Abstract
Bone regeneration, following fracture, relies on autologous and allogenic bone grafts. However, majority of fracture population consists of older individuals with poor quality bone associated with loss and/or modification of matrix proteins critical for bone formation and mineralization. Allografts suffer from same limitations and carry the risk of delayed healing, infection, immune rejection and eventual fracture. In this work, we apply a synergistic biomimetic strategy to develop matrices that rapidly form bone tissue - a critical aspect of fracture healing of weight bearing bones. Collagen matrices, enhanced with two selected key matrix proteins, osteocalcin (OC) and/or osteopontin (OPN), increased the rate and quantity of synthesized bone matrix by increasing mesenchymal stem/stromal cell (MSC) proliferation, accelerating osteogenic differentiation, enhancing angiogenesis and showing a sustained bone formation response from MSC obtained from a variety of human tissue sources (marrow, fat and umbilical cord). In vivo assessment of OC/OPN mineralized scaffolds in a critical sized-defect rabbit long-bone model did not reveal any foreign body reaction while bone tissue was being formed. We demonstrate a new biomimetic strategy to rapidly form mineralized bone tissue and secure a sustained bone formation response by MSC from multiple sources, thus facilitating faster patient recovery and treatment of non-union fractures in aging and diseased population. Acellular biomimetic matrices elicit bone regeneration response from MSC, obtained from multiple tissue sources, and can be used in variety of scaffolds and made widely available.
Highlights
New promising solutions for bone reconstruction have been developed due to the increased clinical demand for tissue engineered bone[1]
The capacity of the OC/ OPN-enhanced collagen gels to promote BM mesenchymal stem/stromal cell (MSC) proliferation is shown in Fig. 2b,c for cells cultured using Dulbecco’s Modified Eagle Medium (DMEM) + 10% FBS and osteogenic medium
After 15 days, Bone marrow mesenchymal stem/stromal cells (BM MSC) were present in higher number when cultured onto OC/OPN-enhanced collagen gels than onto the control collagen gels, suggesting that the combination of OC and OPN has a significant impact in proliferation of BM MSC
Summary
New promising solutions for bone reconstruction have been developed due to the increased clinical demand for tissue engineered bone[1]. Even though materials science technology has resulted in clear improvements and breakthroughs for bone tissue engineering applications, challenges to achieve functional and mechanically competent bone growth remain[5] It lacks a carefully crafted strategy, similar to one employed in vivo, to address various aspects of forming functional load bearing bone. When investigating protein contents in osteonal versus interstitial bone tissue, our group demonstrated that, compared to older bone, OC and OPN are found in higher levels in younger bone, highlighting the potential role and/or regulation of these non-collagenous proteins in bone formation, remodeling and mineralization[7]. It is well known that the skeletal tissue is controlled by hormonal regulation, bone non-collagenous proteins trapped within bone ECM have been reported to play a critical role in regulating the normal and pathological skeletal growth and remodeling[7,10]
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