IP Library › Granted Patent US 12,465,486
Granted Patent B2
US 12,465,486 · App. 17/614,225 · Granted Nov 11, 2025

Engineered valve and method of making

Inventors: Zeeshan Syedain (Minneapolis, MN); Robert Tranquillo (Arden Hills, MN)
Assignee: Regents of the University of Minnesota
A61F2/2415A61F2/2418A61L27/225A61L27/24A61L27/3691A61L27/3817A61L27/3839A61L27/52B29D23/00C12M21/08C12M23/06C12M25/00C12N5/0656A61F2220/0075A61F2240/001A61L2430/20A61L2430/40B29K2089/00B29K2105/0061
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Quick Facts
Patent No.
US 12,465,486
App. No.
17/614,225
Granted
Nov 11, 2025
Kind
B2
Abstract

This disclosure provides a tissue-engineered transcatheter vein valve and methods of making such a tissue-engineered transcatheter vein valve. Methods of making the valve include casting or molding a polymer into a tubular structure having a first end and a second end, where the first end of the tubular structure is cast or molded around a tubular support structure and where the second end of the tubular structure is cast or molded in the absence of the support structure; everting the polymer at the second end through the support structure; anchoring the second end of the tubular structure to the support structure at a first position and a second position, where the anchored first position and the anchored second position result in commissures, forming leaflets therebetween.

Claims (34)

1 . A method of making an engineered valve, comprising:

casting or molding a hydrogel into a tubular structure having a first end and a second end, wherein the first end of the tubular structure is cast or molded around a tubular support structure, wherein the second end of the tubular structure is cast or molded in the absence of the support structure;

everting the hydrogel at the second end through the support structure;

anchoring the second end of the tubular structure to the support structure at a first position and a second position, wherein the anchored first position and the anchored second position result in commissures, forming leaflets therebetween;

thereby producing an engineered valve.

2 . The method of claim 1 , wherein the hydrogel comprises from agarose, methylcellulose, hyaluronan, collagen, fibrin, fibrinogen, or combinations thereof.

3 . The method of claim 1 , wherein the hydrogel comprises fibrin.

4 . The method of claim 1 , wherein the hydrogel comprises collagen.

5 . The method of claim 1 , wherein the hydrogel comprises matrix-producing cells.

6 . The method of claim 5 , wherein the matrix-producing cells are fibroblasts.

7 . The method of claim 5 , wherein the method further comprises culturing the tubular structure comprising the support structure under conditions in which the hydrogel comprising the matrix-producing cells is remodeled into a tubular extracellular matrix comprising the support structure at the first end.

8 . The method of claim 7 , wherein the method further comprises culturing the tubular structure under conditions in which the tubular extracellular matrix comprises circumferentially aligned fibers.

9 . The method of claim 1 , wherein the support structure is a stent or a wireform.

10 . The method of claim 9 , wherein the stent is a self-expanding stent or a balloon-expanding stent.

11 . The method of claim 1 , wherein the second end of the tubular structure is cast or molded using a mandrel, a mold, or combinations thereof.

12 . The method of claim 1 , wherein the anchoring step comprises stitching, suturing, stapling, gluing, or combinations thereof.

13 . The method of claim 1 , further comprising anchoring the second end of the tubular structure to the support structure at a third position.

14 . The method of claim 1 , wherein a commissure-to-commissure length, when flat, is about 100% to 125% of an inner diameter of the tubular structure.

15 . The method of claim 1 , wherein a commissure-to-commissure length, when flat, is about 110% to 120% of an inner diameter of the tubular structure.

16 . The method of claim 1 , wherein a commissure-to-commissure length, when flat, is about 115% of an inner diameter of the tubular structure.

17 . A method of making a tissue-engineered valve, comprising:

casting or molding a hydrogel comprising matrix-producing cells into a tubular structure having a first end and a second end, wherein the first end of the tubular structure is cast or molded around a stent, wherein the second end of the tubular structure is cast or molded in the absence of the stent;

culturing the tubular structure comprising the stent under conditions in which the hydrogel comprising the matrix-producing cells is remodeled into a tubular extracellular matrix comprising the stent at the first end;

decellularizing the tubular extracellular matrix comprising the stent at the first end;

everting the second end of the tubular extracellular matrix through the stent; and

anchoring the second end of the tubular extracellular matrix to the stent at a first position and a second position, wherein the anchored first position and anchored second position result in commissures, forming leaflets therebetween;

thereby producing a tissue-engineered valve.

18 . The method of claim 17 , wherein the hydrogel comprises fibrin.

19 . The method of claim 17 , wherein the matrix-producing cells are fibroblasts.

20 . The method of claim 17 , wherein the method further comprises culturing the tubular structure under conditions in which the tubular extracellular matrix comprises circumferentially aligned fibers.

21 . The method of claim 17 , wherein the anchoring step comprises stitching, suturing, stapling, gluing, or combinations thereof.

22 . The method of claim 17 , wherein a commissure-to-commissure length, when flat, is about 100% to 125% of an inner diameter of the tubular structure.

23 . The method of claim 17 , wherein a commissure-to-commissure length, when flat, is about 110% to 120% of an inner diameter of the tubular structure.

24 . The method of claim 17 , wherein a commissure-to-commissure length, when flat, is about 115% of an inner diameter of the tubular structure.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2022
From: SYEDAIN, ZEESHAN; TRANQUILLO, ROBERT
To: REGENTS OF THE UNIVERSITY OF MINNESOTA
Reel/Frame 058738/0604 →
Continuity (2)
Provisional Application 62853639 · May 28, 2019
Related Publication 20220168099A1 · Jun 2, 2022
References Cited (99)
US 5957971A · Schwartz · 1999 [cited by applicant]
US 6539984B2 · Lam · 2003 [cited by applicant]
US 6562069B2 · Cai · 2003 [cited by examiner]
US 6666886B1 · Tranquillo et al. · 2003 [cited by applicant]
US 8076137B2 · McAllister et al. · 2011 [cited by applicant]
US 8128681B2 · Shoemaker et al. · 2012 [cited by applicant]
US 8399243B2 · Bouten et al. · 2013 [cited by applicant]
US 10105208B2 · Tranquillo et al. · 2018 [cited by applicant]
US 10111740B2 · Tranquillo et al. · 2018 [cited by applicant]
US 10893928B2 · Tranquillo et al. · 2021 [cited by applicant]
US 20040115176A1 · Swartz et al. · 2004 [cited by applicant]
US 20100228335A1 · Schorgl et al. · 2010 [cited by applicant]
US 20140058496A1 · Tranquillo et al. · 2014 [cited by applicant]
US 20140180399A1 · Alavi et al. · 2014 [cited by applicant]
US 20140330377A1 · Niklason et al. · 2014 [cited by applicant]
US 20150164631A1 · Tranquillo et al. · 2015 [cited by applicant]
US 20190160204A1 · Tranquillo et al. · 2019 [cited by applicant]
US 20230293769A1 · Tranquillo et al. · 2023 [cited by applicant]
KR 1020150036747A · 2015 [cited by applicant]
WO WO2002090528A1 · 2002 [cited by applicant]
WO WO2004038004A2 · 2004 [cited by applicant]
WO WO2005011534 · 2005 [cited by applicant]
WO WO2007025233 · 2007 [cited by applicant]
WO WO2010028197A1 · 2010 [cited by applicant]
WO WO2010120539 · 2010 [cited by applicant]
WO WO2011076186A2 · 2011 [cited by applicant]
WO WO2012111000A1 · 2012 [cited by applicant]
WO WO2012122567 · 2012 [cited by applicant]
WO WO2013090878 · 2013 [cited by applicant]
WO WO2017176919 · 2017 [cited by applicant]
WO WO2018102826 · 2018 [cited by applicant]
WO WO2019006430 · 2019 [cited by applicant]
J.C. Palmaz. Balloon-Expandable Intravascular Stent. AJR (1988), 150, 1263-1269. (Year: 1988). [cited by examiner]
Robinson et al. Functional Tissue-Engineered Valves from Cell-Remodeled Fibrin with Commissural Alignment of Cell-Produced Collagen. Tissue Engineering Part A (2008), 14(1), 83-95 (Year: 2008). [cited by examiner]
Furukoshi et al. “Development of an in vivo tissue-engineered vascular graft with designed wall thickness (biotube type C) based on a novel caged mold,” J. Artif. Organs, Mar. 2016, 19(1):54-61. [cited by applicant]
International Preliminary Report on Patentability in International Application No. PCT/US2017/026204, mailed on Oct. 18, 2018, 9 pages. [cited by applicant]
International Search Report & Written Opinion in International Application No. PCT/US2017/026204 dated Jul. 7, 2017, 20 pages. [cited by applicant]
Kawajiri et al., “Implantation study of a tissue-engineered self-expanding aortic stent graft (bio stent graft) in a beagle model,” J. Artif. Organs, Mar. 2015, 18(1):48-54. [cited by applicant]
Kheradvar et al., “Emerging Trends in Heart Valve Engineering: Part I. Solutions for Future,” Ann. Biomed. Eng., Apr. 2015, 43(4):844-857. [cited by applicant]
Scarritt et al., “A review of cellularization strategies for tissue engineering of whole organs, ” Front. Bioeng. Biotechnol., Mar. 2015, 3:43. [cited by applicant]
Syedain et al., “Tissue-engineered Tavi Valve With Matrix-embedded Stent,” Poster: P148, Presented at the Proceedings of the Heart Valve Society 2018 Annual Scientific Meeting, Apr. 12-14, 2018, New York, New York, 2 pa… [cited by applicant]
Weber et al., “Tissue-engineered fibrin-based heart valve with a tubular leaflet design,” Tissue Eng. Part C Methods, Apr. 2014, 20(4):265-275. [cited by applicant]
Weinandy et al., “The BioStent: novel concept for a viable stent structure,” Tissue Eng. Part A, Sep. 2012, 18(17-18):1818-1826. [cited by applicant]
U.S. Appl. No. 18/123,157, filed Mar. 17, 2023, Robert Tranquillo, Published as U.S. Publication No. 2023/0293769. [cited by applicant]
Ahmann et al., “Shear stress responses of adult blood outgrowth endothelial cells seeded on bioartificial tissue,” Tissue Eng. Part A, Jul. 1, 2011, 17(19-20):2511-2521. [cited by applicant]
Baptista et al., “Whole organ decellularization—a tool for bioscaffold fabrication and organ bioengineering,” Presented at Proceedings of the IEEE 2009 Annual International Conference of the IEEE Engineering in Medicine… [cited by applicant]
Brass et al., “Growth and remodeling of canine common iliac vein in response to venous reflux and hypertension,” J. Vasc. Surg. Venous Lymphat. Disorders, Jul. 2015, 3(3):303-311.e1. [cited by applicant]
Crapo et al., “An overview of tissue and whole organ decellularization processes,” Biomaterials, Apr. 2011, 32(12):3233-3243. [cited by applicant]
Dotter, “Interventional radiology—Review of an emerging field,” Semin. Roentgenology, Jan. 1981, 16(1):7-12. [cited by applicant]
Eberhardt et al., “Chronic Venous Insufficiency,” Circulation, May 10, 2005, 111(18):2398-2409. [cited by applicant]
Fronek et al., “Common femoral vein dimensions and hemodynamics including Valsalva response as a function of sex, age, and ethnicity in a population study,” J. Vasc. Surgery, May 2001, 33(5):1050-1056. [cited by applicant]
Gale et al., “Percutaneous venous valve bioprosthesis: initial observations,” Vasc. Endovascular Surgery, May/Jun. 2004, 38(3):221-224. [cited by applicant]
Glynn et al., “In vivo assessment of two endothelialization approaches on bioprosthetic valves for the treatment of chronic deep venous insufficiency,” J. Biomed. Mater. Res. B Appl. Biomaterials, Nov. 2016, 104(8):1610… [cited by applicant]
Gohel et al., “A randomized trial of early endovenous ablation in venous ulceration,” N. Engl. J. Medicine, May 31, 2018, 378(22):2105-2114. [cited by applicant]
Kearon et al., “Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism,” Blood, Feb. 4, 2014, 123(12):1794-1801. [cited by applicant]
La et al., “Shear Conditioning of Adipose Stem Cells for Reduced Platelet Binding to Engineered Vascular Grafts,” Tissue. Eng. Part A, Aug. 2018, 24(15-16):1242-1250. [cited by applicant]
Laing, “Chronic Venous Diseases of the Leg,” Office of Health Economics, Dec. 1992, 44 pages. [cited by applicant]
L'Heureux et al., “Cytograft Tissue Engineering: A new paradigm in cardiovascular tissue engineering,” Regen. Medicine, Jun. 27, 2008, 3(4):471-475. [cited by applicant]
Lurie et al., “Mechanism of venous valve closure and role of the valve in circulation: a new concept,” J. Vasc. Surgery, Nov. 2003, 38(5):955-961. [cited by applicant]
Lurie et al., “The mechanism of venous valve closure in normal physiologic conditions,” J. Vasc. Surgery, Apr. 2002, 35(4):713-717. [cited by applicant]
Maurins et al., “Distribution and prevalence of reflux in the superficial and deep venous system in the general population—results from the Bonn Vein Study, Germany,” J. Vasc. Surgery, Sep. 2008, 48(3):680-687. [cited by applicant]
Meier et al., “Blood outgrowth endothelial cells alter remodeling of completely biological engineered grafts implanted into the sheep femoral artery,” J. Cardiovasc. Transl. Research, Mar. 2014, 7(2):242-249. [cited by applicant]
Midha et al., “Valve Type, Size, and Deployment Location Affect Hemodynamics in an In Vitro Valve-in-Valve Model,” JACC Cardiovasc. Interventions, Aug. 8, 2016, 9(15):1618-1628. [cited by applicant]
Mogaldea et al., “Tissue Engineering of Vein Valves Based on Decellularized Natural Matrices,” Cells Tissues Organs, Aug. 5, 2017, 204(3-4):199-209. [cited by applicant]
Moreira et al., “Tissue-engineered heart valve with a tubular leaflet design for minimally invasive transcatheter implantation,” Tissue Eng. Part C Methods, Dec. 19, 2014, 21(6):530-540. [cited by applicant]
Mouza et al., “A Simplified model for predicting friction factors of laminar blood flow in small-caliber vessels,” Fluids, Oct. 19, 2018, 3(4):75-87. [cited by applicant]
Næss et al., “Incidence and mortality of venous thrombosis: A population-based study,” J. Thromb. Haemostasis, Apr. 2007, 5(4):692-699. [cited by applicant]
Neidert et al., “Enhanced fibrin remodeling in vitro with TGF-b1, insulin and plasmin for improved tissue-equivalents,” Biomaterials, Sep. 2002, 23(17):3717-3731. [cited by applicant]
Ott et al., “Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart,” Nat. Medicine, Feb. 2008, 14(2):213-221. [cited by applicant]
Pavcnik et al., “Percutaneous autologous venous valve transplantation: short-term feasibility study in an ovine model,” J. Vasc. Surgery, Aug. 2007, 46(2):338-345. [cited by applicant]
Pavcnik et al., “Percutaneous management of chronic deep venous reflux: review of experimental work and early clinical experience with bioprosthetic valve,” Vasc. Medicine, Feb. 2008, 13(1):75-84. [cited by applicant]
Pavcnik et al., “Second-generation percutaneous bioprosthetic valve: a short-term study in sheep,” J. Vasc. Surgery, Dec. 2004, 40(6):1223-1227. [cited by applicant]
PCT International Preliminary Report on Patentability in International Appln. No. PCT/US2020/034916, dated Nov. 16, 2021, 6 pages. [cited by applicant]
PCT International Search Report and Written Opinion in International Appln. No. PCT/US2020/034916, dated Aug. 7, 2020, 9 pages. [cited by applicant]
Reimer et al., “Implantation of a Tissue-Engineered Tubular Heart Valve in Growing Lambs,” Ann. Biomed. Engineering, Feb. 2017, 45(2):439-451. [cited by applicant]
Reimer et al., “Pediatric tubular pulmonary heart valve from decellularized engineered tissue tubes,” Biomaterials, Sep. 2015, 62:88-94. [cited by applicant]
Sathe et al., “Flexible prosthetic vein valve,” J. Med. Devices, Jun. 2007, 1(2):105-112. [cited by applicant]
Syedain et al., “6-month aortic valve implantation of an off-the-shelf tissue-engineered valve in sheep,” Biomaterials, Dec. 2015, 73:175-184. [cited by applicant]
Syedain et al., “A completely biological “off-the-shelf” arteriovenous graft that recellularizes in baboons,” Sci. Transl., Medicine, Nov. 1, 2017, 9(414):eaan4209, 11 pages. [cited by applicant]
Syedain et al., “Controlled cyclic stretch bioreactor for tissue-engineered heart valves,” Biomaterials, Sep. 2009, 30(25):4078-4084. [cited by applicant]
Syedain et al., “Implantable arterial grafts from human fibroblasts and fibrin using a multi-graft pulsed flow-stretch bioreactor with noninvasive strength monitoring,” Biomaterials, Jan. 2011, 32(3):714-722. [cited by applicant]
Syedain et al., “Implantation of completely biological engineered grafts following decellularization into the sheep femoral artery,” Tissue Eng. Part A, Jun. 2014, 20(11-12):1726-1734. [cited by applicant]
Syedain et al., “Tissue engineering of acellular vascular grafts capable of somatic growth in young lambs,” Nat. Communications, Sep. 27, 2016, 7:12951, 10 pages. [cited by applicant]
Syedain et al., “Tissue-engineered Transcatheter Vein Valve,” Biomaterials, Sep. 2019, 216:119229, 9 pages. [cited by applicant]
Syedain et al., “Tubular heart valves from decellularized engineered tissue,” Ann. Biomed. Engineering, Dec. 2013, 41(12):2645-2654. [cited by applicant]
Tanner, “Design, analysis, testing, and evaluation of a prosthetic venous valve,” Thesis for the degree of Master of Science, Georgia Institute of Technology, School of Mechanical Engineering, May 2013, 179 pages. [cited by applicant]
Tien et al., “Role of sinus in prosthetic venous valve,” Eur. J. Vasc. Endovasc. Surgery, Jul. 2014, 48(1):98-104. [cited by applicant]
Tripathi et al., “Five-Year Experience of Valvular Reconstructions for Nonhealing Leg Ulceration due to Deep Venous Reflux: Lessons Learned,” Perspect. Vasc. Surg. Endovasc. Therapy, Mar. 1, 2002, 15(2):87-100. [cited by applicant]
Ulloa et al., “Human trial using the novel bioprosthetic VenoValve in patients with chronic venous insufficiency,” J. Vasc. Surg. Venous Lymphat. Disorders, Nov. 19, 2020, 9(4):938-944. [cited by applicant]
van Langevelde et al., “The effect of aging on venous valves,” Arterioscler. Thromb. Vasc. Biology, Jul. 29, 2010, 30(10):2075-2080. [cited by applicant]
Volkmann et al., “Effect of varicose vein surgery on venous reflux scoring and plethysmographic assessment of venous function,” Eur. J. Vasc. Endovasc. Surgery, Dec. 2008, 36(6):731-737. [cited by applicant]
Vuylsteke et al., “An Epidemiological Survey of Venous Disease Among General Practitioner Attendees in Different Geographical Regions on the Globe: The Final Results of the Vein Consult Program,” Angiology, Oct. 2018, 6… [cited by applicant]
Weber et al., “Living-engineered valves for transcatheter venous valve repair,” Tissue Eng. Part C Methods, Jun. 2014, 20(6):451-463. [cited by applicant]
Wystrychowski et al., “Case study: first implantation of a frozen, devitalized tissue-engineered vascular graft for urgent hemodialysis access,” J. Vasc. Access, Jan.-Mar. 2011, 12(1):67-70. [cited by applicant]
Yuan et al., “Functional analysis in vivo of engineered valved venous conduit with decellularized matrix and two bone marrow-derived progenitors in sheep,” J. Tissue Eng. Regen. Medicine, Jul. 2016, 10(7):554-563. [cited by applicant]
Zervides et al., “The role of venous valves in pressure shielding,” Biomed. Eng. Online, Feb. 15, 2008, 7:8, 10 pages. [cited by applicant]
Zhang et al. “Application of Hydrogels in Heart Valve Tissue Engineering,” J. Long Term Eff. Med. Implants, May 2015, 25(1-2):105-134. [cited by applicant]
Syedain et al., “Pediatric tri-tube valved conduits made from fibroblast-produced extracellular matrix evaluated over 52 weeks in growing lambs,” Sci. Transl. Med., Mar. 2021, 13(585):eabb7225. [cited by applicant]
EP Extended Search Report in European Appln. No. 20814544.1, dated Jul. 1, 2022, 8 pages. [cited by applicant]