Layer-by-Layer Nano Matrix for Growth Plate Regeneration

用于生长板再生的层层纳米基质

基本信息

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
项目类别：
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

项目摘要

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.

抽象的儿童生长板骨折是临床上的一个重大问题，尽管仅占 15-30%。儿童期骨折是生长板骨折，因为生长板决定了骨骼的长度和形状成熟的骨骼，这种类型的骨折可能会导致患者严重的生长异常，已知约1.4%。生长板骨折会导致某种类型的生长停滞，这可能是由以下原因引起的角畸形：当位于中心的病变发生时，会出现周边紊乱或纵向缩短。延伸到骨骺的血液供应，使骨髓和间充质干得以运输细胞（MSC）进入干骺端生长板，导致骨桥的形成和生长停滞。因此，修复生长板损伤的关键挑战是如何介导MSC在空间上的分化损伤部位并恢复与周围未受伤部位暂时相匹配的生长和发育目前，还没有临床批准的组织工程疗法来治疗生长板。手术是唯一可用的治疗方法，并且仅在骨桥形成后才进行。包括移除骨桥并将自体脂肪或软骨组织插入到空的空间中然而，这种手术具有很强的侵入性并且具有一定的破坏性。成功率不理想。为了克服这些限制，本提案的目标是开发一种可注射纳米基质将软骨再生因子直接放入骨折处，并通过多个功能层来控制时机我们的中心假设是我们可以开发一种逐层纳米基质（LbL-NM）来实现空间和时间控制的 SDF1 和 TGF-β1 递送以促进生长板再生。该提案的基本原理是，一旦这种可注射的 LbL-NM 被开发到空间和暂时介导小鼠间充质干细胞分化，它可以进一步开发为微创和高度我们将在更大的动物模型中测试我们的有效组织工程方法来治疗生长板骨折。通过追求两个具体目标来提出中心假设：1）开发 LbL-NM 来空间控制传递体外 TGF-β1 和 SDF1 并评估其体内生长板再生的治疗结果，以及 2) 开发 LbL-NM 以在体外控制 LbL-NM 中 TGF-β1 供应的持续时间并评估其治疗效果随着这项研究的完成，我们期望实现 LbL- 体内生长板再生的结果。 NM 实现空间和时间控制的 TGF-β1 和 SDF1 递送，以介导 MSC 分化受伤的生长板将对第一个组织的发育产生重要的积极影响。生长板愈合的工程方法。