Tubular tissue-engineered constructs
Inventors
Dahl, Shannon L. M. • Niklason, Laura E. • Blum, Juliana • STRADER, Justin T. • Tente, William E. • Prichard, Heather L. • LUNDQUIST, Joseph J.
Assignees
Publication Number
US-9657265-B2
Publication Date
2017-05-23
Expiration Date
2032-01-06
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Abstract
The present invention provides constructs including a tubular biodegradable polyglycolic acid scaffold, wherein the scaffold may be coated with extracellular matrix proteins and substantially acellular. The constructs can be utilized as an arteriovenous graft, a coronary graft, a peripheral artery bypass conduit, or a urinary conduit. The present invention also provides methods of producing such constructs.
Core Innovation
The invention provides tubular biodegradable polyglycolic acid (PGA) constructs with uniform density and thickness, coated with extracellular matrix proteins, and substantially acellular. These constructs are designed for use as vascular grafts or urinary conduits. The scaffolds are non-woven PGA with density around 45-75 mg/cc, thickness about 0.8 to 1.5 mm, and inner diameter generally greater than 3 mm. Methods of producing these constructs involve wrapping a PGA sheet around a mandrel, entangling fibers at the seam for uniformity, treating to remove contaminants and enhance degradation, and optionally attaching non-biodegradable supports at each end.
The invention addresses the significant clinical need for vascular grafts when autologous vessels are unavailable or unsuitable due to disease or prior harvest. Synthetic grafts like PTFE have poor patency in small diameter applications and are prone to infection and thrombosis. Allografts and xenografts face issues of aneurysm, calcification, and thrombosis. Existing tissue-engineered vascular grafts require long culture times and are expensive, limiting availability. Thus there is a need for rapid, reliable, cost-effective tissue engineered constructs that can function long term with minimal side effects.
The invention provides extracellular matrix protein constructs made by culturing human or canine cells on biodegradable PGA scaffolds to produce collagen-rich tissue, followed by decellularization to render the tissue substantially acellular and immune-resistant. The constructs have mechanical properties similar or superior to native vessels, resist intimal hyperplasia, calcification, and dilation, and support remodeling by host cells after implantation. The constructs can be stored for long periods at 2° to 30° C. with retained integrity and are readily available off-the-shelf, offering an advantage over autologous grafts which require lengthy culture periods.
Claims Coverage
The claims include one independent claim detailing a tubular construct and its key structural and functional features.
Tubular construct with defined extracellular matrix and minimal polyglycolic acid content
A tubular construct comprising human extracellular matrix proteins thicker than 200 μm at the thinnest part, internal diameter ≥3 mm, acellular with less than 5% intact cells, polyglycolic acid comprising less than 5% of the cross-sectional area, length at least 10 cm, and substantially free of heavy metal contaminants.
Resistance to intimal hyperplasia and calcification
The tubular construct is intimal hyperplasia resistant and calcification resistant, inducing less than 1% calcification within 6 months and less than 1 mm intimal hyperplasia thickening at native vasculature anastomoses at 6 months post-implantation.
Fluid impermeability and dimensional stability
The construct is impermeable to fluid leakage up to at least 200 mm Hg and does not dilate more than 50% beyond its implant diameter after implantation.
Use as multiple types of grafts and conduits
The construct can be used as arteriovenous grafts, coronary grafts, diseased peripheral artery bypass conduits, fallopian tube replacements, and urinary conduits.
Extracellular matrix protein composition and nucleic acid content
The extracellular matrix proteins include hydroxyproline at over 40 μg/mg dry weight and the construct contains trace or minimal double stranded genomic DNA.
Storage stability
The construct is stable in storage at 2° to 30° C. for at least 12 months.
Tolerance to urine exposure for urinary conduit application
When used as a urinary conduit, the tubular construct tolerates exposure to urine for at least 4 weeks.
Controlled length and contaminant specification
The length ranges from 10 cm to 100 cm and heavy metal contaminants are limited to trace amounts of aluminum, barium, calcium, iodine, lanthanum, magnesium, nickel, potassium and zinc.
The independent claim discloses a biodegradable tubular construct with uniform extracellular matrix and minimal PGA content, characterized by resistance to graft-related pathologies, fluid impermeability, broad clinical applicability, compositional purity, and storage stability.
Stated Advantages
Provides rapidly available, off-the-shelf vascular grafts without the long culture times and high costs of autologous tissue engineering approaches.
Exhibits good long-term patency with resistance to infection, thrombosis, intimal hyperplasia, aneurysmal dilation, and calcification.
Possesses mechanical strength comparable or superior to native vessels, with high burst pressure and suture retention strength.
Supports remodeling and repopulation by host cells after implantation.
Avoids the need for autologous vessel harvest, reducing surgical complications and patient morbidity.
Can be stored at 2° to 30° C. for extended periods, maintaining structural and functional integrity.
Urinary conduits reduce risks associated with ileal conduits, including ischemia, metabolic acidosis, infections, and mucus production.
Documented Applications
Arteriovenous grafts for hemodialysis access in patients lacking suitable autologous vessels.
Coronary artery bypass grafts replacing diseased or occluded coronary arteries.
Peripheral artery bypass conduits for treatment of peripheral arterial disease.
Fallopian tube replacements for restoring patency in cases of scarring or infertility.
Urinary conduits for urinary diversion following cystectomy, avoiding complications of ileal conduits.
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