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See detailDeciphering the combined effect of bone morphogenetic protein 6 (BMP6) and calcium phosphate on bone formation capacity of periosteum derived cells-based tissue engineering constructs
Ji, W.; Kerckhofs, G.; Geeroms, C. et al

in Acta Biomaterialia (2018)

Cell based combination products with growth factors on optimal carriers represent a promising tissue engineering strategy to treat large bone defects. In this concept, bone morphogenetic protein (BMP) and ... [more ▼]

Cell based combination products with growth factors on optimal carriers represent a promising tissue engineering strategy to treat large bone defects. In this concept, bone morphogenetic protein (BMP) and calcium phosphate (CaP)-based scaffolds can act as potent components of the constructs to steer stem cell specification, differentiation and initiate subsequent in vivo bone formation. However, limited insight into BMP dosage and the cross-talk between BMP and CaP materials, hampers the optimization of in vivo bone formation and subsequent clinical translation. Herein, we combined human periosteum derived progenitor cells with different doses of BMP6 and with three types of clinical grade CaP-scaffolds (ChronOs® ReproBone™ & CopiOs®). Comprehensive cellular and molecular analysis was performed based on in vitro cell metabolic activity and signaling pathway activation, as well as in vivo ectopic bone forming capacity after 2 weeks and 5 weeks in nude mice. Our data showed that cells seeded on CaP scaffolds with an intermediate Ca2+ release rate combined with low or medium dosage of BMP6 demonstrated a robust new bone formation after 5 weeks, which was contributed by both donor and host cells. This phenomenon might be due to the delicate balance between Ca2+ and BMP pathways, allowing an appropriate activation of the canonical BMP signaling pathway that is required for in vivo bone formation. For high BMP6 dosage, we found that the BMP6 dosage overrides the effect of the Ca2+ release rate and this appeared to be a dominant factor for ectopic bone formation. Taken together, this study illustrates the importance of matching BMP dosage and CaP properties to allow an appropriate activation of canonical BMP signaling that is crucial for in vivo bone formation. It also provides insightful knowledge with regard to clinical translation of cell-based constructs for bone regeneration. Statement of Significance: The combination of bone morphogenetic proteins (BMP) and calcium phosphate (CaP)-based biomaterials with mesenchymal stromal cells represents a promising therapeutic strategy to treat large bone defects, an unmet medical need. However, there is limited insight into the optimization of these combination products, which hampers subsequent successful clinical translation. Our data reveal a delicate balance between Ca2+ and BMP pathways, allowing an appropriate activation of canonical BMP signaling required for in vivo bone formation. Our findings illustrate the importance of matching BMP dosage and CaP properties in the development of cell-based constructs for bone regeneration. © 2018 Acta Materialia Inc. [less ▲]

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See detailChanges in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography.
Kerckhofs, G.; Durand, M.; Vangoitsenhoven, R. et al

in Scientific Reports (2016), 6

High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 ... [more ▼]

High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 diabetes (T2DM). C57Bl/6J mice were randomly assigned for 14 weeks to either a control diet-fed (CTRL) or a high fat diet (HFD)-fed group developing obesity, hyperglycaemia and insulin resistance. The HFD group showed an increased trabecular thickness and a decreased trabecular number compared to CTRL animals. Midshaft tibia intracortical porosity was assessed at two spatial image resolutions. At 2 mum scale, no change was observed in the intracortical structure. At 1 mum scale, a decrease in the cortical vascular porosity of the HFD bone was evidenced. The study of a group of 8 week old animals corresponding to animals at the start of the diet challenge revealed that the decreased vascular porosity was T2DM-dependant and not related to the ageing process. Our results offer an unprecedented ultra-characterization of the T2DM compromised skeletal micro-architecture and highlight an unrevealed T2DM-related decrease in the cortical vascular porosity, potentially affecting the bone health and fragility. Additionally, it provides some insights into the technical challenge facing the assessment of the rodent bone structure using HR-microCT imaging. [less ▲]

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See detailCombining microCT-based characterization with empirical modelling as a robust screening approach for the design of optimized CaP-containing scaffolds for progenitor cell-mediated bone formation.
Kerckhofs, G.; Chai, Y. C.; Luyten, F. P. et al

in Acta Biomaterialia (2016), 35

Biomaterials are a key ingredient to the success of bone tissue engineering (TE), which focuses on the healing of bone defects by combining scaffolds with cells and/or growth factors. Due to the widely ... [more ▼]

Biomaterials are a key ingredient to the success of bone tissue engineering (TE), which focuses on the healing of bone defects by combining scaffolds with cells and/or growth factors. Due to the widely variable material characteristics and patient-specificities, however, current bone TE strategies still suffer from low repeatability and lack of robustness, which hamper clinical translation. Hence, optimal TE construct (i.e. cells and scaffold) characteristics are still under debate. This study aimed to reduce the material-specific variability for cell-based construct design, avoiding trial-and-error, by combining microCT characterization and empirical modelling as an innovative and robust screening approach. Via microCT characterization we have built a quantitative construct library of morphological and compositional properties of six CE approved CaP-based scaffolds (CopiOs(R), BioOss, Integra Mozaik, chronOS Vivify, MBCP and ReproBone), and of their bone forming capacity and in vivo scaffold degradation when combined with human periosteal derived cells (hPDCs). The empirical model, based on the construct library, allowed identification of the construct characteristics driving optimized bone formation, i.e. (a) the percentage of beta-TCP and dibasic calcium phosphate, (b) the concavity of the CaP structure, (c) the average CaP structure thickness and (d) the seeded cell amount (taking into account the seeding efficiency). Additionally, the model allowed to quantitatively predict the bone forming response of different hPDC-CaP scaffold combinations, thus providing input for a more robust design of optimized constructs and avoiding trial-and error. This could improve and facilitate clinical translation. STATEMENT OF SIGNIFICANCE: Biomaterials that support regenerative processes are a key ingredient for successful bone tissue engineering (TE). However, the optimal scaffold structure is still under debate. In this study, we have provided a useful innovative approach for robust screening of potential biomaterials or constructs (i.e. scaffolds seeded with cells and/or growth factors) by combining microCT characterization with empirical modelling. This novel approach leads to a better insight in the scaffold parameters influencing progenitor cell-mediated bone formation. Additionally, it serves as input for more controlled and robust design of optimized CaP-containing bone TE scaffolds. Hence, this novel approach could improve and facilitate clinical translation. [less ▲]

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