Frontiers in Lab on a Chip Technologies is delighted to present the ‘Reviews in’ series of article collections. Reviews in Organ on a Chip will publish high-quality scholarly review papers on key topics across the field of Organ on a Chip. It aims to highlight recent advances in the field, whilst emphasizing important directions and new possibilities for future inquiries. We anticipate the research presented will promote discussion in the Lab on a Chip community and translate to best practice applications in Organ on a Chip research, as well as stimulating understanding and future research. The Reviews in Organ on a Chip collection welcomes reviews, mini-reviews, and perspective-type articles across the full section scope. New articles will be added to this collection as they are published.

Institute for Bioengineering of Catalonia (IBEC)

Terasaki Institute for Biomedical Innovation

University of California, Berkeley

Frontiers in Lab on a Chip Technologies

Organ on a Chip

Reviews in Organ on a Chip

Inhalation of ultrafine particles, aerosol contaminants, and cigarette smoke can induce respiratory diseases. As humans are constantly exposed to various exogenous substances, it is crucial to study their impacts on respiratory diseases and airway dysfunction. Recently, organ-on-a-chip technology has been applied in many research studies to understand disease mechanisms, drug screening, and drug testing. The combination of organ-on-a-chip technology and the air-liquid interface (ALI) culture method is emerging as a new platform for realistically mimicking the microenvironment and physiological motions of the human lungs. Breathing motion can be simulated through cyclic stretching, while blood flow can be replicated using channel flow within the chip. The ALI system is critical for mucociliary differentiation, pseudostratified morphology, and epithelial barrier function development. The combination of organ-on-a-chip technology and ALI systems allows the integration of cyclic stretch as a breathing motion and microfluidic channels as circulatory systems. The chip system can also integrate the lung epithelial cells, extracellular matrix, and microstructures, providing microenvironments such as fibroblast, collagen, and immune cells to the epithelial cells. This review discusses chip systems as effective tools for recapitulating human lung environments and how they are applied in biological studies against various pulmonary diseases such as infections or inflammation, fibrosis, and malignancy.

Inhalation of ultrafine particles, aerosol contaminants, and cigarette smoke can induce respiratory diseases. As humans are constantly exposed to various exogenous substances, it is crucial to study their impacts on respiratory diseases and airway dysfunction. Recently, organ-on-a-chip technology has been applied in many research studies to understand disease mechanisms, drug screening, and drug testing. The combination of organ-on-a-chip technology and the air-liquid interface (ALI) culture method is emerging as a new platform for realistically mimicking the microenvironment and physiological motions of the human lungs. Breathing motion can be simulated through cyclic stretching, while blood flow can be replicated using channel flow within the chip. The ALI system is critical for mucociliary differentiation, pseudostratified morphology, and epithelial barrier function development. The combination of organ-on-a-chip technology and ALI systems allows the integration of cyclic stretch as a breathing motion and microfluidic channels as circulatory systems. The chip system can also integrate the lung epithelial cells, extracellular matrix, and microstructures, providing microenvironments such as fibroblast, collagen, and immune cells to the epithelial cells. This review discusses chip systems as effective tools for recapitulating human lung environments and how they are applied in biological studies against various pulmonary diseases such as infections or inflammation, fibrosis, and malignancy.

Revolutionizing respiratory health research: “commercially-available lung-on-a-chip and air-liquid interface systems”

Organs-on-chips (OoC) are in vitro models that emulate key functionalities of tissues or organs in a miniaturized and highly controlled manner. Due to their high versatility, OoC have evolved as promising alternatives to animal testing for a more effective drug development pipeline. Additionally, OoC are revealing increased predictive power for toxicity screening applications as well as (patho-) physiology research models. It is anticipated that enabling technologies such as biofabrication, multimodality imaging, and artificial intelligence will play a critical role in the development of the next generation of OoC. These domains are expected to increase the mimicry of the human micro-physiology and functionality, enhance screening of cellular events, and generate high-content data for improved prediction. Although exponentially growing, the OoC field will strongly benefit from standardized tools to upgrade its implementational power. The complexity derived from the integration of multiple technologies and the current absence of concrete guidelines for establishing standards may be the reason for the slower adoption of OoC by industry, despite the fast progress of the field. Therefore, we argue that it is essential to consider standardization early on when using new enabling technologies, and we provide examples to illustrate how to maintain a focus on technology standards as these new technologies are used to build innovative OoC applications. Moreover, we stress the importance of informed design, use, and analysis decisions. Finally, we argue that this early focus on standards in innovation for OoC will facilitate their implementation.

Organs-on-chips (OoC) are in vitro models that emulate key functionalities of tissues or organs in a miniaturized and highly controlled manner. Due to their high versatility, OoC have evolved as promising alternatives to animal testing for a more effective drug development pipeline. Additionally, OoC are revealing increased predictive power for toxicity screening applications as well as (patho-) physiology research models. It is anticipated that enabling technologies such as biofabrication, multimodality imaging, and artificial intelligence will play a critical role in the development of the next generation of OoC. These domains are expected to increase the mimicry of the human micro-physiology and functionality, enhance screening of cellular events, and generate high-content data for improved prediction. Although exponentially growing, the OoC field will strongly benefit from standardized tools to upgrade its implementational power. The complexity derived from the integration of multiple technologies and the current absence of concrete guidelines for establishing standards may be the reason for the slower adoption of OoC by industry, despite the fast progress of the field. Therefore, we argue that it is essential to consider standardization early on when using new enabling technologies, and we provide examples to illustrate how to maintain a focus on technology standards as these new technologies are used to build innovative OoC applications. Moreover, we stress the importance of informed design, use, and analysis decisions. Finally, we argue that this early focus on standards in innovation for OoC will facilitate their implementation.

Guiding organs-on-chips towards applications: a balancing act between integration of advanced technologies and standardization

For patients with end stage organ failure, organ transplant is frequently the only curative option available. However, organs available for transplant are in critically short supply around the world, which has led to lengthy wait times and increased mortality. Increased global life expectancy, coupled with raised age thresholds for recipients, has heightened demand and further compounded the need for alternative strategies. Bioengineering substitutes including organ-on-a-chip and 3D bioprinting technologies have made considerable strides toward whole organ generation. Skin is the organ where the most advances have been made thus far, due to the relatively less complex spatial architecture and industry interest in the development of sophisticated models for pharmaceutical and cosmetics testing. Here, we discuss the challenges of recapitulating the complexity of native skin, including a stratified structure, vascularization, and inclusion of skin appendages, such as hair follicles and sweat glands. We discuss current technological and biological progress in the field of tissue and organ bioengineering as well as highlight future challenges to generate de novo tissue for skin grafting.

For patients with end stage organ failure, organ transplant is frequently the only curative option available. However, organs available for transplant are in critically short supply around the world, which has led to lengthy wait times and increased mortality. Increased global life expectancy, coupled with raised age thresholds for recipients, has heightened demand and further compounded the need for alternative strategies. Bioengineering substitutes including organ-on-a-chip and 3D bioprinting technologies have made considerable strides toward whole organ generation. Skin is the organ where the most advances have been made thus far, due to the relatively less complex spatial architecture and industry interest in the development of sophisticated models for pharmaceutical and cosmetics testing. Here, we discuss the challenges of recapitulating the complexity of native skin, including a stratified structure, vascularization, and inclusion of skin appendages, such as hair follicles and sweat glands. We discuss current technological and biological progress in the field of tissue and organ bioengineering as well as highlight future challenges to generate de novo tissue for skin grafting.

Moving lab-grown tissues into the clinic: organ-on-a-chip and bioengineered skin systems

Inflammatory bowel disease (IBD), celiac disease, and other inflammatory conditions of the gastrointestinal tract are highly prevalent in society. Due to the complexity of factors involved, detailed pathogenesis is difficult to determine and thus remains elusive in many cases. The advent of gut-on-chip devices has permitted more accurate modeling of the gut microenvironment with the inclusion of fluid flow and mechanical cues that are true to intestinal architecture and physiology. This review outlines the evolution of gut-on-chip platforms towards greater physiological relevance and elucidates how these devices have been used to model and study intestinal inflammation in humans. In addition, we identify key elements from both technological and disease standpoints that are integral for accurate gut-on-chip models of IBD and celiac disease.

Inflammatory bowel disease (IBD), celiac disease, and other inflammatory conditions of the gastrointestinal tract are highly prevalent in society. Due to the complexity of factors involved, detailed pathogenesis is difficult to determine and thus remains elusive in many cases. The advent of gut-on-chip devices has permitted more accurate modeling of the gut microenvironment with the inclusion of fluid flow and mechanical cues that are true to intestinal architecture and physiology. This review outlines the evolution of gut-on-chip platforms towards greater physiological relevance and elucidates how these devices have been used to model and study intestinal inflammation in humans. In addition, we identify key elements from both technological and disease standpoints that are integral for accurate gut-on-chip models of IBD and celiac disease.