Engineered osteogenic growth factors for targeted stimulation of bone regeneration

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PROJECT SUMMARY Bone is one of the most commonly transplanted human tissues, second only to blood. Each year, there are over 2 million bone graft procedures performed worldwide, with an estimated financial burden of $5 billion. The demand for bone transplants greatly outstrips the supply of available tissue, and the gap continues to widen due to factors such as rising obesity rates and increasing life expectancy. Stem cell-based bone tissue engineering scaffolds have emerged as a promising and sustainable alternative to natural bone grafts, but clinical advancement of this approach has been limited. A major translational barrier for bone tissue engineering has been poor osteogenic induction and vascularization. This limitation can be addressed through the delivery of growth factors, which provide critical biochemical cues that support regeneration. However, growth factor administration is complicated by the pleiotropic effects of these molecules, which hinder efficacy and can lead to harmful toxicities or development of conditions such as cancer, vascular diseases, and fibrotic disorders. We propose to overcome the challenges associated with growth factor administration by developing a novel system for targeted protein delivery that will enable safe and effective incorporation of growth factors into bone tissue engineering platforms. Leveraging innovative strategies in molecular engineering, we will re-design a homodimeric pro-osteogenic and pro-angiogenic growth factor ligand/receptor pair to exclusively interact with one another and not with any other proteins in the body. This “orthogonal” growth factor ligand/receptor pair will be biophysically characterized and functionally validated in 2D and 3D human stem cell models to demonstrate potent and specific delivery of pro-regenerative signals to engineered cells. We will subsequently evaluate the therapeutic potential for our engineered orthogonal growth factor ligand/receptor pair in craniofacial bone repair by systemically administering the orthogonal ligand concurrently with implantation of orthogonal receptor- expressing stem cells embedded in a biomaterial scaffold into a critical-size mouse calvarial defect model. Successful completion of the impactful objectives laid out in our proposal will represent a tremendous advance in the field of molecular therapeutic design that will have resounding effects throughout the regenerative engineering space. In addition to the important translational implications for our work in the development of next generation bone repair platforms, our versatile approach can be readily extended to other growth factor systems as well as a vast array of other ligand/receptor interactions for a broad scope of medical applications. Our interdisciplinary team of experts in protein engineering, computational design, bone tissue regeneration, and preclinical stem cell therapy models is uniquely poised to pioneer a new design paradigm for developing targeted growth factors that will empower transformative advances in tissue engineering and regenerative medicine.