Decellularization and recellularization of solid organs
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Publication Number
US-10441609-B2
Publication Date
2019-10-15
Expiration Date
Abstract
The invention provides for methods and materials to decellularize a solid organ and to recellularize such a decellularized organ to thereby generate a solid organ.
Core Innovation
The invention provides a recellularized extracellular matrix of a decellularized mammalian organ. The decellularized extracellular matrix retains the morphology prior to decellularization and comprises an intact exterior surface, together with extracellular matrix components of a vascular tree comprising an intact vascular bed, and retains a majority of fluid introduced to the decellularized extracellular matrix vascular tree.
The invention introduces a population of cells, or stem cells, to the decellularized extracellular matrix, or to a vessel, a duct, or a cavity of the decellularized extracellular matrix. A first solution is perfused into the vessel, duct, or cavity of the decellularized extracellular matrix, or injected into the decellularized extracellular matrix, so that at least some of the cells distribute within and on at least a portion of the decellularized extracellular matrix, thereby providing a recellularized extracellular matrix of the decellularized mammalian organ.
The invention also includes ex vivo perfusion-based recellularization in which a decellularized organ is perfused or injected prior to recellularization with a solution comprising one or more compounds, thereby generating a perfused decellularized organ. Cells are then introduced to the perfused decellularized organ so that the compounds stimulate at least some of the cells as compared to a comparable population of cells that undergo introducing but are absent said perfusing. Liver embodiments include endothelial cells that re-endothelialize the vascular tree and liver-specific cells having organ-specific activity of corresponding cells present in the liver prior to decellularization.
Claims Coverage
The document includes multiple independent claims that collectively cover recellularization of a decellularized mammalian organ extracellular matrix with perfusion or injection so cells distribute within and on matrix portions, ex vivo compound-stimulated recellularization prior to introducing cells, stem-cell recellularization, liver-specific recellularization with endothelial re-endothelialization and organ-specific activity, and an at least partially recellularized organ having perfusion-decellularized extracellular matrix with specified structural retention requirements. In total, five independent claims are identified: clm-00001, clm-00026, clm-00033, clm-00035, and clm-00052.
Recellularized mammalian organ extracellular matrix retaining morphology and vascular bed fluid retention
Providing a decellularized extracellular matrix of a decellularized mammalian organ that retains the morphology prior to decellularization, comprising an intact exterior surface, and comprising extracellular matrix components of a vascular tree comprising an intact vascular bed, wherein the decellularized extracellular matrix retains a majority of fluid introduced to the decellularized extracellular matrix vascular tree.
Perfusion or injection with cell distribution within and on the decellularized matrix
Introducing a population of cells, or stem cells, to the decellularized matrix, or to a vessel, a duct, or a cavity of the decellularized extracellular matrix; and perfusing a first solution into the vessel, duct, or cavity of the decellularized extracellular matrix, or injecting the first solution into the decellularized extracellular matrix, so that at least some of said cells distribute within and on at least a portion of said decellularized extracellular matrix, thereby providing a recellularized extracellular matrix.
Compound-stimulated ex vivo recellularization via perfusion or injection prior to cell introduction
Providing a decellularized extracellular matrix of a decellularized mammalian organ having an intact exterior surface, comprising extracellular matrix components of a vascular tree with an intact vascular bed, and retaining a majority of fluid introduced to the decellularized extracellular matrix vascular tree; perfusing or injecting the decellularized organ prior to recellularization with a solution comprising one or more compounds thereby generating a perfused decellularized organ; and introducing a population of cells to the perfused decellularized organ such that the one or more compounds stimulate at least some of the cells as compared to a comparable population of cells that undergo said introducing but are absent said perfusing.
Stem cell recellularization of a decellularized mammalian organ matrix
Providing a decellularized extracellular matrix of a decellularized mammalian organ that retains the morphology prior to decellularization, comprising an intact exterior surface, and comprising extracellular matrix components of a vascular tree comprising an intact vascular bed, wherein the decellularized extracellular matrix retains a majority of fluid introduced to the decellularized extracellular matrix vascular tree; introducing a population of stem cells to the decellularized extracellular matrix, or a vessel, a duct, or a cavity, of said decellularized extracellular matrix; and perfusing a solution into the vessel, duct, or cavity of the decellularized extracellular matrix, or injecting the solution into the decellularized extracellular matrix, so that at least some of said stem cells distribute within and on at least a portion of said decellularized extracellular matrix, thereby providing a recellularized extracellular matrix.
Liver extracellular matrix recellularization with endothelial re-endothelialization and organ-specific activity
Providing a decellularized extracellular matrix of a decellularized mammalian liver that retains the morphology prior to decellularization, comprising an intact exterior surface, comprising extracellular matrix components of a vascular tree comprising an intact vascular bed, and retaining a majority of fluid introduced to the decellularized extracellular matrix vascular tree; and perfusing a population of endothelial cells or liver-specific cells and a first solution into a vessel, a duct or a cavity of said decellularized extracellular matrix so that said endothelial cells distribute and engraft in the vascular tree or said liver-specific cells distribute and engraft in the cavity, and optionally multiply, wherein the endothelial cells re-endothelialize the vascular tree and the liver-specific cells have an organ-specific activity of corresponding cells present in the liver prior to decellularization.
At least partially recellularized perfusion decellularized organ with minimum regenerative cell engraftment
An at least partially recellularized organ comprising a perfusion decellularized extracellular matrix and at least about 10,000,000 regenerative cells engrafted thereon, wherein prior to the recellularization the perfusion decellularized organ included an intact exterior surface, an intact, non-vasculature decellularized extracellular matrix and an intact, vasculature decellularized extracellular matrix, wherein said vasculature decellularized extracellular matrix retains a majority of fluid introduced, wherein said vascular decellularized extracellular matrix comprises human cells, and wherein said decellularized extracellular matrix is from a kidney, lung, liver, pancreas, or spleen.
Across the independent claims, the invention is centered on recellularizing a decellularized mammalian organ extracellular matrix that retains pre-decellularization morphology, including an intact exterior surface and an intact vascular bed that retains a majority of introduced fluid. Recellularization is carried out by introducing cells or stem cells and delivering a first solution via perfusing or injecting so the cells distribute within and on matrix portions. Separate claim coverage adds an ex vivo compound-stimulation step prior to cell introduction, specifies liver embodiments with endothelial re-endothelialization and liver-specific organ activity, and defines an at-least-partially recellularized organ with a minimum engrafted regenerative-cell population together with required intact matrix categories and tissue source limitations.
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