HTK-N: Modified Histidine-Tryptophan-Ketoglutarate Solution—A Promising New Tool in Solid Organ Preservation

To ameliorate ischemia-induced graft injury, optimal organ preservation remains a critical hallmark event in solid organ transplantation. Although numerous preservation solutions are in use, they still have functional limitations. Here, we present a concise review of a modified Histidine-Tryptophan-Ketoglutarate (HTK) solution, named HTK-N. Its composition differs from standard HTK solution, carrying larger antioxidative capacity and providing inherent toxicity as well as improved tolerance to cold aiming to attenuate cold storage injury in organ transplantation. The amino acids glycine, alanine and arginine were supplemented, N-acetyl-histidine partially replaced histidine, and aspartate and lactobionate substituted chloride. Several in vitro studies confirmed the superiority of HTK-N in comparison to HTK, being tested in vivo in animal models for liver, kidney, pancreas, small bowel, heart and lung transplantation to adjust ingredients for required conditions, as well as to determine its innocuousness, applicability and potential advantages. HTK-N solution has proven to be advantageous especially in the preservation of liver and heart grafts in vivo and in vitro. Thus, ongoing clinical trials and further studies in large animal models and consequently in humans are inevitable to show its ability minimizing ischemia-induced graft injury in the sequel of organ transplantation.

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Animal Models in Allogenic Solid Organ Transplantation

Transplantology ◽

10.3390/transplantology2040039 ◽

2021 ◽

Vol 2 (4) ◽

pp. 412-424

Author(s):

Nadine Wenzel ◽

Rainer Blasczyk ◽

Constanca Figueiredo

Keyword(s):

Clinical Trials ◽

Animal Model ◽

Animal Models ◽

Organ Transplantation ◽

Research Question ◽

Solid Organ Transplantation ◽

Therapeutic Interventions ◽

Large Animal ◽

Solid Organ ◽

Large Animal Models

Animal models provide the link between in vitro research and the first in-man application during clinical trials. They provide substantial information in preclinical studies for the assessment of new therapeutic interventions in advance of human clinical trials. However, each model has its advantages and limitations in the ability to imitate specific pathomechanisms. Therefore, the selection of an animal model for the evaluation of a specific research question or evaluation of a novel therapeutic strategy requires a precise analysis. Transplantation research is a discipline that largely benefits from the use of animal models with mouse and pig models being the most frequently used models in organ transplantation research. A suitable animal model should reflect best the situation in humans, and the researcher should be aware of the similarities as well as the limitations of the chosen model. Small animal models with rats and mice are contributing to the majority of animal experiments with the obvious advantages of these models being easy handling, low costs, and high reproductive rates. However, unfortunately, they often do not translate to clinical use. Large animal models, especially in transplantation medicine, are an important element for establishing preclinical models that do often translate to the clinic. Nevertheless, they can be costly, present increased regulatory requirements, and often are of high ethical concern. Therefore, it is crucial to select the right animal model from which extrapolations and valid conclusions can be obtained and translated into the human situation. This review provides an overview in the models frequently used in organ transplantation research.

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Review: Tissue Engineering of Small-Diameter Vascular Grafts and Their In Vivo Evaluation in Large Animals and Humans

Cells ◽

10.3390/cells10030713 ◽

2021 ◽

Vol 10 (3) ◽

pp. 713

Author(s):

Shu Fang ◽

Ditte Gry Ellman ◽

Ditte Caroline Andersen

Keyword(s):

Animal Models ◽

Vascular Grafts ◽

Small Diameter ◽

Large Animal ◽

Large Animal Models ◽

Graft Outcome ◽

Limited Success ◽

Large Animals

To date, a wide range of materials, from synthetic to natural or a mixture of these, has been explored, modified, and examined as small-diameter tissue-engineered vascular grafts (SD-TEVGs) for tissue regeneration either in vitro or in vivo. However, very limited success has been achieved due to mechanical failure, thrombogenicity or intimal hyperplasia, and improvements of the SD-TEVG design are thus required. Here, in vivo studies investigating novel and relative long (10 times of the inner diameter) SD-TEVGs in large animal models and humans are identified and discussed, with emphasis on graft outcome based on model- and graft-related conditions. Only a few types of synthetic polymer-based SD-TEVGs have been evaluated in large-animal models and reflect limited success. However, some polymers, such as polycaprolactone (PCL), show favorable biocompatibility and potential to be further modified and improved in the form of hybrid grafts. Natural polymer- and cell-secreted extracellular matrix (ECM)-based SD-TEVGs tested in large animals still fail due to a weak strength or thrombogenicity. Similarly, native ECM-based SD-TEVGs and in-vitro-developed hybrid SD-TEVGs that contain xenogeneic molecules or matrix seem related to a harmful graft outcome. In contrast, allogeneic native ECM-based SD-TEVGs, in-vitro-developed hybrid SD-TEVGs with allogeneic banked human cells or isolated autologous stem cells, and in-body tissue architecture (IBTA)-based SD-TEVGs seem to be promising for the future, since they are suitable in dimension, mechanical strength, biocompatibility, and availability.

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Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes

Frontiers in Immunology ◽

10.3389/fimmu.2021.664577 ◽

2021 ◽

Vol 12 ◽

Author(s):

Abraham J. Matar ◽

Rebecca L. Crepeau ◽

Gerhard S. Mundinger ◽

Curtis L. Cetrulo ◽

Radbeh Torabi

Keyword(s):

Animal Models ◽

Ex Vivo ◽

Solid Organ Transplantation ◽

Tolerance Induction ◽

Large Animal ◽

Solid Organ ◽

Large Animal Models ◽

Large Animals ◽

And Function ◽

Made In

Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications. Historically, large animals have provided a valuable model for testing the clinical translatability of immune modulating approaches in transplantation, including tolerance induction, co-stimulation blockade, cellular therapies, and ex vivo perfusion. Recently, significant advancements have been made in these arenas utilizing large animal VCA models. In this comprehensive review, we highlight recent immune strategies undertaken to improve VCA outcomes with a focus on relevant preclinical large animal models.

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Adult Canine Intestinal Derived Organoids: A Novel In Vitro System for Translational Research in Comparative Gastroenterology

10.1101/466409 ◽

2018 ◽

Cited By ~ 1

Author(s):

Lawrance Chandra ◽

Dana C Borcherding ◽

Dawn Kingsbury ◽

Todd Atherly ◽

Yoko M Ambrosini ◽

...

Keyword(s):

Animal Models ◽

Translational Research ◽

Three Dimensional ◽

Metabolic Imaging ◽

Large Animal ◽

Large Animal Models ◽

Molecular Features ◽

Naturally Occurring

AbstractBackgroundLarge animal models, such as the dog, are increasingly being used over rodent models for studying naturally occurring diseases including gastrointestinal (GI) disorders. Dogs share similar environmental, genomic, anatomical, and intestinal physiologic features with humans. To bridge the gap between currently used animal models (e.g. mouse) and humans, and expand the translational potential of the dog model, we developed a three dimensional (3D) canine GI organoid (enteroid and colonoid) system. Organoids have recently gained interest in translational research as this model system better recapitulates the physiological and molecular features of the tissue environment in comparison with two-dimensional cultures.ResultsOrganoids were propagated from isolation of adult intestinal stem cells (ISC) from whole jejunal tissue as well as endoscopically obtained duodenal, ileal and colonic biopsy samples of healthy dogs and GI cases, including inflammatory bowel disease (IBD) and intestinal carcinomas. Intestinal organoids were comprehensively characterized using histology, immunohistochemistry, RNA in situ hybridization and transmission electron microscopy, and organoids mimicked the in vivo tissue environment. Physiological relevance of the enteroid system was defined using functional assays such as Optical Metabolic Imaging (OMI), the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function assay, and Exosome-Like Vesicles (EV) uptake assay, as a basis for wider applications of this technology in basic, preclinical and translational GI research.ConclusionsIn summary, our findings establish the canine GI organoid systems as a novel model to study naturally occurring intestinal diseases in dogs and humans. Furthermore, canine organoid systems will help to elucidate host-pathogen interactions contributing to GI disease pathogenesis.

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Atherosclerosis and Thrombosis: Insights from Large Animal Models

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/907575 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 68

Author(s):

Gemma Vilahur ◽

Teresa Padro ◽

Lina Badimon

Keyword(s):

Animal Models ◽

Ex Vivo ◽

Large Animal ◽

Isolated Cells ◽

Large Animal Models ◽

Thrombosis Research ◽

Human Pathology ◽

Thrombotic Complications

Atherosclerosis and its thrombotic complications are responsible for remarkably high numbers of deaths. The combination ofin vitro, ex vivo, andin vivoexperimental approaches has largely contributed to a better understanding of the mechanisms underlying the atherothrombotic process. Indeed, different animal models have been implemented in atherosclerosis and thrombosis research in order to provide new insights into the mechanisms that have already been outlined in isolated cells and protein studies. Yet, although no model completely mimics the human pathology, large animal models have demonstrated better suitability for translation to humans. Indeed, direct translation from mice to humans should be taken with caution because of the well-reported species-related differences. This paper provides an overview of the availableatherothrombotic-likeanimal models, with a particular focus on large animal models of thrombosis and atherosclerosis, and examines their applicability for translational research purposes as well as highlights species-related differences with humans.

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Remaining Physiological Barriers in Porcine Kidney Xenotransplantation: Potential Pathways behind Proteinuria as well as Factors Related to Growth Discrepancies following Pig-to-Kidney Xenotransplantation

Journal of Immunology Research ◽

10.1155/2018/6413012 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Jigesh A. Shah ◽

Miguel A. Lanaspa ◽

Tatsu Tanabe ◽

Hironosuke Watanabe ◽

Richard J. Johnson ◽

...

Keyword(s):

Organ Transplantation ◽

Solid Organ Transplantation ◽

Large Animal ◽

Organ Shortage ◽

Solid Organ ◽

Porcine Kidney ◽

Barriers To Success ◽

Large Animal Models ◽

Number Of Patients ◽

Causative Factors

Considerable shortages in the supply of available organs continue to plague the field of solid organ transplantation. Despite changes in allocation, as well as the utilization of extended criteria and living donors, the number of patients waiting for organs continues to grow at an alarming pace. Xenotransplantation, cross-species solid organ transplantation, offers one potential solution to this dilemma. Previous extensive research dedicated to this field has allowed for resolution of xenograft failure due to acute rejection, leaving new areas of unresolved challenges as barriers to success in large animal models. Specific to kidney xenotransplantation, recent data seems to indicate that graft compromise can occur due to discrepancies in growth between breeds of donors and significant proteinuria leading to nephrotic syndrome in the recipient. Given these potential limitations, herein, we review potential pathways behind proteinuria, as well as potential causative factors related to growth discrepancies. Control of both of these has the potential to allow xenotransplantation to become clinically applicable in an effort to resolve this organ shortage crisis.

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Exploring the Role of Mesenchymal Stem Cells During Normothermic Organ Perfusion: A New Paradigm to Enhance Outcome Following Allograft Transplantation

The Open Stem Cell Journal ◽

10.2174/1876893801805010047 ◽

2018 ◽

Vol 5 (1) ◽

pp. 47-52

Author(s):

Mohamed Morsy ◽

Mohammad Ayaz Hossain ◽

Atul Bagul

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Organ Transplantation ◽

Ex Vivo ◽

Solid Organ Transplantation ◽

Short Review ◽

Solid Organ ◽

New Paradigm ◽

Liver And Kidney

Background: Normothermic Machine Perfusion (NMP) has been established in the field of solid organ transplantation for both liver and kidney allografts. The ability to perfuse organs at body temperature enables viability assessment as well as optimisation prior to implantation. Discussion: A recent in vitro report of the use of Mesenchymal Stem Cells (MSCs) in the use of a normothermic lung perfusion circuit has raised the possibility of their use in solid organ transplantation. The aim of this short review is to outline the potential uses of bone marrow derived MSCs for their use in renal allograft ex vivo NMP. An overview is provided of current literature of NMP as well as theorised uses for MSCs.

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