(I-360) A bioengineered scaffold regulates endogenous stem cells to synergistically augment BMP-2-drived bone regeneration

Introduction:: Recent Bone morphogenetic protein-2 (BMP-2) containing biomaterial scaffolds are becoming widely adopted strategies in treating bone defects. Nevertheless, it has been well documented that delivery of supraphysiological doses of BMP-2 is fraught with risks, including heterotopic mineralization, osteolysis, infection, and potentially life-threatening inflammation/swelling. Hence, it is imperative to design effective treatment approaches to reduce the therapeutic dosing of BMP-2 and, thus, side effects. Considerable advances have been made to regenerate bone tissue using endogenous Mesenchymal stem cells (MSCs). One main reason for the low BMP-2 efficacy for bone regeneration can be attributed to the limited availability of endogenous MSCs at the bone defect site. Hence, it has been postulated that the augmentation of MSC recruitment at the bone defect site by presenting factors on implantable scaffold would synergistically promote BMP-2-mediated bone formation. During the process of bone regeneration, integrins play a critical role in anchoring cells to the surrounding extracellular matrix (ECM), mediating cell migration to their destined positions. Therefore, in this study, we propose to design an integrin-regulated bioengineered scaffold to improve the endogenous MSC recruitment and synergistically amplify bone regeneration achieved by BMP-2.


Materials and Methods:: Using One-Bead One-Compound (OBOC) technology, we identified a potent ligand, LLP2A, targeting integrin α4β1. Binding affinity and functions of LLP2A on MSCs were examined. The bioengineered bone scaffolds were constructed by conjugating LLP2A onto the collagen-based bony scaffolds via a collagen-binding peptide SILY, subsequently loaded BMP-2. The functions of LLP2A-modified, BMP-2-loaded collagen scaffold on MSCs were examined in vitro. The bone formation the LLP2A-modified, BMP-2-loaded collagen scaffold was evaluated in a rat calvarial defect model.


Results, Conclusions, and Discussions:: LLP2A showed strong binding affinity to MSCs derived from different types of tissue. The LLP2A-modified, BMP-2-loaded collagen scaffold significantly improved MSC adhesion, migration, and osteogenic differentiation. At week 2 after implantation, the LLP2A-modified, BMP-2-loaded collagen scaffold significantly improved MSC recruitment comparing to the BMP-2-load collagen scaffold without LLP2A modification. At week 4 after implantation, the LLP2A-modified, BMP-2-loaded collagen scaffold significantly improved bone regeneration comparing to the BMP-2-load collagen scaffold without LLP2A modification.
The proposed multi-disciplinary approach in developing a novel bone regeneration scaffold integrates principles and technologies from biomaterial engineering, bone developmental biology, stem cell biology, and ECM biology, and could significantly advance our knowledge in understanding the synergistic function of integrin activation and BMP-2 signaling in modulating bone regeneration. This study will lead to the development of an innovative, safe, and effective BMP-2 based collagen scaffold. This multifunctional bioengineered scaffold is based on a clinical-grade medical product and pose significant potential for clinical translation in treating bone defects.


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