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Cold flush and static cold storage is the standard preservation technique for donor lungs before transplantations. Several research groups have assessed normothermic perfusion of donor lungs but all devices investigated were non-portable. We report first-in-man experience of the portable Organ Care System (OCS) Lung device for concomitant preservation, assessment, and transport of donor lungs. Between Feb 18, and July 1, 2011, 12 patients were transplanted at two academic lung transplantation centres in Hanover, Germany and Madrid, Spain. Lungs were perfused with low-potassium dextran solution, explanted, immediately connected to the OCS Lung, perfused with Steen's solution supplemented with two red-cell concentrates. We assessed donor and recipient characteristics and monitored extended criteria donor lung scores; primary graft dysfunction scores at 0, 24, 48, and 72 h; time on mechanical ventilation after surgery; length of stays in hospital and the intensive-care unit after surgery; blood gases; and survival of grafts and patients. Eight donors were female and four were male (mean age 44·5 years, range 14–72). Seven recipients were female and five were male (mean age 50·0 years, range 31–59). The preharvest donor ratio of partial pressure of oxyen (PaO2) to fractional concentration of oxygen in inspired air (FIO2) was 463·9 (SD 91·4). The final ratio of PaO2 to FIO2 measured with the OCS Lung was 471·58 (127·9). The difference between these ratios was not significant (p=0·72). All grafts and patients survived to 30 days; all recipients recovered and were discharged from hospital. Lungs can be safely preserved with the OCS Lung, resulting in complete organ use and successful transplantation in our series of high-risk recipients. In November, 2011, we began recruitment for a prospective, randomised, multicentre trial (INSPIRE) to compare preservation with OCS Lung with standard cold storage. TransMedics and German Federal Ministry of Education and Research.

Heart failure (HF) is a growing global health concern, driven by factors such as increased mechanical load of the heart muscle tissue. This pathogenic condition is the result of remodeling processes, partially mediated by the cytokine transforming growth factor β (TGF- β1), with progressive deposition of extracellular matrix within the myocardium that ultimately increases tissue stiffness. To elucidate early cellular and molecular processes underlying cardiac remodeling, translational experimental models are required. Living myocardial slices (LMS) represent a promising ex vivo model with preserved multicellularity, and physiology. In this study, we developed a disease model with hypertrophic and fibrotic features in porcine LMS. For this, LMS were prepared from porcine left ventricular tissue and cultured under mechanical overload with or without TGF-β1 stimulation. LMS cultured under overload showed reduced contractile performance, while adding TGF- β1 resulted in higher collagen deposition in the tissue, increase in secretion levels of pro-fibrotic miR-21 into the culture supernatant and increased expression of pro-fibrotic and hypertrophic marker genes. Our findings demonstrate early fibrotic changes in pig LMS induced by both mechanical and chemical stimulations. This ex vivo model could provide valuable insights into the early changes in heart failure pathogenesis and could be utilized as a screening platform to validate treatment strategies targeting cardiac remodeling.

The machine perfusion (MP) of transplantable grafts has emerged as an upcoming field in Cardiothoracic (CT) transplantation during the last decade. This technology carries the potential to assess, preserve, and even recondition thoracic grafts before transplantation, so it is a possible game-changer in the field. This technology field has reached a critical turning point, with a growing number of publications coming predominantly from a few leading institutions, but still need solid scientific evidence. Due to the increasing need to expand the donor pool, especially in Europe, where the donor age is steeply increased, a consensus has been established to address the growing need and knowledge of machine perfusion in cardiothoracic transplantation, targeting the unmet scientific need in this growing field but also, priorities for development, and regional differences in utilization rates and organizational issues. To address MP in CT, the European Society of Organ Transplantation (ESOT) convened a dedicated Working group comprised of experts in CT to review literature about MP to develop guidelines that were subsequently discussed and voted on during the Consensus Conference that took place in person in Prague during the TLJ 3.0 in November 2022. The findings and recommendations of the Cardiothoracic Working Group on MP are presented in this article.

To provide an alternative treatment option for patients with end-stage lung disease, we aim for biohybrid lung development (BHL) based on hollow fiber membrane (HFM) technology used in extracorporeal membrane oxygenators. For long-term BHL application, complete hemocompatibility of all blood-contacting surfaces is indispensable and can be achieved by their endothelialization. Indeed, albumin/heparin (AH) coated HFM enables initial endothelialization, but as inexplicable cell loss under flow conditions was seen, we assessed an alternative HFM coating using fibronectin (FN). Therefore, endothelial cell (EC) adherence and viability on both coated HFM were analyzed by fluorescence-based staining. Functional leukocyte and thrombocyte adhesion assays were performed to evaluate hemocompatibility, also in comparison to blood plasma coated HFM as a clinically relevant control. To assess monolayer resistance and EC behavior under clinically relevant flow conditions, a mock circulation setup was established, which also facilitates imitation of lung-disease specific blood gas settings. Besides quantification of flow-associated cell loss, endothelial responses towards external stimuli, like flow exposure or TNFα stimulation, were analyzed by qRT-PCR, focusing on inflammation, thrombus formation and extracellular matrix production. Under static conditions, both coated HFM enabled the generation of a viable, confluent, non-inflammatory and anti-thrombogenic monolayer. However, by means of homogenous FN coating, cell retention and physiologic gene regulation towards an improved hemocompatible-and extracellular matrix producing phenotype, was significantly superior compared to the inhomogeneous AH coating. In summary, our adaptable in-house FN coating secures the endothelial requirements for long-term BHL application and may promote monolayer establishment on all other blood contacting surfaces of the BHL (e.g., cannulae).

Current membrane oxygenators for extracorporeal life support (ECLS) are facing their limits regarding gas exchange efficiency and long‐term stability. One aspect adding to these limitations is inhomogeneous blood flow distribution inside the oxygenator's membrane structure. Triply periodic minimal surface (TPMS) lattice structures are proposed to provide increased mass transfer efficiency and local adaptability introducing heterogeneous properties. However, the adaptation of these structures for blood flow, as in ECLS, is challenging as a hemocompatible flow distribution must be established. In this study, this study proposes a novel method for the smooth, multi‐scale modification of TPMS lattice structures creating a tailored flow distribution suited for blood‐gas exchange. It implements this method into an automatic structure optimization within an oxygenator. After manufacturing prototypes, it experimentally evaluate the 3D flow distribution using time‐resolved, contrast enhanced computed tomography comparing the optimized structure to reference geometries. The TPMS structure modification provides a significant change in flow distribution, improving homogeneity by up to 12%. The approach to creating tailored 3D TPMS lattice structures can be directly transferred to various other applications in the field of heat and mass transfer to enhance functionality, e.g., for heat exchangers or membrane contactors.

IntroductionFollowing heart transplantation, a cascade of immunological responses is initiated influencing the clinical outcome and long-term survival of the transplanted patients. The anti-inflammatory cytokine interleukin-10 (IL-10) was shown to be elevated in the blood of heart transplant recipients directly after transplantation but the releasing cell populations and the composition of lymphocyte subsets following transplantation have not been thoroughly studied.MethodsWe identified immune cells by immunophenotyping and analyzed intracellular IL-10 production in peripheral blood mononuclear cells (PBMC) of heart transplanted patients (n= 17) before, directly after and 24h post heart transplantation. The cells were stimulated with lipopolysaccharide or PMA/Ionomycin to enhance cytokine production within leukocytes in vitro .Results and discussionWe demonstrate that intermediate monocytes (CD14highCD16+), but not CD8+ T cells, CD4+ T cells, CD56+ NK cells or CD20+ B cells appeared to be the major IL-10 producers within patients PBMC following heart transplantation. Consequently, the absolute monocyte count and the ratio of intermediate monocytes to classical monocytes (CD14+CD16-) were specifically increased in comparison to pre transplant levels. Hence, this population of monocytes, which has not been in the focus of heart transplantation so far, may be an important modulator of clinical outcome and long-term survival of heart transplant recipients. Alteration of blood-circulating monocytes towards a CD14highCD16+ phenotype could therefore shift the pro-inflammatory immune response towards induction of graft tolerance, and may pave the way for the optimization of immunosuppression.

Low haemocompatibility of left ventricular assist devices (LVAD) surfaces necessitates anticoagulative therapy. Endothelial cell (EC) seeding can support haemocompatibility, however, the availability of autologous ECs is limited. In contrast, allogeneic ECs are readily available in sufficient quantity, but HLA disparities induce harmful immune responses causing EC loss. In this study, we investigated the feasibility of using allogeneic low immunogenic ECs to endothelialize LVAD sintered inflow cannulas (SIC). To reduce the immunogenicity of ECs, we applied an inducible lentiviral vector to deliver short-hairpins RNA to silence HLA class I expression. HLA class I expression on ECs was conditionally silenced by up to 70%. Sufficient and comparable endothelialization rates were achieved with HLA-expressing or HLA-silenced ECs. Cell proliferation was not impaired by cell-to-Sintered Inflow Cannulas (SIC) contact or by silencing HLA expression. The levels of endothelial phenotypic and thrombogenic markers or cytokine secretion profiles remained unaffected. HLA-silenced ECs-coated SIC exhibited reduced thrombogenicity. In contrast to native ECs, HLA-silenced ECs showed lower cell lysis rates when exposed to allogeneic T cells or specific anti-HLA antibodies. Allogeneic HLA-silenced ECs could potentially become a valuable source for LVAD endothelialization to reduce immunogenicity and correspondingly the need for anticoagulative therapy which can entail severe side effects.

Ex vivo machine perfusion (EVMP) is an emerging technique for preserving explanted solid organs with primary application in allogeneic organ transplantation. EVMP has been established as an alternative to the standard of care static-cold preservation, allowing for prolonged preservation and real-time monitoring of organ quality while reducing/preventing ischemia–reperfusion injury. Moreover, it has paved the way to involve expanded criteria donors, e.g., after circulatory death, thus expanding the donor organ pool. Ongoing improvements in EVMP protocols, especially expanding the duration of preservation, paved the way for its broader application, in particular for reconditioning and modification of diseased organs and tumor and infection therapies and regenerative approaches. Moreover, implementing EVMP for in vivo -like preclinical studies improving disease modeling raises significant interest, while providing an ideal interface for bioengineering and genetic manipulation. These approaches can be applied not only in an allogeneic and xenogeneic transplant setting but also in an autologous setting, where patients can be on temporary organ support while the diseased organs are treated ex vivo , followed by reimplantation of the cured organ. This review provides a comprehensive overview of the differences and similarities in abdominal (kidney and liver) and thoracic (lung and heart) EVMP, focusing on the organ-specific components and preservation techniques, specifically on the composition of perfusion solutions and their supplements and perfusion temperatures and flow conditions. Novel treatment opportunities beyond organ transplantation and limitations of abdominal and thoracic EVMP are delineated to identify complementary interdisciplinary approaches for the application and development of this technique.

Although left ventricular assist devices (LVADs) are an alternative to heart transplantation, their artificial surfaces often lead to serious thrombotic complications requiring high‐risk device replacement. Coating blood‐contacting surfaces with antithrombogenic endothelial cells is considered an effective strategy for preventing thrombus formation. However, this concept has not yet been successfully implemented in LVADs, as severe cell loss is to be expected, especially on the impeller surface with high prothrombogenic supraphysiological shear stress. This study presents a strategy that exploits the magnetic attraction of the impeller on ECs loaded with iron oxide nanoparticles (IONPs) to minimize shear stress‐induced cell detachment from the rotating magnetic impeller while ensuring antithrombogenic EC adhesion, especially as a bridge until they formed their adhesion‐promoting matrix. In contrast to polyvinylpyrrolidone (PVP)‐coated IONPs, more efficient and safer cell loading is achieved with sodium citrate (Cit)‐stabilized IONPs, where incubation with 6.6 µg iron mL‐1 Cit‐IONPs for 24 h resulting in an average internalization of 23 pg iron per cell. Internalization of Cit‐IONP significantly improved cell attraction to the highly magnetic impeller surface without affecting cell viability or antithrombogenic function. This protocol is key for the development of a biohybrid LVAD impeller that can prevent life‐threatening thrombosis and hemorrhage in a future clinical application. Pro‐thrombogenic surfaces of left ventricular assist devices (LVAD) require anticoagulant therapy, which leads to bleeding and thrombi in an unbalanced state. To avoid this, an antithrombogenic endothelial cell (EC) layer is applied. The ECs are loaded with citrate‐coated iron oxide nanoparticles (Cit‐IONP) to withstand the high shear stresses in clinical use due to the magnetic attraction of the LVAD impeller.

The overall survival rate of extracorporeal life support (ECLS) remains at 60%. Research and development has been slow, in part due to the lack of sophisticated experimental models. This publication introduces a dedicated rodent oxygenator (“RatOx”) and presents preliminary in vitro classification tests. The RatOx has an adaptable fiber module size for various rodent models. Gas transfer performances over the fiber module for different blood flows and fiber module sizes were tested according to DIN EN ISO 7199. At the maximum possible amount of effective fiber surface area and a blood flow of 100 mL/min, the oxygenator performance was tested to a maximum of 6.27 mL O2/min and 8.2 mL CO2/min, respectively. The priming volume for the largest fiber module is 5.4 mL, while the smallest possible configuration with a single fiber mat layer has a priming volume of 1.1 mL. The novel RatOx ECLS system has been evaluated in vitro and has demonstrated a high degree of compliance with all pre-defined functional criteria for rodent-sized animal models. We intend for the RatOx to become a standard testing platform for scientific studies on ECLS therapy and technology.