Perlecan gradients in hydrogels for spatially-defined growth factor delivery

水凝胶中的基底膜梯度用于空间限定的生长因子递送

基本信息

批准号：
9050864
负责人：
Kelsea Marie Hubka
金额：
$ 3.1万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050864
关键词：
Adult Adverse effects Amylases Binding Binding Sites Biocompatible Biocompatible Materials Biological Biological Assay Bone Morphogenetic Proteins Cells Charge Chemistry Complex Coupling Cultured Cells Deposition Development Devices Diffusion Duct (organ) structure Ductal Encapsulated Ensure Erinaceidae Evaluation Extracellular Matrix Fibroblast Growth Factor Fibroblast Growth Factor 1 Generations Glycosaminoglycans Goals Growth Factor Head and Neck Cancer Heparan Sulfate Proteoglycan Heparin Heparin Binding Growth Factor Heparitin Sulfate Human Human body Hyaluronic Acid Hydrogels Implant In Vitro Infiltration Label Laboratories Mechanics Methods Modeling Morphogenesis Morphology Natural regeneration Nature Normal Cell Normal tissue morphology Nude Rats Outcome Palliative Care Parotid Gland Particulate Pattern Phenotype Property Proteins Proteoglycan Pump Radiation Radiation therapy Rattus Recombinants Regenerative Medicine Research Research Personnel Resected Residual state Salivary Salivary Gland Tissue Salivary Glands Signal Transduction Spatial Distribution Stimulus Structure Syringes System Tissue Engineering Tissues Training Ursidae Family Vertebral column Work Xerostomia base cell behavior cell motility density directional cell experience fibroblast growth factor 10 head and neck cancer patient hyaluronate in vivo injured keratinocyte growth factor morphogens perlecan public health relevance receptor regenerative repaired response restoration salivary cell scaffold soft tissue sulfation tissue regeneration tool wound

项目摘要

DESCRIPTION (provided by applicant): Xerostomia, or dry mouth, is a common and devastating side effect of radiation therapy commonly used to treat head and neck cancer patients. No treatment currently exists to restore salivary function after radiation, and the only available therapies are palliative. Tissue engineering strategies for salivary gland regeneration enable cell encapsulation and survival, but do not fully replicate the intricate 3D patterning observed during development. 3D gradients of heparan sulfate proteoglycans (HSPGs) and heparin-binding growth factors (HBGFs) establish these patterns during development, and facilitate proper embryological and adult tissue organization and repair. Growth factor gradients within hydrogel biomaterials remain a target of tissue engineering researchers, but are rarely produced in a manner that replicates the matrix-directed action of native tissue. The goal of the research proposed herein is to establish biologically-inspired 3D gradients of covalently-bound HSPG within biologically-derived hyaluronic acid-based (HA) hydrogels, employ these to create complementary gradients of relevant HBGFs, and recapitulate the development of salivary glands to promote organized tissue regeneration. Our hypothesis is that HSPG/HBGF gradients within HA hydrogels will enable controlled, asymmetric development of morphology and phenotype of encapsulated primary human salivary cells, supporting branching morphogenesis and duct formation. In Aim 1, gradients of covalently-bound perlecan domain 1 (PlnD1) from the HSPG perlecan will be generated within HA hydrogels using multichannel devices and automated syringe pumps. Hydrogel characterization includes determination of PlnD1 coupling efficiency and gradient profiles. Functional HBGF binding capacity of these PlnD1 gradients will be determined using labeled versions of HBGFs such as FGF-7 and FGF-10, which promote salivary cell branching morphogenesis. In Aim 2, we will evaluate the effects of several PlnD1 and HBGF gradient profiles on encapsulated human salivary acinar-derived cells (hSACs) in vitro. Cell phenotype, motility, and organization will be assessed throughout culture in response to HBGF gradients. In Aim 3, HBGF/PlnD1 gradient hydrogels with encapsulated hSACs will be implanted in a rat model of salivary parotid gland damage and compared to controls. The salivary tissue will be evaluated via a functional amylase assay and histological scoring over several weeks to assess phenotypic function, implant organization, integration into native tissue, and overall tissue morphology. This research will enhance our understanding of cell response to gradients of HSPGs and morphogens for salivary tissue regeneration. Additionally, the research will describe a platform that will be broadly applicable for gradient delivery of any HBGF in regenerative medicine applications.

描述（由申请人证明）：静态疗法的颈癌患者是常见且毁灭性的副作用。在发育过程中观察到的3D模式。在基于生物学的基于生物学的水凝胶中受到启发的3D梯度，用于相关HBGFS的创造梯度，我们的假设是HSPG/HBGF梯度在水凝胶中具有启用受控的，不对称的，不对称的形式和抗态性的Primagencens Salivary Salivary Salivary细胞，支持Primagary Salivary Salivary Salivary Salivary Salivary Salivary Salivary细胞在AIM 1 1中形成了管道（来自HSPG perlecan的PLND1。在AIM 2中，人类唾液腺泡衍生的细胞（HSAC）在体外，将在整个培养物中评估AIM 3中的运动型。腺体损伤与对照组织将通过几周的表型函数来评估唾液组织将描述一个平台，该平台广泛适用于在再生医学应用中的任何HBGF的梯度分类分类范围。