The applications of heparin in vascular tissue engineering
Introduction
Recent advances in tissue engineering have brought about promising alternatives to address the increasing demand of tissue and organ replacement and regeneration; encompassing tissues with low inherent regenerative capacity such as neural, chondral and muscular tissues (Soleimani et al., 2008; Kabiri et al., 2015; Babur et al., 2015; Ramezanifard et al., 2017). Coronary artery occlusion, is the main cause of about 30% of yearly deaths in the world (Heart Disease and Stroke Statistics 2017 At-a-Glance, 2017), raising the need for viable substitutes for cardiovascular tissues. Saphenous vein, internal mammary and radial arteries are the best clinical options to replace blocked coronary arteries (Catto et al., 2014). However, cardiovascular patients often lack healthy vessels to be used as arterial replacements especially if they have already gone under bypass grafting. In addition, harvesting autografts is an expensive, time consuming method (Ravi and Chaikof, 2010). Balloon angioplasty in one approach that flattens the plaques restricting arterial bloodstream that is usually followed by inserting a stent in the formerly blocked area to keep the artery open. However, grafts are used when the blocked vessel replaced by another native vessel (autografts/bypass grafts) or a tissue engineered substitute (Health, 2013; Aslani et al., 2019). There has been significant amount of research conducted for developing a viable small-diameter vascular graft. A successful small-caliber vascular conduit must have mechanical strength comparable to native arteries, a complete endothelial lining in the lumen and resistance to intimal hyperplasia and inflammation (Ercolani et al., 2015). An injured or subconfluent endothelium triggers inflammatory response and platelet activation which in turn leads to thrombotic graft occlusion. Current techniques that are considered for treating coronary artery occlusion are summarized in Fig. 1.
Heparin, a negatively charged natural polysaccharide has been used in fabricating vascular grafts. The addition of heparin to material prevents protein fouling on the modified surfaces by enhancing their wettability and most importantly, impeding thrombosis. Carmeda Bioactive Surface (Carmeda) and Duraflo II (Baxter) are clinically approved techniques for coating vascular stent with heparin (Kidane et al., 2004). Although heparinized vascular grafts such as Propaten and Intergard are commercially available, their long term performance has not been proved yet (Hoshi et al., 2013). In this review, we looked through heparin's chemical properties and mechanisms of function as a bioactive molecule. We mentioned the methods of heparin immobilization on the scaffolds and then previewed the most recent works on the application of heparin in vascular tissue engineering.
Section snippets
Heparin structure, characteristics and physiological roles
Heparin, a relatively large linear anionic polyelectrolyte having an average of −75 net charge per chain, is a member of glycosaminoglycans which is composed of about 20 disaccharide units (Mulloy et al., 2016; Linhardt et al., 2008). Noted as one of the most salient anticoagulants used in clinic, heparin is also able to induce anti-inflammatory responses, along with having complement activation inhibitory, anti-cancer, anti-viral, and angiogenesis regulatory activities, making it a
The role of heparin in quest against intimal hyperplasia
Intimal hyperplasia (over-proliferation of smooth muscle cells (SMCs)), lack of an integrated endothelium and thrombosis are the main challenges in the quest to develop a viable small-diameter vascular stent (Seifu et al., 2013; Zhou et al., 2009). Although application of anti-proliferative agents have shown an effective role in reducing stenosis in damaged vessels, they proved to be harmful to endothelial cells (ECs) (Liu et al., 2014a). Since simultaneous application of anti-proliferative and
Shortcomings of heparin and use of heparin-mimetics
Soluble heparin is a multi-functional drug that has been clinically used for more than a hundred years (Liang and Kiick, 2014). Nevertheless, it faces serious shortcomings. Systemic intravenous administration of heparin can cause hemorrhage, heparin-induced thrombocytopenia which can be fatal circumstantially, difficulty in breathing and swelling of lips, tongue or face (Hoshi et al., 2013; Linhardt et al., 2008). The short serum half-life of heparin causes its low bioactivity (Zia et al., 2016
Heparinization of biomaterials
In order to promote therapeutic efficacy of blood contacting surfaces, heparinized materials have been developed. Treating catheters, stents and other biomedical devices with heparin inhibits blood clotting. A wide range of systems including hydrogels, films, micro and nanoparticle systems and electrospun fibers have been designed that contain heparin for improved biocompatibility (Zia et al., 2016). Due to the abundance of functional groups in heparin's structure, heparinized materials can be
Developing sustained drug release systems using heparin
Increased hydrophilicity, reduced thrombosis and enhanced cell growth are characteristics of heparinized surfaces that have been reported by a significant body of research (Wan et al., 2011; Wang et al., 2013). Because of their increased swelling property, heparinized hydrogels transport nutrients to the cells more easily (Liang and Kiick, 2014). Nevertheless, heparin conjugation methods suffer from several flaws. Heparin binding density is hard to control and thus causes uncontrolled drug
The role of heparin in Increasing biocompatibility
Understanding the hemocompatibility of biomaterials would not be possible without testing protein adsorption as the first event that happens at the interface of biomaterials and living systems (Nie et al., 2015). It takes less than a second for plasma proteins, including fibrinogen and albumin, to recognize and begin to adhere to implanted biomaterials. Platelet adhesion and activation happens when the fibrinogen molecules are adsorbed in high levels and change their conformation in a way that
Heparin in small-diameter vascular tissue engineering
Owing to its high negative charge density, heparin has the potential to impede platelet adhesion, resulting in reduced thrombosis. Various approaches have been taken to make heparinized biomaterials, which include physical adsorption, loading and chemical conjugation. Here, we have summarized studies on heparinized biomaterials with potential applications in VTE based on the method of adding heparin to the biomaterials.
Conclusion
In attempts to answer the urgent need for a viable small-diameter vascular graft with excellent biocompatibility, blood compatibility and high patency rate, various approaches have been tried out. Heparin, as a “polypharmaceutical” is one of the most salient anticoagulants used in clinic, with approved anti-inflammatory, complement activation inhibitory, anti-cancer, anti-viral, and angiogenesis regulatory effects. By incorporating heparin into stents and grafts or developing heparin-mimetic
Declaration of competing interest
The authors declare that there is no conflict of interest.
Acknowledgements
We sincerely thank Iran National Science Foundation for their financial support on this project.
References (87)
- et al.
Heparin-bonded expanded polytetrafluoroethylene vascular graft for femoropopliteal and femorocrural bypass grafting: 1-year results
J. Vasc. Surg.
(2006) - et al.
Preparation and characterization of albumin-heparin microspheres
Biomaterials.
(1994) - et al.
Click-coated, heparinized, decellularized vascular grafts
Acta Biomater.
(2015) - et al.
Controlled and modulated release of basic fibroblast growth factor
Biomaterials.
(1991) - et al.
Sulfated levan from Halomonas smyrnensis as a bioactive, heparin-mimetic glycan for cardiac tissue engineering applications
Carbohydr. Polym.
(2016) - et al.
In vitro studies of heparin-coated magnetic nanoparticles for use in the treatment of neointimal hyperplasia
Nanomedicine
(2018) - et al.
Covalently bound conjugates of albumin and heparin: synthesis, fractionation and characterization
Thromb. Res.
(1983) - et al.
The blood and vascular cell compatibility of heparin-modified ePTFE vascular grafts
Biomaterials.
(2013) - et al.
In vitro and in vivo evaluation of a small-caliber coaxial electrospun vascular graft loaded with heparin and VEGF
Int. J. Surg.
(2017) - et al.
Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly (L-lactide-co-glycolide) nanospheres and fibrin gel
Biomaterials.
(2006)
Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly (L-lactic-co-glycolic acid) scaffold
Biomaterials.
3D mesenchymal stem/stromal cell osteogenesis and autocrine signalling
Biochem. Biophys. Res. Commun.
In vitro cardiomyogenic potential of human umbilical vein-derived mesenchymal stem cells
Biochem. Biophys. Res. Commun.
Heparin-functionalized polymeric biomaterials in tissue engineering and drug delivery applications
Acta Biomater.
Immobilization of heparin/poly-l-lysine nanoparticles on dopamine-coated surface to create a heparin density gradient for selective direction of platelet and vascular cells behavior
Acta Biomater.
Heparin-derived oligosaccharide inhibits vascular intimal hyperplasia in balloon-injured carotid artery
Chin. J. Nat. Med.
Heterogeneity of heparin: characterization of one hundred components with different anticoagulant activities by a combination of electrophoretic and affinity chromatography methods
Int. J. Biol. Macromol.
Production of heparin-functionalized hydrogels for the development of responsive and controlled growth factor delivery systems
J. Control. Release
Nanofibrous heparin and heparin-mimicking multilayers as highly effective endothelialization and antithrombogenic coatings
Biomacromolecules.
Heparin-mimicking polymers: synthesis and biological applications
Biomacromolecules.
Regenerating heart using a novel compound and human Wharton jelly Mesenchymal stem cells
Arch. Med. Res.
Controlled drug release for tissue engineering
J. Control. Release
Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein
J. Thorac. Cardiovasc. Surg.
Incorporation of heparin into biomaterials
Acta Biomater.
Isolation, purification, and characterization of Heparinase from Streptomyces variabilis MTCC 12266
Sci. Rep.
Improved endothelialization of vascular grafts by local release of growth factor from heparinized collagen matrices
J. Control. Release
Endothelial cell seeding of (heparinized) collagen matrices: effects of bFGF pre-loading on proliferation (after low density seeding) and pro-coagulant factors
J. Control. Release
Heparin based polyurethanes: a state-of-the-art review
Int. J. Biol. Macromol.
Vascular tissue engineering: fabrication and characterization of acetylsalicylic acid-loaded electrospun scaffolds coated with amniotic membrane lysate
J. Cell. Physiol.
The rapid manufacture of uniform composite multicellular-biomaterial micropellets, their assembly into macroscopic organized tissues, and potential applications in cartilage tissue engineering
PLoS One
Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials
Stroke.
Vascular tissue engineering: recent advances in small diameter blood vessel regeneration
ISRN Vasc. Med.
Medical technologies evaluation Programme, NICE
PROPATEN heparin-bonded vascular graft for peripheral arterial disease
Progress in heparin and heparin-like/mimicking polymer-functionalized biomedical membranes
J. Mater. Chem. B
Enhanced patency and endothelialization of small-caliber vascular grafts fabricated by coimmobilization of heparin and cell-adhesive peptides
ACS Appl. Mater. Interfaces
A vascular tissue engineering scaffold with core–shell structured nano-fibers formed by coaxial electrospinning and its biocompatibility evaluation
Biomed. Mater.
Comprehensive Biomaterials: Elsevier
Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vasorum in injured rat arteries
J. Clin. Invest.
Vascular tissue engineering of small-diameter blood vessels: reviewing the electrospinning approach
J. Tissue Eng. Regen. Med.
Orthogonally functionalizable polyurethane with subsequent modification with heparin and endothelium-inducing peptide aiming for vascular reconstruction
ACS Appl. Mater. Interfaces
The grafts modified by heparinization and catalytic nitric oxide generation used for vascular implantation in rats
Regen. Biomater.
Failure of heparin to inhibit intimal hyperplasia in injured baboon arteries: the role of heparin-sensitive and-insensitive pathways in the stimulation of smooth muscle cell migration and proliferation
Circulation.
Inhibition of rat arterial smooth muscle cell proliferation by heparin. In vivo studies with anticoagulant and nonanticoagulant heparin
Circ. Res.
Cited by (42)
A review on multifaceted biomedical applications of heparin nanocomposites: Progress and prospects
2024, International Journal of Biological MacromoleculesBiomedical applications of engineered heparin-based materials
2024, Bioactive MaterialsFabrication of heparinized bi-layered vascular graft with PCL/PU/gelatin co-electrospun and chitosan/silk fibroin/gelatin freeze-dried hydrogel for improved endothelialization and enhanced mechanical properties
2023, International Journal of Biological MacromoleculesRecent advances in keratin for biomedical applications
2023, Advances in Colloid and Interface Science