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

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.

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

2020 ◽  
Vol 21 (18) ◽  
pp. 6468
Author(s):  
Annika Mohr ◽  
Jens G. Brockmann ◽  
Felix Becker
Keyword(s):  
Animal Models ◽  
Organ Transplantation ◽  
Organ Preservation ◽  
Solid Organ Transplantation ◽  
Large Animal ◽  
Solid Organ ◽  
Large Animal Models ◽  
Htk Solution

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.

scholarly journals Animal Models in Allogenic Solid Organ Transplantation

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.

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

Cells ◽  
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.

scholarly journals Intratracheal aerosolization of viral vectors to newborn pig airways

BioTechniques ◽  
2020 ◽  
Vol 68 (5) ◽  
pp. 235-239
Author(s):  
Ashley L Cooney ◽  
Patrick L Sinn
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Endotracheal Tube ◽  
Viral Vectors ◽  
Small Animal ◽  
Large Animal ◽  
Large Animal Models ◽  
Airway Diseases ◽  
Efficient Delivery ◽  
Large Animals

Gene therapy for airway diseases requires efficient delivery of nucleic acids to the airways. In small animal models, gene delivery reagents are commonly delivered as a bolus dose. However, large animal models are often more relevant for the transition from preclinical studies to human trials. Aerosolizing viral vectors to the lungs of large animals can maximize anatomical distribution. Here, we describe a technique for aerosolization of viral vectors to the airways of newborn pigs. Briefly, a pig is anesthetized and intubated with an endotracheal tube, and a microsprayer is passed through the endotracheal tube. A fine mist is then sprayed into the distal trachea. Widespread and uniform distribution of transgene expression is critical for developing successful lung gene therapy treatments.

scholarly journals Consequences of mitral valve prolapse on chordal tension: Ex vivo and in vivo studies in large animal models

2011 ◽  
Vol 142 (6) ◽  
pp. 1585-1587 ◽  
Author(s):  
Mathieu Granier ◽  
Morten O. Jensen ◽  
Jesper L. Honge ◽  
Alain Bel ◽  
Philippe Menasché ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Animal Models ◽  
Mitral Valve Prolapse ◽  
Ex Vivo ◽  
In Vivo Studies ◽  
Large Animal ◽  
Large Animal Models

scholarly journals Nerve Allotransplantation as it Pertains to Composite Tissue Transplantation

Hand ◽  
2009 ◽  
Vol 4 (3) ◽  
pp. 239-244 ◽  
Author(s):  
Amy M. Moore ◽  
Wilson Z. Ray ◽  
Kristofer E. Chenard ◽  
Thomas Tung ◽  
Susan E. Mackinnon
Keyword(s):  
Nerve Regeneration ◽  
Solid Organ Transplantation ◽  
Tissue Transplantation ◽  
Large Animal ◽  
Solid Organ ◽  
Composite Tissue ◽  
Allograft Transplantation ◽  
Segmental Nerve ◽  
Composite Tissue Transplantation ◽  
And Function

Nerve allografts provide a temporary scaffold for host nerve regeneration and allow for the repair of significant segmental nerve injuries. From rodent, large animal, and nonhuman primate studies, as well as clinical experience, nerve allografts, with the use of immunosuppression, have the capacity to provide equal regeneration and function to that of an autograft. In contrast to solid organ transplantation and composite tissue transfers, nerve allograft transplantation requires only temporary immunosuppression. Furthermore, nerve allograft rejection is difficult to assess, as the nerves are surgically buried and are without an immediate functional endpoint to monitor. In this article, we review what we know about peripheral nerve allograft transplantation from three decades of experience and apply our current understanding of nerve regeneration to the emerging field of composite tissue transplantation.

scholarly journals Preclinical and Clinical Development of Noncoding RNA Therapeutics for Cardiovascular Disease

2020 ◽  
Vol 126 (5) ◽  
pp. 663-678 ◽  
Author(s):  
Cheng-Kai Huang ◽  
Sabine Kafert-Kasting ◽  
Thomas Thum
Keyword(s):  
Cardiovascular Disease ◽  
Animal Models ◽  
Noncoding Rna ◽  
Ex Vivo ◽  
Human Cells ◽  
Large Animal ◽  
Cardiovascular Research ◽  
In Vivo Models ◽  
Large Animal Models ◽  
Promising Therapeutic Approach

RNA modulation has become a promising therapeutic approach for the treatment of several types of disease. The emerging field of noncoding RNA-based therapies has now come to the attention of cardiovascular research, in which it could provide valuable advancements in comparison to current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on noncoding RNA-based studies conducted mainly in large-animal models, including pigs, rabbits, dogs, and nonhuman primates. The obstacles and promises of targeting long noncoding RNAs and circRNAs as therapeutic modalities in humans are specifically discussed. We also describe novel ex vivo methods based on human cells and tissues, such as engineered heart tissues and living myocardial slices that could help bridging the gap between in vivo models and clinical applications in the future. Finally, we summarize antisense oligonucleotide drugs that have already been approved by the Food and Drug Administration for targeting mRNAs and discuss the progress of noncoding RNA-based drugs in clinical trials. Additional factors, such as drug chemistry, drug formulations, different routes of administration, and the advantages of RNA-based drugs, are also included in the present review. Recently, first therapeutic miRNA-based inhibitory strategies have been tested in heart failure patients as well as healthy volunteers to study effects on wound healing (NCT04045405; NCT03603431). In summary, a combination of novel therapeutic RNA targets, large-animal models, ex vivo studies with human cells/tissues, and new delivery techniques will likely lead to significant progress in the development of noncoding RNA-based next-generation therapeutics for cardiovascular disease.

scholarly journals Large animals in neurointerventional research: A systematic review on models, techniques and their application in endovascular procedures for stroke, aneurysms and vascular malformations

2019 ◽  
Vol 39 (3) ◽  
pp. 375-394 ◽  
Author(s):  
Andrea M Herrmann ◽  
Stephan Meckel ◽  
Matthew J Gounis ◽  
Leona Kringe ◽  
Edith Motschall ◽  
...  
Keyword(s):  
Systematic Review ◽  
Ischemic Stroke ◽  
Animal Models ◽  
Translational Research ◽  
Arteriovenous Malformations ◽  
Vascular Malformations ◽  
Large Animal ◽  
Large Animal Models ◽  
Large Animals ◽  
Study Designs

Neuroendovascular procedures have led to breakthroughs in the treatment of ischemic stroke, intracranial aneurysms, and intracranial arteriovenous malformations. Due to these substantial successes, there is continuous development of novel and refined therapeutic approaches. Large animal models feature various conceptual advantages in translational research, which makes them appealing for the development of novel endovascular treatments. However, the availability and role of large animal models have not been systematically described so far. Based on comprehensive research in two databases, this systematic review describes current large animal models in neuroendovascular research including their primary use. It may therefore serve as a compact compendium for researchers entering the field or looking for opportunities to refine study concepts. It also describes particular applications for ischemic stroke and aneurysm therapy, as well as for the treatment of arteriovenous malformations. It focuses on most promising study designs and readout parameters, as well as on important pitfalls in endovascular translational research including ways to circumvent them.

scholarly journals Mixed chimerism

2001 ◽  
Vol 356 (1409) ◽  
pp. 707-726 ◽  
Author(s):  
Megan Sykes ◽  
David H. Sachs
Keyword(s):  
Lymphocyte Subsets ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Large Animal ◽  
Rodent Models ◽  
Cell Type ◽  
Potential Toxicity ◽  
Large Animal Models ◽  
Conditioning Regimens ◽  
Made In

Induction of mixed chimerism has the potential to overcome the current limitations of transplantation, namely chronic rejection, complications of immunosuppressive therapy and the need for xenografts to overcome the current shortage of allogeneic organs. Successful achievement of mixed chimerism had been shown to tolerize T cells, B cells and possibly natural killer cells, the lymphocyte subsets that pose major barriers to allogeneic and xenogeneic transplants. Current understanding of the mechanisms involved in tolerization of each cell type is reviewed. Considerable advances have been made in reducing the potential toxicity of conditioning regimens required for the induction of mixed chimerism in rodent models, and translation of these strategies to large animal models and in a patient are important advances toward more widespread clinical application of the mixed chimerism approach for tolerance induction.

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