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Hepatology (Baltimore, Md.) Nov 2022Although liver transplantation is a true success story, many patients still die awaiting an organ. The increasing need for liver grafts therefore remains an unsolved... (Review)
Review
Although liver transplantation is a true success story, many patients still die awaiting an organ. The increasing need for liver grafts therefore remains an unsolved challenge to the transplant community. To address this, transplant donor criteria have been expanded and, for example, more liver grafts with significant steatosis or from donors with circulatory death are being used. These marginal grafts, however, carry an increased risk of graft-associated complications, such as primary nonfunction, delayed graft function, or late biliary injuries. Therefore, reliable assessment of graft viability before use is essential for further success. To achieve this, machine liver perfusion, a procedure developed more than 50 years ago but almost forgotten at the end of the last century, is again of great interest. We describe in this review the clinical most applied machine perfusion techniques, their mechanistic background, and a novel concept of combining immediate organ assessment during hypothermic oxygenated perfusion, followed by an extended phase of normothermic machine perfusion, with simultaneous ex situ treatment of the perfused liver. Such a new approach may allow the pool of usable livers to dramatically increase and improve outcomes for recipients.
Topics: Humans; Liver Transplantation; Perfusion; Postoperative Complications; Tissue Donors
PubMed: 35488496
DOI: 10.1002/hep.32546 -
Journal of Hepatology Jun 2023With the increasing number of accepted candidates on waiting lists worldwide, there is an urgent need to expand the number and the quality of donor livers. Dynamic... (Review)
Review
With the increasing number of accepted candidates on waiting lists worldwide, there is an urgent need to expand the number and the quality of donor livers. Dynamic preservation approaches have demonstrated various benefits, including improving liver function and graft survival, and reducing liver injury and post-transplant complications. Consequently, organ perfusion techniques are being used in clinical practice in many countries. Despite this success, a proportion of livers do not meet current viability tests required for transplantation, even with the use of modern perfusion techniques. Therefore, devices are needed to further optimise machine liver perfusion - one promising option is to prolong machine liver perfusion for several days, with ex situ treatment of perfused livers. For example, stem cells, senolytics, or molecules targeting mitochondria or downstream signalling can be administered during long-term liver perfusion to modulate repair mechanisms and regeneration. Besides, today's perfusion equipment is also designed to enable the use of various liver bioengineering techniques, to develop scaffolds or for their re-cellularisation. Cells or entire livers can also undergo gene modulation to modify animal livers for xenotransplantation, to directly treat injured organs or to repopulate such scaffolds with "repaired" autologous cells. This review first discusses current strategies to improve the quality of donor livers, and secondly reports on bioengineering techniques to design optimised organs during machine perfusion. Current practice, as well as the benefits and challenges associated with these different perfusion strategies are discussed.
Topics: Animals; Liver Transplantation; Organ Preservation; Liver; Perfusion; Bioengineering
PubMed: 37208105
DOI: 10.1016/j.jhep.2023.02.009 -
Nature Aug 2022After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death. Yet with...
After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.
Topics: Animals; Cell Death; Cell Survival; Cytoprotection; Gene Expression Profiling; Ischemia; Organ Specificity; Perfusion; Swine; Warm Ischemia
PubMed: 35922506
DOI: 10.1038/s41586-022-05016-1 -
Nature Communications Apr 2023Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing an understanding for the donor organ immune cell composition...
Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing an understanding for the donor organ immune cell composition and its dynamic changes during NMP is essential. We aimed for a comprehensive characterization of immune cell (sub)populations, cell trafficking and cytokine release during liver NMP. Single-cell transcriptome profiling of human donor livers prior to, during NMP and after transplantation shows an abundance of CXC chemokine receptor 1/2 (CXCR1/CXCR2) neutrophils, which significantly decreased during NMP. This is paralleled by a large efflux of passenger leukocytes with neutrophil predominance in the perfusate. During NMP, neutrophils shift from a pro-inflammatory state towards an aged/chronically activated/exhausted phenotype, while anti-inflammatory/tolerogenic monocytes/macrophages are increased. We herein describe the dynamics of the immune cell repertoire, phenotypic immune cell shifts and a dominance of neutrophils during liver NMP, which potentially contribute to the inflammatory response. Our findings may serve as resource to initiate future immune-interventional studies.
Topics: Humans; Aged; Liver Transplantation; Liver; Perfusion; Organ Preservation; Sequence Analysis, RNA
PubMed: 37085477
DOI: 10.1038/s41467-023-37674-8 -
Placenta Apr 2020The isolated perfused placental cotyledon technique has led to numerous advances in placental biology. Combining placental perfusion with mathematical modelling provides... (Review)
Review
The isolated perfused placental cotyledon technique has led to numerous advances in placental biology. Combining placental perfusion with mathematical modelling provides an additional level of insight into placental function. Mathematical modelling of perfusion data provides a quantitative framework to test the understanding of the underlying biology and to explore how different processes work together within the placenta as part of an integrated system. The perfusion technique provides a high degree of control over the experimental conditions as well as regular measurements of functional parameters such as pressure, solute concentrations and pH over time. This level of control is ideal for modelling as it allows placental function to be studied across a wide range of different conditions which permits robust testing of mathematical models. By placing quantitative values on different processes (e.g. transport, metabolism, blood flow), their relative contribution to the system can be estimated and those most likely to become rate-limiting identified. Using a combined placental perfusion and modelling approach, placental metabolism was shown to be a more important determinant of amino acid and fatty acid transfer. In contrast, metabolism was a less important determinant of placental cortisol transfer than initially thought. Identifying the rate-limiting factors in the system allows future work to be focused on the factors that are most likely to underlie placental dysfunction. A combined experimental and modelling approach using placental perfusions promotes an integrated view of placental physiology that can more effectively identify the processes leading to placental pathologies.
Topics: Amino Acids; Biological Transport; Fatty Acids; Female; Humans; Maternal-Fetal Exchange; Models, Biological; Models, Theoretical; Organ Culture Techniques; Perfusion; Placenta; Pregnancy
PubMed: 32250738
DOI: 10.1016/j.placenta.2020.02.015 -
Expert Review of Medical Devices Dec 2022Lung transplantation is the gold standard for the treatment of end stage lung disease but is limited by donor availability. Recently, the donor pool has seen significant... (Review)
Review
INTRODUCTION
Lung transplantation is the gold standard for the treatment of end stage lung disease but is limited by donor availability. Recently, the donor pool has seen significant expansion with liberalization of donor criteria. However, extended criteria donors can require additional time to prepare for implantation, necessitating additional preservation time of donor lungs.
AREAS COVERED
We present a review of current lung transplant storage strategies including new methodologies and technological advancements. The current standard, static cold storage, is a simple and cost-effective method of preserving grafts, but offers little flexibility with limited ability to mitigate ischemic-reperfusion injury, inflammation, and hypothermic tissue damage. Novel ex vivo lung perfusion (EVLP) devices, TransMedics OCS and XVIVO perfusion systems, extend preservation time by perfusing, and ventilating donor lungs while simultaneously allowing for evaluation of lung viability. Perfusate, preservation solutions, additives, temperature regulation, and assessment of organ damage are all critical components when evaluating the success and outcomes of these devices.
EXPERT OPINION
EVLP devices are more costly and often require additional resources and personnel support compared to static cold storage, but may provide the opportunity to extend preservation time, perform functional assessment, mitigate ischemic injury, and optimize extended criteria donors.
Topics: Humans; Organ Preservation; Lung; Lung Transplantation; Perfusion; Tissue Donors
PubMed: 36444725
DOI: 10.1080/17434440.2022.2151359 -
Transplant International : Official... Jan 2021There has been increasing use of organs from extended criteria or donation after circulatory death donors to meet the demands of the transplant waiting list. Over the... (Review)
Review
There has been increasing use of organs from extended criteria or donation after circulatory death donors to meet the demands of the transplant waiting list. Over the past decade, there has been considerable progress in technologies to preserve organs prior to transplantation to improve the function of these marginal organs. This has led to the development of normothermic machine perfusion, whereby an organ is perfused with warmed, oxygenated blood and nutrients to resume normal physiological function in an isolated ex-vivo platform. With this advance in preservation comes significant opportunities to recondition, repair and regenerate organs prior to transplantation using cellular therapies. This review aims to discuss the possibilities of machine perfusion technology; highlighting the potential for organ-directed reconditioning and the future avenues for investigation in this field.
Topics: Cell- and Tissue-Based Therapy; Humans; Liver Transplantation; Organ Preservation; Perfusion; Tissue Donors
PubMed: 33131097
DOI: 10.1111/tri.13780 -
The Journal of Extra-corporeal... Mar 2022Standards and guidelines for cardiopulmonary bypass have been established by various professional societies. They serve as an instrument to guide safe and effective...
Standards and guidelines for cardiopulmonary bypass have been established by various professional societies. They serve as an instrument to guide safe and effective patient care. We conducted a survey of practicing perfusionists in Kenya to learn about their background, education, current clinical practice and about their knowledge, and attitude regarding standards and guidelines. Two multiple-choice surveys were distributed to all known practicing perfusionist in Kenya using SurveyMonkey (San Mateo, CA). Multiple-choice questions related to professional background, training, annual procedure volume, staffing models, clinical practices, the use of safety devices, and the use of checklists were included in the questionnaires. The survey also inquired about familiarity with American and European perfusion practice standards and guidelines and opinions on establishing standards in Kenya. Responses were received from 12 perfusionists practicing at 10 centers. Professional backgrounds included anesthesia nursing, clinical officers, and critical care nursing. Sixty-seven percent (8/12) received formal training and 33% (4/12) trained primarily through clinical instruction. Of those that received formal training, 63% (5/8) received 1-2 years of training, 25% (2/8) <1 year but more than 6 months, and 12.5% (1/8) received 6 months of formal training. The median clinical experience was 5 years (range 1-22). The median annual case load was 54 (range 0-100). Use of safety devices was reported as follows: level sensor 75% (9/12), air bubble detector 17% (2/12), one-way vent valves 67% (8/12), continuous venous oxygen saturation monitoring 25% (3/12), and gas supply analyzers 33% (4/12). More than one-third of the respondents had no knowledge of the American and European perfusion practice standards, and nearly two-thirds were aware of or had read them. This survey provides contextual information about perfusion practice in Kenya in 2021. There was consensus among perfusionists to develop standards and practice guidelines for Kenya.
Topics: Humans; Kenya; Perfusion; Cardiopulmonary Bypass; Surveys and Questionnaires
PubMed: 36380824
DOI: 10.1182/ject-5-18 -
Current Opinion in Organ Transplantation Jun 2023This article will review the evidence behind elements of the lung preservation process that have remained relatively stable over the past decade as well as summarize... (Review)
Review
PURPOSE OF REVIEW
This article will review the evidence behind elements of the lung preservation process that have remained relatively stable over the past decade as well as summarize recent developments in ex-vivo lung perfusion and new research challenging the standard temperature for static cold storage.
RECENT FINDINGS
Ex-vivo lung perfusion is becoming an increasingly well established means to facilitate greater travel distance and allow for continued reassessment of marginal donor lungs. Preliminary reports of the use of normothermic regional perfusion to allow utilization of lungs after DCD recovery exist, but further research is needed to determine its ability to improve upon the current method of DCD lung recovery. Also, research from the University of Toronto is re-assessing the optimal temperature for static cold storage; pilot studies suggest it is a feasible means to allow for storage of lungs overnight to allow for daytime transplantation, but ongoing research is awaited to determine if outcomes are superior to traditional static cold storage.
SUMMARY
It is crucial to understand the fundamental principles of organ preservation to ensure optimal lung function posttransplant. Recent advances in the past several years have the potential to challenge standards of the past decade and reshape how lung transplantation is performed.
Topics: Humans; Temperature; Perfusion; Lung; Extracorporeal Circulation; Organ Preservation; Tissue Donors
PubMed: 37053078
DOI: 10.1097/MOT.0000000000001067 -
Current Opinion in Organ Transplantation Oct 2022Viability assessment is one of the main indications for machine perfusion (MP) in liver transplantation. This review summarizes the rationale, evolution and limitations... (Review)
Review
PURPOSE OF REVIEW
Viability assessment is one of the main indications for machine perfusion (MP) in liver transplantation. This review summarizes the rationale, evolution and limitations of proposed viability criteria and suggests a framework for future studies.
RECENT FINDINGS
Liver viability is most frequently assessed during normothermic MP by combining parameters relative to perfusate and bile composition, vascular flows and macroscopic aspect. Assessment protocols are largely heterogeneous and have significantly evolved over time, also within the same group, reflecting the ongoing evolution of the subject. Several recent preclinical studies using discarded human livers or animal models have explored other approaches to viability assessment. During hypothermic MP, perfusate flavin mononucleotide has emerged as a promising biomarker of mitochondrial injury and function. Most studies on the subject suffer from limitations, including low numbers, lack of multicenter validation, and subjective interpretation of some viability parameters.
SUMMARY
MP adds a further element of complexity in the process of assessing the quality of a liver graft. Understanding the physiology of the parameters included in the different assessment protocols is necessary for their correct interpretation. Despite the possibility of assessing liver viability during MP, the importance of donor-recipient matching and operational variables should not be disregarded.
Topics: Animals; Humans; Liver; Liver Transplantation; Organ Preservation; Perfusion; Tissue Donors
PubMed: 35857341
DOI: 10.1097/MOT.0000000000001004