Muscle cell patches and uses therefor
Inventors
LANCASTER, Jordan J. • Goldman, Steven
Assignees
US Department of Veterans Affairs • University of Arizona
Publication Number
US-10172976-B2
Publication Date
2019-01-08
Expiration Date
2034-10-08
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Abstract
Disclosed herein are contractile cell constructs comprising contractile cells, or progenitors thereof, adhered to a surface of a three dimensional fibroblast containing scaffold (3DFCS) and methods for using them to treat disease. In one aspect, the present invention provides methods for preparing a contractile construct, comprising (a) seeding immature contractile cells onto the surface of a three dimensional fibroblast containing scaffold (3DFCS) to produce a contractile construct; and (b) culturing the contractile construct under conditions to promote differentiation of the immature contractile cells into mature contractile cells, wherein the mature contractile cells form striations. In a further aspect, the invention provides methods for treating a disorder characterized by a lack of functioning contractile cells, comprising contacting a patient with a contractile cell-based disorder with an amount effective to treat the disorder with the construct of any embodiment or combination of embodiments of the invention.
Core Innovation
The invention provides contractile cell constructs comprising contractile cells or progenitors thereof adhered to a surface of a three dimensional fibroblast containing scaffold (3DFCS). These constructs can spontaneously and synchronously contract across the surface of the 3DFCS. The methods include seeding immature contractile cells onto the 3DFCS surface and culturing under conditions that promote maturation of these cells into mature contractile cells, which form striations. The mature contractile cells may be cardiomyocytes, smooth muscle cells, or skeletal muscle cells. The constructs may be implanted in subjects in need, either prior to or after onset of cellular or patch-level contractions.
The problem being addressed is the need for improved treatments for disorders characterized by lack of functioning contractile cells, particularly chronic heart failure (CHF) and related ischemic and non-ischemic cardiac conditions. Existing stem cell injection approaches have yielded disappointing results in clinical trials. The present invention provides a new approach by using three dimensional fibroblast-containing scaffolds seeded with contractile cells that mature and function as contractile patches, which can more effectively restore or enhance contractility in damaged tissues.
The constructs comprise contractile cells seeded at densities between approximately 1.3×105 cells/cm2 and 2.95×106 cells/cm2, with ratios of contractile cells to fibroblasts ranging from about 1:15 to about 6:1. The 3DFCS may be fabricated from various biocompatible materials, including synthetic or biological scaffolds, and the fibroblasts provide a supportive environment secreting growth factors and extracellular matrix components. The invention also includes methods for using these constructs therapeutically to treat disorders such as CHF by contacting the constructs with the subject’s heart, often the epicardium, thereby repopulating the heart tissue with functioning contractile cells that electrically integrate with native myocardium.
Claims Coverage
The patent contains multiple independent claims focused on methods for treating disorders characterized by lack of functioning contractile cells using constructs comprising contractile cells adhered to three dimensional fibroblast-containing scaffolds, with specific cell densities, ratios, and cell types.
Method for treating contractile cell-deficient disorders with cardiomyocyte-based constructs
Contacting a patient with a construct comprising contractile cells or progenitors on a 3DFCS that exhibits spontaneous synchronized contractions, where contractile cells are seeded at densities between 1.3×105 and less than 5×105 cells/cm2, with a cell to fibroblast ratio between about 1:15 and 6:1, and cells being immature, mature, or combinations of cardiomyocytes.
Method of treating cardiac disorders by contacting the heart with contractile constructs
Applying the aforementioned construct directly to the heart of a subject suffering from disorders such as ischemia-induced heart failure, chronic heart failure, cardiomyopathy, and related cardiac conditions.
Attachment of contractile constructs to epicardium in contracting or non-contracting states
Attaching the construct to the epicardium, where the construct may be non-contracting or contracting at the time of contact.
Method for treating contractile cell-deficient disorders with skeletal muscle cell-based constructs
Contacting a patient with a construct comprising immature, mature, or combinations of skeletal muscle cells on a 3DFCS with cell densities between 1.0×105 and 2.95×106 cells/cm2, and cell to fibroblast ratios between about 1:15 and 6:1, showing synchronized contractions.
Method for treating contractile cell-deficient disorders with smooth muscle cell-based constructs
Contacting a patient with a construct comprising immature, mature, or combinations of smooth muscle cells on a 3DFCS with cell densities between 1.0×105 and 2.95×106 cells/cm2, and cell to fibroblast ratios between about 1:15 and 6:1, showing synchronized contractions.
The independent claims cover methods of treating disorders characterized by lack of functioning contractile cells using contractile cell-based constructs adhered to 3DFCS scaffolds at defined cell densities and ratios. The constructs comprise cardiomyocytes, skeletal muscle cells, or smooth muscle cells capable of synchronized contraction. The claims also cover application to cardiac tissues, specifically epicardium attachment, encompassing both contracting and non-contracting states.
Stated Advantages
The constructs promote maturation of immature contractile cells into mature cells forming striations, thus providing functional contractile tissue.
The constructs improve left ventricular function, decrease left ventricular end diastolic pressure, improve myocardial perfusion, and reverse maladaptive left ventricle remodeling in CHF subjects.
The contractile cells electrically integrate into the native myocardium, maintaining normal sinus rhythm and reducing arrhythmia risks.
The fibroblast-containing scaffold supports cell survival, alignment, and angiogenic factor secretion, improving engraftment and tissue healing.
The constructs provide a larger coverage of myocardium compared to isolated cell injections and prevent cells from washing out into the circulation.
The constructs can be used for drug screening with tissue-like development and signaling, allowing assessment of contractile responses to compounds.
Documented Applications
Treatment of ischemia-induced heart failure, chronic heart failure, cardiomyopathy, and various forms of cardiac dysfunction by application of contractile cell-based constructs to the heart.
Treatment of neuromuscular, degenerative, inflammatory, and autoimmune muscle diseases, as well as injuries including trauma, burns, sports injuries, and muscle wasting, using constructs comprising skeletal or smooth muscle cells.
Drug screening involving contacting contractile cell constructs with compounds of interest and determining effects on contraction characteristics.
Use of construct in conjunction with cardiac assist devices, cardiac wrap surgery, or other conventional heart disease treatments.
Application of constructs to ischemic tissues to promote healing, increase blood vessel formation, improve ejection fraction, and enhance cardiac output.
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