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Design and Evaluation of Ultrasound Stimulation Aided Bioreactor Configurations

超声刺激辅助生物反应器配置的设计和评估

基本信息

批准号：
7929627
负责人：
Anuradha Subramanian
金额：
$ 28.38万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-07 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929627
关键词：
3-Dimensional Applications Grants Autologous Back Biochemical Biological Biological Models Biomedical Engineering Bioreactors Cartilage Cartilage Matrix Cell physiology Cells Chemicals Chondrocytes Chondrogenesis Complex Controlled Environment Cues Cytoskeletal Modeling Cytoskeleton Degenerative polyarthritis Development Engineering Environment Evaluation Feedback Frequencies Future Generations Goals Growth Hydrostatic Pressure In Vitro Intervention Joints Laboratories Learning Lesion Life Ligaments Liver Mechanical Stimulation Mechanics Medical Morphology Muscle Natural regeneration Outcome Perfusion Phase Phenotype Physiologic pulse Play Positioning Attribute Process Property Research Retina Role Rotation Science Signal Transduction Skin Staging Stimulus Stress Surface System Technology Tendon structure Testing Tissue Engineering Tissues Trauma Ultrasonic Therapy Ultrasonic wave Ultrasonics Ultrasonography Weight Xenograft procedure articular cartilage base bioprocess bone conditioning design expectation feeding flasks improved in vitro Model novel public health relevance repaired research study response scaffold shear stress time interval vocal cord

项目摘要

DESCRIPTION (provided by applicant): Articular cartilage, the avascular tissue that covers the ends of synovial joints and provides articulating joints with a durable, weight-distributing surface, damaged by illness or trauma has little capacity for self-repair. Current interventions that include autologous or heterologous transplantation, articular resurfacing, are of limited efficacy, and in the long term, untreated lesions may result in large-scale degenerative changes and osteoarthritis. Hence bioreactor and bioprocess strategies to generate tissue-engineered articular cartilage continue to be researched, as replacement of diseased or damaged cartilage represents an important medical problem that remains unsolved. The long-term goal of our research is to design and develop bioreactors or bioprocessing units that can be used to generate engineered-tissues. An important component of our strategy to generate tissue-engineered constructs is the use of bioreactors to provide adequate stimulus to the cell-seeded scaffolds. Our objective in this R21 grant application is to develop a bioreactor that utilizes stimulation by ultrasound, and conduct a detailed study on the effect of ultrasound on chondrocytes cultured in 3-D scaffolds in vitro. We will achieve the objective of this application by pursuing the following specific aims: Specific aim 1: To develop a bioreactor that uses continuous ultrasound to enhance cartilage matrix formation and maintain chondrocyte differentiation. Specific Aim 2: To implement a feedback loop into the US-based bioreactor. Specific Aim 3: To evaluate the effects of continuous ultrasound on the morphology and cytoskeleton of chondrocytes maintained in the bioreactors under development. Public Health Relevance Statement: At the conclusion of the R21 phase of the proceed research, we expect to have designed and developed a novel US-aided bioreactor configuration that incorporates a feed-back control to provide different regimes of mechanical conditioning to engineered tissues at different stages of development. We propose that the novelty of this strategy lies with the assessment of the cellular response to ultrasound exposure and, the application of this technology to efficiently and effectively grow cells (i.e. chondrocytes) in 3D culture systems. While bioreactors based on rotation and compression are well described, much remains to be learned about bioreactors based on US stimulation. In summary, while US has been shown to impact cartilage function at the cellular level, there is still a need to better understand the effect of US stimulation of chondrocytes seeded and maintained in 3-D scaffolds, which are better representatives of chondrocytes in-vitro culture. At the completion of this research, we expect to: 1) better understand how mechanical stimulation by ultrasound influences cell activity in 3-D scaffolds and 2) better understand the complex interplay between various factors (mechanical and biochemical cues) influencing tissue formation. Finally, we expect to have developed a highly reproducible in vitro model system of chondrocyte 3D-culture that likely uses US, which will allow us to carry out a detailed examination of the mechanisms of signal transduction processes in a future R-01 application.

描述（由申请人提供）：关节软骨是覆盖滑液关节末端的无血管组织，为关节提供耐用、重量分布的表面，因疾病或创伤而受损，自我修复能力很小。目前的干预措施，包括自体或异体移植、关节表面置换，效果有限，从长远来看，未经治疗的病变可能会导致大规模退行性改变和骨关节炎。因此，用于产生组织工程关节软骨的生物反应器和生物工艺策略仍在继续研究，因为替换患病或受损的软骨是一个尚未解决的重要医学问题。我们研究的长期目标是设计和开发可用于生成工程组织的生物反应器或生物加工装置。我们生成组织工程构建体的策略的一个重要组成部分是使用生物反应器为细胞接种支架提供足够的刺激。我们在此 R21 拨款申请中的目标是开发一种利用超声波刺激的生物反应器，并详细研究超声波对体外 3D 支架中培养的软骨细胞的影响。我们将通过追求以下具体目标来实现此应用程序的目标：具体目标1：开发一种利用连续超声增强软骨基质形成并维持软骨细胞分化的生物反应器。具体目标 2：在美国生物反应器中实施反馈循环。具体目标 3：评估连续超声对正在开发的生物反应器中维持的软骨细胞的形态和细胞骨架的影响。公共卫生相关性声明：在R21阶段的研究结束时，我们期望设计和开发出一种新型的美国援助的生物反应器配置，该配置包含反馈控制，为不同发育阶段的工程组织提供不同的机械调节机制。我们认为该策略的新颖性在于评估细胞对超声暴露的反应，以及应用该技术在 3D 培养系统中高效且有效地生长细胞（即软骨细胞）。虽然基于旋转和压缩的生物反应器已得到很好的描述，但基于美国刺激的生物反应器还有很多需要了解的地方。总之，虽然超声已被证明可以在细胞水平上影响软骨功能，但仍需要更好地了解超声对接种并维持在 3D 支架中的软骨细胞的刺激效果，3D 支架是软骨细胞体外培养的更好代表。这项研究完成后，我们期望：1）更好地了解超声机械刺激如何影响 3D 支架中的细胞活动，2）更好地了解影响组织形成的各种因素（机械和生化线索）之间的复杂相互作用。最后，我们期望开发出一种高度可重复的体外软骨细胞 3D 培养模型系统，该系统可能使用 US，这将使我们能够在未来的 R-01 应用中对信号转导过程的机制进行详细检查。