Muscle cell patches and uses therefor
Inventors
LANCASTER, Jordan J. • Goldman, Steven
Assignees
US Department of Veterans Affairs • University of Arizona
Publication Number
US-11020510-B2
Publication Date
2021-06-01
Expiration Date
2034-10-08
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Abstract
Disclosed herein are contractile cell constructs, methods for using them to treat disease, and methods for making them.
Core Innovation
The invention provides contractile cell constructs comprising contractile cells or progenitors thereof adhered to three dimensional fibroblast containing scaffolds (3DFCS) capable of synchronized contractions across the scaffold surface. The constructs include contractile cells seeded at specific densities and ratios relative to fibroblasts to promote survival, differentiation, and maturation of immature contractile cells into mature contractile cells exhibiting striations.
The invention addresses the problem of ineffective treatments for chronic heart failure (CHF), which affects millions and leads to high mortality. Existing stem cell injection therapies show disappointing results, and the disclosed constructs provide a novel method to engineer and implant contractile tissue patches that improve contractile function, electrical integration, and survival of implanted cells.
Claims Coverage
The patent includes several independent claims detailing contractile cell constructs with specific cell types, densities, scaffold compositions, and engineered features. The main inventive features involve the construction and composition of contractile constructs differentiated from pluripotent stem cells and adhered to various scaffolds.
Contractile cell constructs seeded at defined densities capable of synchronized contractions
The compositions comprise constructs of contractile cells or progenitors thereof adhered to a scaffold, wherein the construct achieves synchronized contractions. The contractile cells or progenitors are seeded at densities typically ranging between 1.3×10^5 and less than 5×10^5 cells/cm^2 and are derived from pluripotent stem cells.
Use of three dimensional fibroblast containing scaffolds or other biocompatible scaffolds
The scaffold may be a 3DFCS, synthetic, biological, degradable, non-degradable, porous, allogeneic, autologous, xenograft, extracellular matrix-based, or comprise established vessels capable of integration into living vasculature, providing a biocompatible framework for cell adhesion and function.
Specific ratio of contractile cells to fibroblasts within the construct
The contractile cells or progenitors are present in the construct in a ratio ranging from about 1:15 to about 6:1 relative to fibroblasts, ensuring optimal cell-cell interactions for functionality.
Engineering constructs and cells to express biological or pharmacological agents
The contractile cells or the scaffold may be engineered or pretreated to express or contain agents for gene regulation, cell scaffolding, or extracellular matrix development, including proteins, nucleic acids, cytokines, growth factors, or other molecules to enhance therapeutic efficacy or construct function.
Inclusion of various types of contractile cells derived from pluripotent stem cells
Claims cover constructs comprising immature or mature cardiomyocytes, skeletal muscle cells, or smooth muscle cells differentiated from pluripotent stem cells, reflecting a broad applicability of the technology across muscle tissue types.
The claims collectively cover contractile cell constructs with precise cell types, seeding densities, and scaffold compositions capable of synchronized contractions, further enhanced by engineering to express therapeutic agents, addressing both cardiac and other muscle tissue engineering applications.
Stated Advantages
The constructs provide a functional benefit when implanted, improving left ventricular function and electrical stability in heart failure models.
The constructs promote survival and maturation of immature contractile cells, especially cardiomyocytes derived from iPSCs.
They enable synchronized spontaneous contractions, generating contractile force beneficial for cardiac repair.
The constructs enhance myocardial perfusion and help reverse maladaptive cardiac remodeling in chronic heart failure.
The methods allow for covering larger myocardium areas and prevent washout of cells compared to cell injection approaches.
The constructs enable electrical integration into native myocardium without inducing arrhythmias.
They provide a useful model for drug screening by enabling testing on mature contractile cell constructs.
Documented Applications
Treatment of chronic heart failure (CHF) and related ischemic and non-ischemic cardiac disorders by implanting contractile cell constructs on the heart.
Therapeutic use in ischemia-induced heart failure, stable and unstable angina, myocardial infarction, cardiomyopathies, and various heart failure subtypes including left, right, forward, and backward heart failure.
Enhancement, repair, or restoration of skeletal muscle tissue and smooth muscle tissue for neuromuscular, degenerative, inflammatory, autoimmune muscle diseases, trauma, burns, and vascular or respiratory disorders.
Drug screening assays using contractile constructs to evaluate effects of compounds on contraction parameters such as displacement, rate, synchronicity, and velocity.
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