Layer-by-Layer Nano Matrix for Growth Plate Regeneration

用于生长板再生的层层纳米基质

• 批准号: 10373554
• 负责人: Yupeng Chen
• 金额: $ 17.85万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373554
• 关键词: 3-Dimensional; Animal Model; Architecture; Autologous; Behavior; Binding; CXCL12 gene; Cartilage; Cells; Child; Childhood; Chondrocytes; Chondrogenesis; Clinic; Clinical; Collagen Type I; Color; DNA; Deformity; Development; Drug Delivery Systems; Ensure; Epiphysial cartilage; Excision; Fatty acid glycerol esters; Fracture; Goals; Growth; Growth Factor; Growth and Development function; Health; Histology; Homing; Hypertrophy; In Vitro; Injectable; Injury; Knowledge; Lead; Length; Lesion; Life; Light; Limb structure; Location; Mature Bone; Measurement; Measures; Mediating; Mesenchymal Stem Cells; Microscopy; Mission; Mus; Nanotechnology; Nanotubes; Natural regeneration; Nature; Operative Surgical Procedures; Organism; Orthopedics; Osteogenesis; Outcome; Pathway interactions; Patients; Peripheral; Proteins; Public Health; Publishing; Reporter; Research; Shapes; Signal Transduction; Site; Structure; Surgeon; Testing; Tissue Engineering; Tissues; Treatment outcome; United States National Institutes of Health; Vascular blood supply; Work; base; bone; bone marrow mesenchymal stem cell; cartilage regeneration; cartilaginous; chemokine; density; disability; effective therapy; healing; high reward; high risk; in vivo regeneration; injured; matrilin 3; minimally invasive; nano; osteogenic; prevent; progenitor; recruit; repaired; scaffold; stem cell differentiation; stem cell migration; success

Abstract Growth plate fracture in children represents a significant problem in clinics. Although only 15-30% of all childhood fractures are growth plate fractures, because a growth plate determines the length and shape of a mature bone, this type of fracture may result in severe growth abnormalities in patients. It is known that ~1.4% of growth plate fractures result in some type of growth arrest, which can be angular deformities caused by peripheral disturbances or longitudinal shortening when centrally located lesions occur. Growth plate fractures that extend into the blood supply of the epiphysis enable the transport of bone marrow and mesenchymal stem cells (MSCs) into the metaphyseal growth plate leading to the formation of a bony bridge and growth arrest. Therefore, the key challenge to repairing a growth plate injury is how to mediate MSC differentiation spatially at the injury site and restoring a growth and development that temporally matches the surrounding uninjured cartilaginous growth plate. Currently, there is no clinically-approved tissue engineering therapy to treat growth plate fractures. Surgery is the only available treatment, and is only offered after a bony bridge has formed. It includes removing the bony bridge and inserting autologous fat or cartilage tissue into the empty space to discourage bony bridge reformation. However, this surgical procedure is very invasive and has an unsatisfactory success rate. To overcome these limitations, the objective of this proposal is to develop an injectable nano-matrix to place cartilage-regenerating factors directly into the fracture, with multiple functional layers to control the timing of drug delivery. Our central hypothesis is that we can develop a layer-by-layer nano-matrix (LbL-NM) to achieve spatially and temporally controlled SDF1 and TGF-β1 delivery for growth plate regeneration. The rationale that underlies the proposal is that once this injectable LbL-NM is developed to spatially and temporally mediate MSC differentiation in mice, it can be further developed as a minimally invasive and highly effective tissue engineering approach to treat growth plate fracture in a larger animal model. We will test our central hypothesis by pursuing two specific aims: 1) Develop an LbL-NM to spatially control the delivery of TGF-β1 and SDF1 in vitro and evaluate its treatment outcomes for growth plate regeneration in vivo, and 2) Develop an LbL-NM to control the duration of TGF-β1 supply in the LbL-NM in vitro and evaluate its treatment outcomes for growth plate regeneration in vivo. With the completion of this study, we expect to realize an LbL- NM to achieve spatially and temporally controlled TGF-β1 and SDF1 delivery to mediate MSC differentiation in an injured growth plate. This outcome would have an important positive impact on developing the first tissue engineering approach to growth plate healing.

抽象的 儿童的生长板骨折是诊所中的一个重大问题。虽然只有15-30％ 儿童骨折是生长板骨折，因为生长板决定了 成熟的骨骼，这种类型的骨折可能导致患者严重的生长异常。众所周知，〜1.4％ 生长板骨折导致某种形式的生长停​​滞，这可能是由 当发生中心病变时，周围障碍或纵向缩短。生长板骨折 延伸到骨的血液供应使骨髓和间充质茎的运输能够运输 细胞（MSC）进入形而上的生长板，导致形成骨桥和生长停滞。 因此，修复生长板损伤的关键挑战是如何在空间上介导MSC分化 伤害部位并恢复暂时与周围未受伤的增长和发展 软骨生长板。目前，没有临床批准的组织工程疗法来治疗生长 板骨折。手术是唯一可用的治疗方法，仅在骨桥形成后才提供。它 包括卸下骨桥并将自体脂肪或软骨组织插入空白处 劝阻邦迪桥审查。但是，该手术程序非常侵入性，有一个 成功率不令人满意。 为了克服这些局限 将软骨再生因子直接放入断裂中，并具有多个功能层以控制时间 药物输送。我们的中心假设是我们可以开发逐层的纳米矩阵（lbl-nm） 实现空间和临时控制的SDF1和TGF-β1的生长板再生。这 该提案的基本原理是，一旦这种注射的LBL-NM开发到空间上，并且 暂时介导小鼠中的MSC分化，它可以作为微创且高度开发 在较大的动物模型中治疗生长板骨折的有效组织工程方法。我们将测试我们的 通过追求两个具体目标：1）开发一个LBL-NM来空间控制交付 TGF-β1和SDF1在体外评估其体内生长板再生的治疗结果，2） 开发LBL-NM以控制LBL-NM体外TGF-β1供应的持续时间并评估其处理 体内生长板再生的结果。随着这项研究的完成，我们希望实现LBL- NM以空间和临时控制的TGF-β1和SDF1递送以介导MSC分化 受伤的生长板。这种结果将对开发第一组织产生重要的积极影响 生长板愈合的工程方法。