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International Journal of Molecular... May 2021Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine... (Review)
Review
Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine perfusion (NMP) has the potential to extend the donor pool by facilitating the use of marginal quality organs such as those from donors after cardiac death (DCD) and extended criteria donors (ECD). NMP provides a platform for organ quality assessment but also offers the opportunity to treat and eventually regenerate organs during the perfusion process prior to transplantation. Due to their anti-inflammatory, immunomodulatory and regenerative capacity, mesenchymal stem cells (MSCs) are considered as an interesting tool in this model system. Only a limited number of studies have reported on the use of MSCs during ex situ machine perfusion so far with a focus on feasibility and safety aspects. At this point, no clinical benefits have been conclusively demonstrated, and studies with controlled transplantation set-ups are urgently warranted to elucidate favorable effects of MSCs in order to improve organs during ex situ machine perfusion.
Topics: Animals; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Organ Preservation; Organ Transplantation; Perfusion; Regenerative Medicine; Time Factors; Tissue Donors; Tissue and Organ Procurement
PubMed: 34063399
DOI: 10.3390/ijms22105233 -
Current Opinion in Organ Transplantation Jun 2022Significant limitations in organ availability and postoperative graft dysfunction plague lung transplantation and there is continual need for innovation. Ex-vivo lung... (Review)
Review
PURPOSE OF REVIEW
Significant limitations in organ availability and postoperative graft dysfunction plague lung transplantation and there is continual need for innovation. Ex-vivo lung perfusion (EVLP) has emerged over the last decade as an alternative and/or complementary allograft storage and assessment tool, however logistical hurdles have limited its widespread dissemination. As such, the overall current and potential value of EVLP on modern-day lung transplantation should be considered as innovation moves forward.
RECENT FINDINGS
Since inception, EVLP has made important safety strides in conclusively showing noninferiority to cold storage in several trials. Recent advances have highlighted potential mechanisms by which EVLP in its current form may reduce the pathogenic origins of primary graft dysfunction. Exciting work on organ reconditioning with EVLP via reduction in intermediaries of acute inflammation and oxidative stress have been performed in animal models. In addition, cross-circulation during EVLP has emerged as a method to achieve more prolonged ex situ storage. The impending translation of these to clinical use will markedly improve the overall value of EVLP.
SUMMARY
This review will highlight the current status of EVLP as it pertains to overall value in lung transplantation, focusing on historical and recent preclinical work and how innovation therein will improve lung transplantation as a field.
Topics: Animals; Extracorporeal Circulation; Humans; Lung; Lung Transplantation; Perfusion; Tissue and Organ Procurement
PubMed: 35649110
DOI: 10.1097/MOT.0000000000000961 -
International Journal of Molecular... Nov 2023Heart transplantation remains the conventional treatment in end-stage heart failure, with static cold storage (SCS) being the standard technique used for donor... (Review)
Review
Heart transplantation remains the conventional treatment in end-stage heart failure, with static cold storage (SCS) being the standard technique used for donor preservation. Nevertheless, prolonged cold ischemic storage is associated with the increased risk of early graft dysfunction attributed to residual ischemia, reperfusion, and rewarming damage. In addition, the demand for the use of marginal grafts requires the development of new methods for organ preservation and repair. In this review, we focus on current knowledge and novel methods of donor preservation in heart transplantation. Hypothermic or normothermic machine perfusion may be a promising novel method of donor preservation based on the administration of cardioprotective agents. Machine perfusion seems to be comparable to cold cardioplegia regarding donor preservation and allows potential repair treatments to be employed and the assessment of graft function before implantation. It is also a promising platform for using marginal organs and increasing donor pool. New pharmacological cardiac repair treatments, as well as cardioprotective interventions have emerged and could allow for the optimization of this modality, making it more practical and cost-effective for the real world of transplantation. Recently, the use of triiodothyronine during normothermic perfusion has shown a favorable profile on cardiac function and microvascular dysfunction, likely by suppressing pro-apoptotic signaling and increasing the expression of cardioprotective molecules.
Topics: Humans; Tissue Donors; Heart Transplantation; Organ Preservation; Perfusion; Ischemia
PubMed: 38069017
DOI: 10.3390/ijms242316693 -
Journal of Applied Physiology... May 2020Cardiac-coronary interaction and the effects of its pathophysiological variations on spatial heterogeneity of coronary perfusion and myocardial work are still poorly...
Cardiac-coronary interaction and the effects of its pathophysiological variations on spatial heterogeneity of coronary perfusion and myocardial work are still poorly understood. This hypothesis-generating study predicts spatial heterogeneities in both regional cardiac work and perfusion that offer a new paradigm on the vulnerability of the subendocardium to ischemia, particularly at the apex. We propose a mathematical and computational modeling framework to simulate the interaction of left ventricular mechanics, systemic circulation, and coronary microcirculation. The computational simulations revealed that the relaxation rate of the myocardium has a significant effect whereas the contractility has a marginal effect on both the magnitude and transmural distribution of coronary perfusion. The ratio of subendocardial to subepicardial perfusion density () changed by -12 to +6% from a baseline value of 1.16 when myocardial contractility was varied by +25 and -10%, respectively; changed by 37% when sarcomere relaxation rate, , was faster and increased by 10% from the baseline value. The model predicts axial differences in regional myocardial work and perfusion density across the wall thickness. Regional myofiber work done at the apex is 30-50% lower than at the center region, whereas perfusion density in the apex is lower by only 18% compared with the center. There are large axial differences in coronary flow and myocardial work at the subendocardial locations, with the highest differences located at the apex region. A mismatch exists between perfusion density and regional work done at the subendocardium. This mismatch is speculated to be compensated by coronary autoregulation. We present a model of left ventricle perfusion based on an anatomically realistic coronary tree structure that includes its interaction with the systemic circulation. Left ventricular relaxation rate has a significant effect on the regional distribution of coronary flow and myocardial work.
Topics: Coronary Circulation; Coronary Vessels; Heart; Myocardium; Perfusion
PubMed: 32078466
DOI: 10.1152/japplphysiol.00450.2019 -
Clinical Transplantation Jul 2022Ex vivo lung perfusion (EVLP) is used to assess and preserve lungs prior to transplantation. However, its inherent immunomodulatory effects are not completely...
BACKGROUND
Ex vivo lung perfusion (EVLP) is used to assess and preserve lungs prior to transplantation. However, its inherent immunomodulatory effects are not completely understood. We examine perfusate and tissue compartments to determine the change in immune cell composition in human lungs maintained on EVLP.
METHODS
Six human lungs unsuitable for transplantation underwent EVLP. Tissue and perfusate samples were obtained during cold storage and at 1-, 3- and 6-h during perfusion. Flow cytometry, immunohistochemistry, and bead-based immunoassays were used to measure leukocyte composition and cytokines. Mean values between baseline and time points were compared by Student's t test.
RESULTS
During the 1st hour of perfusion, perfusate neutrophils increased (+22.2 ± 13.5%, p < 0.05), monocytes decreased (-77.5 ± 8.6%, p < 0.01) and NK cells decreased (-61.5 ± 22.6%, p < 0.01) compared to cold storage. In contrast, tissue neutrophils decreased (-22.1 ± 12.2%, p < 0.05) with no change in monocytes and NK cells. By 6 h, perfusate neutrophils, NK cells, and tissue neutrophils were similar to baseline. Perfusate monocytes remained decreased, while tissue monocytes remained unchanged. There was no significant change in B cells or T cell subsets. Pro-inflammatory cytokines (IL-1b, G-CSF, IFN-gamma, CXCL2, CXCL1 granzyme A, and granzyme B) and lymphocyte activating cytokines (IL-2, IL-4, IL-6, IL-8) increased during perfusion.
CONCLUSIONS
Early mobilization of innate immune cells occurs in both perfusate and tissue compartments during EVLP, with neutrophils and NK cells returning to baseline and monocytes remaining depleted after 6 h. The immunomodulatory effect of EVLP may provide a therapeutic window to decrease the immunogenicity of lungs prior to transplantation.
Topics: Cytokines; Humans; Leukocytes; Lung; Lung Transplantation; Perfusion; Tissue Donors
PubMed: 35396887
DOI: 10.1111/ctr.14670 -
Scientific Reports Aug 2023We hypothesized that the association between BP and endovascular treatment (EVT) outcomes would differ by baseline perfusion and recanalization status. We identified 388...
We hypothesized that the association between BP and endovascular treatment (EVT) outcomes would differ by baseline perfusion and recanalization status. We identified 388 ICA or M1 occlusion patients who underwent EVT ≤ 24 h from onset with successful recanalization (TICI ≥ 2b). BP was measured at 5-min intervals from arrival and during the procedure. Systolic BPs (SBP) were summarized as dropmax (the maximal decrease over two consecutive measurements), incmax (the maximal increase), mean, coefficient of variation (cv), and standard deviation. Adequate baseline perfusion was defined as hypoperfusion intensity ratio (HIR) ≤ 0.5; infarct proportion as the volume ratio of final infarcts within the T > 6 s region. In the adequate perfusion group, infarct proportion was closely associated with SBP (β ± SE (P-value); 1.22 ± 0.48, (< 0.01)), SBP (1.12 ± 0.33, (< 0.01)), SBP (0.61 ± 0.15 (< 0.01)), SBP (0.66 ± 0.08 (< 0.01)), and SBP (0.71 ± 0.37 (0.053) before recanalization. The associations remained significant only in SBP, SBP, and SBP after recanalization. SBP, SBP and SBP showed significant associations with modified Rankin Scale score at 3 months in the pre-recanalization period. In the poor perfusion group, none of the SBP indices was associated with any stroke outcomes regardless of recanalization status. BP may show differential associations with stroke outcomes by the recanalization and baseline perfusion status.
Topics: Humans; Blood Pressure; Perfusion; Reperfusion; Stroke; Treatment Outcome
PubMed: 37612355
DOI: 10.1038/s41598-023-40572-0 -
Frontiers in Immunology 2021Although solid organ transplantation remains the definitive management for patients with end-stage organ failure, this ultimate treatment has been limited by the number... (Review)
Review
Although solid organ transplantation remains the definitive management for patients with end-stage organ failure, this ultimate treatment has been limited by the number of acceptable donor organs. Therefore, efforts have been made to expand the donor pool by utilizing marginal organs from donation after circulatory death or extended criteria donors. However, marginal organs are susceptible to ischemia-reperfusion injury (IRI) and entail higher requirements for organ preservation. Recently, machine perfusion has emerged as a novel preservation strategy for marginal grafts. This technique continually perfuses the organs to mimic the physiologic condition, allows the evaluation of pretransplant graft function, and more excitingly facilitates organ reconditioning during perfusion with pharmacological, gene, and stem cell therapy. As mesenchymal stem cells (MSCs) have anti-oxidative, immunomodulatory, and regenerative properties, mounting studies have demonstrated the therapeutic effects of MSCs on organ IRI and solid organ transplantation. Therefore, MSCs are promising candidates for organ reconditioning during machine perfusion. This review provides an overview of the application of MSCs combined with machine perfusion for lung, kidney, liver, and heart preservation and reconditioning. Promising preclinical results highlight the potential clinical translation of this innovative strategy to improve the quality of marginal grafts.
Topics: Animals; Humans; Mesenchymal Stem Cells; Organ Preservation; Perfusion
PubMed: 35024039
DOI: 10.3389/fimmu.2021.713920 -
Physiological Reports Mar 2023The inotropic effects of glucagon have been recognized for many years, but it has remained unclear whether glucagon signaling is beneficial to cardiac function. We...
The inotropic effects of glucagon have been recognized for many years, but it has remained unclear whether glucagon signaling is beneficial to cardiac function. We evaluated the effects of glucagon alone and in combination with the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide in the isolated perfused rat heart. The isolated perfused rat heart was used to investigate the initial inotropic and chronotropic effects of glucagon and exenatide during aerobic perfusion, and recovery of contractile function following ischaemia/reperfusion. Glucagon, but not exenatide, elicited an acute chronotropic and inotropic response during aerobic perfusion of the rat heart. Compared with control, glucagon improved recovery of left ventricular developed pressure (LVDP) by 33% (p < 0.05) and rate-pressure product (RPP) by 66% (p < 0.001) following ischaemia/reperfusion and amplified the mild recovery enhancement elicited by exenatide in a dose-dependent manner. Glucagon shows inotropic properties in the isolated perfused rat heart and improves contractile recovery following ischaemia/reperfusion, both alone and when co-administered with a GLP-1 receptor agonist. Glucagon and exenatide, a GLP-1 receptor agonist, combine to stimulate greater recovery of postischaemic contractile function in the Langendorff heart. Glucagon was inotropic and chronotropic, yet this initial effect decreased over time and did not account for the increased contractility observed postischaemia/reperfusion.
Topics: Rats; Animals; Exenatide; Glucagon; Glucagon-Like Peptide-1 Receptor; Heart; Reperfusion; Myocardial Contraction; Ischemia
PubMed: 36946315
DOI: 10.14814/phy2.15597 -
Langenbeck's Archives of Surgery Jan 2023Incorrect assessment of tissue perfusion carries a significant risk of complications in surgery. The use of near-infrared (NIR) fluorescence imaging with Indocyanine... (Review)
Review
PURPOSE
Incorrect assessment of tissue perfusion carries a significant risk of complications in surgery. The use of near-infrared (NIR) fluorescence imaging with Indocyanine Green (ICG) presents a possible solution. However, only through quantification of the fluorescence signal can an objective and reproducible evaluation of tissue perfusion be obtained. This narrative review aims to provide an overview of the available quantification methods for perfusion assessment using ICG NIR fluorescence imaging and to present an overview of current clinically utilized software implementations.
METHODS
PubMed was searched for clinical studies on the quantification of ICG NIR fluorescence imaging to assess tissue perfusion. Data on the utilized camera systems and performed methods of quantification were collected.
RESULTS
Eleven software programs for quantifying tissue perfusion using ICG NIR fluorescence imaging were identified. Five of the 11 programs have been described in three or more clinical studies, including Flow® 800, ROIs Software, IC Calc, SPY-Q™, and the Quest Research Framework®. In addition, applying normalization to fluorescence intensity analysis was described for two software programs.
CONCLUSION
Several systems or software solutions provide a quantification of ICG fluorescence; however, intraoperative applications are scarce and quantification methods vary abundantly. In the widespread search for reliable quantification of perfusion with ICG NIR fluorescence imaging, standardization of quantification methods and data acquisition is essential.
Topics: Humans; Indocyanine Green; Perfusion
PubMed: 36700999
DOI: 10.1007/s00423-023-02780-0 -
Military Medicine Jan 2020Ex-vivo normothermic limb perfusion (EVNLP) has been proven to preserve limb viability better than standard cold storage. Perfusates containing packed red blood cells...
INTRODUCTION
Ex-vivo normothermic limb perfusion (EVNLP) has been proven to preserve limb viability better than standard cold storage. Perfusates containing packed red blood cells (pRBC) improve outcomes when compared to acellular perfusates. Limitations of pRBC-based perfusion include limited availability, need for cross match, mechanical hemolysis, and activation of pro-inflammatory proteins. Hemoglobin-based oxygen carrier (HBOC)-201 (Hemopure) is a solution of polymerized bovine hemoglobin, characterized by low immunogenicity, no risk of hemolytic reaction, and enhanced convective and diffusive oxygen delivery. This is a preliminary study on the feasibility of EVNLP using HBOC-201 as an oxygen carrier.
MATERIALS AND METHODS
Three porcine forelimb perfusions were performed using an established EVNLP model and an HBOC-201-based perfusate. The perfusion circuit included a roller pump, oxygenator, heat exchanger, and reservoir. Electrolytes, limb temperature, weight, compartment pressure, nerve conduction, and perfusion indicated by indocyanine green angiography and infra-red thermography were monitored. Histological evaluation was performed with hematoxylin and eosin and electron microscopy.
RESULTS
Three limbs were perfused for 21.3 ± 2.1 hours. Muscle contractility was preserved for 10.6 ± 2.4 hours. Better preservation of the mitochondrial ultrastructure was evident at 12 hours in contrast to crystallization and destruction features in the cold-storage controls.
CONCLUSIONS
An HBOC-201-EVNLP produced outcomes similar to RBC-EVNLP with preservation of muscle contractility and mitochondrial structure.
Topics: Animals; Disease Models, Animal; Extremities; Hemoglobins; Organ Preservation Solutions; Oxygen; Perfusion; Swine
PubMed: 32074378
DOI: 10.1093/milmed/usz314