*2.2. Methodology*

The whole design chain is described through the flowchart in Figure 1: starting from the CT scan of the sheep skull, the Region of Interest (ROI) was then identified, and the bone surface acquired. 

**Figure 1.** Schematic overview of the complete procedure for designing and producing titanium cranial prostheses.

The CAD reconstruction of the bone region (where the defect had to be intentionally created) represented the starting point for the design of the prosthesis geometry that, in turns, was the input data for the manufacturing process design by means of an FEbased approach. Prostheses were then manufactured—using both the SPF and the SPIF process—according to the results of the numerical simulations and finally implanted.

The starting point, after the CT scan, was the Digital Imaging and COmmunications in Medicine (DICOM) manipulation to obtain the 3D model of the skull. Figure 2 shows a typical overview resulting from the imported DICOM files into a dedicated software together with the reconstruction of the skull volume (in the bottom right corner). ‐

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‐ **Figure 2.** Schematic overview of the imported DICOM files and the resulting 3D skull volume reconstruction: (**a**) axial slice, (**b**) sagittal slice, (**c**) coronal slice and (**d**) 3D volume.

‐ This volume was then exported in the Standard Triangulation Language (STL) format. The data, represented by a point cloud, were subsequently imported and processed with a CAD software. When required, these points were divided into significant groups and, if necessary, filtered. However, the goal was to obtain a virtual model of the portion of the skull on which the prosthesis had to be implanted (ROI), fundamental for the virtual modelling of the defect to be intentionally created. Therefore, from this point, only the surface correspondent to the ROI was considered for subsequent manipulation.

‐ ‐ An elliptical damage geometry was defined, characterized by the dimension of the largest and smallest axes equal to 34 mm and 28 mm, respectively. The identification of the damaged zone, under the advice of the surgeon, was conducted by taking as landmarks four points: points 1 and 2 identify an area immediately adjacent to the point of attachment of the nuchal tendons to the skull, whereas points 3 and 4 identify the sagittal plane. In this way, the prosthetic geometry (also elliptical) was characterized by such a positioning that its major axis will be oriented according to the just-defined sagittal plane, and the lower point is located near the point 4, as reported in Figure 3.

‐ **Figure 3.** Position of the nuchal tendon attachment points on the skull, the 4 landmarks and representation of both the defect and the prosthetic geometry: attachment of the nuchal tendons (points 1 and 2), sagittal plane (points 3 and 4).

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Subsequently, to define the CAD model of the prosthesis, the analytical surfaces close to the ROI were reconstructed starting from the obtained points. Figure 4 shows the reconstructed surface geometry compared with the original point cloud (red mesh) to verify the accuracy of the whole routine. ‐

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**Figure 4.** (**a**) Lateral view and (**b**) top view of the reconstructed analytical surface of the ROI and the original portion of the skull (red mesh) including the ROI.

The prosthesis geometry was designed as elliptical by enlarging the value of the main axes from the elliptical damage up to 42 mm and 36 mm. The final 3D model of the prosthesis was obtained by making a thickening of this surface.

‐ The approach of skull geometry reconstruction was also used to create a customized "guiding mask", therefore perfectly respectful of bone geometry, to guide the surgeon during the intentional defect creation, and also to make the prosthesis positioning highly accurate. Since this mask was made on the specific anatomy of the skull, it minimized the error of positioning by the surgeon: in fact, being the position of the mask completely univocal with respect to the cranial case, such an approach made the operations of generating the damage highly accurate and less affected by positioning errors. Figure 5 shows the guiding mask and its position on the skull together with the geometry of the defect.

**Figure 5.** Geometry and positioning of the guiding mask on the skull with respect to the 4 landmarks and to the defect geometry: attachment of the nuchal tendons (points 1 and 2), sagittal plane (points 3 and 4).

Figure 6 shows the final geometry of the prosthesis placed on the skull using point 4 as reference. The four holes visible on the prosthesis coincided in position and size with those present on the guiding mask. The role of the mask, in addition to guiding the surgeon during the defect creation, could also help to create the holes for the implant anchorage, thus allowing the correct positioning of the implant (Figure 3).

‐ **Figure 6.** The final geometry of the prosthesis placed on the skull: attachment of the nuchal tendons (points 1 and 2), sagittal plane (points 3 and 4).
