Mechanosensitive synthetic cell-regulatable hydrogels for tissue engineering

用于组织工程的机械敏感合成细胞调节水凝胶

基本信息

批准号：
10570918
负责人：
Eben Alsberg
金额：
$ 20.04万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2022-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570918
关键词：
Acceleration Address Affect Alginates Automobile Driving Biochemical Biocompatible Materials Biology Calcium Cartilage Cell Proliferation Cell Size Cell Survival Cell Transplantation Cell physiology Cells Chelating Agents Congenital Abnormality Coupled Cues Defect Development Dextrans Disease Dyes Elements Encapsulated Engineering Environment Enzymes Extracellular Matrix Fluorescence Fluorescence Microscopy Glutathione Human Hydrogels Injury Light Lipid Bilayers Mechanical Stress Mechanics Mediating Medical Membrane Mesenchymal Stem Cells Metalloproteases Microfluidics Modeling Organ Osmolar Concentration Physical Chemistry Physical environment Play Process Production Proliferating Property Proteins Reaction Reader Regulation Reporting Research Rheology Rhodamine Role Stimulus Stress Supporting Cell Swelling System Technology Testing Therapeutic Thinness Time Tissue Engineering Tissues Vesicle Work biodegradable scaffold biomaterial compatibility bioscaffold bone cell behavior cell growth constriction crosslink design disulfide bond experience extracellular healing implantation improved in vivo inhibitor interest mechanical force mechanical properties mechanical signal mechanical stimulus mechanotransduction migration physical property physical state release factor repaired replacement tissue response restoration scaffold sensor spatiotemporal synthetic biology tissue regeneration

项目摘要

Abstract There is great need for engineered functional tissues to address currently unmet medical need for replacement or restoration of damaged tissues and organs due to disease, injury and congenital defects. Biomaterial scaffolds can play a key role in engineering tissues because they not only provide mechanical support and deliver bioactive molecules and/or cells, but they also degrade to provide new space to support cell growth and extracellular matrix production. It is desirable for the scaffold to degrade in concert with the rate of new tissue formation. Scaffold degradation also dynamically affects its mechanical properties, which has been shown to regulate host and transplanted cell behaviors, such as spreading, proliferation, migration and differentiation. Although attempts have been made to predict and tailor the degradation rate of employed biodegradable scaffolds prior to implantation for specific tissue regeneration applications, it is currently difficult to control their degradation after implantation. To regulate scaffold degradation in a triggered fashion, exogenous or external stimuli, such as enzymes, pH, and light, have been employed. Few have considered forces as a trigger input. Biochemical molecules, such as enzymes secreted from hosted/transplanted cells, have already been reported in efforts to control the degradation rate of biomaterial scaffolds. However, there are still challenges regarding regulating the production amount of those molecules at a rate and level needed to match scaffold degradation profile with engineered tissue formation while providing a minimal loss in mechanical support. Therefore, dynamic regulation of the degradation of a tissue engineering scaffold via its response to its mechanical environment may allow for design of smart biomaterials that resorb as the newly formed tissue is able to support the required loads. A synthetic biology approach to create mechanosensitive synthetic cells (MSSCs) harboring mechanosensitive channels for mimicking the ability of cells to secrete biochemicals for dynamically degrading biomaterial scaffolds in response to environment mechanical signals is proposed. Synthetic cells are cell-sized lipid bilayer vesicles encapsulating cell-free expression system expressing proteins of interest. MSSCs loaded with different sized cargos will be created and their capability to release the payloads under compressive stress will be examined (Aim 1). The MSSCs will then be encapsulated in a hydrogel system for examining the capacity of external compressive stress-mediated payload release from MSSCs to regulate hydrogel degradation (Aim 2). Lastly, the capacity of external compressive stress-controlled hydrogel degradation in driving the function of hydrogel co-encapsulated cells will be examined (Aim 3). This work will create a new class of hydrogels with a distinct mechanism of mechanoresponsiveness that dynamically react to their physical environment and are anticipated to be valuable for engineering a wide range of tissues.

抽象的工程功能组织非常需要解决目前未满足的医疗需求或由于疾病，损伤和先天性缺陷而导致的组织和器官恢复。生物材料脚手架可以在工程组织中发挥关键作用，因为它们不仅提供机械支撑和提供生物活性分子和/或细胞，但它们也降解以提供新的空间来支持细胞生长和细胞外基质产生。希望脚手架与新组织的速度一起降解形成。脚手架降解也会动态影响其机械性能，这已被证明调节宿主和移植细胞行为，例如扩散，增殖，迁移和分化。尽管已经尝试预测和量身定制可生物降解的降解率在植入之前进行特定组织再生应用的脚手架，目前很难控制其植入后退化。以触发的方式，外源或外部调节脚手架退化已经采用了酶，pH和光的刺激。很少有人将力视为触发输入。已经报道了生化分子，例如托管/移植细胞分泌的酶为了控制生物材料支架的降解率。但是，关于以匹配支架降解所需的速率和水平来调节这些分子的生产量具有工程组织形成的剖面，同时提供了机械支撑的最小损失。所以，组织工程支架降解的动态调节通过其对机械的响应环境可能允许设计智能生物材料，作为新形成的组织能够吸收智能生物材料支持所需的负载。一种创建机械敏感合成细胞（MSSC）的合成生物学方法携带机械敏感的通道，以模仿细胞分泌生化物的能力提出了响应环境机械信号的生物材料支架的降解。合成细胞是细胞大小的脂质双层囊泡封装了无细胞表达系统，表达感兴趣的蛋白质。将创建装有不同尺寸的磅的MSSC，并将其释放有效载荷的能力将检查压力应力（AIM 1）。然后，MSSC将封装在水凝胶系统中检查来自MSSC的外部压力介导的有效载荷释放的能力以调节水凝胶降解（AIM 2）。最后，外部压缩应力控制水凝胶的能力将检查驱动水凝胶共同封装细胞功能的降解（AIM 3）。这项工作将创建一种新的水凝胶，具有不同的机械回应机制，可以动态反应到他们的物理环境，预计将对工程多种组织有价值。