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Bioregenerative Engineering Principles and Applications - Shu Q. Liu

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656 CARDIAC REGENERATIVE ENGINEERING

14.55. Tissue Regenerative Engineering for Ischemic Heart Disease

Kochupura PV, Azeloglu EU, Kelly DJ, Doronin SV, Badylak SF et al: Tissue-engineered myocardial patch derived from extracellular matrix provides regional mechanical function, Circulation 112:I-144–9, 2005.

Matsubayashi K, Fedak PW, Mickle DA, Weisel RD, Ozawa T et al: Improved left ventricular aneurysm repair with bioengineered vascular smooth muscle grafts, Circulation 108(Suppl 1): II219–25, Sept 2003.

Robinson KA, Li J, Mathison M, Redkar A, Cui J et al: Extracellular matrix scaffold for cardiac repair, Circulation 112(Suppl 9):I135–43, Aug 2005.

14.56. Artificial Cardiac Valves

Yoganathan AP: Cardiac valve prostheses, in Biomedical Engineering Handbook, Bronzino JD, ed, CRC Press/IEEE Press, Boca Raton, FL, 1995, pp 1847–70.

Vesely I: Heart valve tissue engineering, Circ Res 97(8):743–55, 2005.

14.57. Tissue-Engineered Cardiac Valves

Vesely I: Heart valve tissue engineering, Circ Res 97:743–55, 2005.

Stock UA, Nagashima M, Khalil PN, Nollert GD, Herden T et al: Tissue-engineered valved conduits in the pulmonary circulation, J Thor Cardiovasc Surg 119(4 Pt 1):732–40, 2000.

Sodian R, Hoerstrup SP, Sperling JS, Daebritz S, Martin DP et al: Early in vivo experience with tissue-engineered trileaflet heart valves, Circulation 102(Suppl III):22–9, 2000.

Rezai N, Podor TJ, McManus BM: Bone marrow cells in the repair and modulation of heart and blood vessels: Emerging opportunities in native and engineered tissue and biomechanical materials, Artif Organs 28(2):142–51, 2004.

Leyh RG, Wilhelmi M, Walles T, Kallenbach K, Rebe P et al: Acellularized porcine heart valve scaffolds for heart valve tissue engineering and the risk of cross-species transmission of porcine endogenous retrovirus, J Thor Cardiovasc Surg 126(4):1000–4, 2003.

Sarraf CE, Harris AB, McCulloch AD, Eastwood M: Heart valve and arterial tissue engineering, Cell Prolif 36(5):241–54, 2003.

Simon P, Kasimir MT, Seebacher G, Weigel G, Ullrich R et al: Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients, Eur J Cardiothor Surg 23(6):1002–6, 2003.

Mol A, Bouten CV, Zund G, Gunter CI, Visjager JF et al: The relevance of large strains in functional tissue engineering of heart valves, Thor Cardiovasc Surg 51(2):78–83, 2003.

Dohmen PM, Ozaki S, Nitsch R, Yperman J, Flameng W et al: Tissue engineered heart valve implanted in a juvenile sheep model, Med Sci Monit 9(4):BR97–104, 2003.

Barron V, Lyons E, Stenson-Cox C, McHugh PE, Pandit A: Bioreactors for cardiovascular cell and tissue growth: A review, Ann Biomed Eng 31:1017–30, 2003.

Breuer CK, Mettler BA, Anthony T, Sales VL, Schoen FJ et al: Application of tissue-engineering principles toward the development of a semilunar heart valve substitute, Tissue Eng 10:1725–36, 2004.

Elkins RC: Tissue-engineered valves, Ann Thor Surg 74:1434, 2002.

Hopkins RA: Tissue engineering of heart valves: Decellularized valve scaffolds, Circulation 111:2712–4, 2005.

Korossis SA, Fisher J, Ingham E: Cardiac valve replacement: A bioengineering approach, Biomed Mater Eng 10:83–124, 2000.

BIBLIOGRAPHY 657

Mayer JE Jr, Shin’oka T, Shum-Tim D: Tissue engineering of cardiovascular structures, Curr Opin Cardiol 12:528–32, 1997.

Mol A, Bouten CV, Baaijens FP, Zund G, Turina MI et al: Review article: Tissue engineering of semilunar heart valves: current status and future developments, J Heart Valve Dis 13:272–80, 2004.

Nugent HM, Edelman ER: Tissue engineering therapy for cardiovascular disease, Circ Res 92:1068–78, 2003.

Rabkin-Aikawa E, Mayer JE Jr, Schoen FJ: Heart valve regeneration, Adv Biochem Eng Biotechnol 94:141–79, 2005.

Rashid ST, Salacinski HJ, Hamilton G, Seifalian AM: The use of animal models in developing the discipline of cardiovascular tissue engineering: A review, Biomaterials 25:1627–37, 2004.

Stock UA, Vacanti JP: Tissue engineering: Current state and prospects, Annu Rev Med 52:443–51, 2001.

Stock UA, Vacanti JP, Mayer JE Jr, Wahlers T: Tissue engineering of heart valves–current aspects,

Thor Cardiovasc Surg 50:184–93, 2002.

Vesely I, Noseworthy R, Pringle G: The hybrid xenograft/autograft bioprosthetic heart valve: in vivo evaluation of tissue extraction, Ann Thor Surg 60:S359–64, 1995.

Zimmermann WH, Eschenhagen T: Tissue engineering of aortic heart valves, Cardiovasc Res 60:460–2, 2003.

Berthiaume F, Yarmush ML: Tissue engineering, in: The Biomedical Engineering Handbook, Bronzino JD ed, CRC Press, Boca Raton, FL, 1995, pp 1556–66.

Schoen FJ, Levy RJ: Founder’s Award, 25th Annual Meeting of the Society for Biomaterials, perspectives, Providence, RI, April 28–May 2, 1999. Tissue heart valves: Current challenges and future research perspectives, J Biomed Mater Res 47:439–65, 1999.

Courtman DW, Pereira CA, Omar S, Langdon SE, Lee JM et al: Biomechanical and ultrastructural comparison of cryopreservation and a novel cellular extraction of porcine aortic valve leaflets, J Biomed Mater Res 29:1507–16, 1995.

Schenke-Layland K, Riemann I, Opitz F, Konig K et al: Comparative study of cellular and extracellular matrix composition of native and tissue engineered heart valves, Matrix Biol 23:113–25, 2004.

Sodian R, Sperling JS, Martin DP, Egozy A, Stock U et al: Fabrication of a trileaflet heart valve scaffold from a polyhydroxyalkanoate biopolyester for use in tissue engineering, Tissue Eng 6:183–8, 2000.

Shi Y, Vesely I: Fabrication of mitral valve chordae by directed collagen gel shrinkage, Tissue Eng 9:1233–42, 2003.

Girton TS, Oegema TR, Tranquillo RT: Exploiting glycation to stiffen and strengthen tissue equivalents for tissue engineering, J Biomed Mater Res 46:87–92, 1999.

Grinnell F: Fibroblast biology in three-dimensional collagen matrices, Trends Cell Biol 13:264–9, 2003.

Cuy JL, Beckstead BL, Brown CD, Hoffman AS, Giachelli CM: Adhesive protein interactions with chitosan: Consequences for valve endothelial cell growth on tissue-engineering materials,

J Biomed Mater Res A 67:538–47, 2003.

Masters KS, Shah

DN,

Leinwand LA, Anseth KS: Crosslinked hyaluronan scaffolds as

a biologically

active

carrier for valvular interstitial cells, Biomaterials 26:2517–25,

2005.

 

 

Rothenburger M, Volker W, Vischer P, Glasmacher B, Scheld HH et al: Ultrastructure of proteoglycans in tissue-engineered cardiovascular structures, Tissue Eng 8:1049–56, 2002.

658 CARDIAC REGENERATIVE ENGINEERING

Rothenburger M, Volker W, Vischer JP, Berendes E, Glasmacher B et al: Tissue engineering of heart valves: formation of a three-dimensional tissue using porcine heart valve cells, ASAIO J 48:586–91, 2002.

Vesely I, Boughner DR, Leeson-Dietrich J: Bioprosthetic valve tissue viscoelasticity: Implications on accelerated pulse duplicator testing, Ann Thor Surg 60: S379–82, 1995.

Liao J, Vesely I: Relationship between collagen fibrils, glycosaminoglycans, and stress relaxation in mitral valve chordae tendineae, Ann Biomed Eng 32:977–83, 2004.

Sacks MS, Smith DB, Hiester ED: The aortic valve microstructure: effects of transvalvular pressure, J Biomed Mater Res 41:131–41, 1998.

15

VASCULAR REGENERATIVE

ENGINEERING

A

B

100 μm

Influence of vortex bloodflow on intimal hyperplasia in experimental vein grafts. Panel A shows the bloodflow pattern in a rat vein graft. Vortex flow develops in the proximal anastomotic region due to divergent geometry from the host artery to the vein graft. Panel B is a fluorescent micrograph produced from an axial specimen section from the proximal host–vein graft junction of a rat vein graft at day 10, showing intimal hyperplasia at the site of vortex bloodflow. Red: mRNA of the angiotensin II type 1 receptor. Green: smooth muscle α-actin. Blue: cell nuclei. Note that the expression of the angiotensin II type 1 receptor, which mediates proliferative cell activities, was consistent with the presence of vortex bloodflow. When the divergent geometry and vortex bloodflow were eliminated by using a mechanical engineering approach, the expression of the angiotensin II type 1 receptor, smooth muscle cell proliferation, as well as intimal hyperplasia were significantly reduced. See color insert.

Bioregenerative Engineering: Principles and Applications, by Shu Q. Liu

Copyright © 2007 John Wiley & Sons, Inc.

659

660 VASCULAR REGENERATIVE ENGINEERING

ANATOMY AND PHYSIOLOGY OF THE VASCULAR SYSTEM

Structure and Organization of Blood Vessels [15.1]

The vascular system is composed of three subsystems: arteries, capillaries, and veins. The arterial subsystem conducts oxygenated blood from the heart to peripheral tissues and consists of various generations of arteries, including elastic arteries, muscular arteries, and arterioles. Elastic arteries are defined as arteries characterized by the presence of three distinct layers, including the tunica intima, tunica media, and tunica adventitia and the presence of multiple elastic laminae in the tunica media. Aorta is the largest elastic artery, which includes two segments: the thoracic and abdominal aorta. The thoracic aorta bifurcates into the brachiocephalic artery (a short artery extending from the aorta to the right common carotid and right subclavian arteries), left common carotid artery, left subclavian artery, and intercostal arteries. The abdominal aorta bifurcates into celiac, superior and inferior mesenteric, renal, and common iliac arteries. These arteries supply blood to the peripheral organs: the common carotid arteries to the head, the subclavian arteries to the upper arms, the intercostal arteries to the chest wall, the celiac artery to the liver and stomach, the mesenteric arteries to the intestines, the renal arteries to the kidneys and adrenal glands, and the common iliac arteries to the lower abdominal organs and lower limbs. The large elastic arteries are further bifurcated into various generations of muscular arteries, which contain the three tunica layers described above, but are characterized by the presence of a single internal elastic lamina and rich smooth muscle cells in the tunica media. Smallest muscular arteries are defined as arterioles, which are connected to the capillary network.

Capillaries are the smallest blood vessels that contain a single layer of endothelial cells and a subendothelial basal lamina. Such a thin-walled structure is designed for effective transport of oxygen and nutrients from the blood to the peripheral tissue as well as transport of carbon dioxide and waste products from the peripheral tissue to the blood. Capillaries are connected to the venous system at the distal end. The venous system includes venules and small, medium-sized, and large veins. Capillary blood is converged to the venules, various generations of veins, and eventually to the largest vein, the vena cava, which conducts blood to the right atrium. The vena cava is divided into two portions: the superior and inferior vena cava. The superior vena cava collects blood from the head and upper arms, whereas the inferior vena cava collects blood from the remaining parts of the body. Each vein is composed of three layers: the tunica intima, tunica media, and tunica adventitia. While the tunica intima and adventitia are similar in structure to those of the arteries, the tunica media is considerably different. The venous tunica media contains loosely organized elastic fibers instead of multilayered elastic laminae. In addition, a vein contains a single layer of smooth muscle cells, whereas an artery contains multiple layers of smooth muscle cells.

Types and Functions of Vascular Cells [15.1]

The vascular system consists of several cell types, including the endothelial cell (EC), smooth muscle cell (SMC), and fibroblast, which reside in the extracellular matrix of the blood vessel wall. The vascular cells possess distinct structure and function. The structural and functional characteristics of each cell type are discussed as follows.

ANATOMY AND PHYSIOLOGY OF THE VASCULAR SYSTEM

661

Endothelial Cells. Endothelial cells are monolayered squamous epithelial cells, which line the blood-contacting surface of blood vessels. These cells are primarily aligned along the direction of bloodflow (Fig. 15.1). Endothelial cells express several surface molecules specific to endothelial cells, including von Willebrand factor, vascular endothelial growth factor receptor 1 (VEGFR1 or Flt-1), vascular endothelial growth factor receptor 2 (VEGFR2 or Flk-1), and factor VIII. These molecules can be used to identify endothelial cells. Endothelial cells possess a number of functions, including selective transport of plasma substances and molecules, regulation of antiand pro-anticoagulation activities, regulation of leukocyte and platelet adhesion and trans-migration, regulation of vascular contractility, and regulation of vascular cell proliferation and migration. These functions are mediated by various molecular processes and are essential for maintenance of the homeostatic state.

Endothelial Barrier Function. Endothelial cells serve as a barrier that allows free transport of lipid-soluble molecules and regulated transport of ions, glucose, amino acids, and

A

EC

EL

SMC

B

100 μm

Figure 15.1. Structure and organization of vascular endothelial cells in the rat aorta. (A) Electron micrograph of vascular endothelial and smooth muscle cells. (B) En face fluorescent micrograph of vascular endothelial cells labeled with an anti-ICAM1 antibody. EC: endothelial cell. EL: elastic lamina. SMC: smooth muscle cell.

662 VASCULAR REGENERATIVE ENGINEERING

proteins. Endothelial cells control the exchange of substances and fluids between blood and tissue. This function is the basis for maintaining the stability of a physiological environment, which is essential to cell survival and function. It is known that the endothelium is permeable to lipid-soluble molecules, water and ionic solutes, and is impermeable to plasma proteins, although a small amount of proteins are able to escape from the capillary network to the interstitial space. This selective barrier function has been studied by using radioactive and fluorescent tracers, such as 3H-water, 125I-albumin, rhodamine-albumin, and 14C-sucrose. The flux rate of each selected tracer across an endothelial membrane can be measured and used to estimate the permeability of the endothelial cells. For a selected substance and a specified tissue type, the flux rate across the endothelium depends on the concentration gradient, molecular weight and size, electrical charges, and chemical properties of the substance. Among commonly used tracers such as water, sucrose and albumin, water has highest flux rate, followed by sucrose and albumin, as shown in studies by using cultured endothelial cells.

Several endothelial transport pathways have been identified. These include the cell membrane, the plasmalemmal vesicles, the transendothelial channels, the intercellular junction pores, the receptor-mediated pathways, and the open and closed fenestrae. Certain molecules, such as water, small lipid-soluble substances, and ionic solutes, may be passively or actively transported across the endothelial membrane, intercellular junctions, transendothelial channels and other openings. Certain molecules, such as albumin and dextran, may be transported through the transendothelial channels and plasmalemmal vesicles. Other molecules, such as low-density lipoproteins, insulin, and transferrin, may be transported through the receptor-mediated pathways and endocytosis. The open fenestrae of the endothelium in some tissues may allow large molecular weight plasma proteins, except for cellular components, to escape from the capillaries.

Endothelial permeability to plasma substances depends on the state of the endothelial cells. Injured endothelial cells due to exposure to mechanical stress, such as excessive tensile stress, and chemical toxins may exhibit reduced barrier function and increase permeability. Endothelial mitosis is associated with endothelial junction leakage and an increase in endothelial permeability. An exposure to histamine in inflammatory reactions may induce endothelial cell injury or endothelial junction dilatation, leading to an increase in endothelial permeability. Biochemical regulatory factors, such as atrial natriuretic peptide, can induce an increase in endothelial permeability.

The permeability of endothelial cells varies from one organ to another. For instance, the cerebral capillaries, which form a blood–brain barrier, are less permeable to plasma substances than are capillaries in other organs. This feature is partially attributed to the presence of tighter intercellular junctions and the scarcity of transport vesicles, and is crucial to the protection of central nervous cells from exposure to harmful substances and microbiological organisms. In contrast, the renal glomerular endothelium is more permeable than that in other organs, which is attributed to the presence of fenestrae and is essential to the renal functions such as fluid filtration and clearance. Other organs, which exhibit high endothelial permeability, include the liver, glands, and bone marrow. In these organs, high endothelial permeability is necessary for facilitating the transport of enzymes and hormones. From the developmental point of view, a specified structure of endothelial cells in each organ is a result of cell differentiation based on the functional necessity. However, the identification of the determinants of cell differentiation remains a difficult task in developmental research.

ANATOMY AND PHYSIOLOGY OF THE VASCULAR SYSTEM

663

Regulation of Antiand Procoagulation Activities [15.2]. Endothelial cells participate in the regulation of blood coagulation and ular fibrinolysis, two important functions for the maintenance of the homeostatic internal environment in multicelled mammalian systems. These functions are regulated coordinately in the vascular system. The coagulation function allows rapid formation of insoluble blood plug at locations of vascular injury so that hemorrhage can be rapidly stopped. On the other hand, the anticoagulation and fibrinolytic function not only assures blood fluidity and vascular patency under physiological conditions but also prevents the spreading of coagulation activities from injured to normal blood vessels. (Characteristics of anti/procoagulation molecules are listed in Table 15.1.)

Endothelial cells regulate anticoagulation activities by expressing and secreting heparan sulfate proteoglycan (a heparin-like proteoglycan expressed in the membrane of endothelial cells), plasminogen activators (specific serine proteases that convert plasminogen into plasmin, a hydrolase capable of converting coagulant fibrin into a soluble form), and protein C (an enhancer of fibrinolysis). These factors play critical roles in the maintenance of the blood fluidity and the prevention of blood coagulation and thrombogenesis under physiological conditions.

Endothelial cells participate in the regulation of procoagulation activities in the event of vascular trauma and injury. Injured endothelial cells can express and release procoagulants such as von Willebrand factor (mediating platelet adhesion), tissue thromboplastin (a cell surface prothrombin activator that converts prothrombin to thrombin, a pivotal enzyme capable of converting soluble fibrinogen (a bloodborne glycoprotein composed of three pairs of polypeptide chains, α, β, and γ) to insoluble gel-like coagulant fibrin), leading to the activation of the coagulation cascade and the formation of solid blood plugs and thrombi. In such a coagulation process, intact endothelial cells near the injury site are able to prevent the spreading of coagulation and platelet aggregation through several mechanisms, including the release of prostaglandins, plasminogen activators, and protein C. Several factors, such as endotoxin, tumor necrosis factor, and interleukin 1, can induce a shift of the balance of coagulation activities in favor of coagulation activation. It is important to note that blood coagulation and thrombosis are considered the initial steps in the development of atherosclerosis.

Regulation of Vascular Contractility [15.3]. Endothelial cells regulate vascular contractility by secreting regulatory factors, such as endothelial cell-derived vasorelaxants and endothelial cell-derived vasoconstrictors (see Table 15.2). Endothelial cell-derived vasorelaxants, such as nitric oxide, induce rapid smooth muscle relaxation and blood vessel dilation, leading to an increase in local bloodflow. In contrast, endothelial cell-derived vasoconstrictors, such as endothelin, induce smooth muscle contraction and blood vessel constriction, leading to a decrease in local bloodflow. In a homeostatic state, vasorelaxants and vaso-constrictors are released in a coordinated manner to maintain a basal smooth muscle activity and a basal vascular tone. Endothelial cell injury or denudation may influence the release of these vasoactive molecules and, thus, influence the activity of smooth muscle cells. In general, the vasoconstrictor system is activated in response to endothelial or vascular injury. Such a reaction often contributes to proliferation of blood and vascular cells as well as to intimal hyperplasia and atherogenesis. In contrast, the activation of the vasorelaxant system results in the suppression of these pathogenic processes.

Regulation of Leukocyte and Platelet Adhesion [15.4]. Endothelial cells participate in the regulation of leukocyte activities by expressing and releasing several cytokines, such

664

TABLE 15.1. Characteristics of Selected Antiand Procoagulation Molecules*

 

 

Amino

Molecular

 

 

Proteins

Alternative Names

Acids

Weight (kDa)

Expression

Functions

 

 

 

 

 

 

Plasminogen activator

Tissue type plasminogen

562

63

Endothelial cells, skin, lung,

A serine protease that converts the

 

activator (TPA), Alteplase,

 

 

uterus

proenzyme plasminogen to

 

Reteplase, tPU

 

 

 

plasmin, a fibrinolytic

 

 

 

 

 

enzyme

Plasminogen

Microplasmin, angiostatin

810

91

Brain, liver, blood cells,

Forming plasmin, a hydrolase

 

 

 

 

kidney, testis, cornea

capable of converting

 

 

 

 

 

coagulant fibrin into a soluble

 

 

 

 

 

form

Protein C

PROC, PC, blood coagulation

461

52

Blood cells, liver, blood

Enhancing fibrinolysis and

 

factor XIV, anticoagulant

 

 

vessels, skeletal muscle

inhibiting coagulation

 

protein C, autoprothrombin

 

 

 

 

 

IIA, vitamin K-dependent

 

 

 

 

 

protein C

 

 

 

 

von Willebrand factor

Coagulation factor VIII VWF

2813

309

Endothelial cells, platelets,

Serving as an antihemophilic

 

 

 

 

bone marrow, lung, eye,

factor and mediating platelet–

 

 

 

 

kidney, skin

endothelial interaction

Tissue thromboplastin

Tissue factor (TF),

295

33

Monocytes, lymphocytes,

Interacting with coagulation factor

 

thromboplastin tissue

 

 

epidermis, brain, kidney,

VII and activating coagulation

 

factor, CD142 antigen,

 

 

heart, lung

protease cascades

 

coagulation factor III, F3

 

 

 

 

Prothrombin

Coagulation factor II, factor

622

70

 

II, F2

 

 

Fibrinogen α

FGA

866

95

Fibrinogen β

FGB

491

56

Fibrinogen γ

FGG

453

51

Ovary, liver

Forming thrombin (via

 

proteolytic cleavage), which

 

converts fibrinogen to fibrin

Leukocytes, platelets, bone

Forming fibrin (via thrombin-

marrow, brain, liver, lung,

mediated cleavage), which

ovary

participates in coagulation,

 

regulates cell adhesion,

 

spreading, and proliferation via

 

cleavage products and mediates

 

vasoconstriction and chemotaxis

 

via cleavage products

Leukocytes, platelets, bone

Forming complex with fibrinogen

marrow, brain, liver, lung,

α and γ and possessing

and ovary

identical function as

 

fibrinogen α

Leukocytes, platelets, bone

Forming complexes with

marrow, brain, liver, lung,

fibrinogen β and γ and

and ovary

possessing function identical to

 

that of fibrinogen α

*Based on bibliography 15.2.

665