Biomaterials Science Part II: Materials in Medicine Synthetic Vascular Grafts March 6, 2010 assignment reading: Brett C. Isenberg, Chrysanthi Williams and Robert T. Tranquillo Small-Diameter Artificial Arteries Engineered In Vitro Circ. Res. 2006;98;25-35

Atherosclerosis is the hardening of the blood vessels due to deposition of LDL cholesterol and macrophages. Early deposition of cholesterol is considered as an ‘injury’. - occlusion of coronary artery - occlusion of peripheral artery (usually leg) Atherosclerosis

Heart attack, stroke, peripheral artery occlusive disease ages/en/19134.jpg

Bypass surgery Autologous saphenous vein (ASV): causes site morbidity and patients might not have a suitable vein. However, it yields the best result. Synthetic vascular graft: re-occurrence of thrombus formation but can be made available off-the-shelve Cell-based graft: time to process each layer of the blood vessels Acellularized matrix: immune rejection Endothelialization of synthetic grafts to minimize or prevent thrombosis.

Structure of natural blood vessel Elastin layer Endothelial cells are capable of releasing NO, prostalcyclin, heparin, tissue plasminogen activator---inhibit thrombosis, vasoconstriction and intimal hyperplasia.

Synthetic vascular grafts: introduction The rationale for developing synthetic grafts are based on 1. Need to replace or bypass occluded large vessels such as aorta 2. Unsatisfactory results from homografts and xenografts 3. Unavailability of a suitable autologous vein Among various polymers, ePTFE (expanded polytetrafluoroethylene), has proved to be the most satisfactory in terms of requisite tensile strength and low incidence of occlusion. However, thrombosis remains an issue when the size of ePTFE graft is < 4 mm in diameter.

Synthetic vascular grafts: introduction Knitted Dacron (poly(ethylene terephthalate)) is the most widely used prosthetic arterial graft for medium and large- dimater (> 4 mm) site. To prevent bleeding through the woven and knitted surface, the grafts are usually pre-clotted with patient’s own blood prior to implantation.

Synthetic vascular grafts: introduction Many attempts are made to bind molecules that prevent blood coagulation such as heparin, platelet adhesion (prostacyclin), enhance fibrinolysis (urokinase) on the luminal surface of the grafts. However, these attempts have not yet been carefully evaluated in clinical trials. Seeding the luminal surface of the grafts with endothelial cells is a more promising alternative due to satisfactory results in animals. Concerns over mechanical mismatch between grafts and native vessels --- usually the native vessels are much more compliant.

Small-Diameter Artificial Engineered in vitro B.C. Isenberg, C. Williams, R. T. Tranquillo Circulation Res 2006, 98, Terminology: Anastomosis = a connection of the two structures Aneurysm = a dilation of a blood vessel due to weakening of the vessel wall Synthetic, prosthetic = artificial Graft = material or tissue that is affixed to the existing host tissue as a replacement Conduit = a tube thats convey fluid Neointimal hyperplasia = thickening of the vessel (decreasing lumen size) due to excessive proliferation of smooth muscle cells Endothelium = the innermost layer of natural blood vessel composed of a monolayer (confluent sheet) of endothelial cells sitting on a basement membrane Media = the middle layer of the blood vessel composed of smooth muscle cells and elastin Adventitia = the outermost layer of the blood vessel composed of fibroblasts and collagen

Abstract 1.Describe the physiological blood flow inside small vs. big diameter synthetic grafts. 2. What is the standard graft used by the doctor in bypass surgery? What is the problem associated with that standard graft? 3. What are alternative choices to replace autologous vein?

Introduction 1.Under what circumstances Dacron and ePTFE are shown to have long patency without the reoccurring thrombosis? 2. What are the problems associated with synthetic grafts? 3. What are the required properties of a biocompatible? 4. What are the 3 components the authors think is the most important in design criteria?

Fabrication Methods: Decellularized Tissues 1.What are the advantages of decellularized tissue? 2.What are the reagents used to prepare a decellularized tissue? 3. What are the drawbacks of decellularized tissue?

Fabrication: biodegradable polymer scaffolds 1.What is the basic idea of this approach? 2.What could be a potential pitfall of a biodegradable graft? 3.How would you test if ECM is formed inside the biodegradable graft? 4.How did the researcher prevent PGA from being rapidly resorped? 5.Describe the in vivo experiments that use PGA-based scaffold as a vascular substitute. 6.What potentially remains a problem for a biodegradable graft?

Fabrication: Cell sheets 1.What makes the cell sheets method the holy grail for tissue-engineered blood vessel (TEBV)? 2.Describe the cell sheets method. 3.What’s the major drawback of this approach? 4.What are the characteristics of a healthy and functional endothelial cells? 5.How is the burst strength of TEBV compared to the gold standard, saphenous vein? 6. What remains a problem for a stiff (not compliant) graft?

Fabrication: Biopolymer scaffolds 1.What is the important message delivered by the pioneers Weinberg and Bell that becomes the main approach in the development of a synthetic vascular grafts (either biodegradable or biopolymer)? 2. What makes the biopolymer scaffold as an attractive approach? 3. What ECM component derived from an animal that is FDA approved? 4. What is the problem with collagen? 5. What is used as a natural sealant at sulture? What is another important finding about this natural sealant?

Novel biomimetic materials From the material perspective, what would you do? As an engineer who has some knowledge about cells, what would you add to your design?

Flow 1.Which cells of the vessel directly experience the shear force generated by flow? 2.Which intracellular organelle transmit the shear force? 3.Why is it important to test endothelial cell adhesion under flow?

Take home message 1.Mechanical property of the graft  compliance with good burst strength 2.Biocompatibility 3.Ability of cells to maintain their normal function on a synthetic graft as on their native one 4.Good endothelial cell retention after flow  indicative of a good adhesion under hemodynamic environment