Lung-Mimetic Hydrofoam Sealant to Treat Pulmonary Air Leak.

Pulmonary air leak is the most common complication of lung surgery, contributing to post-operative morbidity in up to 60% of patients; yet, there is no reliable treatment. Available surgical sealants do not match the demanding deformation mechanics of lung tissue; and therefore, fail to seal air leak. To address this therapeutic gap, a sealant with structural and mechanical similarity to subpleural lung is designed, developed, and systematically evaluated. This "lung-mimetic" sealant is a hydrofoam material that has alveolar-like porous ultrastructure, lung-like viscoelastic properties (adhesive, compressive, tensile), and lung extracellular matrix-derived signals (matrikines) to support tissue repair. In biocompatibility testing, the lung-mimetic sealant shows minimal cytotoxicity and immunogenicity in vitro. Human primary monocytes exposed to sealant matrikines in vitro upregulate key genes (MARCO, PDGFB, VEGF) known to correlate with pleural wound healing and tissue repair in vivo. In rat and swine models of pulmonary air leak, this lung-mimetic sealant rapidly seals air leak and restores baseline lung mechanics. Altogether, these data indicate that the lung-mimetic sealant can effectively seal pulmonary air leak and promote a favorable cellular response in vitro.

Sound-guided assessment and localization of pulmonary air leak.

Pulmonary air leak is the most common complication of lung surgery, with air leaks that persist longer than 5 days representing a major source of post-surgery morbidity. Clinical management of air leaks is challenging due to limited methods to precisely locate and assess leaks. Here, we present a sound-guided methodology that enables rapid quantitative assessment and precise localization of air leaks by analyzing the distinct sounds generated as the air escapes through defective lung tissue. Air leaks often present after lung surgery due to loss of tissue integrity at or near a staple line. Accordingly, we investigated air leak sounds from a focal pleural defect in a rat model and from a staple line failure in a clinically relevant swine model to demonstrate the high sensitivity and translational potential of this approach. In rat and swine models of free-flowing air leak under positive pressure ventilation with intrapleural microphone 1 cm from the lung surface, we identified that: (a) pulmonary air leaks generate sounds that contain distinct harmonic series, (b) acoustic characteristics of air leak sounds can be used to classify leak severity, and (c) precise location of the air leak can be determined with high resolution (within 1 cm) by mapping the sound loudness level across the lung surface. Our findings suggest that sound-guided assessment and localization of pulmonary air leaks could serve as a diagnostic tool to inform air leak detection and treatment strategies during video-assisted thoracoscopic surgery (VATS) or thoracotomy procedures.

A clinically relevant model of acute respiratory distress syndrome in human-size swine.

Despite over 30 years of intensive research for targeted therapies, treatment of acute respiratory distress syndrome (ARDS) remains supportive in nature. With mortality upwards of 30%, a high-fidelity pre-clinical model of ARDS, on which to test novel therapeutics, is urgently needed. We used the Yorkshire breed of swine to induce a reproducible model of ARDS in human-sized swine to allow the study of new therapeutics, from both mechanistic and clinical standpoints. For this, animals were anesthetized, intubated and mechanically ventilated, and pH-standardized gastric contents were delivered bronchoscopically, followed by intravenous infusion of Escherichia coli-derived lipopolysaccharide. Once the ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FIO2) had decreased to <150, the animals received standard ARDS treatment for up to 48 h. All swine developed moderate to severe ARDS. Chest radiographs taken at regular intervals showed significantly worse lung edema after induction of ARDS. Quantitative scoring of lung injury demonstrated time-dependent increases in interstitial and alveolar edema, neutrophil infiltration, and mild to moderate alveolar membrane thickening. This pre-clinical model of ARDS in human-sized swine recapitulates the clinical, radiographic and histopathologic manifestations of ARDS, providing a tool to study therapies for this highly morbid lung disease.

Pathological remodeling of distal lung matrix in end-stage cystic fibrosis patients.

BACKGROUND: Manifestations of cystic fibrosis, although well-characterized in the proximal airways, are understudied in the distal lung. Characterization of the cystic fibrosis lung 'matrisome' (matrix proteome) has not been previously described, and could help identify biomarkers and inform therapeutic strategies. METHODS: We performed liquid chromatography-mass spectrometry, gene ontology analysis, and multi-modal imaging, including histology, immunofluorescence, and electron microscopy for a comprehensive evaluation of distal human lung extracellular matrix (matrix) structure and composition in end-stage cystic fibrosis. RESULTS: Quantitative proteomic profiling identified sixty-eight (68) matrix constituents with significantly altered expression in end-stage cystic fibrosis. Over 90% of significantly different matrix peptides detected, including structural and basement membrane proteins, were expressed at lower levels in cystic fibrosis. However, the total abundance of matrix in cystic fibrosis lungs was not significantly different from control lungs, suggesting that cystic fibrosis leads to loss of diversity among lung matrix proteins rather than an absolute loss of matrix. Visualization of distal lung matrix via immunofluorescence and electron microscopy revealed pathological remodeling of distal lung tissue architecture and loss of alveolar basement membrane, consistent with significantly altered pathways identified by gene ontology analysis. CONCLUSIONS: Dysregulation of matrix organization and aberrant wound healing pathways are associated with loss of matrix protein diversity and obliteration of distal lung tissue structure in end-stage cystic fibrosis. While many therapeutics aim to functionally restore defective cystic fibrosis transmembrane conductance regulator (CFTR), drugs that target dysregulated matrix pathways may serve as adjunct interventions to support lung recovery.

Cross-Circulation for Extracorporeal Liver Support in a Swine Model.

Although machine perfusion has gained momentum as an organ preservation technique in liver transplantation, persistent organ shortages and high waitlist mortality highlight unmet needs for improved organ salvage strategies. Beyond preservation, extracorporeal organ support platforms can also aid the development and evaluation of novel therapeutics. Here, we report the use of veno-arterial-venous (V-AV) cross-circulation (XC) with a swine host to provide normothermic support to extracorporeal livers. Functional, biochemical, and morphological analyses of the extracorporeal livers and swine hosts were performed over 12 hours of support. Extracorporeal livers maintained synthetic function through alkaline bile production and metabolic activity through lactate clearance and oxygen consumption. Beyond initial reperfusion, no biochemical evidence of hepatocellular injury was observed. Histopathologic injury scoring showed improvements in sinusoidal dilatation and composite acute injury scores after 12 hours. Swine hosts remained hemodynamically stable throughout XC support. Altogether, these outcomes demonstrate the feasibility of using a novel V-AV XC technique to provide support for extracorporeal livers in a swine model. V-AV XC has potential applications as a translational research platform and clinical biotechnology for donor organ salvage.

Considerations in the Surgical Management of Unicuspid Aortic Stenosis.

Unicuspid aortic valve (UAV) stenosis is a rare condition accounting for 5% of non-rheumatic aortic stenosis. The diagnosis can be difficult to make prior to surgical intervention and transesophageal echocardiography has been demonstrated to be more accurate in making the diagnosis compared to transthoracic echocardiography. The presence of a posteriorly located aortic orifice on the short-axis views, with one or two visible raphe anteriorly; the absence of commissures (acommissural); or the presence of a lone commissure (unicommissural) between the left and noncoronary, or the left and right cusps suggests the diagnosis. Patients with UAV are predominantly males and present with stenosis about a decade earlier than those with the more prevalent bicuspid aortic valves (BAV). They more commonly present with aortic annular dilatation and have fewer comorbidities at presentation compared to patients with BAV. Surgical management of UAV stenosis includes aortic valve replacement through standard open heart surgery or percutaneous transcatheter aortic valve replacement (TAVR), aortic valve repair either by bicuspidization, tricuspidization or trileaflet reconstruction, or the Ross procedure. Patients with UAV stenosis require less concomitant coronary or other cardiac procedures when they need surgical intervention, but are about a decade younger at the time of their death. UAV stenosis is a distinct congenital anomaly with a different natural course than BAV. Surgical management should be individualized based on the patient's age at presentation, aortoannular anatomy, and associated cardiac conditions.

Xenogeneic cross-circulation for extracorporeal recovery of injured human lungs.

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering.