Lung quantitative ultrasound to stage and monitor interstitial lung diseases.

Chronic interstitial lung diseases (ILDs) require frequent point-of-care monitoring. X-ray-based methods lack resolution and are ionizing. Chest computerized tomographic (CT) scans are expensive and provide more radiation. Conventional ultrasound can detect severe lung damage via vertical artifacts (B-lines). However, this information is not quantitative, and the appearance of B-lines is operator- and system-dependent. Here we demonstrate novel ultrasound-based biomarkers to assess severity of ILDs. Lung alveoli scatter ultrasound waves, leading to a complex acoustic signature, which is affected by changes in alveolar density due to ILDs. We exploit ultrasound scattering in the lung and combine quantitative ultrasound (QUS) parameters, to develop ultrasound-based biomarkers that significantly correlate (p = 1e-4 for edema and p = 3e-7 for fibrosis) to the severity of pulmonary fibrosis and edema in rodent lungs. These innovative QUS biomarkers will be very significant for monitoring severity of chronic ILDs and response to treatment, especially in this new era of miniaturized and highly portable ultrasound devices.

Instantly adhesive and ultra-elastic patches for dynamic organ and wound repair.

Bioadhesive materials and patches are promising alternatives to surgical sutures and staples. However, many existing bioadhesives do not meet the functional requirements of current surgical procedures and interventions. Here, we present a translational patch material that exhibits instant adhesion to tissues (2.5-fold stronger than Tisseel, an FDA-approved fibrin glue), ultra-stretchability (stretching to >300% its original length without losing elasticity), compatibility with rapid photo-projection (<2 min fabrication time/patch), and ability to deliver therapeutics. Using our established procedures for the in silico design and optimization of anisotropic-auxetic patches, we created next-generation patches for instant attachment to tissues while conforming to a broad range of organ mechanics ex vivo and in vivo. Patches coated with extracellular vesicles derived from mesenchymal stem cells demonstrate robust wound healing capability in vivo without inducing a foreign body response and without the need for patch removal that can cause pain and bleeding. We further demonstrate a single material-based, void-filling auxetic patch designed for the treatment of lung puncture wounds.

Design Optimization and Tradeoff Analysis of an Actuated Continuum Probe for Pulmonary Nodule Localization and Resection.

Pulmonary nodules are abnormal tissue masses in the lungs, typically less than 3.0 cm in diameter, commonly detected during imaging of the chest and lungs. While most pulmonary nodules are not cancerous, surgical resection may be required if growth is detected between scans. This resection is typically performed without the benefit of intraoperative imaging, making it difficult for surgeons to confidently provide appropriate margins. To enhance the efficacy of wedge resection, researchers have developed a modified ultrasound imaging approach that utilizes both multiple scattering (MS) and single scattering (SS) to enhance the accuracy of margin delineation. Clinical deployment of this novel ultrasound technology requires a highly maneuverable ultrasound probe, ideally one that could be deployed and actuated with minimal invasiveness. This study details the design optimization and tradeoff analysis of an actuated continuum probe for pulmonary nodule localization and resection. This device, deployed through intercostal ports, would enable the intraoperative imaging and precise mapping of nodules for improved margin delineation and patient outcomes. To achieve this objective, multiple objective genetic algorithms (MOGAs) and a design of experiments (DOE) study are used to explore the design space and quantify key dimensional relationships and their effects on probe actuation.

Lung Quantitative Ultrasound to Stage and Monitor Interstitial Lung Diseases.

Chronic interstitial lung diseases (ILDs) require frequent point-of-care monitoring. X-ray-based methods lack resolution and are ionizing. Chest computerized tomographic (CT) scans are expensive and provide more radiation. Conventional ultrasound can detect severe lung damage via vertical artifacts (B-lines). However, this information is not quantitative, and the appearance of B-lines is operator- and system-dependent. Here we demonstrate novel ultrasound-based biomarkers to assess severity of ILDs. Lung alveoli scatter ultrasound waves, leading to a complex acoustic signature, which is affected by changes in alveolar density due to ILDs. We exploit ultrasound scattering in the lung and combine Quantitative Ultrasound (QUS) parameters, to develop ultrasound-based biomarkers that significantly correlate to the severity of pulmonary fibrosis and edema in rodent lungs. These innovative QUS biomarkers will be very significant for monitoring severity of chronic ILDs and response to treatment, especially in this new era of miniaturized and highly portable ultrasound devices.

Outcomes Following Lung Transplant for COVID-19-Related Complications in the US.

Importance: The COVID-19 pandemic led to the use of lung transplant as a lifesaving therapy for patients with irreversible lung injury. Limited information is currently available regarding the outcomes associated with this treatment modality. Objective: To describe the outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis. Design, Setting, and Participants: In this cohort study, lung transplant recipient and donor characteristics and outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis were extracted from the US United Network for Organ Sharing database from March 2020 to August 2022 with a median (IQR) follow-up period of 186 (64-359) days in the acute respiratory distress syndrome group and 181 (40-350) days in the pulmonary fibrosis group. Overall survival was calculated using the Kaplan-Meier method. Cox proportional regression models were used to examine the association of certain variables with overall survival. Exposures: Lung transplant following COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis. Main Outcomes and Measures: Overall survival and graft failure rates. Results: Among 385 included patients undergoing lung transplant, 195 had COVID-19-related acute respiratory distress syndrome (142 male [72.8%]; median [IQR] age, 46 [38-54] years; median [IQR] allocation score, 88.3 [80.5-91.1]) and 190 had COVID-19-related pulmonary fibrosis (150 male [78.9%]; median [IQR] age, 54 [45-62]; median [IQR] allocation score, 78.5 [47.7-88.3]). There were 16 instances of acute rejection (8.7%) in the acute respiratory distress syndrome group and 15 (8.6%) in the pulmonary fibrosis group. The 1-, 6-, and 12- month overall survival rates were 0.99 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.91-0.98), and 0.88 (95% CI, 0.80-0.94) for the acute respiratory distress syndrome cohort and 0.96 (95% CI, 0.92-0.98), 0.92 (95% CI, 0.86-0.96), and 0.84 (95% CI, 0.74-0.90) for the pulmonary fibrosis cohort. Freedom from graft failure rates were 0.98 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.90-0.97), and 0.88 (95% CI, 0.79-0.93) in the 1-, 6-, and 12-month follow-up periods in the acute respiratory distress cohort and 0.96 (95% CI, 0.92-0.98), 0.93 (95% CI, 0.87-0.96), and 0.85 (95% CI, 0.74-0.91) in the pulmonary fibrosis cohort, respectively. Receiving a graft from a donor with a heavy and prolonged history of smoking was associated with worse overall survival in the acute respiratory distress syndrome cohort, whereas the characteristics associated with worse overall survival in the pulmonary fibrosis cohort included female recipient, male donor, and high recipient body mass index. Conclusions and Relevance: In this study, outcomes following lung transplant were similar in patients with irreversible respiratory failure due to COVID-19 and those with other pretransplant etiologies.

In vivo assessment of pulmonary fibrosis and edema in rodents using the backscatter coefficient and envelope statistics.

Quantitative ultrasound methods based on the backscatter coefficient (BSC) and envelope statistics have been used to quantify disease in a wide variety of tissues, such as prostate, lymph nodes, breast, and thyroid. However, to date, these methods have not been investigated in the lung. In this study, lung properties were quantified by BSC and envelope statistical parameters in normal, fibrotic, and edematous rat lungs in vivo. The average and standard deviation of each parameter were calculated for each lung as well as the evolution of each parameter with acoustic propagation time within the lung. The transport mean free path and backscattered frequency shift, two parameters that have been successfully used to assess pulmonary fibrosis and edema in prior work, were evaluated in combination with the BSC and envelope statistical parameters. Multiple BSC and envelope statistical parameters were found to provide contrast between control and diseased lungs. BSC and envelope statistical parameters were also significantly correlated with fibrosis severity using the modified Ashcroft fibrosis score as the histological gold standard. These results demonstrate the potential for BSC and envelope statistical parameters to improve the diagnosis of pulmonary fibrosis and edema as well as monitor pulmonary fibrosis.

Detecting pulmonary nodules by using ultrasound multiple scattering.

Although X-Ray Computed Tomography (CT) is widely used for detecting pulmonary nodules inside the parenchyma, it cannot be used during video-assisted surgical procedures. Real-time, non-ionizing, ultrasound-based techniques are an attractive alternative for nodule localization to ensure safe resection margins during surgery. Conventional ultrasound B-mode imaging of the lung is challenging due to multiple scattering. However, the multiple scattering contribution can be exploited to detect regions inside the lung containing no scatterers. Pulmonary nodules are homogeneous regions in contrast to the highly scattering parenchyma containing millions of air-filled alveoli. We developed a method relying on mapping the multiple scattering contribution inside the highly scattering lung to detect and localize pulmonary nodules. Impulse response matrices were acquired in ex-vivo pig and dog lungs using a linear array transducer to semi-locally investigate the backscattered field. Extracting the multiple-scattering contribution using singular-value decomposition and combining it with a depression detection algorithm allowed us to detect and localize regions with less multiple scattering, associated with the nodules. The feasibility of this method was demonstrated in five ex-vivo lungs containing a total of 20 artificial nodules. Ninety-five percent of the nodules were detected. Nodule depth and diameter significantly correlated with their ex-vivo CT-estimated counterparts (R = 0.960, 0.563, respectively).

Donation after circulatory death donors in lung transplantation.

Transplantation of any organ into a recipient requires a donor. Lung transplant has a long history of an inadequate number of suitable donors to meet demand, leading to deaths on the waiting list annually since national data was collected, and strict listing criteria. Before the Uniform Determination of Death Act (UDDA), passed in 1980, legally defined brain death in the U.S., all donors for lung transplant came from sudden death victims [uncontrolled Donation after Circulatory Death donors (uDCDs)] in the recipient's hospital emergency department. After passage of the UDDA, uDCDs were abandoned to Donation after Brain Death donors (DBDs)-perhaps prematurely. Compared to livers and kidneys, many DBDs have lungs that are unsuitable for transplant, due to aspiration pneumonia, neurogenic pulmonary edema, trauma, and the effects of brain death on lung function. Another group of donors has become available-patients with a devastating irrecoverable brain injury that do not meet criteria for brain death. If a decision is made by next-of-kin (NOK) to withdraw life support and allow death to occur by asphyxiation, with NOK consent, these individuals can have organs recovered if death occurs relatively quickly after cessation of mechanical ventilation and maintenance of their airway. These are known as controlled Donation after Circulatory Death donors (cDCDs). For a variety of reasons, in the U.S., lungs are recovered from cDCDs at a much lower rate than kidneys and livers. Ex-vivo lung perfusion (EVLP) in the last decade has had a modest impact on increasing the number of lungs for transplant from DBDs, but may have had a larger impact on lungs from cDCDs, and may be indispensable for safe transplantation of lungs from uDCDs. In the next decade, DCDs may have a substantial impact on the number of lung transplants performed in the U.S. and around the world.

In Vivo Assessment of Pulmonary Fibrosis and Pulmonary Edema in Rodents Using Ultrasound Multiple Scattering.

Idiopathic pulmonary fibrosis (IPF) affects 200 000 patients in the United States of America. IPF is responsible for changes in the micro-architecture of the lung parenchyma, such as thickening of the alveolar walls, which reduces compliance and elasticity. In this study, we verify the hypothesis that changes in the microarchitecture of the lung parenchyma can be characterized by exploiting multiple scattering of ultrasound waves by the alveolar structure. Ultrasound propagation in a highly scattering regime follows a diffusion process, which can be characterized using the diffusion constant. We hypothesize that in a fibrotic lung, the thickening of the alveolar wall reduces the amount of air (compared with a healthy lung), thereby minimizing the scattering events. Pulmonary fibrosis is created in Sprague-Dawley rats by instilling bleomycin into the airway. The rats are studied within 3 weeks after bleomycin administration. Using a 128-element linear array transducer operating at 7.8 MHz, in vivo experimental data are obtained from Sprague-Dawley rats and the transport mean free path (L*) and backscatter frequency shift (BFS) are evaluated. Significant differences ( ) in the L* values between control and fibrotic rats and in the BFS values between fibrotic and edematous rats showcase the potential of these parameters for diagnosis and monitoring of IPF.

How Should Lungs Be Allocated for Transplant?

As lung transplantation became established therapy for end-stage lung disease, there were not nearly enough suitable lungs from brain-dead organ donors to meet the need, leading to a focus on how lungs are allocated for transplant. Originally lungs were allocated by the United Network for Organ Sharing (UNOS) like hearts-by waiting time, first to listed recipients in the organ procurement organization of the donor, then to potential recipients in concentric 500 nautical mile circles. This resulted in long waiting times and increasing waitlist deaths. In 1999, the Health Resources and Services Administration published a Final Rule, requesting UNOS to review organ allocation algorithms to ensure that they complied with the desire to allocate organs based on urgency, avoiding futile transplants, and minimizing the role of waiting time in organ allocation. This led to development of the lung allocation score (LAS), which allocates lungs based on urgency and transplant benefit, introduced in 2005. The U.S. LAS system was adopted by Eurotransplant to allocate unused lungs between donor countries, and by both Germany and the Netherlands for lung allocation in their countries. This article will review the history of lung allocation, discuss the impact of LAS and its shortcomings, suggest recommendations to increase the number of lungs for transplant, and improve allocation of donated lungs. Ultimately, the goal of organ transplant research is to have so many organs to transplant that allocation systems are unnecessary.