Medeiros Savi, Flavia (Queensland University of Technology )


"Introduction. Irrespective of the several scaffold designs that have been investigated in the last 30 years, the actual number of scaffold guided bone tissue engineering (SGBTE) approaches that were able to reach clinical application are few. Most of these approaches fail translation into clinical settings firstly because outcomes of scaffold design properties and host immune responses results are poorly correlated, and secondly because accurate prediction on how they will behave in humans are mostly based on lower levels of organization animal model findings. To develop a de novo understanding of the biocompatible mechanisms of SGBTE processes upon implantation of 3D printed medical grade Polycaprolactone (mPCL) scaffolds, and the prospective of exploiting novel concepts and material design innovation, requires a rigorous pre-clinical experimental demonstration of therapeutic promise in clinically relevant animal models. Over the last twelve years, our research group has trialled a number of SGBTE concepts using our established sheep animal model as a pre-clinical tool for evaluating bone tissue reconstruction. Here we provide an overview of the pre-clinical segmental bone defect studies performed by our group in the last twelve years, as well as an overview of the SGBTE concepts that were able to reach clinical applications. Methodology. Studies used 3D printed mPCL scaffolds (Osteopore International, Singapore) in combination with a variety of mediators, including autologous bone grafts, autologous and allogenic mesenchymal bone marrow precursor, platelet rich plasma, and bone morphogenic proteins. Scaffold mechanical properties have been assessed. Merino sheep aged ≥ 6years old was the animal model used for all studies. Conventional X-rays, ex-vivo biomechanical testing, Micro computed tomography (µCT), histology, immunohistochemistry, scanning electron microscopy, and histomorphometry were used to monitor healing progression. Results. A total of eighteen pre-clinical and seven clinical studies were performed in the last twelve years. All animals recovered from surgical interventions and completed the experimental period uneventfully. Using state-of-art µCT, histological, immunohistochemical, image analysis techniques and innovative quantitative analysis, these studies have led to significant understanding of the bone biology, on the biocompatible mechanisms of SGBTE during the regeneration processes, as well as, on providing new insights into mimicking the natural bone tissue regeneration environment in large animal models. These studies were paramount in the development of a pre-clinical model protocol for assessing bone regeneration in large bone defects, instrumental on the world-first patient and largest segmental bone defect to be successfully reconstructed using a mPCL scaffold (not published) and on a femoral shaft critical-sized bone defect reconstruction.
Conclusion. While a lot of effort has been invested in optimization scaffold parameters, currently, there is a growing interest with much of the focus on profiling large animal model’s bone responses to 3D printed medical devices, with further emerging evidence suggesting that the scaffold architecture is a niche where adaptative immune cells are decoding scaffold features. As such, the in vivo evaluation of the bone responses through pre-clinical large animal models is an unavoidable component of translational research and should be used to justify and establish scaffold guided tissue engineering concepts in clinical settings."


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