A composite, off-the-shelf osteoinductive material for large, vascularized bone flap prefabrication

We previously described an immortalized, genetically-engineered human M esenchymal stromal cell line to generate B MP2-enriched C hondrogenic M atrices (MB-CM), which after devitalization and storage could efficiently induce ectopic bone tissue by endochondral ossification. In order to increase the efficiency of MB-CM utilization towards engineering scaled-up bone structures, here we hypothesized that MB-CM can retain osteoinductive properties when combined with an osteoconductive material. We first tested different volumetric ratios of MB-CM:SmartBone (R) (as clinically used, osteoconductive reference material) and assessed the bone formation capacity of the resulting composites following ectopic mouse implanta-tion. After 8 weeks, as little as 25% of MB-CM was sufficient to induce bone formation and fusion across SmartBone (R) granules, generating large interconnected bony structures. The same composite percentage was then further assessed in a scaled-up model, namely within an axially-vascularized, confined, ectopi-cally prefabricated flap (0.8 cm3) in rats. The material efficiently induced the formation of new bone (31% of the cross-sectional area after 8 weeks), including bone marrow and vascular elements, throughout the flap volume. Our findings outline a strategy for efficient use of MB-CM as part of a composite material, thereby reducing the amount required to fill large spaces and enabling utilization in critically sized grafts, to address challenging clinical scenarios in bone reconstruction.Statement of significanceMost bone repair strategies rely either on osteconductive properties of ceramics and devitalized bone, or osteoinductive properties of growth factors and extracellular matrices (ECM). Here we designed a composite material made of a clinically accepted osteoconductive material and an off-the-shelf tissue engineered human cartilage ECM with strong osteoinductive properties. We showed that low amount of osteoinductive ECM potentiated host cells recruitment to form large vascularized bone structures in two different animal models, one being a challenging prefabricated bone-flap model targeting challeng-ing clinical bone repair. Overall, this study highlights the use of a promising human off-the-shelf material for accelerated healing towards clinical applications.(c) 2022 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Automated summary

We developed a composite material consisting of an osteoconductive material and a tissue engineered human cartilage extracellular matrix (ECM) with strong osteoinductive properties. The low amount of osteoinductive ECM enhanced host cell recruitment and promoted the formation of large vascularized bone structures in two different animal models, including a challenging prefabricated bone-flap model. This study demonstrates the potential of this off-the-shelf human material for accelerated healing in clinical applications.