Need for heart valves with improved functionality

Though primitive measures to engineer heart valves promise to improve survival period, they come with disadvantages : 1. Coagulation 2. Mechanical instability ( to match and withstand pressure) 3.Need for heart function and support cell grow Failure to valves with 4. improved functionality ECM production and organisation Though primitive measures to engineer heart valves promise Appropriateperiod, they come with 5. to improve survival degrading nature of scaffold. disadvantages :
1. Coagulation 2. Mechanical instability ( to match and withstand pressure) 3. Failure to function and support cell grow 4. ECM production and organisation 5. Appropriate degrading nature of scaffold.

Topics to be discussed
Structure and function of heart valves: Cell types Prosthetic heart valves
Mechanical valve prosthesis: Bio prosthetic Valves:

Dynamic loading of heart valves

Loading on natural heart valve Modelling of flow dynamics

Introduction
Applications of tissue engineering in regenerative medicine range from structural tissue (eg: cartilage, bone) to complex organs (e.g., heart, liver, kidney and pancreas) . Cardiovascular tissue engineering has primarily considered blood vessels, myocardium and heart valves. This review focuses on the application of tissue engineering technology to heart valves. Conventional surgical procedures and artificial synthetic prosthetic devices offer serious complications in heart valve replacements. Each of the following, even though they offer increased survival life, has its own set of limitations . The disadvantages of mechanical heart valves include thromboemolic complication . However, a tissue-engineered valve has the ability to function as a living implant like the natural heart valves, growing and lasting a lifetime . This article focus mainly on the types of bio prosthetic valves and the methods to seed and culture cells on them.

Extra cellular matrix

It has also been emphasized that the extracellular matrix plays a critical role in the effective functioning of the valves. Its production, composition, along with the remodelling processes is critical. So, the ECM should be stimulated in such a way that they result in a valve organization similar to the native valve . It has been hypothesized that the physical strain inside the leaflets has a more dominant effect on their development than the flow over them .

Heart valves

The efficiency of the heart as a pump depends not only on the force of its contractions but also on the correct functioning of its four valves. The heart has four valves. Two of them are situated between the upper and lower chambers (atrium and ventricle) on each side of the heart, the tricuspid valve on the right and the mitral valve on the left. The other two lie at the exit of each ventricle into the two large arteries carrying blood from the heart, the pulmonary valve at the exit from the right ventricle into the pulmonary artery, and the aortic valve at the exit from the left ventricle into the aorta.

Structure of Heart valves

Together collagen, elastin, and GAGs comprise the valvular ECM. Important structures in the aortic and pulmonary valves are the cusps, commissures, and the supporting structures in the aortic and pulmonary roots. The key components of the mitral and tricuspid valves , are the leaflets, commissures, annulus, chordate tendineae, papillary muscles, and atrial and ventricular myocardium. Cusps are cupped, or bowl shaped, segments . When blood is moving in the right direction the cusps separate widely; when blood tries to move in the opposite direction the cusps close tightly and form a watertight seal direction. Valve cusps and leaflets are sufficiently thin to be nourished predominantly by diffusion from the hearts blood hence they have only focal blood vessels and nerves . Microscopically, the heart valves have same structure and composed of three layers, (1) Ventricularis - closest to the inflow surface and rich in radially aligned elastin fibres (2) Fibrosa - closest to the outflow layer, containing predominantly circumferentially aligned, macroscopically crimped, densely packed collagen. (3) Spongiosa - located in the central part and rich in glycosoaminoglycans 6 (GAGs) and loosely packed collagen

Structure of Heart valve

Mechanical Stress:
During every cardiac cycle the leaflets undergo complex mechanical stresses (1) sheer stress due to blood flow (open valve) (2) flexture - opening and closing of valve (3) tension (closed valve). Forces acting on the wall on the macroscopic level are translated into biochemical responses at the tissue level which are transduced into VIC( Vascular Interstitial cells) response on cellular level.

Function of heart valves

The valves allow blood to pass into and out of the heart chambers in one direction only, with no backflow of blood The aortic valve allows the flow of blood from the left ventricle to the aorta during left ventricular contraction. It also prevents backward flow of blood during its relaxation. The mitral valve allows the flow of blood from the left atrium into the left ventricle during left ventricular relaxation. It also prevents leaking of blood from the left ventricle to the left atrium during left ventricular contraction. The tricuspid valve allows the flow of blood from the right atrium into the right ventricle during right ventricular relaxation. It also prevents leaking of blood from the right ventricle to the right atrium during left ventricular contraction. The pulmonary valve allows the flow of blood from the right ventricle to the pulmonary artery during right ventricular contraction. It also prevents backward flow during its relaxation.

Properties of Heart valves:

Viability Sufficient strength to withstand repetitive and substantial mechanical stress Ability to adapt and repair injury by connective tissue remodelling.
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Cell types
Generally heart valves are made up of different kinds of cells they are, Endothelial cells - They are non thrombogeneic surface cells that control inflammatory and immune reactions Vascular interstitial cells (VIC) - They are responsible for stability and integrity of valves and involved in synthesis and remodelling of valve ECM Nerve cells - Their role is not clearly known. The valve leaflets contract in response to a variety of neurotransmitters Smooth muscle cells (SMC) - In the valves they are present in very low concentration

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Prosthetic heart valves

Currently used heart valve prostheses can be divided into two basic groups, Mechanical prostheses Biological prostheses

Mechanical valve prosthesis: It provide good structural durability but also have the risk of prosthetic valve endocarditic and high rates of thromboemolic complication caused by their nonphysiological surface and flow abnormalities. Anticoagulation therapy is needed for those patients for entire life which causes spontaneous bleeding and embolism; particularly patients aged 70 years . Hence bio prosthetic heart valves came into existence.

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Bio prosthetic Valves: There are three types of bio prosthetic valves are available: Porcine xenograft valves and bovine pericardial valves ( implants derived from species other than human ), Allograft valves ( homograft- derived from humans other than patients ), Auto graft (derived from autologous patients tissue ). The advantages : Xenograft are chemically crosslinked which inhibits autolysis, enhances mechanical stability, creating possibility of having valves of different sizes, risk of thromboembolic complication is much lower. Due to chemical pre treatment they differ from native valves in their closing and opening behaviour that is xenografts were stiffer in radial manner whereas less stiff in circumferential manner compared to native porcine valves. The disadvantages : The durability of the valve is much lower, structural failure is strongly age limited that is xenografts are suitable for elders more than children and young adults.

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Examples of heart valve prostheses: (A) Mechanical heart valve (Medtronic) including sewing ring (B) Biological heart valve (non-living fixed tissue) surrounded by a sewing ring. (C) Living, tissue engineered trileaflet heart valve based on human marrow stromal cells .

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Dynamic loading on Heart Valves

EFFECT OF BLOOD FLOW

Systolic and diastolic pressures lead to tensile and compressive stress development on the valves. Change in bending nature of the valve. This is due to change in shear stress and pressure load Blood flow also varies on the inward and outward sides of the heart valves Blood flow on the ventricularis side UNIDIRECTIONAL AND PULSATILE Blood flow on the fibrosa side SLOWER AND OSCILLATORY
DATAS :
SYSTOLE VALVE OPEN ZERO PRESSURE GRADIENT DIASTOLE VALVE CLOSED 80 mmHg PRESSURE GRADIENT SHEAR STRESS ACTING ON VALVE SURFACE l 30-1500 dynes/cm sq.

EFFECT ON ENDOTHELIAL CELLS OF HEART VALVE

Valvular Endothelial Cells Valvular Interstitial Cells Dynamic loading induces the formation of ECM by VICs. During this process there will be deposition of : 1.Collagen 2. GAGs. This was confirmed with the execution of Ross Operation. Alignment of VECs perpendicular to flow direction

VORTEX FORMATION Sinus of Valsalva

vortex formation harmony with the aortic sinus and its curved geometry provides a closure mechanism for the aortic Valve. NOTE: Velocity profile, time course of blood flow and magnitude of the peak velocity

 Vortex formation Eddying motion deceleration of blood flow stimuli for vave closure

Modelling of Flow Dynamics

Flow based deformation measurement

Local tissue strains volumetric changes of heart valves

Flow based deformation measurement - Apparatus

Fluid injected inside upper chamber valves deform signal recorded fluid enters lower chamber valves return to original shape corresponding signal recorded

Mechanism of valve closure

Scaling levels
A single scaling level promises bulk properties but effective functioning not proved. Various levels:
1. Molecular level laser focusing on collagen 2. Cellular level * continuum * fluid and solid 3. Tissue level Anisotropic, non-linear properties of tissues. 4. Organ level physiclal examinations