Improving Solutions to Valvular Heart Disease

Team Backdoor Nash Anderson, Griffin Beemiller, Kyle Logan, Greg Olen, Blake Reller Mate 310/350 Winter Quarter 3/17/2011

Abstract In order to test the theory of modifying the material of bio-prosthetic heart valves, an experiment was conducted to determine whether elastomer films could be used as replacements for the porcine tissue in bio-prosthetic heart valves. The elastic moduli and fatigue resistance of the elastomers were tested to determine if they would be an acceptable mechanical replacement. The results were found to be inconclusive due to improper testing methods and small sample size. Background/Project Overview Valvular heart disease (VHD) is characterized by the presence of a defect or damage to one of the four heart valves. The defect or damage may be congenital or acquired. The damaged valve either becomes too narrow to open fully, preventing normal blood flow; or unable to close completely, resulting in back flow. About 5 million Americans are diagnosed with valvular heart disease each year[1]. In mild cases valvular heart disease can be treated with medication, but in most cases the valve must be replaced or repaired. Valvular repair is the best possible solution to VHD, but when a patients heart valve is severely damaged, repair is not an option. In these cases the patients valve must be replaced with a either a mechanical or a bio-prosthetic valve. Mechanical heart valves are made out of pyrolitic carbon and can last an entire lifetime, but the patient must take anticoagulant medication such as Warfarin on a daily basis. Without a frequent regimen of anticoagulant medication the valve will clot at the mechanical hinges of the valve resulting in failure. The valve hinges tend to clot due to their shape which causes turbidity of flow. Bio-prosthetic valves are the most common valvular replacement, being used in about 80% of patients today[2]. These valves are made out of pericardium tissue (often from a pig), and closely mimic the shape of actual heart valves. Because of this unique shape, these valves have a minimal turbulence of flow. Therefore bio-prosthetic valves do not require anticoagulant medication, which is why they are so popular amongst patients. The drawback to these valves is that they need to be replaced every 10-15 years due to degradation and calcification of the

pericardium tissue. The pericardium tissue degrades and calcifies because it is foreign tissue to the body, even though it is treated with chemicals to decrease this effect. Problem Statement All replacement heart valves either have a limited lifespan or require the patient to take anticoagulant medication for the remainder of their lives. The patient must choose which type of valve is less inconvenient for them. User Needs/ Current Solutions The user needs a prosthetic heart valve that will not require long term medication regimens and that will have a lifespan longer than 25 years. The valve must last long enough so it will not have to be replaced in the majority of patients. Design Requirements Bio Compatible - not incurring a toxic or detrimental immunological response. Resist blood coagulation without use of anticoagulant medication Undergo elastic shear deformation Maintain a seal that does not permit back flow Maintain elastic properties under cyclic shear load (>1.05 billion cycles)

Proposed Solution Theory Behind Solution The design of the bio-prosthetic valve has preferred flow characteristics in comparison to all mechanical valves. The only problem with the bio-prosthetic valve is the tendency of the pericardium tissue leaflets to degrade and calcify over time. A synthetic material would not degrade, therefore if a synthetic material can be found which replicates the mechanical behavior of the pericardium tissue; a valve could be designed with the flow characteristics of a bioprosthetic valve and the durability and lifetime of a mechanical valve.

How Solution Meets Design Requirements and user needs The proposed heart valve will not require the patient to be put on an anti-coagulant regimen, and will outlast bio-prosthetic heart valves. Explanation of design The pericardium tissue used in bio-prosthetic heart valves will be replaced with an artificial elastomer. The proposed heart valve will maintain the design and function of the bioprosthetic valve, but will last longer because the elastomer will not break down and calcify over time. Materials Science Hypothesis Elastomers closely resemble the mechanical properties of pericardial tissue. Therefore they are a suitable material to mimic the function of a healthy heart valve. Elastomers are chemical compounds whose molecules consist of several thousand smaller molecules called monomers linked together by covalent bonds. These monomers repeat and are linked together to form long chains. These chains have a backbone most often made up of carbon bonds, either (C-C) or (C=C). These long carbon chains are highly flexible, disordered and intertwined. The chains are flexible because rotation around (C-C) bonds allows the molecules to take up many different configurations. [3] In an elastomers normal state, it is highly disordered with a degree of high entropy. This is the preferred state of the elastomer. When the elastomer is put under tensile stress, the molecular chains are pulled into alignment and often take on aspects of a crystalline arrangement. When the chains are lined up under a load, they are at a lower disorder resulting in a lower entropy. Upon release they spontaneously return to their naturally disordered and entangled state allowing the polymer to maintain its shape.[3] Both the deformation and the subsequent recovery are time-dependent, suggesting that some part of their behavior is viscous. Elastomers show a combination of elastic and viscous behavior known as viscoelasticity. The degree of viscoelasticity is strongly dependent upon temperature and the rate of deformation, as well as such structural variables as degree of crystallinity, crosslinking, and molecular weight.

In order to be useful for various applications, elastomers must be strengthened by cross-linking the polymer chains. With a low frequency of the branching cross links, a soft rubbery material is produced. Silicones and polyurethanes can be cast this way, using low-viscosity liquid precursors with reactive end groups. If an elastomer is stretched, as shown in Figure 1, energy is stored in it. Just as in the application of a slingshot, the elastomer used in the propulsion mechanism will snap back into place after being stretched.

Figure 1: The figure (A) portrays a molecular view of an elastomer in its preferred highly disordered state with high entropy. Picture (B) shows the elastomer when stretched to become partially crystalline with aligned chains. The dots in the picture represent crosslinking between chains. 1

Materials To pick the materials for testing a CES plot from the biomaterials database was created looking for low Youngs Modulus (.8-12MPa) [2] and high Fatigue Strength. Fatigue Strength will be one of the most important factors in the decision because the material will have to withstand over 1 billion cycles. Youngs Modulus was chosen because it is closely related to Shear Modulus through the equation: Shear Modulus: G = E / [2(1+v)] v = poissons ratio = - t / = (lateral or transverse strain) / (axial strain) For elastomers v = ~ ( G = ~ .333333E) After research on availability of materials and consideration of the CES plot, shown in Figure 2, Thermo Polyurethane and PDMS were chosen for testing.

Figure 2: Biomaterials database CES plot comparing Fatigue Strength v. Youngs Modulus. A limit was set to exclude non biocompatible materials.

Thermo Polyurethane:

Figure 3: Schematic of a monomer of a polyurethane molecule. 5

Thermo Polyurethane, shown in Figure 3, is a polymer formed through step-growth polymerization. Step-growth polymerization refers to a type of polymerization mechanism in which bifunctional or multifunctional monomers react to form first dimers, then trimers, longer oligomers and eventually long chain polymers. Many of these are naturally occurring polymers but some synthetic polymers exist such as polyesters, polyamides, polyurethanes, and many more. Due

to the nature of the polymerization mechanism, a high extent of reaction is required to achieve high molecular weight. The polyurethane chain is a complex structure. Due to the presence of benzene rings, the structure has hard and soft areas within the chains. This results in a structure that will organize into stronger, less flexible areas and other areas that are weak and elastic. The stiffer areas are the result of the benzene rings from multiple chains lining up and stacking on top of each other. The weaker areas in the material are the areas where the benzene rings have not lined up, and they form a regular disordered elastomer structure. These softer areas will stretch and result in the elastic properties of polyurethane, whereas the benzene alignment results in the materials strength. When stretched, the soft areas double bonded oxygen molecule forms a hydrogen bond with a methyl from another chain within the structure, resulting in higher strength between chains. Polydimethylsiloxane (PDMS):

Figure 4: Schematic of a monomer of a PDMS molecule. 6

Silicones are inert synthetic compounds, formed through chain growth polymerization. Chain growth polymerization is when unsaturated monomer molecules add onto a growing polymer chain one at a time. The structure consists of an -O-Si-O-Si- backbone replacing the common -C-C-C-C- in carbon-based elastomers. This results in a linear polymer with lower bond angles than the common carbon backbone, making the polymer viscous. This requires the polymer chains to be crosslink in order to form silicone rubber and useful in engineering applications. In crosslinking, methyl groups are substituted by vinyl groups to form crosslinking sites between entangled chains. Crosslinked polymers have good stability of rubber properties over large temperature range of -50C to 200C. Silicones are chemically resistant and have good sealing capability. They are commonly used in biomedical applications for seals and o-rings.

Silicone chains have a simple structure with low bond angularity and evenly bonded methyl-groups that surround the chains. These molecular properties result linear molecules. Silicone molecules will thus slide past each other easily when, for example, a tensile load is applied. This is why the material results in a lower elastic modulus than that of polyurethane. Testing Objective The goal of our testing procedures was to obtain values of elastic modulus for elastomers PDMS and TPU and compare these values to those recommended for elastomers being used in this application. For elastomers, the shear modulus can be approximated to be one third of the elastic modulus. It was also an objective to observe if these values for elastic modulus would be changed after putting the samples through multiple cycles of fatigue. Design of Experiment Values for elastic modulus would be obtained using an Instron Tester. An instron tester that was more sensitive to strain would have been ideal but was unavailable. The variables in the experiment were chosen to be materials, amount of cyclic fatigue, and thickness of elastomer film. Controls included shape of the sample, temperature, and rate of deformation. These values can be seen in: Input Variables Factors: Levels Materials: PDMS and TPU Thickness: .01 in and .02 in Fatigue: 0 cycles and 8,000 cycles Fatigued Samples Samples subjected to shear bending for 8,000 cycles, a cycle being one shear bend to 90 degrees and back to 0 degrees. Controls Rate of deformation: 500mm/min Geometry of sample: Gage length: 1 inch Width: 1 inch Temperature: 25C Response Variable Elastic modulus

Expected Results For a material to be considered for the heart valve application, it must have no difference in elastic modulus between fatigued and non fatigued samples. It is expected that the PDMS elastomer will have no significant change in elastic modulus due to its ease of chains sliding past one another at low stresses, and that it will out-perform the TPU samples. Results of Test A statistical analysis of our results in terms of main effects and interactions of variables can be seen below (Figure 5).

Figure 5. Main Effects and Interaction Plots of our data generated by Minitab software.

Both of these plots show that the only factor that had a significant effect on our data was the material of the samples. When the values we obtained were compared to the recommended values for elastomers in this application, both of our materials fell short. Obtained E Values: PDMS = 0.003 MPa TPU = 0.15 MPa Recommended elastic modulus values [2] for heart valve leaflet: > .8 MPa < 12 MPa

Discussion Our results did show, as expected, that PDMS has a lower modulus than TPU, but that is as far as we are able to conclude due to lack of power in our experiment. The obtained values for the elastic modulus of the polymers did not compare closely to the recommended values for elastomeric elastic modulus2, nor the pericardial tissue values. This result is likely due to the location of the obtained slope on the stress strain diagram. Figure 6 depicts one of our experimentally obtained stress strain diagrams for TPU. As shown in the figure, the difference the location of the line results in a very different slope. This difference results in our obtained values of elastic modulus being much lower than the recommended. There are few experiments on elastomers that depict an elastic modulus from the initial slope (approx. <25% strain) which is the area in question for our application.

Figure 6: The figure above depicts one of the trials of tensile testing TPU. Line A portrays the slope that was used to obtain our value of the elastic modulus. Line B is the line that was likely used to obtain the recommended values for elastic modulus, as well as the elastic modulus values found in CES.

Due to the uncertainty of the elastic modulus values and our low sample size in testing, there is considerable room for improvement in our methods and results. A promising place to begin improving would be to establish a better foundational knowledge of he high-cycle fatigue behavior of elastomers. There is scarce information in this area since the vast majority of elastomers are not used in applications where cyclic fatigue is a factor (particularly above 1 billion cycles). It is also possible that we could have obtained more valid results by changing our test method. This would include testing more samples of each material and testing them differently.

As opposed to simple tensile tests, generation of hysteresis curves for the elastomers would yield useful information concerning cyclic elastic loading and unloading. These are obtained by measuring the force of the elastomer as it returns to its original arrangement. The hysteresis curves would yield useful information pertaining to the elastomers ability to conform back to its original formation after an applied load. Conclusions Neither PDMS nor TPU can be accepted for use as heart valve leaflets based on our findings. However, these materials should not necessarily be ruled out either. With more accurate testing tools and methods, valid elastic modulus values could have been attained, which could yield a definitive answer as to whether our samples of PDMS and TPU would exhibit acceptable mechanical properties for use in heart valves. We recommend further mechanical testing of the elastomers. Once a material is found with sufficient mechanical properties we suggest testing surface coagulation properties as well as the fluid dynamics of a prototype elastomer heart valve.

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Elastomeric Sheet Materials for Heart Valve and Other Prosthetic Implants. US Patent, July

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"Heart Disease: Heart Valve Disease." MedicineNet. 22 Feb. 2011.

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Interview with Dr. Luke Faber on February 3, 2011 "Polyurethane." Wikipedia The Free Encyclopedia. 3 Mar. 2011. Wikipedia.

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