Tissue-engineered constructs
Inventors
Dahl, Shannon L. M. • Niklason, Laura E. • STRADER, Justin T. • Tente, William E. • LUNDQUIST, Joseph J.
Assignees
Publication Number
US-10619132-B2
Publication Date
2020-04-14
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 tissue-engineered constructs comprising tubular biodegradable polyglycolic acid (PGA) scaffolds with uniform density between about 45 mg/cc to 75 mg/cc, thickness of about 0.8 to 1.5 mm, fibers of 5 to 20 μm, and porosity from 90% to 98%. These scaffolds may be coated with extracellular matrix proteins, be substantially acellular, and combined with non-biodegradable polyethylene terephthalate supports at each end. Methods of producing these constructs include wrapping PGA sheets around mandrels, pulling fibers across seams to entangle and form uniform tubular scaffolds, and treating the scaffolds to remove heavy metals and modify degradation properties.
The constructs are useful as arteriovenous grafts, coronary grafts, peripheral artery bypass conduits, fallopian tube replacements, and urinary conduits. The invention also encompasses decellularized versions of these constructs that are immune- and calcification-resistant, comprising less than 5% cells and less than 33% polyglycolic acid by cross-sectional area, produced by culturing human cells on scaffolds to produce extracellular matrix proteins, then decellularizing and partially degrading PGA material. These constructs show high burst pressure (>2000 mm Hg), suture strength (>120 g), impermeability to fluids, and durability.
The background section identifies the problem that autologous vessels for vascular grafts are often unavailable or unsuitable, synthetic grafts like PTFE have poor patency and complications such as infection and thrombosis, and other graft materials are prone to aneurysm, calcification, and thrombosis. Current tissue-engineered grafts require long culture times and are costly, limiting availability. Thus, there is a significant unmet need for effective, rapidly available, reliable, and cost-effective tissue-engineered constructs with good long-term function and minimal side effects in vivo.
Claims Coverage
The patent contains two independent claims describing the tubular scaffold and the composition involving the scaffold and cell culture.
Tubular scaffold with uniform polyglycolic acid density and defined fiber and scaffold thickness
A tubular biodegradable non-woven polyglycolic acid scaffold with polyglycolic acid density of 45 mg/cc to 75 mg/cc uniform across the entire scaffold, thickness of 0.8 to 1.2 mm, polyglycolic acid fibers of 5 to 20 μm thickness, substantially free of heavy metal contaminants, and suitable for ex vivo cell culture.
Composition comprising the biodegradable polyglycolic acid scaffold seeded with human cells and culture medium
A composition includes the tubular biodegradable non-woven polyglycolic acid scaffold with uniform density and fiber/thickness parameters, human cells seeded on this scaffold, and cell culture medium optionally including human serum; human cells are preferably smooth muscle cells passaged fewer than 10 times upon seeding.
The independent claims cover the biodegradable tubular scaffold with uniformly distributed polyglycolic acid fibers and specific dimension ranges along with its use as a cell culture scaffold seeded with human cells and culture medium, highlighting structural and compositional features critical for tissue-engineered construct formation.
Stated Advantages
Provides tissue-engineered constructs that are effective, rapidly available, reliable, and cost-effective with good long-term function and minimal side effects in vivo.
Overcomes limitations of previous grafts by resisting dilatation, calcification, and intimal hyperplasia, and showing immune and calcification resistance.
Decellularized constructs can be stored at 2° to 30° C. for at least 12 months without compromising strength or implantability, enabling immediate availability to patients.
Use of allogeneic cells combined with decellularization maximizes donor impact and allows production of many grafts from one cell bank, achieving economies of scale and eliminating patient wait times.
Constructs demonstrate high burst pressures (up to >2000 mm Hg), suture retention strength (>120 g), and impermeability to fluids up to at least 400 mm Hg, maintaining mechanical robustness.
Unlike intestinal conduits, urinary conduits from the invention resist crystallization and urine absorption, reduce infection risks, and avoid mucus production, improving patient outcomes.
The constructs integrate well with native vasculature, resist immunogenicity as evidenced by minimal T-cell response and inflammation, and avoid calcification upon implantation.
Documented Applications
Use as arteriovenous grafts for hemodialysis access in patients with end-stage renal disease.
Use as coronary grafts for coronary artery bypass surgery.
Use as peripheral artery bypass conduits to treat peripheral arterial disease.
Use as urinary conduits for urinary diversion after cystectomy, providing an improved alternative to ileal conduits.
Use as fallopian tube replacements to address infertility caused by fallopian tube scarring or damage.
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