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

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

International Journal of Molecular Sciences ◽

10.3390/ijms21186468 ◽

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.

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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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Intratracheal aerosolization of viral vectors to newborn pig airways

BioTechniques ◽

10.2144/btn-2019-0150 ◽

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.

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Different degradation rates of nanofiber vascular grafts in small and large animal models

Journal of Tissue Engineering and Regenerative Medicine ◽

10.1002/term.2977 ◽

2020 ◽

Vol 14 (2) ◽

pp. 203-214

Author(s):

Takuma Fukunishi ◽

Chin Siang Ong ◽

Pooja Yesantharao ◽

Cameron A. Best ◽

Tai Yi ◽

...

Keyword(s):

Animal Models ◽

Vascular Grafts ◽

Large Animal ◽

Large Animal Models ◽

Degradation Rates

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A Novel Approach to Drug Delivery for Hepatities C Virus (HCV) for High Immune Responses

Journal of Medical Devices ◽

10.1115/1.2932336 ◽

2008 ◽

Vol 2 (2) ◽

Author(s):

W. T. Chen ◽

C. Zhang

Keyword(s):

Immune Responses ◽

High Strength ◽

Azomethine Ylides ◽

Enzyme Linked Immunosorbent Assay ◽

Large Animal ◽

Testing Environment ◽

Large Animal Models ◽

Novel Approach ◽

Large Animals

Hepatities C Virus (HCV) is a significant health problem worldwide due to the lack of effective vaccines. HCV plasmid DNA (pDNA) vaccine represents a promising means to induce a Th1-biased cell-mediated response which tends to be associated with HCV clearance. However, the immune responses induced by naked pDNA vaccine in large animals as well as in humans are usually too weak to show sufficient protection against new infections. Therefore, it is interesting to look for new ways to deliver HCV pDNA vaccine. In this research, carbon nanotube (CNT) is used as a carrier to deliver the pDNA vaccine of HCV to induce high immune responses, because CNT has some excellent properties such as high strength and good biocompatibility. One of the key approaches to make this idea work is to treat CNT so that it can bind with HCV pDNA with good stability. An approach called 1, 3-dipolar cycloaddition of azomethine ylides was modified. We analyzed the complex of f-CNTs combined with pDNA vaccines expressing HCV E2 protein by using Enzyme-linked immunospot (ELISPOT) or Enzyme-linked immunosorbent assay (ELISA) assay in vitro. The result showed that the CNT approach can induce stronger protective immune responses than the needle delivery of naked pDNA vaccine. We have also found an optimal way to treat CNT in light of the highest immune response in the same testing environment. The success of this research will warrant testing HCV vaccine in large animal models and human clinical trials.

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

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2011.08.035 ◽

2011 ◽

Vol 142 (6) ◽

pp. 1585-1587 ◽

Cited By ~ 13

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

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BIODEGRADABLE VASCULAR GRAFT MODIFIED BY RGD-PEPTIDES: EXPERIMENTAL RESEARCH

Siberian Medical Journal ◽

10.29001/2073-8552-2019-34-2-129-137 ◽

2019 ◽

Vol 34 (2) ◽

pp. 129-137

Author(s):

E. O. Krivkina ◽

V. N. Silnikov ◽

A. V. Mironov ◽

E. A. Velikanova ◽

E. A. Senokosova ◽

...

Keyword(s):

Endothelial Cells ◽

Vascular Grafts ◽

Small Diameter ◽

Internal Surface ◽

Mechanical Tests ◽

Laboratory Animals ◽

Rgd Peptides ◽

Peptide Modification

Research goals. To study the effectiveness of RGD-peptide modification of the small-diameter biodegradable vascular grafts depending on the type of a linker and RGD configuration.Material and Methods. Tubular scaffolds with a diameter of 1.5 and 4.0 mm were produced by electrospinning from polyhydroxybutyrate/valerate (PHBV) and polycaprolactone (PCL). The PHBV/PCL grafts were modified with RGD peptides. In vitro experiments showed the degree of erythrocyte hemolysis and adhesion of the platelets and endothelial cells when in contact with a modified surface. The physico-mechanical properties and the structure of graft surface were studied before and after modification. The PHBV/PCL and PHBV/PCL/RGD vascular grafts were implanted into the abdominal aorta of rats for the periods of 1 and 3 months. Explant samples were studied using confocal microscopy and histological methods.Results. The results of physical and mechanical tests showed a significant decrease in the strength properties of the PHBV/PCL/RGD grafts relative to the unmodified analogs. A significant increase in platelet aggregation was found in the modified grafts. The level of adhesion of the endothelial cells on the modified surfaces was higher than that on the unmodified surfaces. Shortterm implantation of the grafts for 1 and 3 months showed that the modified grafts had higher patency and a less tendency to calcification compared with the unmodified grafts. Immunofluorescence study demonstrated the significant superiority of the modified vascular grafts in terms of stimulating the formation of a mature endothelial monolayer. A longer linker of 4,7,10-trioxa-1,13-tridecane diamine was found to increase the bioavailability of RGD peptides; the use of RGDK and c[RGDFK] for surface modification of the grafts stimulated early endothelialization of the internal surface of the implants and reduced the prosthetic wall calcification tendency, which together increased the patency of the implanted grafts.Conclusion. In short-term implantation of biodegradable vascular grafts modified with RGD peptides, the grafts with RGDK and c[RGDFK], attached to the surface of the prostheses through the 4,7,10-triox-1,13-tridecane diamine linker, showed the best results in terms of endothelial adhesion and maintenance of the viability of the endothelial cells in vitro and endothelialization in vivo; these grafts had high patency after implantation into the bloodstream of small laboratory animals and a less tendency to calcification.

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