Clinical trials in lung transplantation have been hindered by a lack of clarity on the formulation and significance of endpoints for evaluating therapeutic efficacy. To address this challenge, a multidisciplinary working group from the International Society for Heart and Lung Transplantation developed consensus recommendations on endpoints beyond mortality. These endpoints include primary graft dysfunction (PGD), chronic lung allograft dysfunction (CLAD), acute cellular rejection (ACR), antibody-mediated rejection (AMR), immunosuppression-related complications, patient-reported outcomes (PROs), and pediatric-specific considerations. For each endpoint, a subgroup reviewed measurement best practices, assessed links to clinical benefit, and evaluated the evidence supporting their utility in clinical trial settings. Consensus was established through a Delphi process involving three rounds of voting. This document provides practical guidance for operationalizing these endpoints and outlines their optimal use in clinical trials. By standardizing trial design, these recommendations aim to accelerate the development of urgently needed therapies to improve lung transplantation outcomes.

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.

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.

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 ultrasound imaging is challenging due to multiple scattering (MS) from alveoli. Conventional B-mode does not provide lung microstructure images. However, MS signals can provide valuable information about structure and alveolar distribution and investigating conditions such as pulmonary edema. Lung edema results in fluid buildup in interstitial spaces and alveoli, affecting density of alveoli. Previously, we demonstrated that changes in the distribution of scatterers due to edema result in changes in the wave diffusion regime and the scattering mean free path was sensitive to lung injury due to induced edema in rodents. In the present study, we introduce a novel way of quantifying MS in lungs by isolating the single scattering (SS) and MS contributions and processing them separately. After inducing different severity of edema using ischemia reperfusion injury in 18 rats, full synthetic aperture transmit sequences were used to acquire backscattered signals. The SS/MS contributions were separated using singular value decomposition. The separated SS/MS intensities were calculated and a new parameter defined as the rate of decay in intensity with depth. To assess edema severity and method validation, ex vivo CT lung images were assigned scores compared with this novel biomarker (R = 0.47, p = 0.021). Lung wet/dry ratio was also compared (R = 0.52, p = 0.009).

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.

We are writing about the Point/Counterpoint discussion recently published in CHEST (August 2022) on the ethics of the use of normothermic regional perfusion in the recovery of organs from controlled donation after circulatory determination of death (cDCD).1DeCamp M. Snyder Sulmasy L. Fins J.J. Point: Does normothermic regional perfusion violate the ethical principles underlying organ procurement? Yes.Chest. 2022; 162: 288-290Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,2James L. Parent B. Moazami N. Smith D.E. Counterpoint: Does normothermic regional perfusion violate the ethical principles underlying organ procurement? No.Chest. 2022; 162: 290-292Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Both articles misrepresented the definition of death and failed to consider the ethical obligation to the donor, in particular registered organ donors (RODs) under state Uniform Animal Gift Act (UAGA) laws. The Uniform Definition of Death Act, which defines death as “irreversible cessation of circulatory and respiratory functions…,” was drafted after a President’s Commission published “Defining Death.”3President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral ResearchDefining death: a report on the medical, legal and ethical issues in the determination of death.http://tinyurl.com/zq6p5toDate accessed: August 6, 2022Google Scholar The President’s Commission clearly articulated that respiratory function required functioning muscles of respiration; maintaining ventilation with a mechanical ventilator does not restore function, which requires a functioning brainstem, and respiratory muscles. Similarly, the President’s Commission understood that restoring circulatory function requires a functioning heart and that maintaining circulation artificially did not prevent death declaration. Restarting circulation does not restart circulatory function. The President’s Commission erred by implying a precise time of death could be determined. We understand now that death of the brain is a process after circulation stops. Even if resuming circulation briefly prolongs that process, that is not illegal or unethical. More than 50% of Americans are RODs. All states have passed the amended UAGA, which specifically excludes next-of-kin from participating in the organ donation decision of RODs, clearly explained by Kurtz et al,4Kurtz S.F. Strong C.W. Gerasimow D. The 2006 Revised Uniform Anatomical Gift Act: a law to save lives. Health Lawyers News, 2007: 44-49Google Scholar first-authored by the attorney who was the reporter for the group who wrote the amended UAGA. The UAGA makes the ROD’s decision practically equivalent to an advanced directive. We may have not only an ethical obligation to honor the expressed consent to donate organs from RODs, but we may also have a legal obligation to do so. The UAGA has a serious impact on organ donation from cDCDs, which was not mentioned in either article or rebuttals.1DeCamp M. Snyder Sulmasy L. Fins J.J. Point: Does normothermic regional perfusion violate the ethical principles underlying organ procurement? Yes.Chest. 2022; 162: 288-290Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,2James L. Parent B. Moazami N. Smith D.E. Counterpoint: Does normothermic regional perfusion violate the ethical principles underlying organ procurement? No.Chest. 2022; 162: 290-292Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar If individuals expressed a desire to be organ donors on their death, and death is “planned” by withdrawal of life support, when is it appropriate to recover organs? And what should be done to maintain or enhance function of organs from RODs? These are critically important ethical issues. We believe adhering to the expressed premortal ROD consent has a substantial impact on the ethics and timing of normothermic regional perfusion in cDCDs and that normothermic regional perfusion in cDCDs does not restore circulatory function. T. M. E. was supported, in part, by the UNC Lung Transplant Research Fund, with generous contributions from the Ferguson family and John Doherty.

We exploit the random matrix theory to detect changes in rodent lungs exhibiting pulmonary fibrosis and edema. Coherences in the backscattered signals are stronger when single scattering dominates (fibrosis/edema). On the contrary, healthy lungs exhibit more apparent randomness due to multiple scattering. This leads to differences in the distribution of eigenvalues, which can be retrieved using Singular Value Decomposition of the Inter-elementResponse Matrix (IRM). We use features of the eigenvalue distribution (E(x), the expected value, and, the eigenvalue with the highest probability) to quantify changes in lung parenchyma and investigate whether they can improve the specificity of quantitative ultrasound to lung diseases. IRMs were acquired from 51 rat lungs (10 controls, 18 edematous, 17 fibrotic, 6 fibrotic rats, which were treated with Nintedanib) using a 128-element linear array (Verasonics L11-4v, 7.8 MHz). Severity of fibrosis and edema were quantified by histology and the ratio of wet to dry weight. Both parameters showed significant differences between edematous and fibrotic lungs, and between control and fibrotic lungs, which was significantly correlated to both the severity of fibrosis and edema. E(x) was significantly correlated to the severity of fibrosis. This suggests that these parameters could be part of a toolkit for the quantitative assessment of lung diseases.

Due to the scarcity of donor organs, transplant surgeons are actively looking for ways to improve the benefit and equity of organ allocation. One such undertaking occurred in 2005 with the introduction of the Lung Allocation Score (LAS) system. 1 Egan TM Murray S Bustami RT et al. Development of the new lung allocation system in the United States. Am J Transplant. 2006; 6: 1212-1227 Crossref PubMed Scopus (619) Google Scholar The primary changes that occurred with the LAS included incorporation of estimated waitlist survival and 1-year post-transplant survival instead of solely time accrued on the waitlist to determine priority. After introduction of the LAS, numerous analyses were performed that demonstrated that waitlist times were shortened, waitlist mortality decreased, and 1-year post-transplant survival was unaffected, even though sicker patients were being transplanted. 2 Kozower BD Meyers BF Smith MA et al. The impact of the lung allocation score on short-term transplantation outcomes: a multicenter study. J Thorac Cardiovasc Surg. 2008; 135: 166-171 Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar , 3 Merlo CA Weiss ES Orens JB et al. Impact of U.S. Lung Allocation Score on survival after lung transplantation. J Heart Lung Transplant. 2009; 28: 769-775 Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar , 4 Egan TM Edwards LB Effect of the lung allocation score on lung transplantation in the United States. J Heart Lung Transplant. 2016; 35: 433-439 Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar The LAS was modified in 2014 by addition of other factors, and a major change occurred in late 2017 when a court required the Organ Procurement and Transplant Network (OPTN) contractor, the United Network for Organ Sharing (UNOS), to abandon lung distribution first within a donor service area (DSA), and provide access over a larger geographic area. 5 Robbins-Callahan L. Modifications to the Distribution of Deceased Donor Lungs, 2018. Available at: https://optn.transplant.hrsa.gov/media/2400/thoracic_publiccomment_distribution_20180122.pdf. Google Scholar This requirement was to encourage UNOS to finally comply with the Final Rule to reduce the impact of geography on allocation. 6 Final Rule Organ Procurement and Transplant Network, 2000. Available at: https://optn.transplant.hrsa.gov/about/final-rule/ https://optn.transplant.hrsa.gov/about/final-rule/. Google Scholar In response to the court order, lungs were allocated first to Zone-A (within 250 nautical miles of the donor); usually a larger distance than within a DSA. 7 Egan TM From 6 years to 5 days for organ allocation policy change. J Heart Lung Transplant. 2018; 37: 675-677 Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar This change resulted in reduced disparities between regions 8 Benvenuto LJ Anderson MR Aversa M et al. Geographic disparities in lung transplantation in the United States before and after the November 2017 allocation change. J Heart Lung Transplant. 2022; 41: 382-390 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar and increased lung allocation score at the time of transplant, with no change in early post-transplant survival. 9 Goff RR, Wilk A. Monitoring of the Lung Allocation Change, 2 Year Report: Removal of DSA as a Unit of Allocation, 2020. Available at: https://optn.transplant.hrsa.gov/media/3661/item_25_thoracic_committee_20200212.pdf. Google Scholar

Background and Aims Following success in thoracic surgery, ultrasound guided fascial plane blocks as effective analgesia for chest wall trauma have increased in popularity over the last decade due to wider patient inclusion and an enhanced safety profile. Fascial plane local anaesthetic can be delivered by continuous infusion or intermittent boluses. Recent evidence promotes programmed intermittent boluses through a peripheral nerve catheter, with a larger volume aiding diffusion, leading to improved pain scores, reduced rescue opioid use and improved patient satisfaction. Royal London Hospital is a MTC; between January 1st2019 and December 1st 2021, 1119 trauma patients were treated with chest injuries. Thoracic epidural analgesia is our current standard analgesia in appropriate chest trauma patients. This requires trained anaesthetic staff, experienced nursing care post-procedure and has an accompanying low but significant complication list. Our project objective is to implement fascial plane chest wall blocks in eligible trauma patients delivered via intermittent programmed boluses to increase the provision of effective analgesia to our trauma cohort. We will record pain scores, rescue analgesic needs and total block duration. Methods An electronic pump system will deliver a pre-programmed intermittent bolus of 0.125% Levobupivicaine 15 mls every 3 hours alongside a protocolised multimodal analgesic regimen. Results We hope to demonstrate an increase in fascial plane chest wall blocks at Royal London Hospital and therefore improve our chest trauma care service with the aforementioned benefits of this technique. Conclusions The reduction in risks associated with insertion and side effects along with minimal contraindications will undeniably transform the care of our trauma patients.

Lung alveoli constitute a complex distribution of strong ultrasound scatterers, leading to multiple scattering (USMS). Conventional ultrasound cannot be utilized to produce images that would accurately render lung structure. Pulmonary fibrosis affects lung microstructure by thickening alveolar walls, which changes wave diffusion and scattering patterns by modifying the distribution and size of scatterers. We present a method for the quantitative approach of structural changes in lung parenchyma based on diffusion of ultrasound waves, relying on measurement of the scattering mean free path (SMFP). We quantify severity of lung damage due to bleomycin-induced fibrosis in rats, and to monitor response to Nintedanib treatment by comparing the SMFP in 6 control (normal) lungs, 6 fibrotic lungs, and 6 fibrotic lungs from rats treated with Nintedanib. We observed significant differences in SMFP among control lungs (483 ± 50 μm), fibrotic lungs (1433 ± 612 μm), and lungs from Nintedanib-treated rats (835 ± 149 μm) (mean ± sd). Strong correlations were observed between SMFP and fibrosis severity score on inflated ex vivo CT lung images (p = 0.076, r = 0.43), as well as between SMFP and modified Ashcroft score of inflation-fixed lungs stained with H&E and Sirius red (p = 0.008, r = 0.61). This suggests SMFP may be useful to monitor response to treatment of pulmonary fibrosis.

Using conventional ultrasound to image pulmonary nodules is elusive due to multiple scattering in highly heterogeneous lung tissue. It is possible to leverage multiple scattering as a source of contrast between nodules and healthy lung parenchyma, because lung nodules do not contain air-filled alveoli. We developed a method based on the separation of multiple and single scattering using singular value decomposition. When combined with a depression detection algorithm, this allows us to render a map of the regions exhibiting less multiple scattering, associated with the presence of nodules. These techniques allowed for localization of 55 out of 59 nodules placed in ten lungs, as small as 5 mm diameter. In this study, we are demonstrating the feasibility of the method to locate nodules with respect to a surgical stapler by merging the rendered nodule map with a B-mode image of the surgical device. Using Verasonics Vantage scanner with array transducer, inter-element responses matrices were acquired from ex vivo pig/dog lungs, in which artificial nodules were implanted. We show that the relative position of nodule to the stapler can be measured. By measuring the distance of the nodule to the surgical stapler, it is possible to resect the nodule with safe margins.

Random matrix theory (RMT) exploits the distribution of singular values of the inter-element response matrix (IRM). If multiple scattering dominates the propagation, the singular value distribution follows the quarter circle law. However, dominance of single scattering results in Henkel function behavior of the singular value distribution. In our previous work, we have shown that this can be exploited to estimate severity of bleomycin-induced fibrosis (measured by histology) in rodent lungs. We showed that E(x), the expected value of the singular value distribution, as well as the singular value with the highest probability, correlated significantly with histology scores. Here, we investigate the sensitivity of these metrics to the time window duration used for the Singular Value Decomposition of the IRM, which is performed in the frequency domain, using overlapping time windows. A linear transducer with a central frequency of 7.8 MHz and a Verasonics scanner were used to obtain IRMs in 24 rat lungs. Different degrees of pulmonary fibrosis were induced using bleomycin in 18 rats while 6 rats were left as controls. The IRMs were time-windowed with different duration of 2T, 4T, and 6T where T is the transmitted pulse period. E(x) and were evaluated for each time window duration for all rat lungs. For all time window durations significant correlations were observed between and E(x), and histology scores. Wilcoxon ranksum tests show that the distributions obtained for and E(x) are not affected by the time window duration.

We investigate random matrix theory (RMT) as a tool to detect and quantify pulmonary fibrosis in rodents in vivo. Highly scattering structures such as lung alveoli result in specific characteristics in the distribution of singular values of the inter-element response matrix (IRM). When multiple scattering dominates (healthy lung), the distribution of singular values of the IRM is expected to follow a quarter circle law. However, when single scattering regime dominates, the singular values distribution is closer to a Henkel distribution. We propose to exploit this feature to detect pulmonary fibrosis and quantify its severity. Two metrics are defined to describe the singular value distribution: the expected value E(x), which is the weighted average of all singular values, and, the singular value with the highest probability. A 128-element linear transducer operating at 7.8 MHz and a Verasonics scanner were used to collect IRMs from 6 normal and 18 rat lungs with bleomycin-induced fibrosis in vivo. Significant correlations were observed between E(x) (r = −0.46, p = 0.02) and (r = 0.52, p = 0.01) with the severity of fibrosis independently assessed by histology. These preliminary results show the potential of RMT metrics E(x) and to quantify structural changes in the lung parenchyma.

Conventional ultrasound (US) cannot quantitatively evaluate lung tissue because of US multiple scattering (USMS). Pulmonary edema causes vertical artifacts -B-lines- which provide qualitative information about alveolar flooding. We showed that Scattering mean free path (SMFP), a measure of the density of air-filled alveoli, is longer in edematous than normal lungs. Here, we show that SMFP correlates with wet:dry weight ratio of lung tissue (W/D) and CT-scan assessment of edema. Ischemia-reperfusion injury (IRI) was created in lungs of anesthetized rats. The left lung hilum was clamped for 20, 40, or 60 minutes (n = 6/group) then reperfused for 60 minutes before ligating the apical portion of each lung to measure W/D, removing inflated lung blocks, then measuring SMFP and backscatter frequency shift (BFS) with a Verasonics scanner and L11-4v US probe. Six lung blocks were removed from healthy rats as Controls. Inflated lung blocks had ex vivo CT scans, followed by inflation-fixed histology. By logistic regression, there was a correlation between SMFP and W/D in 18 edematous and 12 Control lungs (r2 = 0.27, p < 0.004) and a significant correlation between edema extent by CT and SMFP and W/D. BFS was larger, and histology confirmed edema in IRI lungs. SMFP may be useful to quantify lung edema.

Thoracic organ transplantation improves the length and quality of life of patients with severe heart or lung disease using a vital organ donated from a human being. It is both a medical and societal endeavor that is bound by ethical principles. Among these principles are autonomy and respect for persons, utility which includes beneficence and non-maleficence, and justice, which includes fair allocation, health equity, and legal responsibilities. Together, these principles provide a general framework for navigating the complex ethical issues that arise in thoracic organ transplantation.

Current hydrogel or fabric patches for organ repair are generally not designed to conform to the complex mechanics of dynamic organs such as the lung or heart. This study presents a new, biocompatible and bilayered, hydrogel‐based patch platform, consisting of a non‐fouling top layer and a cell adhesive bottom layer, that caters to the anisotropic and auxetic characteristics of dynamic organs. Integrated computational and experimental studies are used to screen over 116 unique anisotropic‐auxetic architectures to establish design rules and tailor the patches to a broad range of target organ dynamics. The patches are then validated in ex vivo and in vivo animal models, where the auxetic patches outperformed non‐auxetic patches in conforming to the volumetric dilation‐contraction of dynamic organs. To further expand the functionality of the auxetic patch platform, novel hole‐filling auxetic patches are developed. These hole‐filling patches composited with fibrin robustly reduce pulmonary air leakage in rats with surgically induced lung puncture. This is the first demonstration of a rational patch design framework that features both anisotropic and auxetic properties to cater to a wide range of organ dynamics. These studies pave the way for future clinical development of biomimetic patches.