Biocompatible hydrogel compositions and uses thereof
Inventors
Ruel, Marc • Suuronen, Erik • Alarcon, Emilio
Assignees
Publication Number
US-11497832-B2
Publication Date
2022-11-15
Expiration Date
2038-05-04
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Abstract
Provided herein are biocompatible and/or biodegradable hydrogel compositions comprising native collagen and chondroitin sulfate, the collagen and chondroitin sulfate being chemically cross-linked thereby forming a matrix. The native collagen may comprise recombinant human collagen type I (rHCI), recombinant human collagen type III (rHCIII), or a combination thereof, for example. Methods and uses thereof for regeneration or repair of tissue, improvement of tissue function, mechanical stabilization of tissue, prevention of tissue damage, or prevention of tissue loss of function are described, particularly with respect to cardiac tissue and myocardial infarction events.
Core Innovation
The invention provides biocompatible and/or biodegradable hydrogel compositions comprising native collagen and chondroitin sulfate, where the collagen and chondroitin sulfate are chemically cross-linked to form a matrix. The native collagen may comprise recombinant human collagen type I (rHCI), recombinant human collagen type III (rHCIII), or a combination thereof. The hydrogel compositions are chemically cross-linked, for example by EDC-NHS chemical coupling reaction, forming a 3D porous matrix with properties suitable for injection and in vivo gelation.
The invention addresses the problem of heart diseases, particularly myocardial infarction (MI), which cause irreversible muscle loss and heart failure despite existing medical interventions and surgical procedures. Current therapies including drugs, growth factors, and cell-based therapies show limited success in restoring heart function. The hostile post-MI heart environment and degradation of the cardiac extracellular matrix (ECM) limit cell engraftment and tissue regeneration. The invention overcomes limitations of animal-derived collagen biomaterials and previous hydrogel materials by using recombinant human collagen types I and III cross-linked with chondroitin sulfate to form injectable hydrogels that support tissue repair, mechanical stabilization, and functional improvement of cardiac tissue post-MI.
The hydrogel compositions are designed to mimic the ECM, providing structural support, promoting cell migration, angiogenesis, tissue integration, and modulating inflammation in the infarcted myocardium. The hydrogels feature gelation at body temperature within about 10 minutes, denaturation temperatures above 45° C., viscosities suitable for injection and in situ formation of a matrix with a pore size ranging from about 5 to 50 μm. In vivo studies using a clinically relevant mouse MI model demonstrate that injection of these hydrogels improves or preserves cardiac function, reduces infarct size, prevents adverse remodeling, and promotes vascular density and cardiomyocyte survival, especially with rHCI-based hydrogels.
Claims Coverage
The patent includes 21 claims, with independent claims focusing on the hydrogel composition, methods of using the hydrogel composition for tissue regeneration and repair, and methods of preparing the hydrogel composition. The independent claims cover the biocompatible hydrogel composition itself, use of the composition in cardiac treatment, and preparation methods involving chemical cross-linking.
Hydrogel composition comprising native recombinant human collagen and chondroitin sulfate cross-linked to form a matrix
A hydrogel composition containing native collagen (1% w/v solution of recombinant human collagen type I (rHCI), type III (rHCIII), or both) chemically cross-linked with chondroitin sulfate to form a matrix that gels at 37° C. in less than about 10 minutes.
Chemical cross-linking by EDC-NHS reaction
The native collagen and chondroitin sulfate are chemically cross-linked via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-N-hydroxysuccinimide (NHS) chemical coupling reaction, with a specified approximate mass ratio of collagen to chondroitin sulfate to NHS to EDC of about 1:4:0.5:0.3.
Hydrogel characteristics including denaturation temperature, viscosity, pore size, and degradability
The hydrogel composition has denaturation temperature greater than about 45° C., viscosity about 0.5 to 4.5 Pa·s prior to cross-linking and about 9 to 150 Pa·s after cross-linking at 37° C., pore size in the range of about 5 to 50 μm (specifically 10 to 25 μm), and is biodegradable by type I collagenase at rates about 0.1 to 2 mg/s under defined conditions.
Use of hydrogel composition for regeneration or repair of cardiac tissue and treatment of myocardial infarction
The hydrogel composition is used by administering to affected tissue, particularly cardiac tissue, via injection following myocardial infarction or ischemic events to regenerate tissue, improve function, mechanically stabilize tissue, prevent damage or loss of function, reduce fibrosis and infarct size, and improve vascularity and cardiac function.
Method of preparing hydrogel composition via mixing
A method comprising providing solutions of native collagen, chondroitin sulfate, and EDC/NHS, mixing collagen and chondroitin sulfate to form a mixture, and then mixing with EDC and NHS solution to initiate chemical cross-linking and formation of the hydrogel matrix, with optional pH adjustment by NaOH addition.
The claims define an injectable, biocompatible, and biodegradable hydrogel composed of recombinant human collagen type I and/or III chemically cross-linked with chondroitin sulfate using EDC-NHS chemistry, possessing specified physical and biochemical properties, and methods of its use for cardiac tissue repair and myocardial infarction treatment, as well as methods for preparation.
Stated Advantages
The hydrogel compositions provide mechanical stabilization of infarcted cardiac tissue and prevent adverse ventricular remodeling post-myocardial infarction.
They improve cardiac function, as demonstrated by increased left ventricle ejection fraction, stroke volume, and cardiac output compared to controls.
The hydrogels promote vascular density and cardiomyocyte survival, supporting tissue regeneration and repair.
They modulate inflammatory responses by increasing pro-healing M2 macrophage populations within the infarct area.
The hydrogels are injectable, thermoresponsive, and biodegradable, allowing minimally invasive delivery and in situ gelation at body temperature.
Use of recombinant human collagen reduces risks associated with animal-derived materials, such as immune reactions and pathogen transmission.
Documented Applications
Use as injectable hydrogel compositions for regeneration or repair of cardiac tissue following myocardial infarction or ischemic events.
Treatment to improve cardiac function, prevent loss of mechanical properties, cardiac remodeling, and reduce fibrosis or infarct size.
Mechanical stabilization of infarcted heart tissue post-myocardial infarction to improve vascularity and survival of cardiac muscle.
Use in administering cross-linked collagen hydrogels by injection to the heart at single or multiple time-points following myocardial infarction.
Formation of hydrogel matrices from recombinant human collagen type I and III for cardiac tissue repair.
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