## 4 Discussion  
Unique design characteristics and limited available supply time may impede profound pre-clinical in vitro biomechanical testing of custom-made knee implants. An individual simulation of the biomechanical testing via FEA does not yield a conclusion, since an acceptance criterion for the FEA results cannot be defined in advance. For cases where the custom-made knee implant is comparable to a reference implant (in terms of intended use, design, material, bone-implant interface, and manufacturing) and a biomechanical test of this reference implant is available, this study suggests a method to draw a conclusion on the suitability of the design of a custom-made implant solely based on FEA results. The suggested method comprises six steps: (1) identification of the main potential failure mechanism and its corresponding FEA quantity of interest, (2) reproduction of the biomechanical test of the reference implant via FEA, (3) identification of the maximum value of the corresponding FEA quantity of interest at the required load level, (4) definition of this value as the acceptance criterion for the FEA of the custom-made implant, (5) reproduction of the biomechanical test with the custom-made implant via FEA, (6) conclusion, whether the acceptance criterion is fulfilled or not. The method was applied to two exemplary custom-made knee implants. It is hypothesized that the mechanical performance of these two custom-made implants can be evaluated solely by FEA. In custom-made implant 1, a geometrical modification of reference implant 1 had to be evaluated. In accordance with the suggested method, (1) mechanical fatigue was identified as the main potential failure mechanism, with tensile stress as the corresponding FEA quantity of interest, (2) the biomechanical test of reference implant 1 was reproduced by FEA, where (3) a maximum tensile stress of 1 736 MPa resulted. (4) This maximum tensile stress was defined as the acceptance criterion for the FEA of custom-made implant 1. (5) The FEA of custom-made implant 1 revealed a maximum tensile stress of 628 MPa, which (6) implied that the acceptance criterion was fulfilled. In custom-made implant 2, the taper junction from an off-the-shelf implant to a custom-made implant had to be evaluated. Therefore, (1) fretting and corrosion at the taper junction was identified as the main potential failure mechanism with micromotion as its corresponding FEA quantity of interest, (2) the biomechanical test of reference implant 2 was reproduced by FEA, where (3) a maximum micromotion of 0.0237 mm resulted. (4) This maximum micromotion was defined as the acceptance criterion for the FEA of custom-made implant 2. (5) The FEA of custom-made implant 2 revealed a maximum micromotion of 0.0206 mm, which (6) implied that the acceptance criterion for custom-made implant 2 was fulfilled. In order to validate the FEA results, both custom-made implants were manufactured and biomechanically tested. The biomechanical tests were performed according to the required standards for off-the-shelf knee implants. Both custom-made implants withstood the required mechanical loading and fulfilled the acceptance criterion. For these two examples, the hypothesis could be proven. The employment of computer modelling and simulation to evaluate the safety and efficacy of a medical product are referred to as in silico trials. Recently, in silico trials have been considered as a new methodology for the regulatory evaluation of a medical product [30]. It is our view that the use of in silico trials could augment and complement clinical in vivo studies [31; 32; 33]. Previously, FEA studies were commonly used to predict the clinical behavior of different knee implant aspects, for example, wear performance of the polyethylene inlay [34], tibial malalignment [35] or micromotion on a modular taper connection [36].