Current thoracic artificial lungs (TALs) have blood flow impedances greater than the natural lungs, which can result in abnormal pulmonary hemodynamics. This study investigated the impedance and gas transfer performance of a TAL with a compliant housing (cTAL). Fluid-structure interaction (FSI) analysis was performed using ADINA to examine the effect of the inlet and outlet expansion angle, θ, on device impedance and blood flow patterns. Based on the results, the θ=45° model was chosen for prototyping and in vitro testing. Glycerol was pumped through this cTAL at 2, 4, and 6 L/min at 80 and 100 beats/min, and the zeroth and first harmonic impedance moduli, Z0 and Z1, were calculated. Gas transfer testing was conducted at blood flow rates of 3, 5, and 7 L/min. FSI results indicated that the 45° model had an ideal combination of low impedance and even blood flow patterns, and was thus chosen for prototyping. In vitro, Z0=0.53 ± 0.06 mmHg/(L/min) and Z1=0.86 ± 0.08 mmHg/(L/min) at 4 L/min and 100 beats/min. Outlet PO2 and SO2 values were above 200 mmHg and 99.5%, respectively, at each flow rate. Thus, the cTAL had lower impedance than hard-shell TALs and excellent gas transfer.

The compliant Thoracic Artificial Lung (cTAL) has been studied in acute in vivo and in vitro experiments. The cTAL’s long term function and potential use as a bridge to lung transplantation are assessed presently. The cTAL without anti-coagulant coatings was attached to sheep (n=5) via the pulmonary artery and left atrium for 14 days. Systemic heparin anticoagulation was utilized. cTAL resistance, cTAL gas exchange, hematologic parameters, and organ function were recorded. Two sheep were euthanized for non-device related issues. The cTAL’s resistance averaged 1.04±0.05 mmHg/(L/min) with no statistically significant increases. The cTAL transferred 180±8 mL/min of oxygen with 3.18±0.05 L/min of blood flow. Except for transient surgical effects, organ function markers were largely unchanged. Necropsies revealed pulmonary edema and atelectasis, but no other derangements. Hemoglobin levels dropped with device attachment but remained steady at 9.0±0.1 g/dL thereafter. In a fourteen day experiment, the cTAL without anti-coagulant coatings exhibited minimal clot formation. Sheep physiology was largely unchanged, except for device attachment related hemodilution. This suggests that patients treated with the cTAL shouldn’t require multiple blood transfusions. Once tested with anti-coagulant coatings and plasma resistant gas exchange fiber, the cTAL could serve as a bridge to transplantation.

The large, densely packed artificial surface area of artificial lungs results in rapid clotting and device failure. Surface generated nitric oxide (NO) can be used to reduce platelet activation and coagulation on gas exchange fibers, while not inducing patient bleeding due to its short half-life in blood. To generate NO, artificial lungs can be manufactured with PDMS hollow fibers embedded with copper nanoparticles (Cu NP) and supplied with an infusion of the NO donor S-nitroso-Nacetyl-penicillamine (SNAP). The SNAP reacts with Cu NP to generate NO. This study investigates clot formation and gas exchange performance of artificial lungs with either NOgenerating Cu-PDMS or standard polymethylpentene (PMP) fibers. One miniature artificial lung (MAL) made with 10 wt% Cu-PDMS hollow fibers and one PMP control MAL were attached to sheep in parallel in a veno-venous extracorporeal membrane oxygenation circuit (n = 8). Blood flow through each device was set at 300 mL/min, and each device received a SNAP infusion of 0.12 μmol/min. The ACT was between 110-180s in all cases. Blood flow resistance was calculated as a measure of clot formation on the fiber bundle. Gas exchange experiments comparing the two groups were conducted every 24 hours at blood flow rates of 300 and 600 mL/ min. Devices were removed once the resistance reached 3x baseline (failure) or following 72 hours. All devices were imaged using scanning electron microscopy (SEM) at the inlet, outlet, and middle of the fiber bundle. The Cu-PDMS NO generating MALs had a significantly smaller increase in resistance compared to the control devices. Resistance rose from 26 ± 8 and 23 ± 5 in the control and Cu-PDMS devices, respectively, to 35 ± 8 mmHg/(mL/min) and 72 ± 23 mmHg/(mL/min) at the end of each experiment. The resistance and SEM imaging of fiber surfaces demonstrate lower clot formation on Cu-PDMS fibers. Although not statistically significant,

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.

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The next-generation of mesenchymal stromal cell (MSC) therapies aim to enhance efficacy via in vitro licensing. Various stimuli initiate immune regulation and the secretion of immunomodulatory molecules, such as anti-inflammatory mediators and antioxidants, prior to administration. Pro-inflammatory cytokines are a recognized catalyst of inflammatory licensing; however, biomechanical forces, such as fluid shear stress, are a second, distinct class of stimuli that incite functional maturation. Here we show mechanotransduction, achieved by exposing MSC to various grades of wall shear stress (WSS = 4, 8, and 12 dyne/cm2) within a scalable conditioning platform, enhances the immunomodulatory potential of MSC independent of classical pro-inflammatory cytokines. A modular parallel plate bioreactor was designed in CAD software to apply precise WSS upon adherent MSC populations. The novel bioreactor's inlet and outlet geometries were iteratively designed until computational fluid dynamic simulations confirmed >95% of the channel surface area experienced the target WSS +/-1 dyne/cm2. In vitro studies showed a dose-dependent effect of WSS on potency, evidenced by adipose tissue and bone marrow-derived MSC production of prostaglandin E2 (PGE2) and indoleamine 2,3 dioxygenase 1 (IDO1). Consistent, reproducible licensing occurred with significant impacts on cell viability and cellular yield at greater WSS magnitudes. These results suggest mechanotransduction as a viable, scalable pre-conditioning alternative to pro-inflammatory cytokines. Enhancing the immunomodulatory capacity of MSC via biomechanical conditioning represents a novel cell therapy manufacturing approach.

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