Regeneration and Experimental Orthotopic Transplantation of a Bioengineered Kidney

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Abstract

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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Most cited references 27

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Regeneration and orthotopic transplantation of a bioartificial lung.

Harald Ott, Ben Clippinger, Claudius Conrad … (2010)

About 2,000 patients now await a donor lung in the United States. Worldwide, 50 million individuals are living with end-stage lung disease. Creation of a bioartificial lung requires engineering of viable lung architecture enabling ventilation, perfusion and gas exchange. We decellularized lungs by detergent perfusion and yielded scaffolds with acellular vasculature, airways and alveoli. To regenerate gas exchange tissue, we seeded scaffolds with epithelial and endothelial cells. To establish function, we perfused and ventilated cell-seeded constructs in a bioreactor simulating the physiologic environment of developing lung. By day 5, constructs could be perfused with blood and ventilated using physiologic pressures, and they generated gas exchange comparable to that of isolated native lungs. To show in vivo function, we transplanted regenerated lungs into orthotopic position. After transplantation, constructs were perfused by the recipient's circulation and ventilated by means of the recipient's airway and respiratory muscles, and they provided gas exchange in vivo for up to 6 h after extubation.

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Decellularized tissue-engineered blood vessel as an arterial conduit.

Laura Niklason, Yuka Kondo, Alan Dardik … (2011)

Arterial tissue-engineering techniques that have been reported previously typically involve long waiting times of several months while cells from the recipient are cultured to create the engineered vessel. In this study, we developed a different approach to arterial tissue engineering that can substantially reduce the waiting time for a graft. Tissue-engineered vessels (TEVs) were grown from banked porcine smooth muscle cells that were allogeneic to the intended recipient, using a biomimetic perfusion system. The engineered vessels were then decellularized, leaving behind the mechanically robust extracellular matrix of the graft wall. The acellular grafts were then seeded with cells that were derived from the intended recipient--either endothelial progenitor cells (EPC) or endothelial cell (EC)--on the graft lumen. TEV were then implanted as end-to-side grafts in the porcine carotid artery, which is a rigorous testbed due to its tendency for graft occlusion. The EPC- and EC-seeded TEV all remained patent for 30 d in this study, whereas the contralateral control vein grafts were patent in only 3/8 implants. Going along with the improved patency, the cell-seeded TEV demonstrated less neointimal hyperplasia and fewer proliferating cells than did the vein grafts. Proteins in the mammalian target of rapamycin signaling pathway tended to be decreased in TEV compared with vein grafts, implicating this pathway in the TEV's resistance to occlusion from intimal hyperplasia. These results indicate that a readily available, decellularized tissue-engineered vessel can be seeded with autologous endothelial progenitor cells to provide a biological vascular graft that resists both clotting and intimal hyperplasia. In addition, these results show that engineered connective tissues can be grown from banked cells, rendered acellular, and then used for tissue regeneration in vivo.

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Decellularization methods of porcine kidneys for whole organ engineering using a high-throughput system.

David C Sullivan, Sayed-Hadi Mirmalek-Sani, Daniel B Deegan … (2012)

End-stage renal failure is a devastating disease, with donor organ transplantation as the only functional restorative treatment. The current number of donor organs meets less than one-fifth of demand, so regenerative medicine approaches have been proposed as potential therapeutic alternatives. One such approach for whole large-organ bioengineering is to combine functional renal cells with a decellularized porcine kidney scaffold. The efficacy of cellular removal and biocompatibility of the preserved porcine matrices, as well as scaffold reproducibility, are critical to the success of this approach. We evaluated the effectiveness of 0.25 and 0.5% sodium dodecyl sulfate (SDS) and 1% Triton X-100 in the decellularization of adult porcine kidneys. To perform the decellularization, a high-throughput system was designed and constructed. In this study all three methods examined showed significant cellular removal, but 0.5% SDS was the most effective detergent (<50 ng DNA/mg dry tissue). Decellularized organs retained intact microarchitecture including the renal vasculature and essential extracellular matrix components. The SDS-treated decellularized scaffolds were non-cytotoxic to primary human renal cells. This method ensures clearance of porcine cellular material (which directly impacts immunoreactivity during transplantation) and preserves the extracellular matrix and cellular compatibility of these renal scaffolds. Thus, we have developed a rapid decellularization method that can be scaled up for use in other large organs, and this represents a step toward development of a transplantable organ using tissue engineering techniques. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med.

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 1 March 2013

Publication date (Electronic): 14 April 2013

Publication date (Print): May 2013

Publication date PMC-release: 01 November 2013

Volume: 19

Issue: 5

Pages: 646-651

Affiliations

[1 ]Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital

[2 ]Center for Regenerative Medicine, Massachusetts General Hospital

[3 ]Division of Pediatric Surgery, Department of Surgery, Massachusetts General Hospital

[4 ]Harvard Medical School

Author notes

Corresponding Author: Harald C Ott, MD, PD, Harvard Medical School, Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, GRB – 425, Boston, MA 02114, hott@ 123456partners.org

Article

Manuscript ID: NIHMS444902

DOI: 10.1038/nm.3154

PMC ID: 3650107

PubMed ID: 23584091

SO-VID: 832c0f20-1c1f-4aca-b021-903886d1d175

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Regeneration and Experimental Orthotopic Transplantation of a Bioengineered Kidney

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Abstract

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Vascular Biology

Most cited references 27

Regeneration and orthotopic transplantation of a bioartificial lung.

Decellularized tissue-engineered blood vessel as an arterial conduit.

Decellularization methods of porcine kidneys for whole organ engineering using a high-throughput system.

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