# Heparin-Eluting Tissue-Engineered Bioabsorbable Vascular Grafts
###### Abstract  
The creation of small-diameter tissue-engineered vascular grafts using biodegradable materials has the potential to change the quality of cardiovascular surgery in the future. The implantation of these tissue-engineered arterial grafts has yet to reach clinical application. One of the reasons for this is thrombus occlusion of the graft in the acute phase. In this paper, we first describe the causes of accelerated thrombus formation and discuss the drugs that are thought to inhibit thrombus formation. We then review the latest research on methods to locally bind the anticoagulant heparin to biodegradable materials and methods to extend the duration of sustained heparin release. We also discuss the results of studies using large animal models and the challenges that need to be overcome for future clinical applications. tissue-engineered vascular grafts; biodegradable material; anticoagulation; medication; heparin; large-animal study +
Footnote †: journal: Medical  
migration, adhesion, and remodeling onto the scaffold. However, increasing graft porosity comes at the cost of losing mechanical properties and strength of the original scaffold [9]. Additionally, electrospinning is popular because of its ability to incorporate drugs, growth factors, and helpful peptides into the scaffold [10]. These helpful graft modifiers are often co-spun with various polymers during the scaffold fabrication process. Much has been written about the polymers used in bioabsorbable grafts and their various fabrication methods, so we will not go over them in much detail. The materials most often used are PGA, PLA, and PCL [11]. Using these polymers individually, or as blends, can create a wide range of mechanical properties and degradation periods. Additionally, these polymers are the widely used because they have been approved by the FDA for numerous medical applications, thereby making new device regulatory approval much simpler [12]. This brings us to our first challenge, that these graft materials have been susceptible to thrombosis. Thrombosis is largely due to the surface charge of a given graft polymer, which has little interaction with serum and allows for platelet deposition [13]. In general, graft polymers are positively charged materials, whereas albumin, the most abundant blood protein, and fibrinogen, a protein important for platelet-mediated blood clotting, both have negative charges at blood pH [14]. This is a major problem, because when the opposite charges of the material proteins attract, a coagulation cascade begins that often leads to thrombosis [15]. Thankfully, material surface charge can be manipulated by chemical and/or cellular modification. Although there are many approaches for chemical surface modification, the binding of heparin continues to be the most widely used and promising method to prevent thrombosis. The reason for this is that heparin has the highest negative charge density and electrostatically repels a variety of blood proteins of similar charge. Conjugating heparin to polymers effectively changes a scaffold's surface from positive to negative. Static repulsion, between heparin and these proteins, prevents albumin and fibrinogen from adhering to the graft [16]. The second major hurdle is a graft's ability to resist intimal hyperplasia (smooth muscle cell (SMC) overgrowth) [17; 18]. Heparin has so far been the best candidate in the search for an anticoagulant to inhibit a graft's SMC proliferative response while promoting endothelial cell (EC) proliferation [19]. In fact, in vitro studies have shown that it inhibits SMC, but enhances EC proliferation. However, in vivo studies have been inconsistent. Heparin can be used directly as a coating inside of the graft (physical conjugation) or indirectly via additional linkers or spacers (chemical/plasma conjugation). However, it is not enough for heparin to be properly bound to the graft surface; it must be released in a controlled manner at sufficient concentrations [20; 21].