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Dr. Nicolas L'Heureux

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Contact

Linkedin biotis-bordeaux

Secretary Email

33 (0)5 57 57 14 88

Bioingénierie Tissulaire (BioTis)       

Physical Address:

Batiment BBS (Bordeaux Biologie Santé), 5e étage

2, rue du Dr Hoffmann Martinot,

33000, Bordeaux, France

Mailing Address:

Université de Bordeaux, Campus Carreire

146, rue Léo Saignat, Case 84,

33076, Bordeaux Cedex, France

Abstract

Reference

Dr. Diane Potart

Project Leader

Small- to mid-diameter vascular grafts are implanted daily by surgeons for indications such as lower limb revascularization, coronary artery bypass grafting, and the creation of arteriovenous shunts. Autologous blood vessels remain the gold standard; however, these conduits are often limited in availability and may not always be in optimal condition. Although synthetic prostheses are available off-the-shelf, they are prone to thrombosis, intimal hyperplasia, and infection [1,3]. More than 30 years ago, Weinberg and Bell laid the foundation for tissue-engineered vascular grafts (TEVGs) with the development of the first biological blood vessel model [4]. Since then, numerous strategies have been proposed to produce optimal TEVGs, primarily based on scaffolds made from synthetic or natural materials [for reviews see 5,6].

▷[1] Klinkert P, Post P N, Breslau P J and van Bockel J H 2004 Saphenous vein versus PTFE for above-knee femoropopliteal bypass. A review of the literature Eur. J. Vasc. Endovasc. Surg. 27 357–62

▷[2] Rotmans J I, Heyligers J M M, Stroes E S G, Pasterkamp G and Verma S 2006 Endothelial progenitor cell-seeded grafts: rash and risky Can. J. Cardiol. 22 1113–6

▷[3] Sayers R D, Raptis S, Berce M and Miller J H 1998 Long-term results of femorotibial bypass with vein or polytetrafluoroethylene Br. J. Surg. 85 137 17

▷[4] Weinberg C B and Bell E 1986 A blood vessel model constructed from collagen and cultured vascular cells Science 231 397–400

▷[5] Kimicata M, Swamykumar P and Fisher J P 2020 Extracellular matrix for small-diameter vascular grafts Tissue Eng. A 26 1388–401

▷[6] Moore M J, Tan R P, Yang N, Rnjak-kovacina J and Wise S G 2022 Bioengineering artificial blood vessels from natural materials Trends Biotechnol. 40 1–15

▷[7] Hussey G S, Dziki J L and Badylak S F 2018 Extracellular matrix-based materials for regenerative medicine Nat. Rev. Mater. 3 159–73

▷[8] Goldstein J D, Tria A J, Zawadsky J P, Kato Y P, Christiansen D and Silver F H 1989 Development of a reconstituted collagen tendon prosthesis. A preliminary implantation study J. Bone Jt. Surg. 71 1183–91

▷[9] Law J K, Parsons J R, Silver F H and Weiss A B 1989 An evaluation of purified reconstituted type I collagen fibers J. Biomed. Mater. Res. 23 961–77

▷[10] Zhang F, Bambharoliya T, Xie Y, Liu L, Celik H, Wang L, Akkus O and King M W 2021 A hybrid vascular graft harnessing the superior mechanical properties of synthetic

fibers and the biological performance of collagen filaments Mater. Sci. Eng. C 118 111418

▷[11] Syedain Z H, Graham M L, Dunn T B, O’Brien T, Johnson S L, Schumacher R J and Tranquillo R T 2017 A completely biological “ off-the-shelf ” arteriovenous graft that recellularizes in baboons Sci. Transl. Med. 9 eaan4209

▷[12] Motta S E et al 2019 Human cell-derived tissue-engineered heart valve with integrated Valsalva sinuses: towards native-like transcatheter pulmonary valve replacements npj Regen. Med. 4 14

▷[13] Lawson J H et al 2016 Bioengineered human acellular vessels for dialysis access in patients with end-stage renal disease: two phase 2 single-arm trials Lancet 387 2026–34

▷[14] Gutowski P et al 2022 Six-year outcomes of a phase II study of human-tissue engineered blood vessels for peripheral arterial bypass JVS-Vasc. Sci. 4 100092

▷[15] Jakimowicz T, Przywara S, Turek J, Pilgrim A, Macech M, Zapotoczny N, Zubilewicz T, Lawson J H and Niklason L E 2022 Five year outcomes in patients with end stage renal disease who received a bioengineered human acellular vessel for dialysis access EJVES Vasc. Forum 54 58–63

▷[16] Kirkton R D, Santiago-Maysonet M, Lawson J H, Tente W E, Dahl S L M, Niklason L E and Prichard H L 2019 Bioengineered human acellular vessels recellularize and evolve into living blood vessels after human implantation Sci. Transl. Med. 11 1–11

▷[17] L’Heureux N et al 2006 Human tissue-engineered blood vessels for adult arterial revascularization Nat. Med. 12 361–5

▷[18] L’Heureux N, Pˆ aquet S, Labbé R, Germain L and Auger F A 1998 A completely biological tissue-engineered human blood vessel FASEB J. 12 47–56

▷[19] Wystrychowski W, McAllister T N, Zagalski K, Dusserre N, Cierpka L and L’Heureux N 2014 First human use of an allogeneic tissue-engineered vascular graft for hemodialysis access J. Vasc. Surg. 60 1353–7

▷[20] McAllister T N et al 2009 Effectiveness of haemodialysis access with an autologous tissue-engineered vascular graft: a multicentre cohort study Lancet 373 1440–6

▷[21] Post A, Diaz-Rodriguez P, Balouch B, Paulsen S, Wu S, Miller J, Hahn M and Cosgriff-Hernandez E 2019 Elucidating the role of graft compliance mismatch on intimal hyperplasia using an ex vivo organ culture model Acta Biomater. 89 84–94

▷[22] Jeong Y, Yao Y and Yim E K F 2020 Current understanding of intimal hyperplasia and effect of compliance in synthetic small diameter vascular grafts Biomater. Sci. 8 4383–95

▷[23] Abbott W M, Megerman J, Hasson J E, L’Italien G and Warnock D F 1987 Effect of compliance mismatch on vascular graft patency J. Vasc. Surg. 5 376–82

▷[24] Biofabrication 16 (2024) 015015 [24] Ballyk P D, Walsh C and Butany J 1997 Compliance mismatch may promote graft–artery intimal hyperplasia by altering suture-line stresses J. Biomech. 31 229–37

▷[25] Kidson I G 1983 The effect of wall mechanical properties on patency of arterial grafts Ann. R. Coll. Surg. Engl. 65 24–29

▷[26] Trubel W, Schima H, Moritz A, Raderer F, Windisch A, Ullrich R, Windberger U, Losert U and Polterauer P 1995 Compliance mismatch and formation of distal

anastomoticintimal hyperplasia in externally stiffened and lumen-adapted venous grafts Eur. J. Vasc. Endovasc. Surg. 10 415–23


▷[27] Singh C, Wong C S and Wang X 2015 Medical textiles as vascular implants and their success to mimic natural arteries J. Funct. Biomater. 6 500–25

▷[28] Akbari M, Tamayol A, Bagherifard S, Serex L, Mostafalu P, Faramarzi N, Mohammadi M H and Khademhosseini A 2016 Textile technologies and tissue engineering: a path toward organ weaving Adv. Healthcare Mater. 5 751–66

▷[29] Magnan L et al 2020 Human textiles: a cell-synthesized yarn as a truly “bio” material for tissue engineering applications Acta Biomater. 105 111–20

▷[30] Potart D, Gluais M, Gaubert A, Da Silva N, Hourques M, Sarrazin M, Izotte J, Mora Charrot L and L’Heureux N 2023 The cell-assembled extracellular matrix: a focus on  

the storage stability and terminal sterilization of this human “ bio ” material Acta Biomater. 166 133–46


▷[31] Torres Y, Gluais M, Da Silva N, Rey S, Grémare A, Magnan L, Kawecki F and L’Heureux N 2021 Cell-assembled extracellular matrix (CAM) sheet production: translation from using human to large animal cells J. Tissue Eng. 12 1–14

▷[ref X] Roudier, G., Hourques, M., Da Silva, N., Gluais, M., Binyet, E., Olive, J.-M., and L’Heureux, N. Effects of weaving parameters on the properties of completely biological tissue-engineered vascular grafts. Biofabrication, (16), 015015, doi: 10.1088/1758-5090/ad0d14 (2024)

Gaëtan Roudier

Dr. Julien Vitry

Dr. Yoann Torres

Collaborator


Biological scaffolds derived from mammalian extracellular matrix (ECM) have shown considerable promise in tissue engineering applications [for review see 7]. ECM is present in every tissue and plays a key role in regulating cellular responses, tissue healing, and regeneration. However, purified ECM proteins isolated from animals or cadaveric tissues lack a physiological organization and are therefore rapidly degraded after implantation in vivo [8,10]. In contrast, ECM assembled by cells in vitro more closely reproduces the native architecture and can thus provide a more stable material for tissue engineering applications [11,15]. TEVGs based on ECM synthesized by cells in vitro have been proposed as promising alternatives to synthetic grafts, notably because this cell-friendly material promotes in vivo remodeling while reducing the risk of infection [11,16,17].

Our work was the first to demonstrate the use of cell-assembled extracellular matrix (CAM) to produce completely biological, implantable vascular substitutes [18]. These grafts were generated by rolling CAM sheets to form a biological tube and were successfully implanted in humans [19,20]. Although these TEVGs yielded positive clinical outcomes, their production required several months, relied on costly bioreactors, and offered limited control over mechanical properties.

To address these limitations, our group developed threads from devitalized CAM sheets [21]. These threads have been shown to remain stable in vitro for up to one year and can be sterilized with minimal denaturation [22]. This new material format enables the use of textile-based fabrication strategies to engineer CAM-derived constructs, referred to as Human Textiles. Among these assembly techniques, weaving offers the advantage of creating leak-proof walls, a critical property for vascular grafts. Our first woven TEVG prototype exhibited extremely high burst pressure and suture retention strength. However, these supraphysiological mechanical properties were associated with poor compliance, resulting in a mechanical mismatch with native blood vessels. Additionally, the prototype had thick walls and limited flexibility, which made puncturing and suturing difficult [23].

After miniaturization, we evaluated woven human TEVGs in nude rats, demonstrating graft persistence for up to 12 months (under revision in Biomaterials). In parallel studies, we showed that CAM produced by ovine cells can also be used to fabricate woven TEVGs with properties closely resembling those produced using human cells [24]. We further demonstrated that the textile approach allows tuning of TEVG mechanical properties by adjusting assembly parameters [ref X]. Using CAM produced from ovine cells, we are currently evaluating woven TEVGs in an allogeneic setting as carotid interposition grafts and as carotid–jugular arteriovenous shunts to mimic the clinical setting. In addition, other vascular graft designs are currently under development.



Cécile Monfoulet

Dr. Fabien Kawecki

Tissue-Engineered Vascular Grafts using Cell-Assembled extracellular matrix (CAM) and a textile approach