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Micromachines
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Microengineered Physiological Systems for Disease Modeling and Drug Testing
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Microengineered Physiological Systems for Disease Modeling and Drug Testing

A special issue of Micromachines (ISSN 2072-666X). This special issue belongs to the section "B：Biology and Biomedicine".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 67337

Special Issue Editor

Dr. YongTae Kim

E-Mail Website
Guest Editor
George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
Interests: lab-on-a-chip; organ-on-a-chip; nanotechnology; drug delivery; microfluidics

Special Issue Information

Dear Colleagues,

Reconstituting organ-level functions on chips is an emerging field in an attempt to create physiologically relevant environments in microscale devices and mimic the structure, function, and resulting physiology of human organs. Microphysiological systems (also termed organ-on-a-chip) is a 3D microfluidic cell culture system that represents key functional units of living human organs and simulates the physiological response for better predictive drug development and mechanistic disease modeling. The use of human cells to recapitulate the chemical and mechanical microenvironments within human organs and simulate the critical aspects will facilitate the examination of the interaction of drugs or multifunctional nanomaterials with biologically relevant microenvironments and ultimately contribute to rapid clinical translation of drugs, thereby bringing drugs to market more quickly and perhaps even eliminating the need for animal testing. This Special Issue of Micromachines aims at reviewing the current state-of-the-art and presenting perspectives of further development. Contributions related to organ-on-a-chip approaches reproducing tissue interface barriers, building tissue-level organization of parenchymal cells, and modeling systematic interactions of organs with functional scaling are welcome. Efforts to build advanced organ-on-a-chip technologies, including development of advanced biomaterials for 3D scaffolds, spatiotemporal regulation of 3D cellular environments, combination of in vitro and ex vivo experimental test-beds, and integrative approaches for organ–organ interactions will also be welcome. Finally, advanced studies on the applications of organ-on-a-chip technologies for drug screening and nanomedicine development are highly encouraged for submission.

Dr. YongTae Kim
Guest Editor

Manuscript Submission Information

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Keywords

  • microfluidics
  • lab-on-a-chip
  • organ-on-a-chip
  • organoid-on-a-chip
  • microphysiological systems

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Published Papers (11 papers)

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Research

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16 pages, 4031 KiB  
Article
Perfusion System for Modification of Luminal Contents of Human Intestinal Organoids and Realtime Imaging Analysis of Microbial Populations
by Nicholas J. Ginga, Raleigh Slyman, Ge-Ah Kim, Eric Parigoris, Sha Huang, Veda K. Yadagiri, Vincent B. Young, Jason R. Spence and Shuichi Takayama
Micromachines 2022, 13(1), 131; https://doi.org/10.3390/mi13010131 - 14 Jan 2022
Cited by 8 | Viewed by 3609
Abstract
Intestinal organoids are 3D cell structures that replicate some aspects of organ function and are organized with a polarized epithelium facing a central lumen. To enable more applications, new technologies are needed to access the luminal cavity and apical cell surface of organoids. [...] Read more.
Intestinal organoids are 3D cell structures that replicate some aspects of organ function and are organized with a polarized epithelium facing a central lumen. To enable more applications, new technologies are needed to access the luminal cavity and apical cell surface of organoids. We developed a perfusion system utilizing a double-barrel glass capillary with a pressure-based pump to access and modify the luminal contents of a human intestinal organoid for extended periods of time while applying cyclic cellular strain. Cyclic injection and withdrawal of fluorescent FITC-Dextran coupled with real-time measurement of fluorescence intensity showed discrete changes of intensity correlating with perfusion cycles. The perfusion system was also used to modify the lumen of organoids injected with GFP-expressing E. coli. Due to the low concentration and fluorescence of the E. coli, a novel imaging analysis method utilizing bacteria enumeration and image flattening was developed to monitor E. coli within the organoid. Collectively, this work shows that a double-barrel perfusion system provides constant luminal access and allows regulation of luminal contents and luminal mixing. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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13 pages, 3601 KiB  
Article
Toward Vasculature in Skeletal Muscle-on-a-Chip through Thermo-Responsive Sacrificial Templates
by Li Wan, James Flegle, Burak Ozdoganlar and Philip R. LeDuc
Micromachines 2020, 11(10), 907; https://doi.org/10.3390/mi11100907 - 30 Sep 2020
Cited by 17 | Viewed by 4881
Abstract
Developing new approaches for vascularizing synthetic tissue systems will have a tremendous impact in diverse areas. One area where this is particularly important is developing new skeletal muscle tissue systems, which could be utilized in physiological model studies and tissue regeneration. To develop [...] Read more.
Developing new approaches for vascularizing synthetic tissue systems will have a tremendous impact in diverse areas. One area where this is particularly important is developing new skeletal muscle tissue systems, which could be utilized in physiological model studies and tissue regeneration. To develop vascularized approaches a microfluidic on-chip design for creating channels in polymer systems can be pursued. Current microfluidic tissue engineering methods include soft lithography, rapid prototyping, and cell printing; however, these have limitations such as having their scaffolding being inorganic, less desirable planar vasculature geometry, low fabrication efficiency, and limited resolution. Here we successfully developed a circular microfluidic channel embedded in a 3D extracellular matrix scaffolding with 3D myogenesis. We used a thermo-responsive polymer approach with micromilling-molding and designed a mixture of polyester wax and paraffin wax to fabricate the sacrificial template for microfluidic channel generation in the scaffolding. These findings will impact a number of fields including biomaterials, biomimetic structures, and personalized medicine in the future. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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12 pages, 2433 KiB  
Article
Lipopolysaccharide-Induced Vascular Inflammation Model on Microfluidic Chip
by Ungsig Nam, Seunggyu Kim, Joonha Park and Jessie S. Jeon
Micromachines 2020, 11(8), 747; https://doi.org/10.3390/mi11080747 - 31 Jul 2020
Cited by 20 | Viewed by 4735
Abstract
Inflammation is the initiation of defense of our body against harmful stimuli. Lipopolysaccharide (LPS), originating from outer membrane of Gram-negative bacteria, causes inflammation in the animal’s body and can develop several diseases. In order to study the inflammatory response to LPS of blood [...] Read more.
Inflammation is the initiation of defense of our body against harmful stimuli. Lipopolysaccharide (LPS), originating from outer membrane of Gram-negative bacteria, causes inflammation in the animal’s body and can develop several diseases. In order to study the inflammatory response to LPS of blood vessels in vitro, 2D models have been mainly used previously. In this study, a microfluidic device was used to investigate independent inflammatory response of endothelial cells by LPS and interaction of inflamed blood vessel with monocytic THP-1 cells. Firstly, the diffusion of LPS across the collagen gel into blood vessel was simulated using COMSOL. Then, inflammatory response to LPS in engineered blood vessel was confirmed by the expression of Intercellular Adhesion Molecule 1 (ICAM-1) and VE-cadherin of blood vessel, and THP-1 cell adhesion and migration assay. Upregulation of ICAM-1 and downregulation of VE-cadherin in an LPS-treated condition was observed compared to normal condition. In the THP-1 cell adhesion and migration assay, the number of adhered and trans-endothelial migrated THP-1 cells were not different between conditions. However, migration distance of THP-1 was longer in the LPS treatment condition. In conclusion, we recapitulated the inflammatory response of blood vessels and the interaction of THP-1 cells with blood vessels due to the diffusion of LPS. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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18 pages, 5039 KiB  
Article
Three-Dimensional Regeneration of Patient-Derived Intestinal Organoid Epithelium in a Physiodynamic Mucosal Interface-on-a-Chip
by Yong Cheol Shin, Woojung Shin, Domin Koh, Alexander Wu, Yoko M. Ambrosini, Soyoun Min, S. Gail Eckhardt, R. Y. Declan Fleming, Seung Kim, Sowon Park, Hong Koh, Tae Kyung Yoo and Hyun Jung Kim
Micromachines 2020, 11(7), 663; https://doi.org/10.3390/mi11070663 - 7 Jul 2020
Cited by 52 | Viewed by 6782
Abstract
The regeneration of the mucosal interface of the human intestine is critical in the host–gut microbiome crosstalk associated with gastrointestinal diseases. The biopsy-derived intestinal organoids provide genetic information of patients with physiological cytodifferentiation. However, the enclosed lumen and static culture condition substantially limit [...] Read more.
The regeneration of the mucosal interface of the human intestine is critical in the host–gut microbiome crosstalk associated with gastrointestinal diseases. The biopsy-derived intestinal organoids provide genetic information of patients with physiological cytodifferentiation. However, the enclosed lumen and static culture condition substantially limit the utility of patient-derived organoids for microbiome-associated disease modeling. Here, we report a patient-specific three-dimensional (3D) physiodynamic mucosal interface-on-a-chip (PMI Chip) that provides a microphysiological intestinal milieu under defined biomechanics. The real-time imaging and computational simulation of the PMI Chip verified the recapitulation of non-linear luminal and microvascular flow that simulates the hydrodynamics in a living human gut. The multiaxial deformations in a convoluted microchannel not only induced dynamic cell strains but also enhanced particle mixing in the lumen microchannel. Under this physiodynamic condition, an organoid-derived epithelium obtained from the patients diagnosed with Crohn’s disease, ulcerative colitis, or colorectal cancer independently formed 3D epithelial layers with disease-specific differentiations. Moreover, co-culture with the human fecal microbiome in an anoxic–oxic interface resulted in the formation of stochastic microcolonies without a loss of epithelial barrier function. We envision that the patient-specific PMI Chip that conveys genetic, epigenetic, and environmental factors of individual patients will potentially demonstrate the pathophysiological dynamics and complex host–microbiome crosstalk to target a patient-specific disease modeling. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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20 pages, 2865 KiB  
Article
Chemotactic Responses of Jurkat Cells in Microfluidic Flow-Free Gradient Chambers
by Utku M. Sonmez, Adam Wood, Kyle Justus, Weijian Jiang, Fatima Syed-Picard, Philip R. LeDuc, Pawel Kalinski and Lance A. Davidson
Micromachines 2020, 11(4), 384; https://doi.org/10.3390/mi11040384 - 4 Apr 2020
Cited by 8 | Viewed by 4781
Abstract
Gradients of soluble molecules coordinate cellular communication in a diverse range of multicellular systems. Chemokine-driven chemotaxis is a key orchestrator of cell movement during organ development, immune response and cancer progression. Chemotaxis assays capable of examining cell responses to different chemokines in the [...] Read more.
Gradients of soluble molecules coordinate cellular communication in a diverse range of multicellular systems. Chemokine-driven chemotaxis is a key orchestrator of cell movement during organ development, immune response and cancer progression. Chemotaxis assays capable of examining cell responses to different chemokines in the context of various extracellular matrices will be crucial to characterize directed cell motion in conditions which mimic whole tissue conditions. Here, a microfluidic device which can generate different chemokine patterns in flow-free gradient chambers while controlling surface extracellular matrix (ECM) to study chemotaxis either at the population level or at the single cell level with high resolution imaging is presented. The device is produced by combining additive manufacturing (AM) and soft lithography. Generation of concentration gradients in the device were simulated and experimentally validated. Then, stable gradients were applied to modulate chemotaxis and chemokinetic response of Jurkat cells as a model for T lymphocyte motility. Live imaging of the gradient chambers allowed to track and quantify Jurkat cell migration patterns. Using this system, it has been found that the strength of the chemotactic response of Jurkat cells to CXCL12 gradient was reduced by increasing surface fibronectin in a dose-dependent manner. The chemotaxis of the Jurkat cells was also found to be governed not only by the CXCL12 gradient but also by the average CXCL12 concentration. Distinct migratory behaviors in response to chemokine gradients in different contexts may be physiologically relevant for shaping the host immune response and may serve to optimize the targeting and accumulation of immune cells to the inflammation site. Our approach demonstrates the feasibility of using a flow-free gradient chamber for evaluating cross-regulation of cell motility by multiple factors in different biologic processes. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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Review

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17 pages, 16524 KiB  
Review
The Future Application of Organ-on-a-Chip Technologies as Proving Grounds for MicroBioRobots
by Haley C. Fuller, Ting-Yen Wei, Michael R. Behrens and Warren C. Ruder
Micromachines 2020, 11(10), 947; https://doi.org/10.3390/mi11100947 - 20 Oct 2020
Cited by 8 | Viewed by 5153
Abstract
An evolving understanding of disease pathogenesis has compelled the development of new drug delivery approaches. Recently, bioinspired microrobots have gained traction as drug delivery systems. By leveraging the microscale phenomena found in physiological systems, these microrobots can be designed with greater maneuverability, which [...] Read more.
An evolving understanding of disease pathogenesis has compelled the development of new drug delivery approaches. Recently, bioinspired microrobots have gained traction as drug delivery systems. By leveraging the microscale phenomena found in physiological systems, these microrobots can be designed with greater maneuverability, which enables more precise, controlled drug release. Their function could be further improved by testing their efficacy in physiologically relevant model systems as part of their development. In parallel with the emergence of microscale robots, organ-on-a-chip technologies have become important in drug discovery and physiological modeling. These systems reproduce organ-level functions in microfluidic devices, and can also incorporate specific biological, chemical, and physical aspects of a disease. This review highlights recent developments in both microrobotics and organ-on-a-chip technologies and envisions their combined use for developing future drug delivery systems. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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22 pages, 5651 KiB  
Review
Lab-on-a-Chip for Cardiovascular Physiology and Pathology
by Sean Beverung, Jingwen Wu and Robert Steward, Jr.
Micromachines 2020, 11(10), 898; https://doi.org/10.3390/mi11100898 - 28 Sep 2020
Cited by 13 | Viewed by 4334
Abstract
Lab-on-a-chip technologies have allowed researchers to acquire a flexible, yet relatively inexpensive testbed to study one of the leading causes of death worldwide, cardiovascular disease. Cardiovascular diseases, such as peripheral artery disease, arteriosclerosis, and aortic stenosis, for example, have all been studied by [...] Read more.
Lab-on-a-chip technologies have allowed researchers to acquire a flexible, yet relatively inexpensive testbed to study one of the leading causes of death worldwide, cardiovascular disease. Cardiovascular diseases, such as peripheral artery disease, arteriosclerosis, and aortic stenosis, for example, have all been studied by lab-on-a-chip technologies. These technologies allow for the integration of mammalian cells into functional structures that mimic vital organs with geometries comparable to those found in vivo. For this review, we focus on microdevices that have been developed to study cardiovascular physiology and pathology. With these technologies, researchers can better understand the electrical–biomechanical properties unique to cardiomyocytes and better stimulate and understand the influence of blood flow on the human vasculature. Such studies have helped increase our understanding of many cardiovascular diseases in general; as such, we present here a review of the current state of the field and potential for the future. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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24 pages, 3665 KiB  
Review
Microphysiological Systems for Neurodegenerative Diseases in Central Nervous System
by Mihyeon Bae, Hee-Gyeong Yi, Jinah Jang and Dong-Woo Cho
Micromachines 2020, 11(9), 855; https://doi.org/10.3390/mi11090855 - 16 Sep 2020
Cited by 11 | Viewed by 5748
Abstract
Neurodegenerative diseases are among the most severe problems in aging societies. Various conventional experimental models, including 2D and animal models, have been used to investigate the pathogenesis of (and therapeutic mechanisms for) neurodegenerative diseases. However, the physiological gap between humans and the current [...] Read more.
Neurodegenerative diseases are among the most severe problems in aging societies. Various conventional experimental models, including 2D and animal models, have been used to investigate the pathogenesis of (and therapeutic mechanisms for) neurodegenerative diseases. However, the physiological gap between humans and the current models remains a hurdle to determining the complexity of an irreversible dysfunction in a neurodegenerative disease. Therefore, preclinical research requires advanced experimental models, i.e., those more physiologically relevant to the native nervous system, to bridge the gap between preclinical stages and patients. The neural microphysiological system (neural MPS) has emerged as an approach to summarizing the anatomical, biochemical, and pathological physiology of the nervous system for investigation of neurodegenerative diseases. This review introduces the components (such as cells and materials) and fabrication methods for designing a neural MPS. Moreover, the review discusses future perspectives for improving the physiological relevance to native neural systems. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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25 pages, 2719 KiB  
Review
Immune Organs and Immune Cells on a Chip: An Overview of Biomedical Applications
by Margaretha A. J. Morsink, Niels G. A. Willemen, Jeroen Leijten, Ruchi Bansal and Su Ryon Shin
Micromachines 2020, 11(9), 849; https://doi.org/10.3390/mi11090849 - 12 Sep 2020
Cited by 46 | Viewed by 11752
Abstract
Understanding the immune system is of great importance for the development of drugs and the design of medical implants. Traditionally, two-dimensional static cultures have been used to investigate the immune system in vitro, while animal models have been used to study the immune [...] Read more.
Understanding the immune system is of great importance for the development of drugs and the design of medical implants. Traditionally, two-dimensional static cultures have been used to investigate the immune system in vitro, while animal models have been used to study the immune system’s function and behavior in vivo. However, these conventional models do not fully emulate the complexity of the human immune system or the human in vivo microenvironment. Consequently, many promising preclinical findings have not been reproduced in human clinical trials. Organ-on-a-chip platforms can provide a solution to bridge this gap by offering human micro-(patho)physiological systems in which the immune system can be studied. This review provides an overview of the existing immune-organs-on-a-chip platforms, with a special emphasis on interorgan communication. In addition, future challenges to develop a comprehensive immune system-on-chip model are discussed. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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19 pages, 2636 KiB  
Review
Advanced Fabrication Techniques of Microengineered Physiological Systems
by Joseph R. Puryear III, Jeong-Kee Yoon and YongTae Kim
Micromachines 2020, 11(8), 730; https://doi.org/10.3390/mi11080730 - 28 Jul 2020
Cited by 29 | Viewed by 4326
Abstract
The field of organs-on-chips (OOCs) has experienced tremendous growth over the last decade. However, the current main limiting factor for further growth lies in the fabrication techniques utilized to reproducibly create multiscale and multifunctional devices. Conventional methods of photolithography and etching remain less [...] Read more.
The field of organs-on-chips (OOCs) has experienced tremendous growth over the last decade. However, the current main limiting factor for further growth lies in the fabrication techniques utilized to reproducibly create multiscale and multifunctional devices. Conventional methods of photolithography and etching remain less useful to complex geometric conditions with high precision needed to manufacture the devices, while laser-induced methods have become an alternative for higher precision engineering yet remain costly. Meanwhile, soft lithography has become the foundation upon which OOCs are fabricated and newer methods including 3D printing and injection molding show great promise to innovate the way OOCs are fabricated. This review is focused on the advantages and disadvantages associated with the commonly used fabrication techniques applied to these microengineered physiological systems (MPS) and the obstacles that remain in the way of further innovation in the field. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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32 pages, 3301 KiB  
Review
Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling
by Aria R. Henderson, Hyoann Choi and Esak Lee
Micromachines 2020, 11(2), 147; https://doi.org/10.3390/mi11020147 - 29 Jan 2020
Cited by 37 | Viewed by 10281
Abstract
The human circulatory system is divided into two complementary and different systems, the cardiovascular and the lymphatic system. The cardiovascular system is mainly concerned with providing nutrients to the body via blood and transporting wastes away from the tissues to be released from [...] Read more.
The human circulatory system is divided into two complementary and different systems, the cardiovascular and the lymphatic system. The cardiovascular system is mainly concerned with providing nutrients to the body via blood and transporting wastes away from the tissues to be released from the body. The lymphatic system focuses on the transport of fluid, cells, and lipid from interstitial tissue spaces to lymph nodes and, ultimately, to the cardiovascular system, as well as helps coordinate interstitial fluid and lipid homeostasis and immune responses. In addition to having distinct structures from each other, each system also has organ-specific variations throughout the body and both systems play important roles in maintaining homeostasis. Dysfunction of either system leads to devastating and potentially fatal diseases, warranting accurate models of both blood and lymphatic vessels for better studies. As these models also require physiological flow (luminal and interstitial), extracellular matrix conditions, dimensionality, chemotactic biochemical gradient, and stiffness, to better reflect in vivo, three dimensional (3D) microfluidic (on-a-chip) devices are promising platforms to model human physiology and pathology. In this review, we discuss the heterogeneity of both blood and lymphatic vessels, as well as current in vitro models. We, then, explore the organ-specific features of each system with examples in the gut and the brain and the implications of dysfunction of either vasculature in these organs. We close the review with discussions on current in vitro models for specific diseases with an emphasis on on-chip techniques. Full article
(This article belongs to the Special Issue Microengineered Physiological Systems for Disease Modeling and Drug Testing)
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