Elsevier

Microvascular Research

Volume 131, September 2020, 104027
Microvascular Research

The applications of heparin in vascular tissue engineering

https://doi.org/10.1016/j.mvr.2020.104027Get rights and content

Highlights

  • There is urgent need for a viable bio/blood compatible small-diameter vascular graft with high patency rate.

  • Heparin, a polypharmaceutical, is an anticoagulant with anti-inflammatory/-cancer/-viral & angiogenesis regulatory effects.

  • Heparin-mimetic polymers can restrain restenosis by preventing non-specific protein adsorption.

  • Heparin physical encapsulation, covalent conjugation and immobilization on ionized surfaces is reviewed.

  • Applications of spacer/linkers used to improve heparin bioactivity with reduced thrombotic is reviewed.

Abstract

Cardiovascular diseases, among all diseases, are taking the most victims worldwide. Coronary artery occlusion, takes responsibility of about 30% of the yearly global deaths in the world (Heart Disease and Stroke Statistics 2017 At-a-Glance, 2017), raising the need for viable substitutes for cardiovascular tissues. Depending on a number of factors, blocked coronary arteries are now being replaced by autografts or stents. Since the autografts, as the gold standard coronary artery replacements, are not available in adequate quality and quantity, the demand for small diameter vascular substitute comparable to native vessels is rapidly growing. Synthetic grafts have been successfully approved for developing vascular replacements but regarding the special conditions in small-caliber vessels, their use is limited to large-diameter vascular tissue engineering. The major problems associated with the vascular tissue engineered grafts are thrombosis and intimal hyperplasia. Heparin, a negatively charged natural polysaccharide has been used in fabricating vascular grafts since it prevents protein fouling on the surfaces and most importantly, impeding thrombosis. Herein, we focused on heparin, as a multifunctional bioactive molecule that not only serves as an anticoagulant with frequent clinical use but also acts as an anti-inflammatory and angiogenic regulatory substance. We summarized heparin incorporation into stents and grafts and their applicability to restrain restenosis. Also, the applications of heparinzation of biomaterials and heparin mimetic polymers and different approaches invoked to improve heparin bioactivity have been reviewed. We summarized the methods of adding heparin to matrices as they were explained in the literature. We reviewed how heparin influences the biocompatibility of the scaffolds and discussed new advances about using heparin in small-diameter 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)

  • O. Jeon et al.

    Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly (L-lactic-co-glycolic acid) scaffold

    Biomaterials.

    (2007)
  • M. Kabiri et al.

    3D mesenchymal stem/stromal cell osteogenesis and autocrine signalling

    Biochem. Biophys. Res. Commun.

    (2012)
  • M. Kadivar et al.

    In vitro cardiomyogenic potential of human umbilical vein-derived mesenchymal stem cells

    Biochem. Biophys. Res. Commun.

    (2006)
  • Y. Liang et al.

    Heparin-functionalized polymeric biomaterials in tissue engineering and drug delivery applications

    Acta Biomater.

    (2014)
  • T. Liu et al.

    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.

    (2014)
  • Jie-Ru Liu et al.

    Heparin-derived oligosaccharide inhibits vascular intimal hyperplasia in balloon-injured carotid artery

    Chin. J. Nat. Med.

    (2017)
  • H.B. Nader et al.

    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.

    (1981)
  • T. Nie et al.

    Production of heparin-functionalized hydrogels for the development of responsive and controlled growth factor delivery systems

    J. Control. Release

    (2007)
  • C. Nie et al.

    Nanofibrous heparin and heparin-mimicking multilayers as highly effective endothelialization and antithrombogenic coatings

    Biomacromolecules.

    (2015)
  • S.J. Paluck et al.

    Heparin-mimicking polymers: synthesis and biological applications

    Biomacromolecules.

    (2016)
  • S. Rabbani et al.

    Regenerating heart using a novel compound and human Wharton jelly Mesenchymal stem cells

    Arch. Med. Res.

    (2017)
  • K.J. Rambhia et al.

    Controlled drug release for tissue engineering

    J. Control. Release

    (2015)
  • M. Ruel et al.

    Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein

    J. Thorac. Cardiovasc. Surg.

    (2002)
  • S.E. Sakiyama-Elbert

    Incorporation of heparin into biomaterials

    Acta Biomater.

    (2014)
  • V. Singh et al.

    Isolation, purification, and characterization of Heparinase from Streptomyces variabilis MTCC 12266

    Sci. Rep.

    (2019)
  • M. Wissink et al.

    Improved endothelialization of vascular grafts by local release of growth factor from heparinized collagen matrices

    J. Control. Release

    (2000)
  • M. Wissink et al.

    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

    (2000)
  • F. Zia et al.

    Heparin based polyurethanes: a state-of-the-art review

    Int. J. Biol. Macromol.

    (2016)
  • S. Aslani et al.

    Vascular tissue engineering: fabrication and characterization of acetylsalicylic acid-loaded electrospun scaffolds coated with amniotic membrane lysate

    J. Cell. Physiol.

    (2019)
  • B.K. Babur et al.

    The rapid manufacture of uniform composite multicellular-biomaterial micropellets, their assembly into macroscopic organized tissues, and potential applications in cartilage tissue engineering

    PLoS One

    (2015)
  • P.M. Bath et al.

    Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials

    Stroke.

    (2000)
  • V. Catto et al.

    Vascular tissue engineering: recent advances in small diameter blood vessel regeneration

    ISRN Vasc. Med.

    (2014)
  • E.A.C. Cedar

    Medical technologies evaluation Programme, NICE

    PROPATEN heparin-bonded vascular graft for peripheral arterial disease

    (2015)
  • C. Cheng et al.

    Progress in heparin and heparin-like/mimicking polymer-functionalized biomedical membranes

    J. Mater. Chem. B

    (2014)
  • W.S. Choi et al.

    Enhanced patency and endothelialization of small-caliber vascular grafts fabricated by coimmobilization of heparin and cell-adhesive peptides

    ACS Appl. Mater. Interfaces

    (2016)
  • N. Duan et al.

    A vascular tissue engineering scaffold with core–shell structured nano-fibers formed by coaxial electrospinning and its biocompatibility evaluation

    Biomed. Mater.

    (2016)
  • P. Ducheyne

    Comprehensive Biomaterials: Elsevier

    (2015)
  • E.R. Edelman et al.

    Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vasorum in injured rat arteries

    J. Clin. Invest.

    (1992)
  • E. Ercolani et al.

    Vascular tissue engineering of small-diameter blood vessels: reviewing the electrospinning approach

    J. Tissue Eng. Regen. Med.

    (2015)
  • J. Fang et al.

    Orthogonally functionalizable polyurethane with subsequent modification with heparin and endothelium-inducing peptide aiming for vascular reconstruction

    ACS Appl. Mater. Interfaces

    (2016)
  • J. Gao et al.

    The grafts modified by heparinization and catalytic nitric oxide generation used for vascular implantation in rats

    Regen. Biomater.

    (2018)
  • R.L. Geary et al.

    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.

    (1995)
  • J.R. Guyton et al.

    Inhibition of rat arterial smooth muscle cell proliferation by heparin. In vivo studies with anticoagulant and nonanticoagulant heparin

    Circ. Res.

    (1980)
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