Engineering Spatiotemporal Osteochondral Tissue Formation with Tunable 3D-Printed Scaffolds

使用可调谐 3D 打印支架工程设计时空骨软骨组织形成

• 批准号: 10629168
• 负责人: Lesley W Chow
• 金额: $ 19.25万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629168
• 关键词: 3D Print; Address; Adult; Affect; Age; American; BMP2 gene; Binding; Biochemical; Biocompatible Materials; Bone Marrow; Cartilage; Cartilage injury; Cell Culture Techniques; Cells; Chemistry; Chondrocytes; Chondrogenesis; Clinical; Clinical Engineering; Cues; Defect; Degenerative polyarthritis; Deposition; Development; Disease; Early treatment; Economic Burden; Engineering; Event; Fibrocartilages; Growth Factor; Healthcare Systems; Human; Implant; In Situ; In Vitro; Inferior; Ink; Intervention; Joints; Life; Location; Mechanics; Medicare; Medicine; Mesenchymal Stem Cells; Natural regeneration; Operative Surgical Procedures; Orthopedics; Osteoblasts; Osteogenesis; Outcome; Pain; Pathology; Patients; Peptides; Polymers; Proteins; Quality of life; Reaction; Repeat Surgery; Replacement Arthroplasty; Research; Resolution; Second Look Surgery; Surface; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissue constructs; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; United States; Work; adult stem cell; articular cartilage; biodegradable scaffold; bone; cartilage development; cartilage regeneration; cartilage repair; clinically relevant; debilitating pain; design; drug discovery; functional improvement; human old age (65+); improved; in vitro Model; innovation; joint destruction; joint function; knowledge integration; osteochondral tissue; osteogenic; patient mobility; peptidomimetics; prevent; programs; repaired; replacement tissue; response; scaffold; spatiotemporal; stem cell differentiation; stem cells; success

PROJECT SUMMARY Osteoarthritis is a degenerative joint disease that affects 70% of adults over age 65, but the initial cartilage injury usually occurs much earlier in life. Progressive joint degeneration during adulthood continues because cartilage has very limited ability to self-repair. Current surgical interventions to repair cartilage defects at early stages result in low quality tissue with limited long-term success. The new tissue degrades over time, which increases exposure of the underlying bone and leads to debilitating pain. Many patients ultimately seek relief through total joint replacement to regain mobility and improve quality of life. However, over half of all joint replacement patients in the United States are under age 65. These younger patients are expected to outlive their implants and may require one or more revision surgeries over their lifetime. This places a significant burden on the healthcare system, especially the Medicare program. The objective of this project is to develop a promising biomaterials-based approach that addresses a persistent challenge in orthopaedic medicine—the need for long-lasting treatments for early-stage cartilage defects. This work involves an innovative combination of 3D printing and biomaterials design to fabricate biodegradable scaffolds for functional cartilage repair. To achieve this, the scaffolds are engineered to guide regeneration of the entire osteochondral tissue to improve bone-cartilage integration and durability. Scaffolds will be fabricated by 3D printing polymer-based “inks” that include special chemistries to localize specific biochemical cues called peptides. These peptides can be designed to direct formation of bone or cartilage tissue. The inks will be spatially deposited using 3D printing to create distinct bone-promoting and cartilage-promoting regions within a continuous construct. Notably, the bioactive peptides can be introduced over time to mimic compositional changes that occur during articular cartilage development. The proposed research plan includes two specific aims designed to study how human mesenchymal stem cells (adult stem cells found in bone marrow) respond to scaffolds presenting bone-promoting and cartilage-promoting peptides. We hypothesize that spatially presenting these peptides over time to mimic events that occur during development will promote stable osteochondral tissue formation. The first aim will investigate how modifying the presentation of these peptides over time in the presence of stem cells influences their differentiation, or transition, into bone-like or cartilage-like states. The second aim will examine how spatially presenting both peptides in the same scaffold guides local stem cell differentiation into bone-like and cartilage-like tissue regions. The proposed approach is powerful because it exploits high-resolution 3D printing to produce scaffolds with highly tunable compositions designed to direct osteochondral interface regeneration. This is a key requirement for long-term functional cartilage repair. This work will lead to breakthroughs in the ability to engineer clinically relevant tissue replacements that prevent the onset or debilitating progression of osteoarthritis.

项目摘要 骨关节炎是一种退行性关节疾病，影响70%的65岁以上的成年人， 通常发生在生命的早期。在成年期进行性关节退化继续，因为软骨 自我修复的能力非常有限早期修复软骨缺损的外科干预措施 导致低质量组织，长期成功有限。新的组织会随着时间的推移而降解， 暴露下面的骨头，并导致衰弱性疼痛。许多患者最终通过全 关节置换术，以恢复活动能力和改善生活质量。然而，超过一半的关节置换患者 在美国，年龄在65岁以下。这些年轻的患者预计将超过他们的植入物， 在其一生中需要进行一次或多次翻修手术。这给医疗保健带来了沉重的负担。 特别是医疗保险制度。 该项目的目标是开发一种有前途的基于生物材料的方法， 骨科医学的挑战-需要长期治疗早期软骨缺损。这 工作涉及3D打印和生物材料设计的创新组合，以制造可生物降解的 用于功能性软骨修复的支架。为了实现这一点，支架被设计成引导再生。 整个骨软骨组织，以改善骨软骨整合和耐久性。将制作脚手架 通过3D打印基于聚合物的“墨水”，包括特殊的化学物质，以定位特定的生化线索， 缩氨酸这些肽可以被设计成指导骨或软骨组织的形成。墨水将在空间上 使用3D打印沉积，以在骨内创建不同的骨促进和软骨促进区域， 连续构造值得注意的是，可以随时间引入生物活性肽以模拟组成肽。 在关节软骨发育过程中发生的变化。 拟议的研究计划包括两个具体目标，旨在研究人类间充质干细胞如何 （骨髓中发现的成体干细胞）对支架有反应， 缩氨酸我们假设，随着时间的推移，空间呈现这些肽，以模拟发生在 发育将促进稳定的骨软骨组织形成。第一个目标将研究如何修改 这些肽在干细胞存在下随时间的呈递影响它们的分化，或转化， 变成骨样或软骨样状态。第二个目标将研究如何在空间上呈现两种肽在 相同的支架引导局部干细胞分化成骨样和软骨样组织区域。拟议 这种方法是强大的，因为它利用高分辨率3D打印来生产高度可调的支架。 设计用于指导骨软骨界面再生的组合物。这是长期的关键要求。 功能性软骨修复这项工作将导致突破的能力，工程临床相关组织 预防骨关节炎的发作或衰弱进展的替代品。