- Award ID(s):
- 1650601
- PAR ID:
- 10074142
- Date Published:
- Journal Name:
- Lab on a Chip
- Volume:
- 17
- Issue:
- 15
- ISSN:
- 1473-0197
- Page Range / eLocation ID:
- 2561 to 2571
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
Bacterial infections frequently occur within or near the vascular network as the vascular network connects organ systems and is essential in delivering and removing blood, essential nutrients, and waste products to and from organs. In turn, the vasculature plays a key role in the host immune response to bacterial infections. Technological advancements in microfluidic device design and development have yielded increasingly sophisticated and physiologically relevant models of the vasculature including vasculature-on-a-chip and organ-on-a-chip models. This review aims to highlight advancements in microfluidic device development that have enabled studies of the vascular response to bacteria and bacterial-derived molecules at or near the vascular interface. In the first section of this review, we discuss the use of parallel plate flow chambers and flow cells in studies of bacterial adhesion to the vasculature. We then highlight microfluidic models of the vasculature that have been utilized to study bacteria and bacterial-derived molecules at or near the vascular interface. Next, we review organ-on-a-chip models inclusive of the vasculature and pathogenic bacteria or bacterial-derived molecules that stimulate an inflammatory response within the model system. Finally, we provide recommendations for future research in advancing the understanding of host–bacteria interactions and responses during infections as well as in developing innovative antimicrobials for preventing and treating bacterial infections that capitalize on technological advancements in microfluidic device design and development.more » « less
-
ABSTRACT Transplantation remains the preferred treatment for end‐stage kidney disease but is critically limited by the number of available organs. Xenografts from genetically modified pigs have become a promising solution to the loss of life while waiting for transplantation. However, the current clinical model for xenotransplantation will require off‐site procurement, leading to a period of ischemia during transportation. As of today, there is limited understanding regarding the preservation of these organs, including the duration of viability, and the associated molecular changes. Thus, our aim was to evaluate the effects of static cold storage (SCS) on α1,3‐galactosyltransferase knockout (GGTA1 KO) kidney. After SCS, viability was further assessed using acellular sub‐normothermic ex vivo perfusion and simulated transplantation with human blood. Compared to baseline, tubular and glomerular interstitium was preserved after 2 days of SCS in both WT and GGTA1 KO kidneys. Bulk RNA‐sequencing demonstrated that only eight genes were differentially expressed after SCS in GGTA1 KO kidneys. During sub‐normothermic perfusion, kidney function, reflected by oxygen consumption, urine output, and lactate production was adequate in GGTA1 KO grafts. During a simulated transplant with human blood, macroscopic and histological assessment revealed minimal kidney injury. However, GGTA1 KO kidneys exhibited higher arterial resistance, increased lactate production, and reduced oxygen consumption during the simulated transplant. In summary, our study suggests that SCS is feasible for the preservation of porcine GGTA1 KO kidneys. However, alternative preservation methods should be evaluated for extended preservation of porcine grafts.
-
Kidney exchanges allow patients with end-stage renal disease to find a lifesaving living donor by way of an organized market. However, not all patients are equally easy to match, nor are all donor organs of equal quality---some patients are matched within weeks, while others may wait for years with no match offers at all. We propose the first decision-support tool for kidney exchange that takes as input the biological features of a patient-donor pair, and returns (i) the probability of being matched prior to expiry, and (conditioned on a match outcome), (ii) the waiting time for and (iii) the organ quality of the matched transplant. This information may be used to inform medical and insurance decisions. We predict all quantities (i, ii, iii) exclusively from match records that are readily available in any kidney exchange using a quantile random forest approach. To evaluate our approach, we developed two state-of-the-art realistic simulators based on data from the United Network for Organ Sharing that sample from the training and test distribution for these learning tasks---in our application these distributions are distinct. We analyze distributional shift through a theoretical lens, and show that the two distributions converge as the kidney exchange nears steady-state. We then show that our approach produces clinically-promising estimates using simulated data. Finally, we show how our approach, in conjunction with tools from the model explainability literature, can be used to calibrate and detect bias in matching policies.
-
Abstract Engineering physiologically relevant in vitro models of human organs remains a fundamental challenge. Despite significant strides made within the field, many promising organ‐on‐a‐chip models fall short in recapitulating cellular interactions with neighboring cell types, surrounding extracellular matrix (ECM), and exposure to soluble cues due, in part, to the formation of artificial structures that obstruct >50% of the surface area of the ECM. Here, a 3D cell culture platform based upon hydrophobic patterning of hydrogels that is capable of precisely generating a 3D ECM within a microfluidic channel with an interaction area >95% is reported. In this study, for demonstrative purposes, type I collagen (COL1), Matrigel (MAT), COL1/MAT mixture, hyaluronic acid, and cell‐laden MAT are formed in the device. Three potential applications are demonstrated, including creating a 3D endothelium model, studying the interstitial migration of cancer cells, and analyzing stem cell differentiation in a 3D environment. The hydrophobic patterned‐based 3D cell culture device provides the ease‐of‐fabrication and flexibility necessary for broad potential applications in organ‐on‐a‐chip platforms.
-
Abstract Despite decades of effort, the preservation of complex organs for transplantation remains a significant barrier that exacerbates the organ shortage crisis. Progress in organ preservation research is significantly hindered by suboptimal research tools that force investigators to sacrifice translatability over throughput. For instance, simple model systems, such as single cell monolayers or co‐cultures, lack native tissue structure and functional assessment, while mammalian whole organs are complex systems with confounding variables not compatible with high‐throughput experimentation. In response, diverse fields and industries have bridged this experimental gap through the development of rich and robust resources for the use of zebrafish as a model organism. Through this study, we aim to demonstrate the value zebrafish pose for the fields of solid organ preservation and transplantation, especially with respect to experimental transplantation efforts. A wide array of methods were customized and validated for preservation‐specific experimentation utilizing zebrafish, including the development of assays at multiple developmental stages (larvae and adult), methods for loading and unloading preservation agents, and the development of viability scores to quantify functional outcomes. Using this platform, the largest and most comprehensive screen of cryoprotectant agents (CPAs) was performed to determine their toxicity and efficiency at preserving complex organ systems using a high subzero approach called partial freezing (i.e., storage in the frozen state at −10°C). As a result, adult zebrafish cardiac function was successfully preserved after 5 days of partial freezing storage. In combination, the methods and techniques developed have the potential to drive and accelerate research in the fields of solid organ preservation and transplantation.