Liver transplantation is the key treatment for liver failure, yet organ scarcity, exacerbated by high discard rates of steatotic livers, leads to high waitlist mortality. Preclinical models of steatosis are necessary to understand the pathophysiology of the disease and to develop pharmacological interventions to decrease disease burden and liver discard rate. In this paper, we develop an expedited 3D steatotic organoid model containing primary human hepatocytes and non-parenchymal cells. We present our iterative approach as we transition from 2D to 3D models and from immortalized to primary cells to optimize conditions for the development of a 3D human steatosis model. Both primary cell aggregation and steatosis induction time were reduced from the standard, 5-7 days, to 2 days. Our 3D model incorporates human primary hepatocytes from discarded liver tissues, which have not been used in organoids previously due to their rapid loss of phenotype in culture. After optimizing our steatosis induction media there was a mix of macro- and micro-steatosis in these primary hepatocytes which is consistent with the human pathology. Our approach achieves a model reflective of the liver pathology, preserving cellular phenotypes and viability while exhibiting markers of oxidative stress, a key factor contributing to complications in the transplantation of steatotic livers.

Background. The pulmonary assist system (PAS) is a wearable respiratory support system that is currently under development for patients with chronic lung disease as a bridge to lung transplantation or as destination therapy. This study evaluates the long-term performance and biocompatibility of the PAS in a 5-d awake, ovine model. Methods. The PAS was attached to normal sheep in venovenous configuration. Components of the PAS included a 0.9 m2 surface area oxygenator and a lightweight, battery-powered axial flow pump. The system was also tested using the Abbott PediMag as the control pump. Each sheep was supported on the PAS for 5 d with 2 L/min blood flow and 4 L/min sweep gas. Activated clotting times of 200-240 s were maintained using intravenous heparin. Pump performance, oxygen transfer, oxygenator resistance, and hematologic parameters were measured throughout the support. Results. The PAS, either using the axial flow pump or PediMag (n = 4 each), was well tolerated by the sheep without signs of device-related organ damage or hemolysis. All the studies achieved the full, 5-d study duration. The oxygenator resistance remained consistent without significant clot formation in all experiments with an average resistance of 2.55 +/- 0.10 mm Hg/(L/min). The system achieved an average oxygen transfer rate of 116.4 +/- 5.5 mL/min, with an average Hb concentration of 9.2 +/- 0.6 g/dL. White blood cell, platelet, and hematocrit levels also remained stable and within normal limits throughout the study period. Conclusions. The PAS provided 5 d of uncomplicated ambulatory respiratory support with minimal clot formation, stable gas exchange, blood flow resistance, and hematologic parameters.

Blood-contacting medical devices, especially extracorporeal membrane oxygenators (ECMOs), are highly susceptible to surface-induced coagulation because of their extensive surface area. This can compromise device functionality and lead to life-threatening complications. High doses of anticoagulants, combined with anti-thrombogenic surface coatings, are typically employed to mitigate this risk, but such treatment can lead to hemorrhagic complications. Therefore, bioactive surface coatings that mimic endothelial blood regulation are needed. However, evaluating these coatings under realistic ECMO conditions is both expensive and challenging. This study utilizes microchannel devices to simulate ECMO fluid dynamics and assess the clot-lysis efficacy of a self-activating fibrinolytic coating system. The system uses antifouling polymer brushes combined with tissue plasminogen activator (tPA) to induce fibrinolysis at the surface. Here, tPA catalyzes the conversion of blood plasminogen into plasmin, which dissolves clots. This positive feedback loop enhances clot digestion under ECMO-like conditions. This findings demonstrate that this coating system can significantly improve the hemocompatibility of medical device surfaces.

Although the high surface area-to-volume ratio of the artificial lung fiber bundle enhances gas exchange, the large surface area, dense arrangement, and surface chemistries of the fibers are major contributors to thrombosis. To mitigate this, it is essential to uniformly modify the surface chemistries to effectively reduce non-specific protein fouling, which can help limit thrombosis and lower the risk of thromboembolism or bleeding caused by systemic anticoagulants. In this study, we explored the application and antifouling properties of zwitterionic polymer grafts on polypropylene fiber bundles. The grafting process involved priming the artificial lung device with zwitterionic polysulfobetaine molecules and polydopamine linkers for in situ coating. The antifouling performance was evaluated using standard fibrinogen enzyme-linked immunosorbent assay (ELISA) and platelet lactate dehydrogenase fouling assays. X-ray Photoelectron Spectroscopy confirmed the surface coating, and significant reductions in fouling were observed on coated fibers compared to uncoated ones, demonstrating the utility of the grafting process and the promise of its antifouling effects. However, differences in the appearance of the coating on fibers within the bundle were noted with the coating by priming process, which could affect the overall antifouling performance. Addressing this issue could further enhance the antifouling efficiency of lung fiber bundles modified through in situ grafting.

Blood-bearing medical devices are essential for the delivery of critical care medicine and are often required to function for weeks to months. However, thrombus formation on their surfaces can lead to reduced device function and failure and expose patients to systemic thrombosis risks. While clinical anticoagulants reduce device related thrombosis, they also increase patient bleeding risk. The root cause of device thrombosis and inflammation is protein adsorption on the biomaterial surfaces of these devices. Protein adsorption activates the coagulation cascade and complement, and this, in turn, activates platelets and white blood cells. Surface modifications with zwitterionic polymers are particularly effective at reducing protein adsorption as well as conformational changes in proteins due to their hydrophilicity. Multiple coating strategies have been developed using carboxybetaine (CB), sulfobetaine (SB), and 2-methacryloyloxyethyl phosphorylcholine (MPC) zwitterionic polymers applied to the metals and hydrophobic polymers that make up the bulk of blood-bearing medical devices. These coatings have been highly successful at creating large reductions in protein adsorption and platelet adhesion during studies on the order of hours on flat surfaces and at reducing thrombus formation for up to a few days in full medical devices. Future work needs to focus on their ability to limit inflammation, particularly during hemodialysis, and in providing anticoagulation on the order of weeks, particularly in artificial lungs.

The hollow fiber membrane bundle is the functional component of artificial lungs, transferring oxygen to and carbon dioxide from the blood. It is also the primary location of blood clot formation and propagation in these devices. The geometric design of fiber bundles is defined by a narrow set of parameters that determine gas exchange efficiency and blood flow resistance, principally: fiber packing density, path length, and frontal area. These same parameters also affect thrombosis. This study investigated the effect of these parameters on clot formation using 3D printed flow chambers that mimic the geometry and blood flow patterns of fiber bundles. Hollow fibers were represented by an array of vertical micro-rods (380 μm diameter) arranged with three packing densities (40%, 50%, and 60%) and two path lengths (2 and 4 cm). Blood was pumped through these devices corresponding to three mean blood flow velocities (16, 20, and 25 cm/min). Results showed that (1) clot formation decreases dramatically with decreasing packing density and increasing blood flow velocity, (2) clot formation at the outlet of the fiber bundle enhances deposition upstream, and consequently (3) greater path length provides greater clot-free fiber surface area for gas exchange than a shorter path length. These results can help guide the design of less thrombogenic, more efficient artificial lung designs.

BACKGROUND: Right heart failure is the major cause of death in pulmonary hypertension. Lung transplantation is the only long-term treatment option for patients who fail medical therapy. Due to the scarcity of donor lungs, there is a critical need to develop durable mechanical support for the failing right heart. A major design goal for durable support is to reduce the size and complexity of devices to facilitate ambulation. Toward this end, we sought to deploy wearable mechanical support technology in a sheep disease model of chronic right heart failure. METHODS: In 6 sheep with chronic right heart failure, a mechanical support system consisting of an extracorporeal blood pump coupled with a gas exchange unit was attached in a right atrium-to-left atrium configuration for up to 7 days. Circuit performance, hematologic parameters, and animal hemodynamics were analyzed. RESULTS: Six subjects underwent the chronic disease model for 56 to 71 days. Three of the subjects survived to the 7-day end-point for circulatory support. The circuit provided 2.8 (0.5) liter/min of flow compared to the native pulmonary blood flow of 3.5 (1.1) liter/min. The animals maintained physiologically balanced blood gas profile with a sweep flow of 1.2 (1.0) liter/min. Two animals freely ambulated while wearing the circuit. CONCLUSIONS: Our novel mechanical support system provided physiologic support for a large animal model of pulmonary hypertension with right heart failure. The small footprint of the circuit and the low sweep requirement demonstrate the feasibility of this technology to enable mobile ambulatory applications. J Heart Lung Transplant 2024;43:293-302 (c) 2023 International Society for Heart and Lung Transplantation. All rights reserved.

The Pulmonary Assist System (PAS) is currently under development as a wearable respiratory assist system. In this study, the hemocompatibility of the PAS’s axial-flow mechanical pump (AFP) was compared to other contemporary mechanical pumps in an acute ovine model. The PAS was attached to a normal sheep in a venovenous configuration using one of three pumps: 1) AFP, 2) ReliantHeart HeartAssist 5 (control), or 3) Abbott Pedimag (control) (n = 5 each). Each sheep was supported on the PAS for 12 hours with two L/minute of blood flow and four L/minute of sweep gas. Hemolysis, coagulation, inflammation, and platelet activation and loss were compared among the groups. In this study, the plasma-free hemoglobin (pfHb) was less than 10 mg/dl in all groups. The pfHb was significantly lower in the AFP group compared to other groups. There was no significant clot formation in the pumps and oxygenators in all groups. Furthermore, no significant differences in coagulation (oxygenator resistance, fibrinopeptide A), inflammation (white blood cell counts, IL-8), and platelet activation and loss (p-selectin, platelet counts) were observed among the groups (all, p > 0.05). This study demonstrates equivalent hemocompatibility of the PAS’s AFP to other contemporary mechanical pumps with a reduced level of hemolysis on startup.

The artificial lung has provided life-saving support for pulmonary disease patients and recently afforded patients with severe cases of COVID-19 better prognostic outcomes. While it addresses a critical medical need, reducing the risk of clotting inside the device remains challenging. Herein, a two-step surface coating process of the lung circuit using Zwitterionic polysulfobetaine methacrylate is evaluated for its nonspecific protein antifouling activity. It is hypothesized that similarly applied coatings on materials integrated (IT) or nonintegrated (NIT) into the circuit will yield similar antifouling activity. The effects of human plasma preconditioned with nitric oxide-loaded liposome on platelet (plt) fouling are also evaluated. Fibrinogen antifouling activities in coated fibers are similar in the IT and NIT groups. It however decreases in coated polycarbonate (PC) in the IT group. Also, plt antifouling activity in coated fibers is similar in the IT and NIT groups and is lower in coated PC and Tygon in the IT group compared to the NIT group. Coating process optimization in the IT lung circuit may help address difference in the coating appearance of outer and inner fiber bundle fibers, and the NO-liposome significantly reduces (86%) plt fouling on fibers indicating its potential use for blood anticoagulation.

BACKGROUND:The pulmonary assist system (PAS) is a wearable respiratory support system that is currently under development for patients with chronic lung disease as a bridge to lung transplantation or as destination therapy. This study evaluates the long-term performance and biocompatibility of the PAS in a 5-d awake, ovine model. METHODS:The PAS was attached to normal sheep in venovenous configuration. Components of the PAS included a 0.9 m 2 surface area oxygenator and a lightweight, battery-powered axial flow pump. The system was also tested using the Abbott PediMag as the control pump. Each sheep was supported on the PAS for 5 d with 2 L/min blood flow and 4 L/min sweep gas. Activated clotting times of 200-240 s were maintained using intravenous heparin. Pump performance, oxygen transfer, oxygenator resistance, and hematologic parameters were measured throughout the support. RESULTS:The PAS, either using the axial flow pump or PediMag (n = 4 each), was well tolerated by the sheep without signs of device-related organ damage or hemolysis. All the studies achieved the full, 5-d study duration. The oxygenator resistance remained consistent without significant clot formation in all experiments with an average resistance of 2.55 ± 0.10 mm Hg/(L/min). The system achieved an average oxygen transfer rate of 116.4 ± 5.5 mL/min, with an average Hb concentration of 9.2 ± 0.6 g/dL. White blood cell, platelet, and hematocrit levels also remained stable and within normal limits throughout the study period. CONCLUSIONS:The PAS provided 5 d of uncomplicated ambulatory respiratory support with minimal clot formation, stable gas exchange, blood flow resistance, and hematologic parameters.

Introduction: Wearable respiratory support technologies are under development as an alternative therapy for patients with advanced lung disease. Heparin and warfarin are the clinical standard anticoagulants for blood-contacting medical devices, but both require frequent anticoagulation monitoring. Direct oral anticoagulants (DOAC) are currently approved at a fixed dose without any monitoring. The present study evaluates the feasibility of rivaroxaban to inhibit artificial surface-induced coagulation. Methods: 12-hour ovine pharmacokinetics and pharmacodynamics of rivaroxaban were evaluated using activated clotting time (ACT), prothrombin time (PT), and plasma concentration using intravenous bolus doses of 0.25, 0.5, and 1mg/kg. The anticoagulation efficacy of these rivaroxaban doses was compared to heparin with an ACT target of 250-290s using a small-scale VV-ECMO circuit. The primary outcome was device failure, defined as a blood flow resistance increase to 20 times the baseline value. Results: Initial experiments demonstrated dose-dependent pharmacodynamics of rivaroxaban, as measured by ACT and PT (n=2, each). However, sheep expressed a higher volume of distribution (2.2+/-0.4L/kg), shorter half-life (1.8+/-0.3hr), and faster clearance (73+/-21L/hr) than humans. Small-scale ECMO experiments (n=4, each) demonstrated dose-dependent device survival with a mean survival of 58+/-26min (heparin), 31+/-9min (0.25mg/kg), 51+/-17min (0.5mg/kg), and 104+/-33min (1mg/kg) (p<0.01), where heparin and 0.5 mg/kg had comparable survival (p=0.59)(Figure). Conclusion: The results demonstrate that sheep are an appropriate model of rivaroxaban activity in humans, and a 0.5 mg/kg rivaroxaban dose provides artificial surface anticoagulation comparable to heparin. Our next step is to evaluate the long-term efficacy of rivaroxaban in 10-day full-scale VV-ECMO experiments in sheep.

Heparin anticoagulation increases the bleeding risk during extracorporeal life support (ECLS). This study determined whether factor XII (FXII) silencing using short interfering RNA (siRNA) can provide ECLS circuit anticoagulation without bleeding. Adult male, Sprague-Dawley rats were randomized to four groups (n = 3 each) based on anticoagulant: (1) no anticoagulant, (2) heparin, (3) FXII siRNA, or (4) nontargeting siRNA. Heparin was administered intravenously before and during ECLS. FXII or nontargeting siRNA were administered intravenously 3 days before the initiation of ECLS via lipidoid nanoparticles. The rats were placed on pumped, arteriovenous ECLS for 8 hours or until the blood flow resistance reached three times its baseline resistance. Without anticoagulant, mock-oxygenator resistance tripled within 7 ± 2 minutes. The resistance in the FXII siRNA group did not increase for 8 hours. There were no significant differences in resistance or mock-oxygenator thrombus volume between the FXII siRNA and the heparin groups. However, the bleeding time in the FXII siRNA group (3.4 ± 0.6 minutes) was significantly shorter than that in the heparin group (5.5 ± 0.5 minutes, p < 0.05). FXII silencing using siRNA provided simpler anticoagulation of ECLS circuits with reduced bleeding time as compared to heparin. http://links.lww.com/ASAIO/A937.

Background: Thrombosis causes rapid failure of oxygenators within extracorporeal life support (ECLS) circuits. To combat this problem, various groups are developing new surface coatings and anticoagulants, but their testing typically relies on either (a) inexpensive, but overly-brief (< 8 hour) in vitro or small animal in vivo testing or (b) expensive, long-term (days to weeks) testing in large animals. A more inexpensive model is thus needed to assess the long-term biocompatibility of new anticoagulant technologies. In this study, the feasibility of a long-term, ambulatory rabbit ECLS model was assessed. Methods: A miniaturized ECLS circuit was attached to rabbits (2.5-4 kg) under anesthesia using a pumpless arteriovenous (AV) configuration. The circuit contained a miniature artificial lung (surface area of 400 cm2) using the same materials as full-scale artificial lungs. The circuit was tunneled behind the animal’s back and secured just below the scruff of the neck. IV heparin was provided via a battery-powered infusion pump (SAI 3D Mini Infusion Pump) within a small jacket. Twelve non-recovery experiments were used to optimize the model, and two subsequent recovery experiments were run until oxygenator failure (blood flow rate below 5 mL/min for over 2 hours and/or resistance > 5x baseline). Non-recovery experiments were used to optimize the cannulation strategy. This included cannula type and circuit placement on the rabbit. Once optimized, two survival studies were performed. The average circuit blood flow during the first experiment was 50-60 mL/min. The circuit blood flow was then limited to 35-45 mL/min with a Hoffman clamp for the second experiment. Blood flow resistance was measured to assess anticoagulation effectiveness, and physiology was monitored through hepatic and renal panels. Results: Bilateral cannulation was ideal for circuit placement. A flexible 16G single-lumen central line was chosen because of its low blood flow resistance and resistance to kinking. The circuit was tunneled 40 cm, emerging just below the scruff. This enabled safe handling of the animal without impacting its mobility and ability to eat. The recovery experiments lasted 47 and 21 hours prior to oxygenator failure. Animals were completely ambulatory with free access to food and water. Heparin delivery could be controlled simply using the infusion pump, and coagulation could be assessed by drawing blood samples and measuring oxygenator resistance. The first survival rabbit developed hyperlipidemia on Day 1. The cause is unclear at this time but could be attributed to high blood flow through AV circuit. Conclusion: This study demonstrates the feasibility of using a lower-cost rabbit model for long-term anticoagulation testing that requires less staffing. Future studies will use this model to compare the anticoagulation effectiveness of heparin, a selective Factor XIIa inhibitor, and surface coatings for a period of five days.

INTRODUCTION: Right ventricular failure (RVF) is a major cause of mortality in pulmonary hyperten-sion (PH). Mechanical circulatory support holds promise for patients with medically refractory PH, but there are no clinical devices for long-term right ventricular (RV) support. Investigations into optimal device parameters and circuit configurations for PH-induced RVF (PH-RVF) are needed.METHODS: Eleven sheep underwent previously published chronic PH model. We then evaluated a low-profile, ventricular assist device (VAD)-quality pump combined with a novel low-resistance membrane oxygenator (Pulmonary Assist Device, PAD) under one of four central cannulation strategies: right atrium-to-left atrium (RA-LA, N = 3), RA-to-pulmonary artery (RA-PA, N=3), pumpless pulmonary artery-to-left atrium (PA-LA, N = 2), and RA-to-ascending aorta (RA-Ao, N = 3). Acute-on-chronic RVF (AoC RVF) was induced, and mechanical support was provided for up to 6 hours at blood flow rates of 1 to 3 liter/min. Circuit parameters, physiologic, hemodynamic, and echocardiography data were collected.RESULTS: The RA-LA configuration achieved blood flow of 3 liter/min. Meanwhile, RA-PA and RA-Ao faced challenges maintaining 3 liter/min of flow due to higher circuit afterload. Pumpless PA-LA was flow-limited due to anatomical limitations inherent to this animal model. RA-LA and RA-Ao dem-onstrated serial RV unloading with increasing circuit flow, while RA-PA did not. RA-LA also improved left ventricular (LV) and septal geometry by echocardiographic assessment and had the lowest inotropic dependence.CONCLUSION: RA-LA and RA-Ao configurations unload the RV, while RA-LA also lowers pump speed and inotropic requirements, and improves LV mechanics. RA-PA provide inferior support for PH-RVF, while an alternate animal model is needed to evaluate PA-LA. J Heart Lung Transplant 2023;42:859-867 & COPY; 2022 International Society for Heart and Lung Transplantation. All rights reserved.

Background: Fifteen million Americans suffer from chronic obstructive pulmonary disease (COPD). After failed optimal medical therapy, the only definitive treatment is lung transplantation, which is limited due to donor scarcity. Extracorporeal membrane oxygenation (ECMO) can be used in acute exacerbations of COPD or as a bridge to transplant for waitlisted COPD patients, but it is not currently suited for long-term respiratory support. Existing venovenous (VV) ECMO configurations often utilize a dual lumen cannula that is inserted into the jugular vein and is designed for short term use. While effective, dual lumen cannulas are associated with high resistance and malposition which limits blood flow, promotes cavitation, and increases blood trauma. Furthermore, patient ambulation is cumbersome because of the difficulty of securing the dual lumen cannula safely to the patient. A novel ECMO system that provides durable respiratory support could reduce morbidity and mortality in patients and facilitate ambulatory use. To this end, a dual lumen cannula that is attached to the heart and tunneled to a more ergonomic position could provide more durable, long term ECMO support. Here, we describe our initial efforts to develop a durable VV ECMO cannula with reduced resistance. Methods: A novel cannula for long-term VV ECMO support was developed using computer aided design. The cannula is designed for surgical attachment to the right atrium with the cannula’s drainage tip at the cavoatrial junction and the reinfusion port directed towards the tricuspid valve to minimize recirculation. Pressure drop was evaluated for the novel cannula, 28Fr, and 32Fr Crescent cannulas (MC3, Dexter, MI) for comparison (N≥5) in circuits primed with deionized water at ambient temperature. A Rotaflow (Maquet, Wayne, NJ) blood pump was operated at 2700-3625 RPM, and pressure drop was assessed for flow rates between 0.1 – 5 LPM. Porcine hearts were harvested from healthy pigs and utilized for ex vivo cannula fit studies. Water flow through the cannula into the right atrium was evaluated using videography. Results: The novel cannula drainage pressure drop (-12±1.1mmHg) was similar to the 28Fr Crescent (-13± 0.3mmHg) and 32Fr Crescent (-9±0.3mmHg) at 2LPM (Figure 1). Reinfusion pressure drop was similar between the novel cannula (22±1.2mmHg) and the 32Fr Crescent (21±0.4mmHg), and higher for the 28Fr Crescent (43±0.9mmHg) at 2LPM. Total pressure drop was similar between the novel cannula (33.4±1.2mmHg) and 32Fr Crescent (29.4±0.5mmHg) and higher for the 28Fr Crescent (57±1.0mmHg) at 2LPM. In ex-vivo heart studies flow through the novel cannula was directed towards the tricuspid valve and entered the right ventricle. Conclusions: Our novel cannula possesses an excellent pressure-flow profile, comparable to the largest-bore commercially available dual lumen cannulas. This novel cannula will enhance durability and ease of use for patients requiring durable mechanical respiratory support.Figure 1. Pressure Flow Curve for Novel VV ECMO Cannula

A new, lightweight (2.3 kg), ambulatory pulmonary assist system (PAS) underwent preliminary evaluation in ambulatory sheep. The PAS was purposefully designed for long-term extracorporeal respiratory support for chronic lung disease and utilizes a novel, small (0.9 m2 surface area) gas exchanger, the pulmonary assist device, with a modified Heart Assist 5 pump fitting in a small wearable pack. Prototype PAS were attached to two sheep in venovenous configuration for 7 and 14 days, evaluating ability to remain thrombus free; maintain gas exchange and blood flow resistance; avoid biocompatibility-related complications while allowing safe ambulation. The PAS achieved 1.56 L/min of flow at 10.8 kRPM with a 24 Fr cannula in sheep one and 2.0 L/min at 10.5 kRPM with a 28 Fr cannula in sheep 2 without significant change. Both sheep walked freely, demonstrating the first application of truly ambulatory ECMO in sheep. While in vitro testing evaluated PAS oxygen transfer rates of 104.6 ml/min at 2 L/min blood flow, oxygen transfer rates averaged 60.6 ml/min and 70.6 ml/min in studies 1 and 2, due to average hemoglobin concentrations lower than humans (8.9 and 10.5 g/dl, respectively). The presented cases support uncomplicated ambulation using the PAS.

Purpose Right ventricular failure (RVF) is a large contributor to morbidity and mortality in pulmonary hypertension (PH). Molecular understanding of RVF may facilitate identification of novel drug and device therapy targets. Using our previously published large animal model of PH-RVF, we performed RNA-seq analysis of RV tissues sampled from healthy sheep, PH sheep, and PH sheep that received mechanical circulatory support (MCS). Methods We assessed RV gene expression in adult sheep prior to and after completion of a previously described PH model. Three PH sheep subsequently underwent acute MCS for 3-6 hours. Right ventricular (RV) free wall tissues were collected prior to PA banding and at termination of MCS (pre-PH vs post-PH, N=3 each). One subject experienced severe maladaptive RVF and expired prior to MCS. This maladaptive characterization was based on its mixed venous saturation below 30% and several liters of ascites and pleural effusion found at necropsy. The pre-PH and post-PH RV tissue samples were analyzed for gene expression profile with RNAseq and studied with over-representation analysis to elucidate enriched pathways. Results RNAseq identified 358 genes with differential expression between pre-PH and post-PH tissue samples (p < 0.01, >2-fold change). Enrichment analysis showed that these genes were related to cardiomyocyte muscularization and proliferation, indicating adaptation to RV loading. The maladaptive RV sample, even when compared to the other PH sheep that received MCS, demonstrated markedly reduced expression of metabolic genes, especially in fatty acid oxidation. Conclusion RV load stress coincides with differential expression of genes related to cardiomyocyte muscularization and proliferation. Observations of reduced expression of fatty acid oxidation genes in a maladaptive subject with RVF warrants further investigation. The role of mechanical support on RV gene expression needs to be further studied in longer-term settings.

Artificial lungs are devices that achieve oxygen and carbon dioxide transfer directly with blood thereby providing respiratory support independently of the native lungs. Early artificial lungs used large interfacial areas of direct contact between blood and air to attain therapeutic levels of gas exchange. Membrane-based devices with a gas-permeable polymer separating blood and air eventually demonstrated the ability to provide much longer durations of support with fewer complications. Advances in membrane fabrication capabilities along with an improved understanding of gas transfer in blood have enabled continuous progression toward smaller and more efficient devices over the past 50 years. Modern-day artificial lungs utilizing microporous hollow fiber membranes can typically be used to provide weeks of support before a device exchange is necessary and are increasingly being used as a bridge to lung transplantation. A primary focus of current artificial lung research is extending the usable device lifetime which is most often limited by intra-device thrombosis. A variety of exciting approaches to selectively inhibiting contact-induced blood coagulation have shown promise in this regard. Additionally, the development of integrated and ultra-compact devices with high gas transfer efficiency is enabling progress toward mobile and wearable systems that may ease implementation of support outside of an intensive care setting. Lastly, research surrounding microchannel-based and biofabricated artificial lungs holds promise for more biomimetic devices that could offer improved support over current systems utilizing hollow fiber membranes.