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Quinn R.W.,Cardiac Regenerative Surgery Research Laboratories
Progress in Pediatric Cardiology

Investigators seeking to select an animal model for use in preclinical research studies prior to FDA submission for allograft heart valves have several types to choose from. Dogs, pigs, cattle, primates and sheep have all served as successful medium and large animal models, and their murine counterparts have also been integral in the advancement of replacement heart valve research. While the national and international regulatory bodies have not specified a universal animal model for use in preclinical research studies, the ovine and porcine models have become the frontrunners within the peer-reviewed literature. Sheep are an excellent model of bioprosthetic valve calcification, with a robust mineralization response that mimics observations of human clinical disease progression, while swine are the model of choice for valves which pose a risk of thrombotic events. In the rapidly advancing field of tissue engineered cardiovascular products, dogs, primates, rodents, sheep and pigs are all valuable models for the study of scaffold remodeling and recellularization. Once an animal model has been chosen, investigators are recommended to consult with the FDA via submission of a Request for Designation in order to identify the type of product and the appropriate Center to which the product should be submitted. Additionally, the investigator should outline a risk analysis plan that categorizes the failure modes of the product, as well as design an in vivo pre-clinical safety and performance study that will capture data applicable to the assessment of the failure modes enumerated in the risk analysis. © 2013 Elsevier Ireland Ltd. Source

Lavin D.M.,Brown University | Zhang L.,Brown University | Furtado S.,Brown University | Hopkins R.A.,Cardiac Regenerative Surgery Research Laboratories | Mathiowitz E.,Brown University
Acta Biomaterialia

Wet spun microfibers have great potential for the design of multifunctional controlled release scaffolds. Understanding aspects of drug delivery and mechanical strength, specific to protein molecular weight, may aid in the optimization and development of wet spun fiber platforms. This study investigated the intrinsic material properties and release kinetics of poly(l-lactic acid) (PLLA) and poly(lactic-co-glycolic acid) (PLGA) wet spun microfibers encapsulating proteins with varying molecular weights. A cryogenic emulsion technique developed in our laboratory was used to encapsulate insulin (5.8 kDa), lysozyme (14.3 kDa) and bovine serum albumin (BSA, 66.0 kDa) within wet spun microfibers (∼100 μm). Protein loading was found to significantly influence mechanical strength and drug release kinetics of PLGA and PLLA microfibers in a molecular-weight-dependent manner. BSA encapsulation resulted in the most significant decrease in strength and ductility for both PLGA and PLLA microfibers. Interestingly, BSA-loaded PLGA microfibers had a twofold increase (8 ± 2 MPa to 16 ± 1 MPa) in tensile strength and a fourfold increase (3 ± 1% to 12 ± 6%) in elongation until failure in comparison to PLLA microfibers. PLGA and PLLA microfibers exhibited prolonged protein release up to 63 days in vitro. Further analysis with the Korsmeyer-Peppas kinetic model determined that the mechanism of protein release was dependent on Fickian diffusion. These results emphasize the critical role protein molecular weight has on the properties of wet spun filaments, highlighting the importance of designing small molecular analogues to replace growth factors with large molecular weights. © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. Source

Bert A.A.,The Miriam Hospital | Bert A.A.,Cardiac Regenerative Surgery Research Laboratories | Drake W.B.,Cardiac Regenerative Surgery Research Laboratories | Quinn R.W.,Cardiac Regenerative Surgery Research Laboratories | And 4 more authors.
Progress in Pediatric Cardiology

Implantable, viable tissue engineered cardiovascular constructs are rapidly approaching clinical translation. Species typically utilized as preclinical large animal models are food stock ungulates for which cross species biological and genomic differences with humans are great. Multiple authorities have recommended developing subhuman primate models for testing regenerative surgical strategies to mitigate xenotransplant inflammation. However, there is a lack of specific quantitative cardiac imaging comparisons between humans and the genomically similar baboons (Papio hamadryas anubis). This study was undertaken to translate to baboons transesophageal echocardiographic functional and dimensional criteria defined as necessary for defining cardiac anatomy and function in the perioperative setting. Seventeen young, healthy baboons (approximately 30. kg, similar to 5. year old children) were studied to determine whether the requisite 11 views and 52 measurement parameters could be reliably acquired by transesophageal echocardiography (TEE). The obtained measurements were compared to human adult normative literature values and to a large relational database of pediatric "normal heart" echo measurements. Comparisons to humans, when normalized to BSA, revealed a trend in baboons toward larger mitral and aortic valve effective orifice areas and much larger left ventricular muscle mass and wall thickness, but similar pulmonary and tricuspid valves. By modifying probe positioning relative to human techniques, all recommended TEE views except transgastric could be replicated. To supplement, two transthoracic apical views were discovered that in baboons could reliably replace the transgastric TEE view. Thus, all requisite echo views could be obtained for a complete cardiac evaluation in P. hamadryas anubis to noninvasively quantify cardiac structural anatomy, physiology, and dimensions. Despite similarities between the species, there are subtle and important physiologic and anatomic differences when compared to human. © 2013 Elsevier Ireland Ltd. Source

Hopkins R.A.,Cardiac Regenerative Surgery Research Laboratories | Bert A.A.,Cardiac Regenerative Surgery Research Laboratories | Bert A.A.,Brown University | Hilbert S.L.,Cardiac Regenerative Surgery Research Laboratories | And 4 more authors.
Journal of Thoracic and Cardiovascular Surgery

Objective: This study assesses in a baboon model the hemodynamics and human leukocyte antigen immunogenicity of chronically implanted bioengineered (decellularized with collagen conditioning treatments) human and baboon heart valve scaffolds. Methods: Fourteen baboons underwent pulmonary valve replacement, 8 with decellularized and conditioned (bioengineered) pulmonary valves derived from allogeneic (N = 3) or xenogeneic (human) (N = 5) hearts; for comparison, 6 baboons received clinically relevant reference cryopreserved or porcine valved conduits. Panel-reactive serum antibodies (human leukocyte antigen class I and II), complement fixing antibodies (C1q binding), and C-reactive protein titers were measured serially until elective sacrifice at 10 or 26 weeks. Serial transesophageal echocardiograms measured valve function and geometry. Differences were analyzed with Kruskal-Wallis and Wilcoxon rank-sum tests. Results: All animals survived and thrived, exhibiting excellent immediate implanted valve function by transesophageal echocardiograms. Over time, reference valves developed a smaller effective orifice area index (median, 0.84 cm2/m2; range, 1.22 cm2/m2), whereas all bioengineered valves remained normal (effective orifice area index median, 2.45 cm2/m2; range, 1.35 cm2/m2; P = .005). None of the bioengineered valves developed elevated peak transvalvular gradients: 5.5 (6.0) mm Hg versus 12.5 (23.0) mm Hg (P = .003). Cryopreserved valves provoked the most intense antibody responses. Two of 5 human bioengineered and 2 of 3 baboon bioengineered valves did not provoke any class I antibodies. Bioengineered human (but not baboon) scaffolds provoked class II antibodies. C1q+ antibodies developed in 4 recipients. Conclusions: Valve dysfunction correlated with markers for more intense inflammatory provocation. The tested bioengineering methods reduced antigenicity of both human and baboon valves. Bioengineered replacement valves from both species were hemodynamically equivalent to native valves. © 2013 by The American Association for Thoracic Surgery. Source

Hopkins R.A.,Cardiac Regenerative Surgery Research Laboratories | Lofland G.K.,Cardiac Regenerative Surgery Research Laboratories
Progress in Pediatric Cardiology

The development of bioengineered heart valves that have prolonged durability and improved hydraulic functionality will significantly improve the management of pediatric congenital cardiac patients by limiting multiple reoperations. However, progressing one step further to tissue engineered heart valves that contain viable and phenotypically appropriate cell populations will result in growth capable heart valves that can remodel constructively and synchronously with the patient's somatic growth. Pediatric cardiac surgical and interventional catheter therapeutics now consists of a huge menu of multistage and palliative procedures. Readily available, patient specific or "personal" tissue engineered viable constructs for use as replacements for missing, hypoplastic, or structurally defective cardiac structures will fundamentally alter therapeutic strategies for numerous diagnoses. These transformational developments will result in definitive operations that can be performed early in the patient's life. Altered strategies that will become available are explored for tetralogy of Fallot, pulmonary atresia, congenital aortic stenosis, the single ventricle, and the "failing Fontan". The barriers and challenges to achieving routinely applicable Tissue Engineered and Regenerative (TERM) Cardiac Surgery Methods are also explored as is a novel concept for the Cardiac Hybrid Operating Room Suite of the 21st Century. © 2013 Elsevier Ireland Ltd. Source

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