**4. Conclusions**

‐ ‐ ‐ ‐ In this study an original methodology based on a coupled mechanical and surgical approach has been proposed. The procedure combines the well assessed prosthesis reconstruction procedures, based on the conversion of DICOM imagine into CAD model, thus ensuring the proper definition of the implant geometry. The manufacturing of an innovative guiding mask can be regarded as an innovative step to ensure the correct and replicable positioning of the implant during the surgery, thus minimizing any mismatch with the per-implant bone. The respect of the bone geometry was then ensured by relying on two innovative and flexible manufacturing processes: the scans on the formed blanks demonstrated not only a high level of the geometry replicability (few hundredths of mm) but also very low deviations from the designed CAD geometry, even lower than what is achievable with alternative manufacturing approaches.

The effectiveness of the design and manufacturing chain, applied to the case study of a customized prosthesis for sheep, was finally evaluated carrying out the in vivo tests. The absence of any side effect (as evidence of the high mechanical fixation of the prosthesis on the surrounding bones) demonstrates that the full application of this methodology ensures both high accuracy and significant replicability of the results, validating the effectiveness of the whole approach.

**Author Contributions:** Formal analysis: A.C. (Alberto Crovace), A.P., A.C. (Angela Cusanno), P.G., L.D.N. and G.S.; Funding acquisition: G.P. and G.A.; Investigation: A.P., A.C. (Angela Cusanno), P.G., A.C. (Alberto Crovace) and G.S.; Methodology: G.P. and G.A.; Supervision: G.P.; Writing—original

draft: A.P., A.C. (Angela Cusanno), P.G. and G.S.; Writing—review & editing: G.P. and G.A. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Italian Ministry of University and Research through the call Proof of Concept 2018 (acronym: FORMAE-BIO), grant number POC01\_00097.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee (protocol code 654/2020 PR).

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors wish to thank Tomaso Villa for his contribution in acquiring the funds.

**Conflicts of Interest:** The authors declare no conflict of interest; the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
