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Publication Number
US-10980916-B2
Publication Date
2021-04-20
Expiration Date
Abstract
The present disclosure relates to methods of preparing personalized blood vessels, useful for transplantation with improved host compatibility and reduced susceptibility to thrombosis. Also provided are personalized blood vessels produced by the methods and use thereof in surgery.
Core Innovation
The invention relates to a method of preparing a personalized blood vessel by contacting a surface of an acellular tubular scaffold with a whole blood sample from a subject in need of the personalized blood vessel. The whole blood sample is diluted in a physiological solution, and the contacting is performed for a defined contacting period. The disclosure supports use of acellular tubular scaffolds such as decellularized vein or bioprinted tubular scaffolds to enable personalized blood vessel formation using whole blood.
The method further includes contacting whole blood under conditions that support graft feasibility and cellularization of the acellular tubular scaffold. The disclosure describes optional addition of anti-thrombotic agents in the whole blood suspension, including heparin and/or dextran and/or ascorbic acid and/or acetylsalicylic acid, and optional inclusion of growth factors in the whole blood suspension, including growth factors selected to be at least at a population average physiological level, including FGF-2 and VEGF.
The disclosure further describes optional monitoring and control related to environmental parameters during contacting, including temperature, pH, oxygen partial pressure, and CO2 partial pressure. It also describes use of a bioreactor with closed recirculation and features such as sampling port and injection port. In vivo work is described for a personalized tissue engineered vein prepared with autologous blood suspension and subsequently implanted, with reported graft patency/open flow and evaluation for thrombosis, endothelial markers such as CD31, and assessment for intimal hyperplasia and valve function.
Claims Coverage
The document includes one independent claim defining a method for preparing a personalized blood vessel by contacting an acellular tubular scaffold with a diluted whole blood sample from a subject, with contacting performed for 3 to 14 days. Dependent claims mainly refine the contacting composition and contacting duration by adding specific anti-thrombotic agents and by specifying growth factors at least equal to population average physiological levels, along with further operational refinements such as sub-ranges of contacting time.
Contacting acellular tubular scaffold with diluted whole blood suspension
Contacting a surface of an acellular tubular scaffold with a suspension comprising a whole blood sample from a subject, wherein the whole blood sample is diluted in a physiological solution.
Contacting period of 3 to 14 days
Performing the contacting for 3 to 14 days.
Whole blood suspension includes growth factor at population average physiological level
Using a suspension in which the whole blood sample comprises a growth factor at least equal to the population average physiological level, selected from the listed growth factors or any combination thereof.
Heparin at start of contacting within a specified concentration range
Using heparin in a whole blood suspension at the start of contacting an acellular tubular scaffold surface at a concentration ranging from about 0.5 IU/mL to about 150 IU/mL.
Ascorbic acid at start of contacting within a specified concentration range
Using ascorbic acid in a whole blood suspension at the start of contacting an acellular tubular scaffold surface at a concentration of about 0.2 µg/mL to about 200 µg/mL.
Whole blood non-cellular factors populating scaffold to promote cellularization and host compatibility
Having a whole blood sample containing one or more non-cellular factors that populate an acellular tubular scaffold, wherein the one or more non-cellular factors promote cellularization of the scaffold and host compatibility of the resulting vessel after grafting.
Contacting for 3 to 9 days
Carrying out the contacting step for 3 to 9 days.
Overall, the claim set centers on contacting an acellular tubular scaffold with diluted whole blood for 3 to 14 days, with inventive refinements including specifying growth factors at or above population average physiological levels and adding anti-thrombotic agents such as heparin and ascorbic acid at defined ranges, as well as emphasizing non-cellular factors from whole blood that support scaffold cellularization and host compatibility and narrowing contacting time to sub-ranges.
Stated Advantages
Reported graft patency/open flow.
No macroscopic thrombosis.
Cellularization and endothelial marker expression including CD31 expression over time.
Absence of intimal hyperplasia.
Functional feasibility for vein transplantation.
Documented Applications
In vivo implantation of a personalized tissue engineered vein (P-TEV) prepared with autologous blood suspension, followed by evaluation including graft patency/open flow and assessments for thrombosis, endothelial markers (CD31), and intimal hyperplasia; described with relevance to vein transplantation.
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