Engineered osteogenic growth factors for targeted stimulation of bone regeneration

用于定向刺激骨再生的工程成骨生长因子

• 批准号: 10459814
• 负责人: Warren L Grayson
• 金额: $ 19.73万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459814
• 关键词: 3-Dimensional; Address; Adipose tissue; Allogenic; Animal Model; Autologous; Biochemical; Biophysics; Blood; Blood Vessels; Bone Marrow; Bone Regeneration; Bone Tissue; Bone Transplantation; Calvaria; Cartilage; Cells; Clinical; Clinical Trials; Cues; Dangerousness; Defect; Development; Disease; Economic Burden; Engineering; Experimental Designs; FDA approved; Fatty acid glycerol esters; Financial Hardship; Generations; Growth Factor; Human; Intervention; Lead; Life Expectancy; Ligands; Malignant Neoplasms; Marrow; Mediating; Medical; Mesenchymal; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Mutate; Natural regeneration; Obesity; Organ Transplantation; Orthopedics; Osteogenesis; PDGFRB gene; Pathogenesis; Performance; Physiological Processes; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Protein Engineering; Proteins; Public Health; Regenerative Medicine; Regenerative engineering; Regenerative pathway; Regimen; Research Personnel; Scheme; Signal Transduction; Signaling Protein; System; Techniques; Technology; Therapeutic; Time; Tissue Donors; Tissue Engineering; Tissue Transplantation; Tissues; Toxic effect; Translations; Transplantation; United States; Universities; Vascular Diseases; Vascularization; Work; base; bioscaffold; bone; bone repair; craniofacial; craniofacial bone; design; diabetic ulcer; engineered stem cells; human stem cells; human tissue; implantation; innovation; interest; multidisciplinary; next generation; novel; novel strategies; osteogenic; platelet-derived growth factor BB; pleiotropism; pre-clinical; progenitor; receptor; regenerative; regenerative therapy; response; scaffold; stem cell model; stem cell therapy; stem cells; success; systemic toxicity; tissue regeneration; translational barrier

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.

项目概要 骨骼是最常移植的人体组织之一，仅次于血液。 全球范围内进行了 200 万例骨移植手术，预计财务负担达 50 亿美元。 对骨移植的需求大大超过可用组织的供应，并且由于这种差距继续扩大 肥胖率上升和预期寿命延长等因素。 支架已成为天然骨移植物的一种有前途且可持续的替代品，但临床 这种方法的进展受到了限制，这是骨组织工程的一个主要转化障碍。 成骨诱导和血管化效果较差，这一限制可以通过提供 生长因子，提供支持再生的关键生化线索。 这些分子的多效性作用使给药变得复杂，这会阻碍功效并可能导致 有害毒性或癌症、血管疾病和纤维化疾病等疾病的发展。 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 用于靶向蛋白质输送的系统，能够安全有效地将生长因子掺入骨中 利用分子工程的创新策略，我们将重新设计一个组织工程平台。 同二聚体促骨生成和促血管生成生长因子配体/受体对专门与 这种“正交”生长因子配体/受体对不会彼此相互作用，并且不会与体内的任何其他蛋白质相互作用。 在 2D 和 3D 人类干细胞模型中进行生物物理表征和功能验证，以证明 我们随后将评估向工程细胞有效且特异性地传递促再生信号。 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 通过在植入正交受体的同时全身施用正交配体- 将嵌入生物材料支架中的干细胞表达到临界尺寸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代表着巨大的进步 在分子治疗设计领域，将在整个再生过程中产生巨大影响 除了对我们下一步开发工作的重要转化意义外。 新一代骨修复平台，我们的多功能方法可以轻松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他配体/受体相互作用。 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具有独特的优势，有望开创一种新的设计范式，用于开发靶向药物 生长因子将推动组织工程和再生医学的变革性进步。