TRAUMA-SHOCK-INDUCED GUT INJURY AND THE PRODUCTION OF BIOLOGICALLY ACTIVE INTESTINAL LYMPH IS ABROGATED BY CASTRATION IN A LARGE ANIMAL PORCINE MODEL

Abstract Emergency resternotomy in the intensive care unit (ICU) is a rarely performed, yet potentially life-saving intervention. Success relies on recognition of a deteriorating clinical condition, timely deployment of equipment/personnel and rapid execution. Given how infrequently it is performed, we sought to develop a large animal model of resternotomy to prepare ICU nurses and technicians at our low-volume cardiac surgery military centre. A porcine model of resternotomy was developed at the end of an already-scheduled trauma lab. Participants worked their way through a pre-planned simulation scenario, culminating in the need for resternotomy. Pre-simulation surveys assessing knowledge and comfort level with aspects of resternotomy were compared to post-simulation surveys. Participants improved their knowledge of resternotomy by 20.4% (P < 0.0001; 14.7% for nurses and 26.9% for technicians). Improvements were seen in all aspects assessed relating to subjective comfort/preparedness of resternotomy. The model was an effective and realistic method to augment training of ICU staff about resternotomy. Costs associated with this model can be reduced when used in conjunction with large animal labs. This model should be used together with mannequin-based methods of resternotomy training to provide a realistic training environment and assessment of skills at capable institutions.

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PLASMA CONCENTRATION OF BIOLOGICALLY ACTIVE FIBRONECTIN AND FIBRONECTIN BOUND TO GELATIN-LIKE MATERIAL IN A PORCINE MODEL OF HYPERDYNAMIC ENDOTOXIC SHOCK

Shock ◽

10.1097/00024382-200014040-00011 ◽

2000 ◽

Vol 14 (4) ◽

pp. 484-489 ◽

Cited By ~ 1

Author(s):

Manfred Nagelschmidt ◽

Andreas D. Rink ◽

Edmund Neugebauer

Keyword(s):

Plasma Concentration ◽

Porcine Model ◽

Endotoxic Shock ◽

Biologically Active

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The Representative Porcine Model for Human Cardiovascular Disease

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/195483 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 40

Author(s):

Yoriyasu Suzuki ◽

Alan C. Yeung ◽

Fumiaki Ikeno

Keyword(s):

Animal Models ◽

Porcine Model ◽

Small Animal ◽

Large Animal ◽

Murine Models ◽

Practical Applications ◽

Large Animal Models ◽

Small Animal Models ◽

Insight Into

To improve human health, scientific discoveries must be translated into practical applications. Inherent in the development of these technologies is the role of preclinical testing using animal models. Although significant insight into the molecular and cellular basis has come from small animal models, significant differences exist with regard to cardiovascular characteristics between these models and humans. Therefore, large animal models are essential to develop the discoveries from murine models into clinical therapies and interventions. This paper will provide an overview of the more frequently used large animal models, especially porcine models for preclinical studies.

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1α,25-Dihydroxyvitamin D3 Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas

Journal of the American Society of Nephrology ◽

10.1681/asn.2020060832 ◽

2021 ◽

Vol 32 (4) ◽

pp. 866-885 ◽

Cited By ~ 1

Author(s):

Avishek K. Singh ◽

Chuanqi Cai ◽

Sreenivasulu Kilari ◽

Chenglei Zhao ◽

Michael L. Simeon ◽

...

Keyword(s):

Gene Expression ◽

Rna Sequencing ◽

Porcine Model ◽

Neointimal Hyperplasia ◽

Peak Systolic Velocity ◽

Plga Nanoparticles ◽

Large Animal ◽

Sequencing Analysis ◽

Arteriovenous Fistulas ◽

Local Release

BackgroundFew therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (Iex-1), also known as Ier3, is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of Ier3 long-acting inhibitor 1α,25(OH)2D3 from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model.MethodsImmediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF.ResultsEncapsulation of 1α,25(OH)2D3 in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)2D3. The 1,25 NP–treated AVFs exhibited lower VNH/VS, Ier3 gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young’s modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFβ1, and apoptotic pathways.ConclusionsLocal release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.

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Multiple stent delivery system Multi-LOC, a new technology for spot-stenting of the femoropopliteal artery – proof of concept study in a preclinical large animal model

VASA ◽

10.1024/0301-1526/a000657 ◽

2017 ◽

Vol 46 (6) ◽

pp. 446-451 ◽

Cited By ~ 4

Author(s):

Martin Sigl ◽

Oliver Dudeck ◽

Johannes Jung ◽

Heinz Koelble ◽

Klaus Amendt

Keyword(s):

Delivery System ◽

Porcine Model ◽

New Technology ◽

Large Animal Model ◽

Lower Percentage ◽

Stent Fracture ◽

Large Animal ◽

Neointimal Formation ◽

Femoropopliteal Artery ◽

Intraindividual Comparison

Abstract. Background: A new stent system was studied in a porcine model to evaluate its feasibility for spot-stenting of the femoropopliteal artery. Materials and methods: In a preliminary study in a single pig, handling and mechanical features of the novel multiple stent delivery system were tested. The Multi-LOC system demonstrated great feasibility regarding its pushability, trackability, and crossability. Excellent visibility of the individual stents allowed exact anatomically controlled implantation. In our main study, four to five short Multi-LOC stents (13 mm long) were implanted into the femoropopliteal arteries of six domestic pigs and long (60 to 100 mm) self-expandable nitinol stents were implanted into the same target vessel contralaterally to allow for intraindividual comparison. After four weeks survival under dual antiplatelet treatment, control angiography was performed. The animals were euthanized, stented vessels were explanted, and histologic sections were examined for the presence of neointimal formation. Results: Multi-LOC stents demonstrated no occlusion of the femoropopliteal axis (0 vs. 1 occlusion distal to a control stent), no stent fractures (0 out of 26 vs. 2 out of 6 control stents), and lower percentage diameter stenosis (0.564 ± 0.056 vs. 0.712 ± 0.089; p = 0.008) and length of stenosis (19.715 ± 5.225 vs. 39.397 ± 11.182; p = 0.007) compared to a standard control stent, which was similar in total length to the multiple stented artery segment. Histological examination confirmed myointimal hyperplasia underlying in-stent stenosis. Conclusions: The multiple stent delivery system was studied in a porcine model, which demonstrated its feasibility. Preclinical experience revealed favourable results concerning stent fracture, restenosis, and patency of spot-stented femoropopliteal arteries.

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Platelet-Targeted Expression of Human BDD-FVIII Reduces Bleeding in Canine Hemophilia A.

Blood ◽

10.1182/blood.v114.22.691.691 ◽

2009 ◽

Vol 114 (22) ◽

pp. 691-691 ◽

Cited By ~ 1

Author(s):

Lily M. Du ◽

Timothy C. Nichols ◽

Sandra L. Haberichter ◽

Paula M. Jacobi ◽

Eric S. Jensen ◽

...

Keyword(s):

Stem Cells ◽

Animal Model ◽

Hematopoietic Stem Cells ◽

Peripheral Blood ◽

Hemophilia A ◽

Biologically Active ◽

Large Animal ◽

Lentivirus Vector ◽

Hematopoietic Stem ◽

One Year

Abstract Abstract 691 Introduction: The goal of our study was to develop a clinically relevant strategy for platelet-targeted gene therapy of the commonly inherited bleeding disorder, Hemophilia A. We hypothesized that adult dogs (25 kg) affected with Hemophilia A could serve as a relevant “large animal” model to test if FVIII could be synthesized and sequestered within platelets derived from lentivirus-transduced hematopoietic stem cells. This approach is novel because it should permit the regulated release of FVIII from activated platelet progeny directly at the wound site as a physiological hemostatic response to bleeding challenges. Methods: cG-CSF/cSCF mobilized peripheral blood stem cells (PBSC) were immuno-selected for CD34 antigen from an apheresis product, transduced with a lentivirus vector under the transcriptional control of platelet-specific integrin αaIIb gene promoter driving expression of human BDD-FVIII. The PBSC (3 × 10 6/kg) were then autologously transplanted into animals that were preconditioned with Bulsulfan (5-10 mg/kg i.v.). After transplant, the dogs received oral cyclosporine to maintain levels at 200–400 ng/ml for 90 days and MMF at 8mg/kg for 35 days. Results: Two transplant recipients underwent periodic testing for incorporation and expression of the FVIII transgene as well as immune tolerance and phenotypic correction of Hemophilia A. PCR analysis detected the lentivirus vector within genomic DNA isolated from circulating peripheral blood leukocytes for more than one year after transplant. Immunofluorescence confocal microscopy showed synthesis of FVIII within tissue cultured canine megakaryocytes and circulating peripheral blood platelets. Chromogenic analysis of platelets isolated from transplanted dogs demonstrated the presence of a biologically active form of FVIII (FVIII:C) at approximately 5 mU/ml/1×108 platelets from 20 weeks through greater than one year after PBSC transplant. In contrast, FVIII:C was not detected within the plasma of these animals. This result coupled with the immunomodulation drugs may help to explain why the dogs failed to develop inhibitory antibodies to human FVIII. Following successful gene transfer and engraftment, both animals showed signs of clinical improvement of Hemophilia A: one dog has had one bleed per year for 2 years (vs expected 5–6/year) and the second dog has had no bleeds for 8 months following transplantation. In addition, one dog showed significant recovery from prolonged (months) history of gastrointestinal bleeding. These data are consistent with our previous results demonstrating synthesis, trafficking and storage of FVIII within αa-granules of human megakaryoyctes in vitro and platelets of the murine “small animal” model for Hemophilia A. Conclusions: This outcome raises the possibility of developing a protocol for delivering a locally inducible secretory pool of FVIII in platelets of patients with Hemophilia A following autologous transplantation of FVIII-transduced hematopoietic stem cells. Disclosures: Montgomery: GTI Diagnostics: Consultancy; Baxter: Consultancy; AstraZeneca: Consultancy; Bayer: Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Wilcox:Amgen, INC: Research Reagents, canine growth factors: cG-CSF and cSCF.

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Safety Evaluation of Human Cord-Lining Epithelial Stem Cells Transplantation for Liver Regeneration in a Porcine Model

Cell Transplantation ◽

10.1177/0963689719896559 ◽

2020 ◽

Vol 29 ◽

pp. 096368971989655

Author(s):

Raymond Hon Giat Lim ◽

Justin Xuan Kai Liew ◽

Aileen Wee ◽

Jeyakumar Masilamani ◽

Stephen Kin Yong Chang ◽

...

Keyword(s):

Stem Cells ◽

Epithelial Cells ◽

Liver Regeneration ◽

Porcine Model ◽

Embryonic Stem ◽

Large Animal ◽

Epithelial Stem Cells ◽

Produce Cell ◽

Stem Cell Delivery ◽

Promising Source

We investigated the safety of using umbilical cord-lining stem cells for liver regeneration and tested a novel method for stem cell delivery. Stem cells are known by their ability to repair damaged tissues and have the potential to be used as regenerative therapies. The umbilical cord’s outer lining membrane is known to be a promising source of multipotent stem cells and can be cultivated in an epithelial cell growth medium to produce cell populations which possess the properties of both epithelial cells and embryonic stem cells—termed cord-lining epithelial cells (CLEC). Hepatocytes are epithelial cells of the liver and their proliferation upon injury is the main mechanism in restoring the liver. Earlier studies conducted showed CLEC can be differentiated into functioning hepatocyte-like cells (HLC) and can survive in immunologically competent specimens. In this study, we chose a porcine model to investigate CLEC as a treatment modality for liver failure. We selected 16 immune competent Yorkshire-Dutch Landrace pigs, with a mean weight of 40.5 kg, for this study. We performed a 50% hepatectomy to simulate the liver insufficient disease model. After the surgery, four pigs were transplanted with a saline scaffold while seven pigs were transplanted with a HLC scaffold. Five pigs died on the surgical table and were omitted from the study analysis. This study addressed the safety of transplanting human CLEC in a large animal model. The transplant interfaces were evaluated and no signs of cellular rejection were observed in both groups.

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PANCREATIC DUCT LIGATION ABROGATES THE TRAUMA HEMORRHAGE-INDUCED GUT BARRIER FAILURE AND THE SUBSEQUENT PRODUCTION OF BIOLOGICALLY ACTIVE INTESTINAL LYMPH

Shock ◽

10.1097/shk.0b013e31804858f2 ◽

2007 ◽

Vol 28 (4) ◽

pp. 441-446 ◽

Cited By ~ 32

Author(s):

Francis J. Caputo ◽

Bobby Rupani ◽

Anthony C. Watkins ◽

Dimitrios Barlos ◽

Dennis Vega ◽

...

Keyword(s):

Pancreatic Duct ◽

Biologically Active ◽

Gut Barrier ◽

Intestinal Lymph ◽

Pancreatic Duct Ligation ◽

Barrier Failure ◽

Duct Ligation ◽

Gut Barrier Failure

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Development of a large animal model of lethal polytrauma and intra-abdominal sepsis with bacteremia

Trauma Surgery & Acute Care Open ◽

10.1136/tsaco-2020-000636 ◽

2021 ◽

Vol 6 (1) ◽

pp. e000636

Author(s):

Rachel L O'Connell ◽

Glenn K Wakam ◽

Ali Siddiqui ◽

Aaron M Williams ◽

Nathan Graham ◽

...

Keyword(s):

Animal Model ◽

Porcine Model ◽

Survival Curve ◽

Abdominal Sepsis ◽

Injury Pattern ◽

Long Bone ◽

Large Animal Model ◽

Therapeutic Drug ◽

Large Animal ◽

Term Survival

BackgroundTrauma and sepsis are individually two of the leading causes of death worldwide. When combined, the mortality is greater than 50%. Thus, it is imperative to have a reproducible and reliable animal model to study the effects of polytrauma and sepsis and test novel treatment options. Porcine models are more translatable to humans than rodent models due to the similarities in anatomy and physiological response. We embarked on a study to develop a reproducible model of lethal polytrauma and intra-abdominal sepsis, which was lethal, though potentially salvageable with treatment.MethodsOur laboratory has a well-established porcine model that was used as the foundation. Animals were subjected to a rectus crush injury, long bone fracture, liver and spleen laceration, traumatic brain injury and hemorrhage that was used as a foundation. We tested various colon injuries to create intra-abdominal sepsis. All animals underwent injuries followed by a period of shock, then subsequent resuscitation.ResultsAll animals had blood culture-proven sepsis. Attempts at long-term survival of animals after injury were ceased because of poor appetite and energy. We shifted to an 8-hour endpoint. The polytrauma injury pattern remained constant and the colon injury pattern changed with the intention of creating a model that was ultimately lethal but potentially salvageable with a therapeutic drug. An uncontrolled cecal injury (n=4) group resulted in very early deaths. A controlled cecal injury (CCI; n=4) group had prolonged time prior to mortality with one surviving to the endpoint. The sigmoid injury (n=5) produced a similar survival curve to CCI but no animals surviving to the endpoint.ConclusionWe have described a porcine model of polytrauma and sepsis that is reproducible and may be used to investigate novel treatments for trauma and sepsis.Level of evidenceNot applicable. Animal study.

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