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The most difficult and complex test design for many biopolymers revolves around implantation risks. It is important not to walk into an implant study with haste and without careful planning. Indeed, in this case, failing to plan could lead to a failing test. It is important that the study is planned in sufficient detail such that all relevant information can be extracted from the study, as the implant test is usually the longest test in the biocompatibility suite, and therefore, it is imperative to have the design right up front.

The main issue with testing a biopolymer in an implant test is the absorption profile. Physical characteristics (such as form, absorption rate, metabolism characteristics, density, and surface hardness) can all influence the tissue response to the test material. Also, the choice of control articles should be matched as closely as reasonably possible to the test sample physical characteristics. This is recommended in order to allow comparison of the specific tissue reaction(s) with that of a similar material whose clinical acceptability and biocompatibility characteristics have been established to determine acceptance criteria for the test.

Another key consideration for the implant test for a biopolymer is with the implantation time points. ISO 10993‐6 states: “For absorbable materials, the test period shall be related to the estimated degradation time of the test product at a clinically relevant implantation site. When determining the time points for sample evaluation, an estimation of the degradation time shall be made.” Usually, in practice we try to estimate the absorption profile based on the specific metabolism rate and method of the material and the implant system. After this, we set three time periods: one where we first see degradation (usually between two and four weeks), second when half the sample is degraded, and third when we see a “steady state” in the sample material. A steady state is defined as a point in time where the body is no longer interacting with the material and no additional changes are happening. For example, in vivo implantation tests with a PLLA density scaffold demonstrated fast degradation in the first three weeks, after which the degradation rate progressively decreased [20]. This milestone is reached when the body has either encapsulated or otherwise dealt with the foreign material or when full degradation of the material has occurred.

As mentioned above, an appropriate control is the basis for the acceptance criteria of the test itself, making it an essential component for a relevant and applicable test system. The implantation test is set up so that the evaluation is conducted by comparing the result of the test site histopathology with the control site. Thus, if the chosen control article is a hard piece of metal or plastic that would not induce interaction with the surrounding tissues, then the comparison with the implant site of the biopolymer would probably not be favorable, leading to a higher tissue reactivity and making it look like the test material is non‐biocompatible. However, if an appropriate control is used, then the histopathological comparison of the test and control article sites can be made with confidence, and a correct understanding of the implantation risk of the material can be drawn.