Engineered osteogenic growth factors for targeted stimulation of bone regeneration

项目摘要 骨是最常移植的人体组织之一，仅次于血液。每年， 全世界进行了200万例骨移植手术，估计经济负担为50亿美元。的 对骨移植的需求大大超过了可用组织的供应，并且由于 肥胖率上升和预期寿命延长等因素。干细胞骨组织工程 支架已经成为天然骨移植物的一种有前途和可持续的替代品，但临床 这种方法的进展是有限的。骨组织工程的一个主要翻译障碍是 成骨诱导和血管化较差。这种局限性可以通过提供 生长因子，提供支持再生的关键生化线索。然而，增长因素 这些分子的多效性作用使给药复杂化，其阻碍功效并可导致 有害的毒性或病症如癌症、血管疾病和纤维化病症的发展。 我们建议通过开发一种新的生长因子来克服与生长因子管理相关的挑战。 能够安全有效地将生长因子掺入骨中的靶向蛋白质递送系统 组织工程平台利用分子工程的创新策略，我们将重新设计一种 同型二聚体促成骨和促血管生成生长因子配体/受体对， 而不是与体内的其他蛋白质相互作用。这种“正交”生长因子配体/受体对将 在2D和3D人类干细胞模型中进行生物病理学表征和功能验证，以证明 将促再生信号有效且特异性地递送至工程化细胞。我们随后将评估 我们的工程正交生长因子配体/受体对在颅面骨修复中的治疗潜力 通过系统地给予正交配体同时植入正交受体， 将包埋在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提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，这将在整个再生过程中产生巨大的影响， 工程空间除了对我们在开发下一代的工作具有重要的翻译意义之外， 第二代骨修复平台，我们的多功能方法可以很容易地扩展到其他生长因子系统 以及用于广泛医学应用的大量其它配体/受体相互作用。我们 跨学科的专家团队在蛋白质工程，计算设计，骨组织再生， 临床前干细胞治疗模型是唯一准备开拓一个新的设计模式，为开发靶向 这些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.