Tissue-engineered constructs
Inventors
Dahl, Shannon L. M. • Niklason, Laura E. • STRADER, Justin T. • Tente, William E. • LUNDQUIST, Joseph J.
Assignees
Publication Number
US-10947498-B2
Publication Date
2021-03-16
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 including tubular biodegradable polyglycolic acid (PGA) scaffolds that have a uniform density of about 45 mg/cc to about 75 mg/cc across the entire scaffold. The scaffold is non-woven and preferably felted, with dimensions varying from about 1 cm to about 100 cm in length and an inner diameter of about 3 mm to about 20 mm. The PGA fibers have a thickness of about 5 to 20 μm, with a porosity of about 90% to 98%, and the scaffold thickness is uniform between about 0.8 to 1.5 mm.
These tubular constructs are substantially acellular and comprise extracellular matrix proteins with a thickness greater than 200 micrometers at the thinnest portion. The constructs are decellularized after cells are cultured on the scaffold and secrete extracellular matrix proteins, and the PGA scaffold degrades during this culture. The final construct includes less than 5% intact cells and the PGA comprises less than 33%, preferably less than 10%, of the cross-sectional area of the construct. The constructs are immune resistant, calcification resistant, mechanically robust with burst pressures at least 2000 mmHg, and resistant to dilation beyond 50% of implant diameter.
The construct production method involves wrapping a biodegradable PGA sheet around a mandrel, entangling PGA fibers at an interface to form a seam with uniform density and thickness, treating the tubular scaffold to remove heavy metals and alter degradation rate and wettability, and optionally attaching non-biodegradable polymer supports. Cells at low passage are seeded onto the scaffold and cultured under conditions promoting extracellular matrix secretion. After culture, constructs are decellularized and the residual PGA degrades, producing a tubular extracellular matrix protein construct.
The invention solves the problem that current vascular grafts, including autologous vessels, synthetic PTFE grafts, and other allografts or xenografts, suffer from poor availability, low long-term patency, infection, thrombosis, intimal hyperplasia, calcification, or require long culture times and high costs. The constructs of the invention provide a readily available, versatile graft with improved patency and mechanical properties, low immune response, calcification resistance, and suitability for various vascular and urinary conduit applications.
Claims Coverage
The patent contains one independent claim defining a decellularized tubular construct with specific structural and functional features. This claim covers several inventive features related to construct composition, properties, and functional performance.
Decellularized tubular construct with human extracellular matrix proteins and PGA
A tubular construct comprising human extracellular matrix proteins with thickness greater than 200 μm at the thinnest portion, an internal diameter greater than 3 mm, calcification resistance, comprising less than 5% polyglycolic acid by cross-sectional area, and substantially acellular with less than 5% intact cells.
Mechanical performance and stability
The tubular construct has a burst pressure of at least 2000 mm Hg, suture strength greater than 90 g, does not dilate more than 50% beyond its implant diameter after implantation, and is substantially free of heavy metal contaminants.
Dimensional and biological features
The tubular construct has length from 1 cm to 100 cm, induces less than 1 mm intimal hyperplasia thickening in native vasculature at anastomoses at 6 months, and may be impermeable to fluid leakage up to at least 200 mm Hg.
Applications and biochemical composition
The construct is selected from arteriovenous graft, coronary graft, diseased peripheral artery bypass conduit, fallopian tube replacement, and urinary conduit, contains extracellular matrix proteins with hydroxyproline greater than 40 μg/mg dry weight, has trace amounts of double stranded genomic DNA, and induces less than 1% calcification within 6 months.
Urinary conduit properties and storage stability
When used as a urinary conduit, the construct tolerates exposure to urine for at least 4 weeks, and the tubular construct is stable in storage at 2° to 30° C. for at least 12 months.
Heavy metal contaminants control
The tubular construct is substantially free of heavy metal contaminants selected from aluminum, barium, calcium, iodine, lanthanum, magnesium, nickel, potassium and zinc.
Specific dimensional ranges
The length of the tubular construct is from 10 cm to 100 cm or 10 cm to 40 cm, with internal diameter from 3 mm to 6 mm.
The independent claim defines an acellular, mechanically robust tubular construct with human-derived extracellular matrix proteins and low residual PGA content, exhibiting resistance to calcification and immune response, suitable for various vascular and urinary applications, and exhibiting defined size, mechanical properties, biocompatibility, and storage stability.
Stated Advantages
Constructs are rapidly available without significant patient wait time, overcoming delays of autologous graft cultivation.
Constructs exhibit superior mechanical strength and stability comparable to or exceeding native vessels and maintain integrity after 12 months of storage.
Constructs resist calcification, immune rejection, intimal hyperplasia, aneurysmal dilation, and infection, ensuring long-term patency.
Constructs provide versatility for various anatomical applications including arteriovenous grafting, coronary and peripheral artery bypass, urinary conduits, and fallopian tube replacement.
Constructs eliminate the need for autologous vessel harvest, reducing surgical morbidity and overcoming lack of suitable native vessels.
Urinary conduit constructs resist active absorption of urine, reduce metabolic acidosis risk, avoid microbial colonization and mucous production compared to ileal conduits.
The use of allogeneic cells combined with decellularization allows manufacturing scalability, enabling one donor to provide grafts for many recipients, improving cost-effectiveness.
Documented Applications
Arteriovenous grafts for hemodialysis access.
Coronary artery bypass grafts.
Peripheral artery bypass conduits.
Urinary conduits for urinary diversion after cystectomy.
Fallopian tube replacement to address infertility from tubal damage or cancer.
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