Preclinical Testing of Radiopharmaceuticals for the Detection and Characterization of Osteomyelitis: Experiences from a Porcine Model

Abstract

The development of new and better radioactive tracers capable of detecting and characterizing osteomyelitis is an ongoing process, mainly because available tracers lack selectivity towards osteomyelitis. An integrated part of developing new tracers is the performance of in vivo tests using appropriate animal models. The available animal models for osteomyelitis are also far from ideal. Therefore, developing improved animal osteomyelitis models is as important as developing new radioactive tracers. We recently published a review on radioactive tracers. In this review, we only present and discuss osteomyelitis models. Three ethical aspects (3R) are essential when exposing experimental animals to infections. Thus, we should perform experiments in vitro rather than in vivo (Replacement), use as few animals as possible (Reduction), and impose as little pain on the animal as possible (Refinement). The gain for humans should by far exceed the disadvantages for the individual experimental animal. To this end, the translational value of animal experiments is crucial. We therefore need a robust and well-characterized animal model to evaluate new osteomyelitis tracers to be sure that unpredicted variation in the animal model does not lead to a misinterpretation of the tracer behavior. In this review, we focus on how the development of radioactive tracers relies heavily on the selection of a reliable animal model, and we base the discussions on our own experience with a porcine model.

Insights into Peptidoglycan-Targeting Radiotracers for Imaging Bacterial Infections: Updates, Challenges, and Future Perspectives

“…Therefore, to successfully provide valid pre-clinical data for clinical translation, the animal model should be standardized and reflect the pathogenesis of infectious disease in humans. Thus, further harmonizing the design and animal study requirements is recommended. , Furthermore, it should be considered that targeting bacteria with low metabolic activity will probably not render sufficient tracer “load” to allow for its visualization. Therefore, the correct window to employ imaging to detect or monitor infection should be considered .…”

“…However, small radiolabeled molecules with high selectivity and specificity for bacteria emerged with great potential as precise agents for non-invasive infection imaging. Despite that, their clinical translation has been limited by access and suitability to appropriate animal infection models as well as the study design that is allowed based on animal pathology or well-being. − The variability in the choice of animal model and study design has been observed across different studies, which might pose a challenge to data interpretation and reproducibility. For example, a previous study reported bacterial uptake of [ 3 H]- l -Met using lung infection models which was not observed in a study using a murine myositis model. , This inconsistency could be due to a number of factors, including the use of different bacterial strains, the number of colonies inoculated, the type of animal infection model, or the imaging time points chosen during the course of infection.…”

“…Thus, further harmonizing the design and animal study requirements is recommended. 151 , 153 Furthermore, it should be considered that targeting bacteria with low metabolic activity will probably not render sufficient tracer “load” to allow for its visualization. Therefore, the correct window to employ imaging to detect or monitor infection should be considered.…”

Choosing the right animal model for osteomyelitis research: Considerations and challenges

“…In HO research, various inoculum routes have been utilized, including arterial (brachial [ 248 ] or femoral [ 252 ] artery), intravenous (ear vein [ 253 ]) and traumatic approaches [ 245 ] ( Fig. 4 c).…”