluripotent stem cells from a patient with Huntington’s disease to create their BBB chip, and demonstrated increased permeability in this chip compared to those from healthy controls. This approach suggests that we can model a vast range of neurological diseases using patient-derived stem cells.
Organ chips present new tools for personalized medicine
The aforementioned organ chips used patient-derived cells to create each organ system, suggesting we can use this technology to learn more about individual patients than ever before.
Personalized medicine demands the use of models that account for individual variations in genetics, physiology, and other biological factors to better understand the patient’s disease and how they might respond to potential treatments.
Organ chips are highly amenable to personalized medicine because they can incorporate a target individual’s genetics if created using patient-derived stem cells.
As mentioned above, Vatine et al. used stem cells from a patient with Huntington’s disease to model barrier permeability in the BBB. This patient was chosen as the source for the BBB chip because the individual had a known disease-causing mutation linked to the disease, allowing the researchers to understand BBB alterations specifically associated with the mutation.
In diseases where different mutations may lead to variations of the same disease, this approach facilitates a more personalized understanding of the pathology at hand.
Perhaps even more importantly, Vatine’s approach could be used to screen for drug efficacy on chips representing individual patients, each with varied genetics and pathophysiology.
Beyond patient genetics, organ chips provide a platform to even further personalize model systems for the patients they represent. Immune responses are a critical component of most known diseases, yet they are frequently excluded from in vitro systems in favor of a more reductionist approach.
Bein and colleagues demonstrated successful integration of immune cells in their enteric coronavirus model by isolating and including the patient’s peripheral blood mononuclear cells (PBMC), providing valuable insight into the individual’s immune response to coronavirus infection.
Others have even demonstrated the ability to colonize gut chips with a stable microbiome, the collection of microorganisms inhabiting an individual’s gastrointestinal tract.
A number of studies have shown that an individual’s microbiome may not only contribute to a variety of diseases, but can also substantially impact patient responses to therapeutics such as cancer immunotherapy.
Thus, the ability to integrate the microbiome into a patient-derived organ chip represents a remarkable advance in our capacity to create models at the patient level, and may further inform treatment strategies for those in need.
Working toward “body-on-a-chip”
Though organ chips have advanced rapidly in a short time span, the field remains a hotbed of innovation. Scientists aiming to enhance modeling for complex systems have created integrated multi-organ chips that replicate the collaborative functions of different body systems.
To that end, Pires de Mello et al. developed a heart-liver chip combined with a synthetic skin surface to create a platform for drug toxicity testing. Topical drugs were applied to the synthetic skin, and the model successfully predicted dosage-dependent effects on cardiac and liver function. This innovative chip demonstrates broad applicability to toxicity screening, and further illustrates the versatility of this technology.
As scientists continue to engineer chips to replicate more complex organ systems, their utility and translatability will continue to expand.
Widespread applications for research and medicine
Organ chips are a primary example of how sophisticated in vitro systems can improve our understanding of diseases and how we treat them. Not only do they dramatically advance the translatability of traditional in vitro systems, but they also alleviate some of the financial and regulatory burden of animal models.
Organ chips can successfully model complex physiological systems, facilitate personalized medicine, and even replicate multi-organ systems. As a relatively new technology, organ chips will continue to evolve and the need for their validation in established animal models should not be understated. Nonetheless, this technology has the potential for widespread research and clinical applications in pathophysiology, and therapeutic safety and efficacy.