Cardiovascular disease is a global leading cause of death, prompting coronary heart diseases and peripheral artery diseases due to atherosclerotic artery narrowing. Currently, the most used vascular grafts are autologous arteries and veins. While considered the gold standard for small-diameter vascular replacements (<6 mm), these autologous vessels have limitations, including the need for invasive harvesting and unsuitability for some patients. Tissue-engineered vascular grafts have become a possible treatment in future cardio-vascular graft surgery. These grafts are designed to incorporate living cells, allowing for physiological remodeling.
Methods:
Cell-free porcine vascular xenografts were implanted surgically into the left carotid arteries of seven recipient sheep, and the subsequent inflammatory and clinical responses were monitored over the following 12 weeks. All seven sheep were euthanized humanely after that period, and a histological examination of the implant site was carried out.
Results:
Results showed that endothelial cells had colonized the luminal surface of the cell-free scaffold, and evidence of calcification associated with the transplant site was absent. This indicates that the material is biocompatible and capable of being repopulated. In two recipients, thrombus occlusions formed.
Conclusions:
We conclude that using a three-dimensional cell-free porous arterial grafting technique may have the potential for in vivo host cellular repopulation in arterial graft surgical treatments.
MathersCDLoncarD.Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med2006; 3(11): e442.
2.
MellyLTorregrossaGLeeT, et al. Fifty years of coronary artery bypass grafting. J Thorac Dis2018; 10(3): 1960–1967.
3.
MasdenDLSeruyaMHigginsJP.A systematic review of the outcomes of distal upper extremity bypass surgery with arterial and venous conduits. J Hand Surg Am2012; 37(11): 2362–2367.
4.
AthanasiouTSasoSRaoC, et al. Radial artery versus saphenous vein conduits for coronary artery bypass surgery: forty years of competition—which conduit offers better patency? A systematic review and meta-analysis. Eur J Cardiothorac Surg2011; 40(1): 208–220.
5.
GoldmanSZadinaKMoritzT, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol2004; 44(11): 2149–2156.
6.
HarskampRELopesRDBaisdenCE, et al. Saphenous vein graft failure after coronary artery bypass surgery: pathophysiology, management, and future directions. Ann Surg2013; 257(5): 824–833.
7.
CarrabbaMMadedduP.Current strategies for the manufacture of small size tissue engineering vascular grafts. Front Bioeng Biotechnol2018; 6: 41.
8.
NaegeliKMKuralMHLiY, et al. Bioengineering human tissues and the future of vascular replacement. Circ Res2022; 131(1): 109–126.
9.
ChenJZhangDWuLP, et al. Current strategies for engineered vascular grafts and vascularized tissue engineering. Polymers (Basel)2023; 15(9): 2015.
10.
ZhaoYZhangSZhouJ, et al. The development of a tissue-engineered artery using decellularized scaffold and autologous ovine mesenchymal stem cells. Biomaterials2010; 31(2): 296–307.
11.
WeinbergCBBellE.A blood vessel model constructed from collagen and cultured vascular cells. Science1986; 231(4736): 397–400.
12.
JenndahlLÖsterbergKBogestålY, et al. Personalized tissue-engineered arteries as vascular graft transplants: a safety study in sheep. Regen Ther2022; 21: 331–341.
13.
WatanabeTSassiSUlziibayarA, et al. The application of porous scaffolds for cardiovascular tissues. Bioengineering (Basel)2023; 10(2): 236.
14.
DiVincentiLJrWestcottRLeeC.Sheep (Ovis aries) as a model for cardiovascular surgery and management before, during, and after cardiopulmonary bypass. J Am Assoc Lab Anim Sci2014; 53(5): 439–448.
15.
LiuRHOngCSFukunishiT, et al. Review of vascular graft studies in large animal models. Tissue Eng Part B Rev2018; 24(2): 133–143.
16.
PavcnikDObermillerJUchidaBT, et al. Angiographic evaluation of carotid artery grafting with prefabricated small-diameter, small-intestinal submucosa grafts in sheep. Cardiovasc Intervent Radiol2009; 32(1): 106–113.
17.
KoobatianMTRowSSmithRJJr, et al. Successful endothelialization and remodeling of a cell-free small-diameter arterial graft in a large animal model. Biomaterials2016; 76: 344–358.
18.
HindsMTRoweRCRenZ, et al. Development of a reinforced porcine elastin composite vascular scaffold. J Biomed Mater Res A2006; 77(3): 458–469.
19.
TamuraNNakamuraTTeraiH, et al. A new acellular vascular prosthesis as a scaffold for host tissue regeneration. Int J Artif Organs2003; 26(9): 783–792.
20.
ConklinBSRichterERKreutzigerKL, et al. Development and evaluation of a novel decellularized vascular xenograft. Med Eng Phys2002; 24(3): 173–183.
21.
ChoSWLimSHKimIK, et al. Small-diameter blood vessels engineered with bone marrow-derived cells. Ann Surg2005; 241(3): 506–515.
22.
Durán-ReyDCrisóstomoVSánchez-MargalloJA, et al. Systematic review of tissue-engineered vascular grafts. Front Bioeng Biotechnol2021; 9: 771400.
23.
PennelTFercanaGBezuidenhoutD, et al. The performance of cross-linked acellular arterial scaffolds as vascular grafts; pre-clinical testing in direct and isolation loop circulatory models. Biomaterials2014; 35(24): 6311–6322.
24.
LaytonGRLadakSSAbbascianoR, et al. The role of preservation solutions upon saphenous vein endothelial integrity and function: systematic review and UK practice survey. Cells2023; 12(5): 815.
25.
Al HusseinHAl HusseinHSircutaC, et al. Challenges in perioperative animal care for orthotopic implantation of tissue-engineered pulmonary valves in the ovine model. Tissue Eng Regen Med2020; 17(6): 847–862.
26.
MathersCDBoermaTMa FatD.Global and regional causes of death. Br Med Bull2009; 92: 7–32.
27.
de VriesMRSimonsKHJukemaJW, et al. Vein graft failure: from pathophysiology to clinical outcomes. Nat Rev Cardiol2016; 13(8): 451–470.
28.
Lopera HiguitaMGriffithsLG. Small diameter xenogeneic extracellular matrix scaffolds for vascular applications. Tissue Eng Part B Rev2020; 26(1): 26–45.
29.
DuJChenXLiangX, et al. Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity. Proc Natl Acad Sci USA2011; 108(23): 9466–9471.
30.
HuleihelLDzikiJLBartolacciJG, et al. Macrophage phenotype in response to ECM bioscaffolds. Semin Immunol2017; 29: 2–13.
31.
BarkerTH.The role of ECM proteins and protein fragments in guiding cell behavior in regenerative medicine. Biomaterials2011; 32(18): 4211–4214.
32.
IwakiRShojiTMatsuzakiY, et al. Current status of developing tissue engineering vascular technologies. Expert Opin Biol Ther2022; 22(3): 433–440.
33.
HielscherDKaebischCBraunBJV, et al. Stem cell sources and graft material for vascular tissue engineering. Stem Cell Rev Rep2018; 14(5): 642–667.
34.
HarpaMMPuscasAIAniteiED, et al. Surgical procedure for acellular vascular xenografts testing in sheep carotid artery. Acta Marisiensis - Seria Medica2024; 70(3): 118–121.
35.
XingHLeeHLuoL, et al. Extracellular matrix-derived biomaterials in engineering cell function. Biotechnol Adv2020; 42: 107421.
36.
KretschmerMRüdigerDZahlerS.Mechanical aspects of angiogenesis. Cancers (Basel)2021; 13(19): 4987.
37.
SheridanWSDuffyGPMurphyBP.Mechanical characterization of a customized decellularized scaffold for vascular tissue engineering. J Mech Behav Biomed Mater2012; 8: 58–70.
38.
LinCHKaoYCLinYH, et al. A fiber-progressive-engagement model to evaluate the composition, microstructure, and nonlinear pseudoelastic behavior of porcine arteries and decellularized derivatives. Acta Biomater2016; 46: 101–111.
39.
YaoYPohanGCutiongcoMFA, et al. In vivo evaluation of compliance mismatch on intimal hyperplasia formation in small diameter vascular grafts. Biomater Sci2023; 11(9): 3297–3307.
40.
ChowJPSimionescuDTWarnerH, et al. Mitigation of diabetes-related complications in implanted collagen and elastin scaffolds using matrix-binding polyphenol. Biomaterials2013; 34(3): 685–695.
41.
XiongYChanWYChuaAW, et al. Decellularized porcine saphenous artery for small-diameter tissue-engineered conduit graft. Artif Organs2013; 37(6): E74–E87.
42.
CampbellEMCahillPALallyC.Investigation of a small-diameter decellularised artery as a potential scaffold for vascular tissue engineering; biomechanical evaluation and preliminary cell seeding. J Mech Behav Biomed Mater2012; 14: 130–142.
43.
ZengWWenCWuY, et al. The use of BDNF to enhance the patency rate of small-diameter tissue-engineered blood vessels through stem cell homing mechanisms. Biomaterials2012; 33(2): 473–484.
44.
GlynnJJHindsMT.Bioactive anti-thrombotic modification of decellularized matrix for vascular applications. Adv Healthc Mater2016; 5(12): 1439–1446.
45.
JiangBSuenRWertheimJA, et al. Targeting heparin to collagen within extracellular matrix significantly reduces thrombogenicity and improves endothelialization of decellularized tissues. Biomacromolecules2016; 17(12): 3940–3948.
46.
KristofikNJQinLCalabroNE, et al. Improving in vivo outcomes of decellularized vascular grafts via incorporation of a novel extracellular matrix. Biomaterials2017; 141: 63–73.
47.
TaoYHuTWuZ, et al. Heparin nanomodification improves biocompatibility and biomechanical stability of decellularized vascular scaffolds. Int J Nanomedicine2012; 7: 5847–5858.
48.
TardalkarKMarsaleTBhamareN, et al. Heparin immobilization of tissue engineered xenogeneic small diameter arterial scaffold improve endothelialization. Tissue Eng Regen Med2022; 19(3): 505–523.
49.
ZhouMLiuZLiuC, et al. Tissue engineering of small-diameter vascular grafts by endothelial progenitor cells seeding heparin-coated decellularized scaffolds. J Biomed Mater Res B Appl Biomater2012; 100(1): 111–120.
50.
Dall’OlmoLZanussoIDi LiddoR, et al. Blood vessel-derived acellular matrix for vascular graft application. Biomed Res Int2014; 2014: 685426.
51.
MovileanuIHarpaMAl HusseinH, et al. Preclinical testing of living tissue-engineered heart valves for pediatric patients, challenges and opportunities. Front Cardiovasc Med2021; 8: 707892.
52.
KennamerASieradLPascalR, et al. Bioreactor conditioning of valve scaffolds seeded internally with adult stem cells. Tissue Eng Regen Med2016; 13(5): 507–515.
53.
SieradLNShawELBinaA, et al. Functional heart valve scaffolds obtained by complete decellularization of porcine aortic roots in a novel differential pressure gradient perfusion system. Tissue Eng Part C Methods2015; 21(12): 1284–1296.
54.
HarpaMMovileanuISieradL, et al. In vivo testing of xenogeneic acellular aortic valves seeded with stem cells. Rev Rom Med Lab2016; 24(3): 343–346.
55.
HarpaMMMovileanuISieradLN, et al. Pulmonary heart valve replacement using stabilized acellular xenogeneic scaffolds; effects of seeding with autologous stem cells. Rev Romana Med Lab2015; 23(4): 415–429.
56.
MaXHeZLiL, et al. Development and in vivo validation of tissue-engineered, small-diameter vascular grafts from decellularized aortae of fetal pigs and canine vascular endothelial cells. J Cardiothorac Surg2017; 12(1): 101.
57.
TedderMELiaoJWeedB, et al. Stabilized collagen scaffolds for heart valve tissue engineering. Tissue Eng Part A2009; 15(6): 1257–1268.
58.
Yu-YueZYu-TingTSen-LiH, et al. Optimizing α-gal epitope removal in porcine dermal matrix: enzyme selection and tissue form matter. Tissue Eng Part C Methods2025; 31(5): 167–173.
59.
ReillyBKhanSDosluogluH, et al. Comparison of autologous vein and bovine carotid artery graft as a bypass conduit in arterial trauma. Ann Vasc Surg2019; 61: 246–253.
60.
LindseyPEcheverriaACheungM, et al. Lower extremity bypass using bovine carotid artery graft (Artegraft): an analysis of 124 cases with long-term results. World J Surg2018; 42(1): 295–301.
