Nano scale decoration of scaffold-free microtissue using functionalised gold nanostructures
Inventors
Nikkhah, Mehdi • Navaei, Ali • Migrino, Raymond
Assignees
US Department of Veterans Affairs • Arizona State University Downtown Phoenix campus
Publication Number
US-11364321-B2
Publication Date
2022-06-21
Expiration Date
2038-10-11
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Abstract
A scaffold-free microtissue is disclosed that includes one or more gold nanostructures linked to a functional moiety, wherein the functional moiety is one or more vasculogenic peptides, one or more anti-inflammatory peptides, one or more antiapoptotic peptides, one or more antinecrotic peptides, one or more antioxidant peptides, one or more oligonucleotides, one or more lipid particles, one or more phospholipid particles, one or more liposomes, one or more nanoliposomes, one or more microRNAs, or one or more siRNAs. The scaffold-free microtissue further includes a plurality of cardiac myocytes or cardiac myoblasts, which are conjugated to the one or more gold nanostructures, wherein the plurality of cardiac myocytes or cardiac myoblasts are arranged in a cluster. The scaffold-free microtissue further includes a plurality of fibroblasts, wherein the fibroblasts are arranged in at least one layer of fibroblasts that substantially surrounds the cluster of gold-nanostructure-conjugated cardiac myocytes or gold-nanostructure-conjugated cardiac myoblasts.
Core Innovation
The invention discloses a scaffold-free microtissue comprising one or more gold nanostructures linked to functional moieties such as vasculogenic, anti-inflammatory, antiapoptotic, antinecrotic, antioxidant peptides, oligonucleotides, lipid particles, phospholipid particles, liposomes, nanoliposomes, microRNAs, or siRNAs. The microtissue contains a plurality of cardiac myocytes or cardiac myoblasts conjugated to the gold nanostructures arranged in a cluster, and a plurality of fibroblasts arranged in at least one layer surrounding the cluster of functionalized cardiac cells. This structure aims to enhance the regenerative capacity of cardiac tissue by integrating electrically conductive, cell-adhesion-promoting, and vasculogenic functionalities into the microtissue.
The problem addressed arises from the high prevalence of heart failure and myocardial infarction, where loss of cardiomyocytes leads to impaired contractility and adverse remodeling. Existing treatments such as heart transplantation and mechanical devices are limited by donor availability and surgical complications. Current myocardial replacement therapies, including cell-based transplantation and scaffold-based approaches, suffer from poor cell retention, inadequate cell-cell coupling, insufficient electromechanical integration, risk of arrhythmias, poor vascularization, and potential immune rejection. Moreover, conventional hydrogels do not replicate the electrical properties of native myocardium, and conductive nanomaterials like carbon nanotubes face cytotoxicity concerns.
This invention provides an injectable, electrically conductive, scaffold-free cardiac microtissue nanoengineered with gold nanostructures, particularly gold nanowires functionalized with peptides such as RGD for cell adhesion and VEGF-mimetic peptides for vasculogenesis. This approach promotes mature cell-cell coupling, synchronous contraction with host myocardium, and neovascular formation. The microtissue's architecture includes a layer of fibroblasts surrounding the functionalized cardiac myocytes, enhancing engraftment and mimicking native myocardium. Delivery via minimally invasive catheter is facilitated by the spheroid structure, offering potential for improved myocardial repair and regeneration.
Claims Coverage
There are two independent claims focusing on microtissues comprising gold nanostructures conjugated with cell adhesion peptides, including specific architectural arrangements and linking methods, covering the core functionalized microtissue concept.
Microtissue with gold nanostructure-linked cell adhesion peptides and fibroblast layering
A scaffold-free microtissue comprising gold nanostructures linked to cell adhesion peptides; a cluster of cardiac myocytes or myoblasts conjugated to the gold nanostructures; and fibroblasts arranged in at least one surrounding layer. The gold nanostructures may also be linked to anti-inflammatory, antiapoptotic, antinecrotic peptides, antioxidant particles, liposomes, nanoliposomes, microRNAs, or siRNAs.
Use of human-induced pluripotent-stem-cell-derived cardiac myocytes functionalized with vasculogenic peptides on gold nanostructures
The microtissue includes human induced pluripotent stem cell-derived cardiac myocytes conjugated with gold nanostructures further linked to vasculogenic peptides, specifically VEGF-mimetic peptides such as VEGF-mimetic QK-peptides, and cell adhesion peptides like RGD peptides. The gold nanostructures are capped with polyethylene glycol bi-linkers and can take forms such as wires, rods, or plates.
Microtissue with gold nanostructures linked to cell-targeting moieties by direct bond or linking groups
A microtissue comprising gold nanostructures linked to cell adhesion peptides and a cluster of functionalized cardiac myocytes or myoblasts surrounded by fibroblasts, where the gold nanostructures are coupled to cell-targeting moieties either via direct chemical bonds or linking groups. The linking groups can be divalent radicals such as —S-(PEG)—C(═O)—, or hydrocarbon chains with defined lengths and substituents. The cell adhesion moieties include peptides such as RGD, DGEA, GRGDSP, or GRGDY.
The claims extensively cover scaffold-free microtissues structured with functionalized cardiac cells conjugated to gold nanostructures linked to cell adhesion and functional peptides, with specific architectures including fibroblast layers, various peptide linkers, and use of human iPSC-derived cardiac cells, addressing both composition and linkage chemistry aspects.
Stated Advantages
Provides enhanced cell-cell coupling and structural integrity through functionalization of gold nanowires with cell adhesion-promoting peptides such as RGD.
Enables electromechanical integration with the host myocardium by incorporation of electrically conductive gold nanostructures, supporting synchronous contraction.
Promotes neovascular formation within the microtissue due to conjugation of vasculogenic VEGF-mimetic peptides to the gold nanostructures.
Minimally invasive delivery via catheter-based injection, avoiding the need for open-heart surgery and potential immune rejection associated with scaffold-based patches.
Improves retention and engraftment of cardiac cells by architectural arrangement with fibroblast layers that support extracellular matrix production and paracrine signaling.
Documented Applications
Regeneration or repair of infarcted myocardium in animals by injecting the scaffold-free microtissue into the infarcted region.
Use as an electrically conductive composition for cardiac microtissue therapy and myocardial tissue regeneration.
In vivo testing and potential clinical application for myocardial replacement therapy through intramyocardial delivery of injectable microtissues.
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