Evaluation of Preclinical Models for Testing of Bone Tissue Engineered Constructs – Need for Optimization

Introduction:

Treatment of large bone defects and fracture non-unions requires bone replacement materials. Autologous bone grafting is the clinical gold standard, which can however only be obtained in limited amounts and associated with donor site morbidity. These challenges might be overcome by tissue engineering (TE). Although promising results have been reported, translation into clinics often fails. Lack of reproducibility in preclinical studies may be one of the reasons. Thus, we were interested to evaluate the preclinical models, which are currently used for testing of TE strategies as well as the perception of researchers and clinicians towards the models.

Methods:

We have performed a review of publications from the last 10 years in order to assess which animal models have been most frequently used. A survey addressed to both clinicians and scientists was conducted to assess the clinical need for bone TE constructs as well as the research efforts. Most importantly, researchers were asked about their satisfaction with the currently available animal models.

Results:

Literature review revealed 167 paper on in vivo studies in the field of bone TE, including 26 studies utilizing large animals and 143 studies in small animals, with rabbits and rats presenting the most commonly used species. The mean age of small animals was 19.9 weeks for rabbits, 11.7 weeks for rats and 10 weeks for mice. The localization of the bone defects varied dependent on the used animal species; generally defects in long bones were performed more often in comparison to flat bones. The majority of defects were segmental bone defects, in 74% of cases referred to as critical size defects and stabilized with variable fixation techniques. We further analyzed the results of 70 surveys (51% surgeons, 42% scientist, 7% clinical scientists), which largely confirmed a great clinical need for TE constructs but also a positive perceptions of all participants towards the future clinical application of TE. Nevertheless, most of the polled individuals highlighted the need for optimization of preclinical models and particularly limitations when it comes to translation of results to the clinical situation (77% of surgeons; 89% of scientists). No clear trends were detected with regards to the preclinical model leading to most satisfying results despite the trend that scientists were generally more satisfied with large animal models compared to small animal models.

Discussion:

Both, results of literature review and the survey reveal the lack of standardized methods. Moreover, despite the affirmed clinical need as well as a very positive perception of clinicians towards the use of TE, the results indicate a critical need to optimize preclinical models and in particular improve translational aspects of the models. A consensus in the field on few very defined models should be reached.