CPM Specifications Document Healthy Vertebral:

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CPM Specifications Document Healthy Vertebral: OSMSC 0078_0000, 0079_0000, 0166_000, 0167_0000 May 1, 2013 Version 1 Open Source Medical Software Corporation 2013 Open Source Medical Software Corporation. All Rights Reserved.

1. Clinical Significance & Condition Stoke is the number 4 leading cause of death in the U.S., killing more than 137,000 people a year [1]. The carotid bifurcation in the neck is the most common location of clinically significant disease. Stenosis of the proximal internal carotid artery in the carotid bulb is a major cause of stroke and hemodynamic forces are thought to play an important role in the pathogenesis of carotid atherosclerosis. Cerebral aneurysms may also form along the major arteries within the brain. If an aneurysm ruptures and subarachnoid hemorrhage occurs, risk of death is 30 to 40% and risk of severe brain damage is 20 to 30% [2]. Again, information on the hemodynamics at the major arteries deep in the brain may be important in understanding aneurysm formation. 2. Clinical Data Patient-specific volumetric image data was obtained to create physiological models and blood flow simulations. Details of the imaging data used can be seen in Table 1. See Appendix 1 for details on image data orientation. Table 1 Patient-specific volumetric image data details (mm) OSMSC ID Modality Voxel Spacing Voxel Dimensions Physical Dimensions R A S R A S R A S 0078_0000 MR 0.4297 0.4297 1.000 512 512 172 220.01 220.01 172.00 0079_0000 MR 0.4297 0.4297 1.000 512 512 172 220.01 220.01 172.00 0166_0000 MR 0.4297 0.4297 1.000 512 512 172 220.01 220.01 172.00 0167_0000 MR 0.4297 0.4297 1.000 512 512 172 220.01 220.01 172.00 Available patient-specific clinical data collected can be seen in Table 2. Table 2 Available patient-specific clinical data OSMSC ID Age Gender 0078_0000 31 F 0079_0000 25 M 0166_0000 23 F 0167_0000 24 F 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 2

3. Anatomic Model Description Anatomic models of the vertebral arteries were created using customized SimVascular software (Simtk.org) and the image data described in Section 2. See Appendix 2 for a description of modeling methods. See Table 3 for a visual summary of the image data, paths, segmentations and solid model constructed. Table 3 Visual summary of image data, paths, segmentations and solid model. OSMSC ID Image Data Paths Paths and Segmentations Model OSMSC0078 sub 0000 Age: 31 OSMSC0079 sub 0000 Age: 25 Gender: M OSMSC0166 sub 0000 Age: 23 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 3

OSMSC0167 sub 0000 Age: 24 Details of anatomic models, such has number of outlets and model volume, can be seen in Table 4. Table 4 Anatomic Model details OSMSC ID Inlets Outlets Volume (cm 3 ) Surface Area (cm 2 ) Vessel Paths 2-D Segmentations 0078_0000 2 12 5.01285 70.458 12 401 0079_0000 2 15 5.16186 73.6133 16 379 0166_0000 2 14 4.27911 58.7013 15 329 0167_0000 2 9 5.726374 71.61265 10 235 4. Physiological Model Description In addition to the clinical data gathered for this model, several physiological assumptions were made in preparation for running the simulation. See Appendix 3 for details. 5. Simulation Parameters & Details 5. 1 Simulation Parameters See Appendix 4 and the peer-reviewed publication featuring these models [3] for information on the physiology and simulation specifications. Solver parameters can be seen in Table 5. Table 5 Solver Parameters OSMSC ID Time Steps per Cycle Time Stepping Strategy 0078_0000 1000 Fixed step - 2 0079_0000 1000 Fixed step - 2 0166_0000 1000 Fixed step - 2 0167_0000 1000 Fixed step - 2 5. 2 Inlet Boundary Conditions Vertebral blood flow waveforms obtained and scaled from literature to be prescribed at the inlets of the computational fluid dynamics (CFD) models (see Figure 1 for total inflow for the model). See Table 6 for more inflow details. 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 4

Table 6 Inflow details from waveforms seen in Figure 1 OSMSC ID Period (sec) Mean Flow (L/min) Profile Type inflow inflow_2 0078_0000 1.00 0.1260 0.0864 parabolic 0079_0000 1.00 0.0498 0.0279 parabolic 0166_0000 1.00 0.0598 0.0574 parabolic 0167_0000 1.00 0.1260 0.0864 parabolic Figure 1 Inflow waveforms in L/min 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 5

5. 3 Outlet Boundary Conditions Resistances boundary conditions were used at the outlets. A total resistance was calculated and distributed amongst the outlets by assuming all outlets act in parallel with values inversely proportional the outlet area. A Mean arterial pressure of 115 mmhg was assumed for these models. See the published journal article featuring these simulations [3] for more details on boundary condition calculations and Exhibit 1 for the applied resistance values. 6. Simulation Results Simulation results were quantified for the last cardiac cycle. Paraview (Kitware, Clifton Park, NY), an opensource scientific visualization application, was used to visualize the results. A volume rendering of velocity magnitude for three time points during the cardiac cycle can be seen in Table 8 for each model. Table 7 Volume rendering velocity during max flow, mid-cycle, and min flow. OSMSC ID Max Flow Mid-Cycle Min Flow OSMSC0078 sub 0000 Age: 31 OSMSC0079 sub 0000 Age: 25 Gender: M 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 6

OSMSC0166 sub 0000 Age: 23 OSMSC0167 sub 0000 Age: 24 Surface distribution of time-averaged blood pressure (TABP), time-averaged wall shear stress (TAWSS) and oscillatory shear index (OSI) were also visualized and can be seen in Table 8. Table 8 Time averaged blood pressure (TABP), time-average wall shear stress (TAWSS), and oscillatory shear index (OSI) surface distributions OSMSC ID Time Averaged Pressure TAWSS OSI OSMSC0078 sub 0000 Age: 31 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 7

OSMSC0079 sub 0000 Age: 25 Gender: M OSMSC0166 sub 0000 Age: 23 OSMSC0167 sub 0000 Age: 24 7. References [1] American Stroke Association, "Impact of," 6 March 2012. [Online]. Available: http://www.strokeassociation.org/strokeorg/aboutstroke/impact-of- Stroke_UCM_310728_Article.jsp#.T3tvM6t8B8E. [Accessed 3 April 2012]. [2] American Stroke Association, "What You Should Know About Cerebral Aneurysms," 22 June 2011. [Online]. Available: http://www.strokeassociation.org/strokeorg/aboutstroke/typesofstroke/what-you-should- Know-About-Cerebral-Aneurysms_UCM_310103_Article.jsp#.T3tweqt8B8E. [Accessed 3 April 2012]. 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 8

[3] M. D. Bockman, A. P. Kansagra, S. C. Shadden, E. C. Wong and A. L. Marsden, "Fluid Mechanics of Mixing in the Vertebrobasilar System," Cardiovascular Engineering and Technology, vol. 3, no. 4, pp. 450-461, 2012. 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 9

Exhibit 1: Simulation Resistance Values Table 9 Resistance Values for 0078_0000 in cgs units ID Face Name Rp 2 outlet_2 790696 3 outlet_3 906811 4 outlet_4 790466 5 outlet_5 978494 6 outlet_6 695135 7 outlet_7 694922 8 outlet_8 1235460 9 outlet_9 623367 10 outlet_10 615575 11 outlet_11 308851 12 outlet_12 790650 13 outlet_13 1779430 Table 10 Resistance Values for 0079_0000 in cgs units ID Face Name Rp 2 outlet_2 1607310 3 outlet_3 1608160 4 outlet_4 2698770 5 outlet_5 1302130 6 outlet_6 2658020 7 outlet_7 1607180 8 outlet_8 2657140 9 outlet_9 1302130 10 outlet_10 2657310 11 outlet_11 1607510 12 outlet_12 2033970 13 outlet_13 2034600 14 outlet_14 1811380 15 outlet_15 1802930 16 outlet_16 1291530 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 10

Table 11 Resistance values for 0166_0000 in cgs units ID Face Name Rp 2 outlet_2 843966 3 outlet_3 1041730 4 outlet_4 1721860 5 outlet_5 1318510 6 outlet_6 940024 7 outlet_7 1721970 8 outlet_8 697416 9 outlet_9 1041900 10 outlet_10 831689 11 outlet_11 2343650 12 outlet_12 1500080 13 outlet_13 934945 14 outlet_14 1721860 15 outlet_15 843745 Table 12 Resistance values for 0167_0000 in cgs units ID Face Name Rp 2 outlet_2 318401 3 outlet_3 501431 4 outlet_4 306909 5 outlet_5 526936 6 outlet_6 632448 7 outlet_7 257759 8 outlet_8 441049 9 outlet_9 526844 10 outlet_10 328771 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 11

Appendix 1. Image Data Orientation The RAS coordinate system was assumed for the image data orientation. Voxel Spacing, voxel dimensions, and physical dimensions are provided in the Right-Left (R), Anterior-Posterior (A), and Superior-Inferior (S) direction in all specification documents unless otherwise specified. 2. Model Construction All anatomic models were constructed in RAS Space. The models are generated by selecting centerline paths along the vessels, creating 2D segmentations along each of these paths, and then lofting the segmentations together to create a solid model. A separate solid model was created for each vessel and Boolean addition was used to generate a single model representing the complete anatomic model. The vessel junctions were then blended to create a smoothed model. 3. Physiological Assumptions Newtonian fluid behavior is assumed with standard physiological properties. Blood viscosity and density are given below in units used to input directly into the solver. Blood Viscosity: 0.04 g/cm s 2 Blood Density: 1.06 g/cm 3 4. Simulation Parameters Conservation of mass and Navier-Stokes equations were solved using 3D finite element methods assuming rigid and non-slip walls. All simulations were ran in cgs units and ran for several cardiac cycles to allow the flow rate and pressure fields to stabilize. 5. Outlet Boundary Conditions 5.1 Resistance Methods Resistances values can be applied to the outlets to direct flow and pressure gradients. Total resistance for the model is calculated using relationships of the flow and pressure of the model. Total resistance is than distributed amongst the outlets using an inverse relationship of outlet area and the assumption that the outlets act in parallel. 5.2 Windkessel Model In order to represent the effects of vessels distal to the CFD model, a three-element Windkessel model can be applied at each outlet. This model consists of proximal resistance (R p ), capacitance (C), and distal resistance (R d ) representing the resistance of the proximal vessels, the capacitance of the proximal vessels, and the resistance of the distal vessels downstream of each outlet, respectively (Figure 1). Figure 2 - Windkessel model 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 12

First, total arterial capacitance (TAC) was calculated using inflow and blood pressure. The TAC was then distributed among the outlets based on the blood flow distributions. Next, total resistance (R t ) was calculated for each outlet using mean blood pressure and PC-MRI or calculated target flow (R t =P mean /Q desired ). Given that R t =R p +R d, total resistance was distributed between R p and R d adjusting the R p to R t ratio for each outlet. 2013 Open Source Medical Software Corporation. All Rights Reserved. Page 13