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19 pages, 6029 KiB

Open AccessArticle

Modular 3D In Vitro Artery-Mimicking Multichannel System for Recapitulating Vascular Stenosis and Inflammation

by Minkyung Cho and Je-Kyun Park

Micromachines 2021, 12(12), 1528; https://doi.org/10.3390/mi12121528 - 08 Dec 2021

Cited by 9 | Viewed by 2749

Inflammation and the immune response in atherosclerosis are complex processes involving local hemodynamics, the interaction of dysfunctional cells, and various pathological environments. Here, a modular multichannel system that mimics the human artery to demonstrate stenosis and inflammation and to study physical and chemical [...] Read more.

Inflammation and the immune response in atherosclerosis are complex processes involving local hemodynamics, the interaction of dysfunctional cells, and various pathological environments. Here, a modular multichannel system that mimics the human artery to demonstrate stenosis and inflammation and to study physical and chemical effects on biomimetic artery models is presented. Smooth muscle cells and endothelial cells were cocultured in the wrinkled surface in vivo-like circular channels to recapitulate the artery. An artery-mimicking multichannel module comprised four channels for the fabrication of coculture models and assigned various conditions for analysis to each model simultaneously. The manipulation became reproducible and stable through modularization, and each module could be replaced according to analytical purposes. A chamber module for culture was replaced with a microfluidic concentration gradient generator (CGG) module to achieve the cellular state of inflamed lesions by providing tumor necrosis factor (TNF)-α, in addition to the stenosis structure by tuning the channel geometry. Different TNF-α doses were administered in each channel by the CGG module to create functional inflammation models under various conditions. Through the tunable channel geometry and the microfluidic interfacing, this system has the potential to be used for further comprehensive research on vascular diseases such as atherosclerosis and thrombosis. Full article

(This article belongs to the Special Issue Microfluidic Artificial Organs)

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14 pages, 3209 KiB

Open AccessArticle

Advancing 3D-Printed Microfluidics: Characterization of a Gas-Permeable, High-Resolution PDMS Resin for Stereolithography

by Elyse Fleck, Alec Sunshine, Emma DeNatale, Charlise Keck, Alexandra McCann and Joseph Potkay

Micromachines 2021, 12(10), 1266; https://doi.org/10.3390/mi12101266 - 18 Oct 2021

Cited by 18 | Viewed by 3647

Abstract

The rapid expansion of microfluidic applications in the last decade has been curtailed by slow, laborious microfabrication techniques. Recently, microfluidics has been explored with additive manufacturing (AM), as it has gained legitimacy for producing end-use products and 3D printers have improved resolution capabilities. [...] Read more.

The rapid expansion of microfluidic applications in the last decade has been curtailed by slow, laborious microfabrication techniques. Recently, microfluidics has been explored with additive manufacturing (AM), as it has gained legitimacy for producing end-use products and 3D printers have improved resolution capabilities. While AM satisfies many shortcomings with current microfabrication techniques, there still lacks a suitable replacement for the most used material in microfluidic devices, poly(dimethylsiloxane) (PDMS). Formulation of a gas-permeable, high-resolution PDMS resin was developed using a methacrylate–PDMS copolymer and the novel combination of a photoabsorber, Sudan I, and photosensitizer, 2-Isopropylthioxanthone. Resin characterization and 3D printing were performed using a commercially available DLP–SLA system. A previously developed math model, mechanical testing, optical transmission, and gas-permeability testing were performed to validate the optimized resin formula. The resulting resin has Young’s modulus of 11.5 MPa, a 12% elongation at break, and optical transmission of >75% for wavelengths between 500 and 800 nm after polymerization, and is capable of creating channels as small as 60

μ

m in height and membranes as thin as 20

μ

m. The potential of AM is just being realized as a fabrication technique for microfluidics as developments in material science and 3D printing technologies continue to push the resolution capabilities of these systems. Full article

(This article belongs to the Special Issue Microfluidic Artificial Organs)

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15 pages, 2091 KiB

Open AccessArticle

Rapid Fabrication by Digital Light Processing 3D Printing of a SlipChip with Movable Ports for Local Delivery to Ex Vivo Organ Cultures

by Megan A Catterton, Alexander G Ball and Rebecca R Pompano

Micromachines 2021, 12(8), 993; https://doi.org/10.3390/mi12080993 - 20 Aug 2021

Cited by 4 | Viewed by 2590

Abstract

SlipChips are two-part microfluidic devices that can be reconfigured to change fluidic pathways for a wide range of functions, including tissue stimulation. Currently, fabrication of these devices at the prototype stage requires a skilled microfluidic technician, e.g., for wet etching or alignment steps. [...] Read more.

SlipChips are two-part microfluidic devices that can be reconfigured to change fluidic pathways for a wide range of functions, including tissue stimulation. Currently, fabrication of these devices at the prototype stage requires a skilled microfluidic technician, e.g., for wet etching or alignment steps. In most cases, SlipChip functionality requires an optically clear, smooth, and flat surface that is fluorophilic and hydrophobic. Here, we tested digital light processing (DLP) 3D printing, which is rapid, reproducible, and easily shared, as a solution for fabrication of SlipChips at the prototype stage. As a case study, we sought to fabricate a SlipChip intended for local delivery to live tissue slices through a movable microfluidic port. The device was comprised of two multi-layer components: an enclosed channel with a delivery port and a culture chamber for tissue slices with a permeable support. Once the design was optimized, we demonstrated its function by locally delivering a chemical probe to slices of hydrogel and to living tissue with up to 120 µm spatial resolution. By establishing the design principles for 3D printing of SlipChip devices, this work will enhance the ability to rapidly prototype such devices at mid-scale levels of production. Full article

(This article belongs to the Special Issue Microfluidic Artificial Organs)

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16 pages, 4590 KiB

Open AccessArticle

Pump-Free Microfluidic Hemofiltration Device

by Takahiro Ito, Takashi Ota, Rei Kono, Yoshitaka Miyaoka, Hidetoshi Ishibashi, Masaki Komori, Akio Yasukawa, Yoshihiko Kanno and Norihisa Miki

Micromachines 2021, 12(8), 992; https://doi.org/10.3390/mi12080992 - 20 Aug 2021

Cited by 1 | Viewed by 4859

Abstract

Hemofiltration removes water and small molecules from the blood via nanoporous filtering membranes. This paper discusses a pump-free hemofiltration device driven by the pressure difference between the artery and the vein. In the design of the filtering device, oncotic pressure needs to be [...] Read more.

Hemofiltration removes water and small molecules from the blood via nanoporous filtering membranes. This paper discusses a pump-free hemofiltration device driven by the pressure difference between the artery and the vein. In the design of the filtering device, oncotic pressure needs to be taken into consideration. Transmembrane pressure (TMP) determines the amount and direction of hemofiltration, which is calculated by subtracting the oncotic pressure from the blood pressure. Blood pressure decreases as the channels progress from the inlet to the outlet, while oncotic pressure increases slightly since no protein is removed from the blood to the filtrate in hemofiltration. When TMP is negative, the filtrate returns to the blood, i.e., backfiltration takes place. A small region of the device with negative TMP would thus result in a small amount of or even zero filtrates. First, we investigated this phenomenon using in vitro experiments. We then designed a hemofiltration system taking backfiltration into consideration. We divided the device into two parts. In the first part, the device has channels for the blood and filtrate with a nanoporous membrane. In the second part, the device does not have channels for filtration. This design ensures TMP is always positive in the first part and prevents backfiltration. The concept was verified using in vitro experiments and ex vivo experiments in beagle dogs. Given the simplicity of the device without pumps or electrical components, the proposed pump-free hemofiltration device may prove useful for either implantable or wearable hemofiltration. Full article

(This article belongs to the Special Issue Microfluidic Artificial Organs)

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17 pages, 2466 KiB

Open AccessArticle

Towards Biohybrid Lung: Induced Pluripotent Stem Cell Derived Endothelial Cells as Clinically Relevant Cell Source for Biologization

by Michael Pflaum, Julia Dahlmann, Lena Engels, Hossein Naghilouy-Hidaji, Denise Adam, Janina Zöllner, Annette Otto, Sabrina Schmeckebier, Ulrich Martin, Axel Haverich, Ruth Olmer and Bettina Wiegmann

Micromachines 2021, 12(8), 981; https://doi.org/10.3390/mi12080981 - 19 Aug 2021

Cited by 8 | Viewed by 2291

Abstract

In order to provide an alternative treatment option to lung transplantation for patients with end-stage lung disease, we aim for the development of an implantable biohybrid lung (BHL), based on hollow fiber membrane (HFM) technology used in extracorporeal membrane oxygenators. Complete hemocompatibility of [...] Read more.

In order to provide an alternative treatment option to lung transplantation for patients with end-stage lung disease, we aim for the development of an implantable biohybrid lung (BHL), based on hollow fiber membrane (HFM) technology used in extracorporeal membrane oxygenators. Complete hemocompatibility of all blood contacting surfaces is crucial for long-lasting BHL durability and can be achieved by their endothelialization. Autologous endothelial cells (ECs) would be the ideal cell source, but their limited proliferation potential excludes them for this purpose. As induced pluripotent stem cell-derived ECs enable the generation of a large number of ECs, we assessed and compared their capacity to form a viable and confluent monolayer on HFM, while indicating physiologic EC-specific anti-thrombogenic and anti-inflammatory properties. ECs were generated from three different human iPSC lines, and seeded onto fibronectin-coated poly-4-methyl-1-pentene (PMP) HFM. Following phenotypical characterization, ECs were analyzed for their thrombogenic and inflammatory behavior with or without TNFα induction, using FACS and qRT-PCR. Complementary, leukocyte- and platelet adhesion assays were carried out. The capacity of the iPSC-ECs to reendothelialize cell-free monolayer areas was assessed in a scratch assay. ECs sourced from umbilical cord blood (hCBECs) were used as control. iPSC-derived ECs formed confluent monolayers on the HFM and showed the typical EC-phenotype by expression of VE-cadherin and collagen-IV. A low protein and gene expression level of E-selectin and tissue factor was detected for all iPSC-ECs and the hCBECs, while a strong upregulation of these markers was noted upon stimulation with TNFα. This was in line with the physiological and strong induction of leukocyte adhesion detected after treatment with TNFα, iPSC-EC and hCBEC monolayers were capable of reducing thrombocyte adhesion and repopulating scratched areas. iPSCs offer the possibility to provide patient-specific ECs in abundant numbers needed to cover all blood contacting surfaces of the BHL with a viable, non-thrombogenic and non-inflammatory monolayer. iPSC-EC clones can differ in terms of their reendothelialization rate, and pro-inflammatory response. However, a less profound inflammatory response may even be advantageous for BHL application. With the proven ability of the seeded iPSC-ECs to reduce thrombocyte adhesion, we expect that thrombotic events that could lead to BHL occlusion can be avoided, and thus, justifies further studies on enabling BHL long-term application. Full article

(This article belongs to the Special Issue Microfluidic Artificial Organs)

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16 pages, 2819 KiB

Open AccessArticle

Toward Development of a Higher Flow Rate Hemocompatible Biomimetic Microfluidic Blood Oxygenator

by Jose Santos, Else M. Vedula, Weixuan Lai, Brett C. Isenberg, Diana J. Lewis, Dan Lang, David Sutherland, Teryn R. Roberts, George T. Harea, Christian Wells, Bryan Teece, Paramesh Karandikar, Joseph Urban, Thomas Risoleo, Alla Gimbel, Derek Solt, Sahar Leazer, Kevin K. Chung, Sivaprasad Sukavaneshvar, Andriy I. Batchinsky and Jeffrey T. Borenstein Show full author list Hide full author list

Micromachines 2021, 12(8), 888; https://doi.org/10.3390/mi12080888 - 28 Jul 2021

Cited by 9 | Viewed by 3061

Abstract

The recent emergence of microfluidic extracorporeal lung support technologies presents an opportunity to achieve high gas transfer efficiency and improved hemocompatibility relative to the current standard of care in extracorporeal membrane oxygenation (ECMO). However, a critical challenge in the field is the ability [...] Read more.

The recent emergence of microfluidic extracorporeal lung support technologies presents an opportunity to achieve high gas transfer efficiency and improved hemocompatibility relative to the current standard of care in extracorporeal membrane oxygenation (ECMO). However, a critical challenge in the field is the ability to scale these devices to clinically relevant blood flow rates, in part because the typically very low blood flow in a single layer of a microfluidic oxygenator device requires stacking of a logistically challenging number of layers. We have developed biomimetic microfluidic oxygenators for the past decade and report here on the development of a high-flow (30 mL/min) single-layer prototype, scalable to larger structures via stacking and assembly with blood distribution manifolds. Microfluidic oxygenators were designed with biomimetic in-layer blood distribution manifolds and arrays of parallel transfer channels, and were fabricated using high precision machined durable metal master molds and microreplication with silicone films, resulting in large area gas transfer devices. Oxygen transfer was evaluated by flowing 100% O₂ at 100 mL/min and blood at 0–30 mL/min while monitoring increases in O₂ partial pressures in the blood. This design resulted in an oxygen saturation increase from 65% to 95% at 20 mL/min and operation up to 30 mL/min in multiple devices, the highest value yet recorded in a single layer microfluidic device. In addition to evaluation of the device for blood oxygenation, a 6-h in vitro hemocompatibility test was conducted on devices (n = 5) at a 25 mL/min blood flow rate with heparinized swine donor blood against control circuits (n = 3). Initial hemocompatibility results indicate that this technology has the potential to benefit future applications in extracorporeal lung support technologies for acute lung injury. Full article

(This article belongs to the Special Issue Microfluidic Artificial Organs)

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Review

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19 pages, 3234 KiB

Open AccessReview

Diversity Models and Applications of 3D Breast Tumor-on-a-Chip

by Kena Song, Xiangyang Zu, Zhe Du, Zhigang Hu, Jingjing Wang and Jinghua Li

Micromachines 2021, 12(7), 814; https://doi.org/10.3390/mi12070814 - 12 Jul 2021

Cited by 12 | Viewed by 3090

Abstract

Breast disease is one of the critical diseases that plague females, as is known, breast cancer has high mortality, despite significant pathophysiological progress during the past few years. Novel diagnostic and therapeutic approaches are needed to break the stalemate. An organ-on-chip approach is [...] Read more.

Breast disease is one of the critical diseases that plague females, as is known, breast cancer has high mortality, despite significant pathophysiological progress during the past few years. Novel diagnostic and therapeutic approaches are needed to break the stalemate. An organ-on-chip approach is considered due to its ability to repeat the real conditions found in the body on microfluidic chips, offsetting the shortcomings of traditional 2D culture and animal tests. In recent years, the organ-on-chip approach has shown diversity, recreating the structure and functional units of the real organs/tissues. The applications were also developed rapidly from the laboratory to the industrialized market. This review focuses on breast tumor-on-a-chip approaches concerning the diversity models and applications. The models are summarized and categorized by typical biological reconstitution, considering the design and fabrication of the various breast models. The breast tumor-on-a-chip approach is a typical representative of organ chips, which are one of the precedents in the market. The applications are roughly divided into two categories: fundamental mechanism research and biological medicine. Finally, we discuss the prospect and deficiencies of the emerging technology. It has excellent prospects in all of the application fields, however there exist some deficiencies for promotion, such as the stability of the structure and function, and uniformity for quantity production. Full article

(This article belongs to the Special Issue Microfluidic Artificial Organs)

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18 pages, 9043 KiB

Open AccessReview

Mechanical Strain-Enabled Reconstitution of Dynamic Environment in Organ-on-a-Chip Platforms: A Review

by Qianbin Zhao, Tim Cole, Yuxin Zhang and Shi-Yang Tang

Micromachines 2021, 12(7), 765; https://doi.org/10.3390/mi12070765 - 28 Jun 2021

Cited by 11 | Viewed by 3966

Abstract

Organ-on-a-chip (OOC) uses the microfluidic 3D cell culture principle to reproduce organ- or tissue-level functionality at a small scale instead of replicating the entire human organ. This provides an alternative to animal models for drug development and environmental toxicology screening. In addition to [...] Read more.

Organ-on-a-chip (OOC) uses the microfluidic 3D cell culture principle to reproduce organ- or tissue-level functionality at a small scale instead of replicating the entire human organ. This provides an alternative to animal models for drug development and environmental toxicology screening. In addition to the biomimetic 3D microarchitecture and cell–cell interactions, it has been demonstrated that mechanical stimuli such as shear stress and mechanical strain significantly influence cell behavior and their response to pharmaceuticals. Microfluidics is capable of precisely manipulating the fluid of a microenvironment within a 3D cell culture platform. As a result, many OOC prototypes leverage microfluidic technology to reproduce the mechanically dynamic microenvironment on-chip and achieve enhanced in vitro functional organ models. Unlike shear stress that can be readily generated and precisely controlled using commercial pumping systems, dynamic systems for generating proper levels of mechanical strains are more complicated, and often require miniaturization and specialized designs. As such, this review proposes to summarize innovative microfluidic OOC platforms utilizing mechanical actuators that induce deflection of cultured cells/tissues for replicating the dynamic microenvironment of human organs. Full article

(This article belongs to the Special Issue Microfluidic Artificial Organs)

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