Engineered osteogenic growth factors for targeted stimulation of bone regeneration

项目总结 骨是仅次于血液的最常见的人体移植组织之一。每年，都有超过 全球进行了200万例骨移植手术，估计经济负担为50亿美元。这个 骨移植的需求大大超过了可用组织的供应，而且缺口还在继续扩大。 这与肥胖率上升和预期寿命延长等因素有关。干细胞为基础的骨组织工程 支架已经成为天然骨移植的一种有前景和可持续发展的替代方案，但在临床上 这一方法的进展一直受到限制。骨组织工程的一个主要翻译障碍是 成骨诱导和血管化能力差。这一限制可以通过交付 生长因子，提供支持再生的关键生化线索。然而，增长因素 这些分子的多效性使给药变得复杂，这阻碍了疗效并可能导致 有害的毒性或疾病的发展，如癌症、血管疾病和纤维性疾病。 我们建议通过开发一种新的方法来克服与生长因子管理相关的挑战 靶向蛋白输送系统，可安全有效地将生长因子整合到骨骼中 组织工程平台。利用分子工程的创新策略，我们将重新设计一个 同源二聚体促成骨和促血管生成生长因子配体/受体对唯一相互作用 相互作用，而不与体内的任何其他蛋白质结合。这种“正交”的生长因子配体/受体对将 在2D和3D人体干细胞模型中进行生物物理表征和功能验证，以演示 将促进再生的信号有效而特异地传递给工程细胞。我们随后会评估 我们设计的正交生长因子配体/受体对在颅面骨修复中的治疗潜力 通过在植入正交受体的同时系统地给药正交配体- 将植入生物材料支架中的干细胞表达到临界大小的小鼠颅骨缺损模型中。 成功完成我们提案中列出的有影响力的目标将是一个巨大的进步 在分子治疗设计领域，将在整个再生过程中产生响亮的效果 工程空间。除了对我们在Next开发中的工作的重要翻译影响之外 世代骨修复平台，我们的通用方法可以很容易地扩展到其他生长因子系统 以及大量的其他配体/受体相互作用，用于广泛的医学应用。我们的 由蛋白质工程、计算设计、骨组织再生和 临床前干细胞治疗模型独一无二地准备开创一种新的设计范式，用于开发有针对性的 生长因子将推动组织工程和再生医学的变革性进展。

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.