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

项目总结 骨关节炎是一种退行性关节疾病，影响70%65岁以上的成年人，但最初的软骨损伤 通常发生在生命的早期。成年期的进行性关节退变仍在继续，因为软骨 自我修复的能力非常有限。目前修复早期软骨缺损的外科干预措施 导致低质量的组织，长期的成功有限。随着时间的推移，新的组织会降解，这会增加 暴露下面的骨头，并导致虚弱的疼痛。许多患者最终通过Total寻求缓解 关节置换以恢复活动能力和提高生活质量。然而，超过一半的关节置换患者 在美国，65岁以下的人。这些较年轻的患者预计将比植入物活得更长，并可能 在其一生中需要一次或多次翻修手术。这给医疗保健带来了沉重的负担 制度，特别是医疗保险计划。 该项目的目标是开发一种基于生物材料的有前景的方法，以解决持久的 骨科医学的挑战--需要对早期软骨缺陷进行长期治疗。这 这项工作涉及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 整个骨软骨组织，提高骨-软骨的整合度和耐久性。脚手架将被制造出来 通过3D打印，以聚合物为基础的“墨水”包括特殊的化学物质，以定位特定的生化线索，称为 多肽。这些多肽可以被设计成直接形成骨或软骨组织。墨水将在空间上 使用3D打印进行存储，在 连续构造。值得注意的是，生物活性多肽可以随着时间的推移而引入，以模拟 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特定的目标，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)对提供骨促进和软骨促进的支架做出反应 多肽。我们假设，随着时间的推移，这些多肽在空间上呈现，以模拟在 发展将促进稳定的骨软骨组织形成。第一个目标将调查如何修改 随着时间的推移，这些多肽在干细胞存在的情况下会影响它们的分化或转变， 进入骨状或软骨状状态。第二个目标将研究如何在空间上呈现这两个多肽 相同的支架引导局部干细胞分化为骨样和软骨样组织区域。建议数 该方法功能强大，因为它利用高分辨率3D打印来生产高度可调的脚手架 旨在引导骨软骨界面再生的组合物。这是长期发展的关键要求。 功能性软骨修复。这项工作将导致临床相关组织工程能力的突破 防止骨性关节炎的发病或衰弱进展的替代物。

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.