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      Renal Bioengineering with Scaffolds Generated from Rat and Pig Kidneys

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          Abstract

          Background: Chronic kidney disease (CKD) is a global public health issue with an estimated prevalence of 8-16% worldwide. End-stage renal disease eventually develops every year in 0.15-0.2% of patients with overt CKD, and renal replacement therapy (RRT) with dialysis or transplantation is required. Although approximately 2 million people worldwide are currently on RRT to sustain life, this likely represents less than 10% of those who need it. The kidney transplant approach is also seriously impaired by limited graft survival and by the scarce availability of donors. Innovative tissue-engineering strategies have been recently proposed to overcome these challenges. It is anticipated that these novel approaches will also be cost-effective in the long term. Although the initial setup of these innovative technologies could be quite expensive, there would be a single application for each patient, with no additional costs thereafter, compared to the lifelong costs of dialysis or immunosuppressive medications required for transplantation. One of the most innovative tools currently being investigated in experimental models is based on the idea of using decellularized kidneys to engineer a new functional organ as a potential future treatment option for end-stage renal disease. Summary: In the last 5 years, several interesting observations have been reported regarding the possibility of using an acellular matrix from the whole kidney and the attempt to recellularize this scaffold using stem or differentiated cells. This review provides an overview of the decellularization methods tested so far and their effects on the resulting extracellular matrix structure and composition. In addition, we also discuss methods recently described by us and others for the perfusion of kidney scaffolds for recellularization. Key Messages: Despite difficulties in achieving the import goal of kidney engineering in the laboratory, we discuss the problems with and limits of the experimental results obtained so far and point out the strategies that need to be adopted in order for this line of research to advance.

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          Most cited references 11

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          Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds.

          The definitive treatment for end-stage organ failure is orthotopic transplantation. However, the demand for transplantation far exceeds the number of available donor organs. A promising tissue-engineering/regenerative-medicine approach for functional organ replacement has emerged in recent years. Decellularization of donor organs such as heart, liver, and lung can provide an acellular, naturally occurring three-dimensional biologic scaffold material that can then be seeded with selected cell populations. Preliminary studies in animal models have provided encouraging results for the proof of concept. However, significant challenges for three-dimensional organ engineering approach remain. This manuscript describes the fundamental concepts of whole-organ engineering, including characterization of the extracellular matrix as a scaffold, methods for decellularization of vascular organs, potential cells to reseed such a scaffold, techniques for the recellularization process and important aspects regarding bioreactor design to support this approach. Critical challenges and future directions are also discussed.
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            Regeneration and Experimental Orthotopic Transplantation of a Bioengineered Kidney

            Over 100,000 individuals in the United States currently await kidney transplantation, while 400,000 individuals live with end-stage kidney disease requiring hemodialysis. The creation of a transplantable graft to permanently replace kidney function would address donor organ shortage and the morbidity associated with immunosuppression. Such a bioengineered graft must have the kidney’s architecture and function, and permit perfusion, filtration, secretion, absorption, and drainage of urine. We decellularized rat, porcine, and human kidneys by detergent perfusion, yielding acellular scaffolds with vascular, cortical and medullary architecture, collecting system and ureters. To regenerate functional tissue, we seeded rat kidney scaffolds with epithelial and endothelial cells, then perfused these cell-seeded constructs in a whole organ bioreactor. The resulting grafts produced rudimentary urine in vitro when perfused via their intrinsic vascular bed. When transplanted in orthotopic position in rat, the grafts were perfused by the recipient’s circulation, and produced urine via the ureteral conduit in vivo.
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              Effectiveness of three extraction techniques in the development of a decellularized bone-anterior cruciate ligament-bone graft.

               P Gratzer,  Andy Woods (2005)
              In this study, porcine bone-anterior cruciate ligament-bone (B-ACL-B) grafts were decellularized using one of three protocols incorporating surfactants lauryl sulfate (SDS), Triton X-100, and/or an organic solvent (tributyl phosphate (TnBP)). The effectiveness of Triton-SDS, Triton-Triton or Triton-TnBP treatments in removing cellular materials was determined and possible changes in biochemical composition and mechanical properties due to each treatment were investigated. Treatment with Triton-SDS was most effective at removing cell nuclei and intracellular protein (vimentin) from the ACL but affected both the collagen and glycosaminoglycan (GAG) components of the extracellular matrix while increasing the tensile stiffness of the ligament. Triton-Triton was the least effective of the three treatments in terms of cellular extraction, but did not significantly change the mechanical and biochemical properties of the ACL. Triton-TnBP matched the level of decellularization achieved by Triton-SDS in terms of visible cell nuclei; however, the extraction of intracellular vimentin was less consistent. TnBP treatment also slightly decreased the collagen content of the ACL but did not alter its mechanical properties. Overall, all three decellularization treatments maintained adequate mechanical and biochemical properties of B-ACL-B grafts to justify the further investigation of all three decellularization protocols. The selection of a superior treatment will depend on future studies of the propensity of treated tissues for repopulation by host ACL fibroblasts and, ultimately, on any immunogenic and/or remodeling host response induced in vivo.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                978-3-318-02677-1
                978-3-318-02678-8
                1660-2129
                2014
                May 2014
                19 May 2014
                : 126
                : 2
                : 113-118
                Affiliations
                aIRCCS - Istituto di Ricerche Farmacologiche ‘Mario Negri', Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, bUnit of Nephrology and Dialysis, Ospedale Giovanni XXIII, Bergamo, and cDepartment of Industrial Engineering, University of Bergamo, Dalmine, Italy
                Author notes
                *Andrea Remuzzi, EngD, Department of Biomedical Engineering, IRCCS - Istituto di Ricerche Farmacologiche, ‘Mario Negri', Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, IT-24126 Bergamo (Italy), E-Mail andrea.remuzzi@marionegri.it
                Article
                360683 Nephron Exp Nephrol 2014;126:113-118
                10.1159/000360683
                24854652
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Pages: 6
                Categories
                Further Section

                Cardiovascular Medicine, Nephrology

                Scaffolds, Regeneration, Chronic kidney disease

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