## 4 Discussion
The approach to reproduce and validate biomechanical tests via FEA and use these measures as a reference for further mechanical implant design modifications has been used in a very interesting study on an energy-harvesting system in an instrumented hip stem [37]. Another common application of FEA in the context of knee implants is the identification of worst-case scenarios of implant combinations, in order to perform the required pre-clinical biomechanical tests only with the implant assembly of the worst-case scenario [38]. The suggested method in this study focused on the pre-clinical testing of custom-made knee implants. The strength of the method is that pre-clinical mechanical evaluation of a custom-made implant, which is often constrained by unique design characteristics and limited supply time, could be performed solely by FEA. Such an in silico trial could support the benefit-risk analysis of a custom-made knee implant. The design of the custom-made implant and its mechanical performance can be assessed without a time-consuming biomechanical test. Thereby, potential flaws in the design and/or potential improvements can be identified and discussed with the responsible surgeons, in order to provide an optimized and safe custom-made implant for the patient. Furthermore, the method provides a quantitative evaluation of the custom-made implant, in addition to the qualitative evaluation of surgeons' and engineers' experience. The strength of the study is that the method was applied to two exemplary custom-made implants to compare in silico results with in vitro results. The study and its method have several limitations. A first limitation is that the application to two exemplary custom-made implants with only one test sample each does not validate a method. The application at these two examples aimed to vividly present the method and to show a proof of concept. A validation of the method should include a larger number of cases, which cover several different modifications. Nevertheless, the proposed method may provide, already at this early stage, benefit to patients, since potential design flaws could be revealed. A second limitation is that different geometrical designs impair the transferability of the biomechanical test results from the reference implant to the custom-made implant. As highlighted above, the comparability of the custom-made implant and the reference implant is a prerequisite of the method. In this study, different manufacturing techniques were applied. The raw parts of the reference implants were manufactured by casting, whereby the raw parts of the custom-made implants were manufactured by additive manufacturing. Both manufacturing methods are validated and fulfill the mechanical requirements defined by the corresponding standard [39, 40], such that the manufacturing technique with respect to mechanical properties could be considered as comparable. The third and main limitation of the study and its method is that it massively underestimates the highly complex mechanical evaluation of knee implant assemblies with its multiple dependencies, which cannot be reduced to the result of one FEA quantity of interest. The method supports the assessment of the mechanical properties of a unique custom-made implant by providing a quantitative comparison to a reference implant. The decision regarding whether a design of a custom-made implant is acceptable or not is multifactorial and several additional aspects need to be considered. This also implies that in cases when the acceptance criterion of the custom-made implant is not fulfilled, it does not necessarily mean that the design is unacceptable and a potential biomechanical test or clinical application would fail. The acceptance criterion for the FEA is defined at the required load level of the corresponding standard. However, the biomechanical tests of the reference implants showed that a stepwise increase in the load does not lead to mechanical failure.