Organs-on-a-chip for drug discovery

https://doi.org/10.1016/j.coph.2013.06.005Get rights and content

Highlights

  • Heart-on-a-chip for cardiac drug development.

  • Microfluidic devices mimicking the lung structure help generate disease models.

  • Microfluidic tissue engineering leads to functional intestine models in vitro.

The current drug discovery process is arduous and costly, and a majority of the drug candidates entering clinical trials fail to make it to the marketplace. The standard static well culture approaches, although useful, do not fully capture the intricate in vivo environment. By merging the advances in microfluidics with microfabrication technologies, novel platforms are being introduced that lead to the creation of organ functions on a single chip. Within these platforms, microengineering enables precise control over the cellular microenvironment, whereas microfluidics provides an ability to perfuse the constructs on a chip and to connect individual sections with each other. This approach results in microsystems that may better represent the in vivo environment. These organ-on-a-chip platforms can be utilized for developing disease models as well as for conducting drug testing studies. In this article, we highlight several key developments in these microscale platforms for drug discovery applications.

Introduction

The conventional drug discovery process is long and costly, as the majority of the drug candidates tend to fail during the clinical trials. A major reason for such a low success rate is our inability to predict the toxicity and efficacy of drugs before expensive human clinical trials. For example, in vivo the tissues reside in a dynamic environment, which is continuously perfused with blood involving interactions between cells and organs. In addition, the cells or the tissues within the body are constantly being stimulated by chemical, mechanical and electrical cues. Finally, human cells are known to respond differently to chemicals compared to animal cells and therefore new, efficient systems must utilize human tissues to be able to predict complex responses. Novel technologies at the interface of tissue engineering and microfluidics are emerging as candidates that may be able to aid this field and accelerate the drug discovery process.

Adopted from the traditional semiconductor industry, microfabrication and microfluidic technologies are powerful approaches to create small structures for a variety of applications in biotechnology. In drug discovery, microscale platforms allow precise delivery of fluids with reduced reagent volumes and can be utilized for high-throughput screening [1, 2, 3, 4]. Microengineering technologies can also be used for fabricating tissue-like structures that mimic the natural complexity of tissues [5]. Such microscale tissue platforms may be useful in recreating the intricacies of the in vivo environment with microscale precision and can also provide chemical, electrical, or mechanical cues representative of the living environment. For example, microscale perfusion bioreactors (devices enabling manipulation of biological materials, such as proteins, cells, or tissues) can be generated through the use of already available microfluidic systems for loading, manipulation, and analysis of a sample [6]. These systems present a dynamic environment for cells, and can be used for drug toxicity studies. Furthermore, the fabrication of metal electrodes on ultra thin stretchable substrates can be used to record or stimulate signals from brain slices [7]. Additionally, on-chip sensors are being developed to monitor tissue viability and functionality in real-time [8]. The technology to create constructs with microscale resolution also provides an opportunity to precisely manipulate a certain number of cells within these platforms [9].

The creation of functional tissue constructs on-chip with an ability to control the cellular microenvironment presents numerous opportunities in basic biology, tissue engineering and drug screening studies. Moving beyond static cultures, this emerging and exciting field termed ‘organs-on-a-chip’ provides opportunities to probe the cellular behavior against a plethora of stimuli [10, 11, 12]. These systems can further be utilized to create disease models, they can be perfused to create dynamic culture environments (Figure 1), and can be exposed to gradients of drugs — all on the same platform [13] (Figure 2). In this review, we highlight several key papers in the organ-on-a-chip field, namely the heart, the lung, and the intestine. Although studies are being conducted to generate tissues representing most, if not all organs in the human body — from the eye and the skin, to the blood–brain barrier and neuronal tissue, to cartilage and bone tissues — we have chosen to focus on recent organs-on-a-chip that have utilized efficient microfluidic solutions.

Section snippets

Heart

Heart disease is responsible for 1 out of 4 of all deaths in the United States, roughly 600 000 cases every year [14]. Hence, research on cardiac drug development, side effects of drugs and the interactions between multiple drugs has been a strong focus in the medical community [15, 16, 17]. It is also important to detect any cardiotoxic effects of medications early in the drug development process, as their withdrawal from the market (e.g., Terfenadine, Astemizole, Grepafloxacin, Cisapride,

Lung

The lung is also subject to a range of diseases, such as asthma, chronic bronchitis, emphysema, and cancer. According to the American Lung Association, close to 9% of all adults in the US suffer from asthma or another condition affecting the lungs [22]. To better understand the changes in lungs due to injuries or cellular decay, or even just the mechanics of breathing, it is vital to study the tissue ex vivo. On-chip solutions utilizing microfluidics have enabled the generation of functional

Intestine

The gastrointestinal (GI) tract is also susceptible to a range of chronic conditions such gastroenteritis, Crohn's and Celiac diseases. Despite its importance, microfabricated devices mimicking the GI tract have only recently become a source of interest. This is partially due to the highly complex nature of the GI tract, including its intricate topography, the contractile motion of the intestines, and the myriads of naturally present bacteria [27, 28, 29]. However, microfluidics offers yet

Conclusions and outlook

In this review, we have provided a glimpse into some of the latest developments in the organ-on-a-chip field with the intent to create biological functions on-chip for disease modeling and drug discovery applications. Among the approaches discussed, the heart-on-a-chip project is enabled by cultivating cardiomyocytes on-chip, where researchers observed increases in beating rates in response to drugs. In another application, using a stretchable chip, the breathing movements of the lung were

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (32)

  • B.G. Chung et al.

    Micro- and nanoscale technologies for tissue engineering and drug discovery applications

    Expert Opin Drug Discov

    (2007)
  • A. Khademhosseini et al.

    Microscale technologies for tissue engineering and biology

    Proc Natl Acad Sci U S A

    (2006)
  • E. Figallo et al.

    Micro-bioreactor array for controlling cellular microenvironments

    Lab on a Chip

    (2007)
  • S. Lacour et al.

    Flexible and stretchable micro-electrodes for in vitro and in vivo neural interfaces

    Med Biol Eng Comput

    (2010)
  • D. Sud et al.

    Optical imaging in microfluidic bioreactors enables oxygen monitoring for continuous cell culture

    J Biomed Opt

    (2006)
  • Y.S. Hwang et al.

    Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11

    Proceedings of the National Academy of Sciences U S A

    (2009)
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