Bioengineering Human Lung Grafts on Porcine Matrix

Zhou, Haiyang; Kitano, Kentaro; Ren, Xi; Rajab, Taufiek Konrad; Wu, Min; Gilpin, Sarah E.; Wu, Tong; Baugh, Lauren; Black, Lauren D.; Mathisen, Douglas J.; Ott, Harald C.

doi:10.1097/sla.0000000000002129

Cited by 85 publications

(74 citation statements)

References 38 publications

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“…Restoration of gas exchange, the most basic function of the lung, involves the reconstruction of the microstructure of the epithelialized airways and endothelialized vessels and is of utmost importance. Endothelial cells have been seeded via the pulmonary artery and the pulmonary vein . The airway epithelium is repopulated through the bronchial system to rebuild the gas exchange surface, whereas the recellularization of the endothelium is performed via a multistep technique with various cells to mimic the native vessel, with perivascular cells supporting endothelial development .…”

Section: Lungmentioning

confidence: 99%

“…The first implantation of a recellularized lung scaffold in rats was published in 2010 . Since the publication of these studies, sufficient gas exchange and perfusion of the recellularized, implanted lung scaffold were successfully reported, and these results have been translated to a humanized porcine model . Furthermore, the first decellularization of human and human‐size grafts showed the feasibility of upscaling this concept.…”

Section: Lungmentioning

confidence: 99%

“…Different techniques and detergents (e.g. SDS, SDC, Triton-X 100 and CHAPS) have been investigated in different species, such as mouse, rat, pig and human [16,76,[101][102][103][104][105]. Unfortunately, the optimal decellularization protocol remains undefined.…”

Section: Lungmentioning

confidence: 99%

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Strategies based on organ decellularization and recellularization

et al. 2019

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Summary Transplantation is the only curative treatment option available for patients suffering from end‐stage organ failure, improving their quality of life and long‐term survival. However, because of organ scarcity, only a small number of these patients actually benefit from transplantation. Alternative treatment options are needed to address this problem. The technique of whole‐organ decellularization and recellularization has attracted increasing attention in the last decade. Decellularization includes the removal of all cellular components from an organ, while simultaneously preserving the micro and macro anatomy of the extracellular matrix. These bioscaffolds are subsequently repopulated with patient‐derived cells, thus constructing a personalized neo‐organ and ideally eliminating the need for immunosuppression. However, crucial problems have not yet been satisfyingly addressed and remain to be resolved, such as organ and cell sources. In this review, we focus on the actual state of organ de‐ and recellularization, as well as the problems and future challenges.

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Section: Lungmentioning

confidence: 99%

Section: Lungmentioning

confidence: 99%

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Strategies based on organ decellularization and recellularization

et al. 2019

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“…In 2010, the studies conducted by Niklason's and Ott's groups on whole lung decellularization and recellularization ex vivo, demonstrated the capability of a decellularized lung graft to support engraftment of multiple cell types, despite the fact that alveolar edema and thrombosis caused lungs to fail after only a few hours following transplant (Ott et al, 2010;Petersen et al, 2010Petersen et al, , 2011Petersen et al, , 2012Song et al, 2011). These studies and other meritorious work (Gilpin et al, 2014;Nichols et al, 2014Nichols et al, , 2018Wagner et al, 2014;Zhou H. et al, 2018) emphasized three major developments in the field of lung bioengineering: (1) the capacity of a properly conditioned lung scaffold to facilitate cell engraftment; (2) the utilization of ex vivo devices, such as EVLP, to support, assess, and optimize lung grafts; (3) the possibility to intervene with cell therapy in lung grafts supported ex vivo. However, these advances also posed a major challenge to researchers: to create a graft with the functional capability of the lung, an extremely complex organ containing more than 40 different cell types (Colby et al, 2007;Franks et al, 2008;Beers and Morrisey, 2011;Wagner et al, 2013).…”

Section: Therapies Based On the Delivery Of Cells And Cell Productsmentioning

confidence: 99%

Bioengineering of Pulmonary Epithelium With Preservation of the Vascular Niche

Dorrello

Vunjak‐Novakovic

2020

Front. Bioeng. Biotechnol.

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The shortage of transplantable donor organs directly affects patients with end-stage lung disease, for which transplantation remains the only definitive treatment. With the current acceptance rate of donor lungs of only 20%, rescuing even one half of the rejected donor lungs would increase the number of transplantable lungs threefold, to 60%. We review recent advances in lung bioengineering that have potential to repair the epithelial and vascular compartments of the lung. Our focus is on the long-term support and recovery of the lung ex vivo, and the replacement of defective epithelium with healthy therapeutic cells. To this end, we first review the roles of the lung epithelium and vasculature, with focus on the alveolar-capillary membrane, and then discuss the available and emerging technologies for ex vivo bioengineering of the lung by decellularization and recellularization. While there have been many meritorious advances in these technologies for recovering marginal quality lungs to the levels needed to meet the standards for transplantation -many challenges remain, motivating further studies of the extended ex vivo support and interventions in the lung. We propose that the repair of injured epithelium with preservation of quiescent vasculature will be critical for the immediate blood supply to the lung and the lung survival and function following transplantation.

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“…Decellularization techniques utilize several harsh detergents to ensure complete removal of cellular debris, but these detergents can drastically alter the ratio of ECM components that are left behind. Matrix proteins such as collagens, elastin, laminin, fibronectin, and glycosaminoglycans (GAGs) are preserved through the decellularization process, but there are reports of up to a 50% loss of most of these components compared to native ECM [32,33]. Variations in ECM composition and stiffness can have a profound effect on cell phenotype, as well as cell attachment and barrier function [34][35][36].…”

Section: Introductionmentioning

confidence: 99%

Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix

Young

Shankar

Tho

et al. 2019

Preprint

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Decellularized tissues offer a unique tool for developing regenerative biomaterials or in vitro platforms for the study of cell-extracellular matrix (ECM) interactions. One main challenge associated with decellularized lung tissue is that ECM components can be stripped away or altered by the detergents used to remove cellular debris. Without characterizing the composition of lung decellularized ECM (dECM) and the cellular response caused by the altered composition, it is difficult to utilize dECM for regeneration and specifically, engineering the complexities of the alveolar-capillary barrier. This study takes steps towards uncovering if dECM must be enhanced with lost ECM proteins to achieve proper epithelial barrier formation. To achieve this, epithelial barrier function was assessed on dECM coatings with and without the systematic addition of several key basement membrane proteins. After comparing barrier function on collagen, fibronectin, laminin, and dECM in varying combinations as an in vitro coating, the alveolar epithelium exhibited superior barrier function when dECM was supplemented with laminin as evidenced by trans-epithelial electrical resistance (TEER) and permeability assays. Increased barrier resistance with laminin addition was associated with upregulation of Claudin-18, Ecadherin, and junction adhesion molecule (JAM)-A, and stabilization of zonula occludens (ZO)-1 at junction complexes. The Epac/Rap1 pathway was observed to play a role in the ECM-mediated barrier function determined by protein expression and Epac inhibition. These findings reveal potential ECM coatings and molecular therapeutic targets for improved regeneration with decellularized scaffolds or edema related pathologies.

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Bioengineering Human Lung Grafts on Porcine Matrix

Cited by 85 publications

References 38 publications

Strategies based on organ decellularization and recellularization

Strategies based on organ decellularization and recellularization

Bioengineering of Pulmonary Epithelium With Preservation of the Vascular Niche

Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix

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