scholarly journals Evolution of the rat hind limb transplant as an experimental model of vascularized composite allotransplantation: Approaches and advantages

2020 ◽  
Vol 8 ◽  
pp. 205031212096872
Author(s):  
Yoram Y Fleissig ◽  
Jason E Beare ◽  
Amanda J LeBlanc ◽  
Christina L Kaufman
Keyword(s):  
Upper Extremity ◽  
Hind Limb ◽  
Large Body ◽  
Surgical Techniques ◽  
Experimental Models ◽  
Tissue Loss ◽  
Large Animal ◽  
Solid Organ ◽  
Vascularized Composite Allotransplantation ◽  
Large Animal Models

As clinical experience with surgical techniques and immunosuppression in vascularized composite allotransplantation recipients has accumulated, vascularized composite allotransplantation for hand and face have become standard of care in some countries for select patients who have experienced catastrophic tissue loss. Experience to date suggests that clinical vascularized composite allotransplantation grafts undergo the same processes of allograft rejection as solid organ grafts. Nonetheless, there are some distinct differences, especially with respect to the immunologic influence of the skin and how the graft is affected by environmental and traumatic insults. Understanding the mechanisms around these similarities and differences has the potential to not only improve vascularized composite allotransplantation outcomes but also outcomes for all types of transplants and to contribute to our understanding of how complex systems of immunity and function work together. A distinct disadvantage in the study of upper extremity vascularized composite allotransplantation recipients is the low number of clinical transplants performed each year. As upper extremity transplantation is a quality of life rather than a lifesaving transplant, these numbers are not likely to increase significantly until the risks of systemic immunosuppression can be reduced. As such, experimental models of vascularized composite allotransplantation are essential to test hypotheses regarding unique characteristics of graft rejection and acceptance of vascularized composite allotransplantation allografts. Rat hind limb vascularized composite allotransplantation models have been widely used to address these questions and provide essential proof-of-concept findings which can then be extended to other experimental models, including mice and large animal models, as new concepts are translated to the clinic. Here, we review the large body of rat hind limb vascularized composite allotransplantation models in the literature, with a focus on the various surgical models that have been developed, contrasting the characteristics of the specific model and how they have been applied. We hope that this review will assist other researchers in choosing the most appropriate rat hind limb transplantation model for their scientific interests.

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 Large animal models of stroke and traumatic brain injury as translational tools

2018 ◽  
Vol 315 (2) ◽  
pp. R165-R190 ◽  
Author(s):  
Annabel J. Sorby-Adams ◽  
Robert Vink ◽  
Renée J. Turner
Keyword(s):  
Traumatic Brain Injury ◽  
Ischemic Stroke ◽  
Brain Injury ◽  
Animal Models ◽  
Animal Species ◽  
Experimental Models ◽  
Clinical Translation ◽  
Large Animal ◽  
Large Animal Models ◽  
Significant Burden

Acute central nervous system injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide. Studies in animal models have greatly enhanced our understanding of the complex pathophysiology that underlies TBI and stroke and enabled the preclinical screening of over 1,000 novel therapeutic agents. Despite this, the translation of novel therapeutics from experimental models to clinical therapies has been extremely poor. One potential explanation for this poor clinical translation is the choice of experimental model, given that the majority of preclinical TBI and ischemic stroke studies have been conducted in small animals, such as rodents, which have small lissencephalic brains. However, the use of large animal species such as nonhuman primates, sheep, and pigs, which have large gyrencephalic human-like brains, may provide an avenue to improve clinical translation due to similarities in neuroanatomical structure when compared with widely adopted rodent models. This purpose of this review is to provide an overview of large animal models of TBI and ischemic stroke, including the surgical considerations, key benefits, and limitations of each approach.

scholarly journals In vivo cerebral aneurysm models

2019 ◽  
Vol 47 (1) ◽  
pp. E20 ◽  
Author(s):  
John W. Thompson ◽  
Omar Elwardany ◽  
David J. McCarthy ◽  
Dallas L. Sheinberg ◽  
Carlos M. Alvarez ◽  
...  
Keyword(s):  
Cerebral Aneurysm ◽  
Surgical Techniques ◽  
Cerebral Aneurysms ◽  
Aneurysm Rupture ◽  
Large Animal ◽  
Pharmacological Interventions ◽  
Large Animal Models ◽  
First Line Therapy ◽  
Endovascular Devices

Cerebral aneurysm rupture is a devastating event resulting in subarachnoid hemorrhage and is associated with significant morbidity and death. Up to 50% of individuals do not survive aneurysm rupture, with the majority of survivors suffering some degree of neurological deficit. Therefore, prior to aneurysm rupture, a large number of diagnosed patients are treated either microsurgically via clipping or endovascularly to prevent aneurysm filling. With the advancement of endovascular surgical techniques and devices, endovascular treatment of cerebral aneurysms is becoming the first-line therapy at many hospitals. Despite this fact, a large number of endovascularly treated patients will have aneurysm recanalization and progression and will require retreatment. The lack of approved pharmacological interventions for cerebral aneurysms and the need for retreatment have led to a growing interest in understanding the molecular, cellular, and physiological determinants of cerebral aneurysm pathogenesis, maturation, and rupture. To this end, the use of animal cerebral aneurysm models has contributed significantly to our current understanding of cerebral aneurysm biology and to the development of and training in endovascular devices. This review summarizes the small and large animal models of cerebral aneurysm that are being used to explore the pathophysiology of cerebral aneurysms, as well as the development of novel endovascular devices for aneurysm treatment.

Rabbit Anti-Thymocyte Globulin (rATG) Administrated Concomitantly with Liver Delivery of AAV2-hFIX Can Promote Inhibitor Formation In Rhesus Macaques.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3765-3765 ◽  
Author(s):  
Jonathan D. Finn ◽  
Patricia Favaro ◽  
J. Fraser Wright ◽  
Federico Mingozzi ◽  
Katherine A. High ◽  
...  
Keyword(s):  
T Cells ◽  
Gene Transfer ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Rescue Therapy ◽  
Factor Ix ◽  
Large Animal ◽  
Solid Organ ◽  
Large Animal Models ◽  
Human Factor Ix

Abstract Abstract 3765 Adeno-associated viral (AAV) vectors are one of the most extensively studied vector platforms for gene therapy applications. Our group is currently developing AAV vectors for the therapeutic treatment of hemophilia B (HB) in humans. The first clinical trial using an AAV2 vector to express human Factor IX (hFIX) (AAV2-hFIX16) from the liver of HB patients revealed a cytotoxic T lymphocyte (CTL) response directed against AAV capsid that occurred 4–6 weeks following treatment that was associated with a decline in transgene expression. Thus, immunosuppressive (IS) therapies may be required during AAV2 vector administration at high doses to prevent or to halt the immune mediated destruction of transduced hepatocytes. Previous work in murine and non-human primate (NHP) models has shown that sustained AAV-mediated expression of transgenes can induce tolerance, and that this is in part, dependent on CD4+ CD25+ FoxP3+ regulatory T cells (Tregs). Here we investigate the safety of a Treg sparing anti-T cell IS regimen in the context of liver mediated AAV2 gene transfer. Rabbit anti-thymocyte globulin (rATG) is an immune suppressive drug that is used in solid organ transplant and autoimmune disease. rATG has been shown to dramatically deplete the majority of T-cells, however some studies have shown that rATG spares Tregs and can induce tolerance in human T cells. rATG was administered to rhesus macaques (along with an 8-week course of Mycophenolate Mofetil (MMF) and sirolimus) either at the time of AAV vector administration (AAV2-hFIX16), or 5 weeks post-vector administration (rescue therapy). The administration of ATG at week 5 had no detrimental effect on hFIX expression and was not associated with inhibitor formation (n=3) indicating that rATG might be safe to use as an IS ‘rescue' agent, after the detection of an ongoing immune response against transduced cells. Interestingly we observed that early administration of rATG prevented tolerance induction and resulted in inhibitor formation in 2 of 3 animals upon withdrawal of IS. The inhibitor formation was associated with transient elevations in circulating levels of IL-2, IL-4, IL-10 and IFN-g. These results are comparable to previous findings in NHP using an anti-CD25 IS regimen (Daclizumab) at the time of vector administration (Blood 2007, 110(7):2334-41). We conclude that the timing of IS regimens is critical, and that IS regimens that alter the numbers, frequency, and/or function of T-cells at the time of vector administration can result in neutralizing antibodies (inhibitors) to the transgene product (hFIX). These data suggest that there might be multiple mechanisms responsible for maintaining tolerance in this model, and that Tregs alone might not be sufficient. This study highlights the critical need for safety studies in large animal models of potential immune suppressive regimens in the context of gene transfer before translating to the clinic. Disclosures: High: Genzyme, Inc: Consultancy, Patents & Royalties; Third Rock Ventures: Consultancy; Novo-Nordisk: Consultancy; Shire, Inc.: Consultancy.

scholarly journals Large Animal Models for Vascularized Composite Allotransplantation

2014 ◽  
Vol 1 (3) ◽  
pp. 190-196 ◽  
Author(s):  
Jhade D. Woodall ◽  
Benjamin D. Schultz ◽  
Michael Sosin ◽  
Rolf N. Barth
Keyword(s):  
Animal Models ◽  
Large Animal ◽  
Vascularized Composite Allotransplantation ◽  
Large Animal Models

scholarly journals How to generate graded spinal cord injuries in swine?: Tools and procedures

2021 ◽  
Author(s):  
Mark Züchner ◽  
Manuel J. Escalona ◽  
Lena Hammerlund Teige ◽  
Evangelos Balafas ◽  
Lili Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Animal Models ◽  
Functional Outcome ◽  
Spinal Cord Injuries ◽  
Large Body ◽  
Swine Model ◽  
Large Animal ◽  
Large Animal Models ◽  
Cord Injury ◽  
The Impact

Spinal cord injury (SCI) is a medically, psychologically and socially disabling condition. A large body of our knowledge on the basic mechanisms of SCI has been gathered in rodents. For preclinical validation of promising therapies, the use of animal models that are closer to humans has several advantages. This has promoted a more intensive development of large animal models for SCI during the past decade. We have recently developed a multimodal SCI apparatus for large animals that generated biomechanically reproducible impacts in vivo. It is composed of a spring-load impactor and support systems for the spinal cord and the vertebral column. We now present the functional outcome of farm pigs and minipigs injured with different lesion strengths. There was a correlation between the biomechanical characteristics of the impact, the functional outcome, and the tissue damage observed several weeks after injury. We also provide a detailed description of the procedure to generate such a SCI in both farm pigs and minipigs, in the hope to ease the adoption of the swine model by other research groups.

Transplantation Principles

2020 ◽  
Author(s):  
Maria Siemionow ◽  
Fatih Zor
Keyword(s):  
Transplant Rejection ◽  
Solid Organ Transplantation ◽  
Surgical Techniques ◽  
Immunosuppressive Drugs ◽  
Organ Shortage ◽  
Solid Organ ◽  
Major Advance ◽  
Vascularized Composite Allotransplantation ◽  
Comprehensive Overview ◽  
Keywords Transplantation

Transplantation is a truly multidisciplinary specialty where a surgical procedure requires inputs from both, the specialists of the specific organ e.g. nephrologist for kidney transplant or hepatologist for liver transplant, as well as from experts of other specialties such as immunology, infectious diseases etc. It is also a rapidly grooving field with the advances in surgical techniques, immunological knowledge and pharmacology. A recent, major advance in the field of transplantation is the emergence of new procedure of vascularized composite allotransplantation, which includes transplantation of non-lifesaving organs such as face, hands, abdominal wall or uterus. Additionally, organ shortage in transplantation yielded a new area of research such as xenotransplantation and regenerative medicine. The specialty of transplantation may be difficult to comprehend for those entering the field; thus, the goal of this chapter is to provide a comprehensive overview of the most important aspects of transplantation. This review contains 2 figures, 3 tables, and 67 references. Keywords: transplantation, solid organ transplantation (SOT), vascularized composite allotransplantation (VCA), transplant immunology, allorecognition, acute rejection, chronic transplant rejection, principles of transplantation, transplantation terminology, immunosuppressive drugs

scholarly journals Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Siemionow ◽  
Aleksandra Klimczak
Keyword(s):  
Current Knowledge ◽  
Cleveland Clinic ◽  
Experimental Studies ◽  
Tolerance Induction ◽  
Experimental Models ◽  
Successful Outcome ◽  
Large Animal ◽  
Research Experience ◽  
Widespread Application ◽  
Large Animal Models

The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice.

scholarly journals Flap Surgical Techniques For Incisional Hernias Reccurences. A Swine Experimental Model

2017 ◽  
Vol 90 (2) ◽  
pp. 203-211
Author(s):  
Florina Popa ◽  
Filip Ardelean ◽  
Cosmin Pestean ◽  
Robert Purdoiu ◽  
Oana Rosca ◽  
...  
Keyword(s):  
Abdominal Wall ◽  
Mesh Repair ◽  
Surgical Techniques ◽  
Careful Examination ◽  
Large Animal ◽  
Abdominal Wall Defects ◽  
Flap Surgery ◽  
Abdominal Wall Repair ◽  
Large Animal Models ◽  
The University

Background and aims. In the age of synthetic prostheses most of hernia studies include a careful examination of the various types of prosthesis, their characteristics and their repair indications. Biological prostheses are also beginning to draw attention. But in terms of recurrence especially for poor or developing countries, the discussion is different, due to their high cost which makes them difficult to afford. In this article we present new flap reconstruction techniques for the reconstruction of the abdominal wall versus mesh repair, applied on swine models, outline the results of each technique, and specify the indications for their use.Methods. An experimental protocol using four swine models (PIC-FII-337 hybrid breed pigs), five months old, was conducted. All animal care and operative procedures were studied following the protocol approved by the Ethics Committee of the University of Medicine and Pharmacy resolution no. 281/2014 of the Department of Surgery of the University of Agricultural Sciences and Veterinary Medicine); the study was carried out between November 2015 and February 2016. The primary objective was to compare the effect of surgical strategies in the treatment of the abdominal wall defect using variable flaps versus mesh repair in a large-animal models. Physical examination and ultrasound imaging of the abdominal wall repair were done on determined periods, during one month. The complications occurring after the abdominal wall repair were edema, collections, superficial dehiscence an recurrences.Results. No recurrences were reported at one month results, all seromas reported were solved over time by natural drainage. Superficial necrosis appeared in two swine models and superficial dehiscence occurred in one model, the perforator ”plus” flap. Mesh infection was detected in the “onlay” swine model.Conclusions. In terms of recurrences, contaminated abdominal wall defects or other contraindications to the use of prosthetic materials, biological mesh repair or flap surgery are the only surgical options. Based on our findings and considering the high cost reported by the biological meshes use, flap surgery becomes the suitable treatment for such cases, allowing a good reconstruction of the abdominal wall.

Surgical Techniques for Revascularization in Abdominal Wall Transplantation

2020 ◽  
Vol 36 (07) ◽  
pp. 522-527
Author(s):  
Andrew Atia ◽  
Andrew Hollins ◽  
Ronnie Shammas ◽  
Brett T. Phillips ◽  
Kadiyala V. Ravindra ◽  
...  
Keyword(s):  
Abdominal Wall ◽  
Organ Transplantation ◽  
Abdominal Wall Reconstruction ◽  
Solid Organ Transplantation ◽  
Surgical Techniques ◽  
Solid Organ ◽  
Vascularized Composite Allotransplantation ◽  
Ischemia Time ◽  
Feasible Option ◽  
Surgical Field

Abstract Background Abdominal wall vascularized composite allotransplantation (AW-VCA) can be considered as a technically feasible option for abdominal wall reconstruction in patients whose abdomen cannot be closed using traditional methods. However, successful initial abdominal wall revascularization in the setting of visceral organ transplantation can pose a major challenge as graft ischemia time, operating in a limited surgical field, and variable recipient and donor anatomy must be considered. Several techniques have been reported to accomplish abdominal wall revascularization. Methods A literature review was performed using PubMed for articles related to “abdominal wall transplantation (AWT).” The authors of this study sorted through this search for relevant publications that describe abdominal wall transplant anatomy, technical descriptions, and outcomes of various techniques. Results A total of four distinct revascularization techniques were found in the literature. Each of these techniques was described by the respective authors and reported varying patient outcomes. Levi et al published a landmark article in 2003 that described technical feasibility of AWT with anastomosis between donor external iliac and inferior epigastric vessels with recipient common iliac vessels in end-to-side fashion. Cipriani et al described a microsurgical technique with anastomosis between donor and recipient inferior epigastric vessels in an end-to-end fashion. Giele et al subsequently proposed banking the abdominal wall allograft in the forearm to reduce graft ischemia time. Recently, Erdmann et al described the utilization of an arteriovenous loop for synchronous revascularization of abdominal wall and visceral transplants for reduction of ischemia time, operative time, while eliminating the need for further operations. Conclusion Vascularized composite allotransplantation continues to advance with improving immunotherapy and outcomes in solid organ transplantation. Optimizing surgical techniques remains paramount as the field continues to grow. Refinement of the presented methods will continue as additional evidence and outcomes become available in AW-VCA.

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