Muscle cell patches and uses therefor
Inventors
LANCASTER, Jordan J. • Goldman, Steven
Assignees
UNITED STATES GOVERNMENT AS REPRESENTED BY DEPARTMENT OF VETERANS AFFIARS • US Department of Veterans Affairs • University of Arizona
Publication Number
US-11980698-B2
Publication Date
2024-05-14
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 present invention provides contractile cell constructs formed by seeding immature contractile cells onto the surface of a three-dimensional fibroblast containing scaffold (3DFCS), followed by culturing under conditions that promote differentiation of these immature cells into mature contractile cells exhibiting striations. The constructs comprise contractile cells or progenitors adhered to 3DFCS surfaces at specified cell densities and ratios with fibroblasts, capable of spontaneous synchronized contractions, and include cells such as immature or mature cardiomyocytes, smooth muscle cells, and skeletal muscle cells. The invention also encompasses methods for treating disorders characterized by a lack of functioning contractile cells by implanting these constructs in subjects in need thereof.
The invention addresses the problem of limited efficacy in current treatments for chronic heart failure (CHF) and related cardiac disorders, which affect millions and have high mortality rates. Existing approaches, including direct injection of stem or progenitor cells, have shown generally disappointing clinical trial results. The invention provides an improved method of delivering contractile cells on a supportive scaffold that enhances cell survival, maturation, and functional integration with host tissue, aiming to overcome limitations like poor cell retention and limited treatment coverage.
The 3DFC is a metabolically active, fibroblast-populated scaffold embedded in bioabsorbable mesh material that secretes growth factors and provides structural support. Contractile cells seeded atop the 3DFC mature in vitro to form striated layers that contract synchronously, yielding constructs that can be implanted prior to or following contraction onset. The invention also contemplates using these constructs for drug screening by assessing effects of compounds on contraction characteristics, thereby offering a tissue-like assay system.
Claims Coverage
The patent contains one independent claim covering a composition comprising a construct with contractile cells adhered to a scaffold, highlighting several key inventive features.
Construct comprising contractile cells adherent to a three-dimensional fibroblast containing scaffold at defined ratios and densities
The composition comprises contractile cells or progenitors thereof adhered to the surface of a three-dimensional fibroblast containing scaffold (3DFCS), where the contractile cells are present on the surface in a specified ratio of about 1:15 to about 6:1 with fibroblasts.
Construct capable of synchronized contractions
The construct is capable of synchronized contractions across the 3DFCS surface, indicating functional integration and coordinated activity of the contractile cells.
Contractile cells selected from smooth muscle, skeletal muscle, and cardiac muscle cells differentiated from pluripotent stem cells
The contractile or progenitor cells in the construct are selected from smooth muscle cells, skeletal muscle cells, and cardiac muscle cells, and were differentiated from pluripotent stem cells.
In summary, the independent claim defines a construct of contractile cells derived from pluripotent stem cells seeded onto a three-dimensional fibroblast scaffold at defined cell ratios, which is capable of synchronized contractions, providing a functional composition useful in therapy or drug screening.
Stated Advantages
The constructs provide a unique and supportive environment that promotes survival and maturation of contractile cells, enhancing therapeutic effectiveness.
The constructs improve left ventricular function and myocardial perfusion when implanted in models of chronic heart failure.
The constructs electrically integrate with host myocardium, maintaining normal sinus rhythm and reducing arrhythmia risk.
The delivery via a scaffold prevents cell washout seen with isolated cell injections and allows coverage of larger myocardial areas.
The fibroblast-containing scaffold secretes angiogenic growth factors supporting vascularization and tissue regeneration.
Cultures of immature cardiomyocytes on the scaffold mature into cells exhibiting striations and enhanced contractile properties.
The constructs can be used for drug screening assays, providing a tissue-like model to evaluate compound effects on contractility and electrophysiology.
Documented Applications
Treatment of disorders characterized by lack of functioning contractile cells, specifically chronic heart failure and related cardiac conditions such as ischemia-induced heart failure, cardiomyopathy, myocardial infarction, coronary artery disease, and valvular heart disease.
Therapeutic application by implanting the contractile cell constructs on the epicardium of subjects to improve myocardial function and promote healing.
Treatment of skeletal muscle and smooth muscle related disorders including neuromuscular, degenerative, inflammatory, autoimmune muscle diseases, trauma-induced muscle injury, vascular and respiratory diseases, hernias, and muscle wasting conditions.
Use in drug screening by contacting the constructs with compounds and assessing effects on contraction parameters such as displacement, rate, synchronicity, and velocity.
Combination use with conventional medical devices and surgical procedures like cardiac wrap surgery, LVADs, cardiac pacemakers, and enhanced external counterpulsation.
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