A surprisingly poor correlation between in vitro and in vivo testing of biomaterials for bone regeneration: results of a multicentre analysis

Abstract

New regenerative materials and approaches need to be assessed through reliable and comparable methods for rapid translation to the clinic. There is a considerable need for proven in vitro assays that are able to reduce the burden on animal testing, by allowing assessment of biomaterial utility predictive of the results currently obtained through in vivo studies. The purpose of this multicentre review was to investigate the correlation between existing in vitro results with in vivo outcomes observed for a range of biomaterials. Members from the European consortium BioDesign, comprising 8 universities in a European multicentre study, provided data from 36 in vivo studies and 47 in vitro assays testing 93 different biomaterials. The outcomes of the in vitro and in vivo experiments were scored according to commonly recognised measures of success relevant to each experiment. The correlation of in vitro with in vivo scores for each assay alone and in combination was assessed. A surprisingly poor correlation between in vitro and in vivo assessments of biomaterials was revealed indicating a clear need for further development of relevant in vitro assays. There was no significant overall correlation between in vitro and in vivo outcome. The mean in vitro scores revealed a trend of covariance to in vivo score with 58 %. The inadequacies of the current in vitro assessments highlighted here further stress the need for the development of novel approaches to in vitro biomaterial testing and validated pre-clinical pipelines.

A comparative multi-parametric in vitro model identifies the power of test conditions to predict the fibrotic tendency of a biomaterial

“…Complementary, screening for biomaterials can be supported by in vitro tests. However, in vitro tests often entail a poor correlation between in vitro and in vivo 19 . By comparing test conditions in a human in vitro biomaterial study, we identified an experimental setup that closely correlates to the fibrotic response observed in animal and clinical studies.…”

“…By complementation of existing in vivo models, such an approach follows the Russell and Burch’s 3R aspect of reducing animal burden 20, 78 . However, a poor correlation between in vitro and in vivo assessments confirms a clear need for predictive in vitro biomaterial tests 19 . The inadequacy of the current in vitro assessment strengthens our comparative approach to identify predictive test conditions for the development of a novel biomaterial in vitro test platform.…”

“…In complement to those long-term in vivo studies, in vitro tests facilitate short-term screening for acute effects of blood-material interaction [ISO 10993-4:2002, Part 4]. However, as inadequate test conditions often result in a poor correlation between in vitro and in vivo 19 , it must be ensured that obtained in vitro results are not biased or even determined by the test conditions or performance of experimental setup. To achieve an in vitro test that correlates to the fibrotic response observed in vivo , our aim was to identify test conditions for the development of a predictive human in vitro test system.…”

Applications of X‐ray computed tomography for the evaluation of biomaterial‐mediated bone regeneration in critical‐sized defects

“…In addition to scaffold microstructure, high‐resolution XCT enables the assessment of newly formed bone and biomaterial degradation in animal models (Gauthier et al ., ; Jones et al ., ; van Lenthe & Müller, ; Boerckel et al ., ; Kerckhofs et al ., ; Sweedy et al ., ). Certainly, bone defect animal models remain essential for preclinical research of novel biomaterials (Hulsart‐Billström et al ., ), overcoming limitations of in vitro studies due to the reduced complexity of the environment. The microstructure, biological properties and mechanical competence of the implanted biomaterials can be then evaluated to demonstrate their ability produce bone that is comparable to the native tissue they are meant to replace, supporting load‐bearing regions.…”

“…Bone defect animal models remain essential tools for preclinical research of novel biomaterials (Pearce et al, 2007;Muschler et al, 2010;Li et al, 2015;El-Rashidy et al, 2017), overcoming limitations of in vitro studies due to the reduced complexity of the environment. Several animal models have been used to study biomaterial-mediated bone regeneration in critical-sized defects: segmental-defects and critical-sized cranial defects models in rats and mice are widely employed for the evaluation of biomaterial capability for bone regeneration (Hulsart-Billström et al, 2016). However, segmental-defect models generally require the use of internal or external fixators, thus bone regeneration is not only affected by the biomaterial action but the stiffness of such fixation device (Einhorn et al, 1984;Yang et al, 2003;Kanczler et al, 2008;Kanczler et al, 2010;Kaipel et al, 2012).…”