Biomimetic Inductive Scaffolds for Tooth Organ Engineering

用于牙齿器官工程的仿生感应支架

• 批准号: 8855266
• 负责人: DONALD E INGBER
• 金额: $ 43.94万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-07 至 2015-11-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8855266
• 关键词: Adhesives; Adult; Animals; Automobile Driving; Biocompatible Materials; Biological Models; Biomedical Engineering; Biomimetic Materials; Biomimetics; Body Temperature; Bone Marrow; Breast; Cartilage; Cells; Cellular biology; Chemicals; Chemistry; Cues; Dental; Dental Enamel; Dentin; Development; Developmental Biology; Embryo; Embryonic Development; Engineering; Epithelial; Epithelial Cells; Epithelium; Extracellular Matrix; Genetic Recombination; Goals; Growth; Hair follicle structure; Health; Heart Valves; Implant; In Vitro; Kidney; Knowledge; Life; Lung; Mechanics; Mediating; Mesenchymal; Mesenchymal Stem Cells; Mesenchyme; Molecular; Movement; Mus; Natural regeneration; Odontogenesis; Oral; Organ; Organogenesis; Pancreas; Physical condensation; Plant Roots; Polymer Chemistry; Polymers; Process; Recombinants; Regenerative Medicine; Salivary Glands; Science; Signal Transduction; Stem cells; Tissue Differentiation; Tissue Engineering; Tissues; Tooth Tissue; Tooth structure; Undifferentiated; Work; base; bone; capsule; design; embryo tissue; in vivo; mature animal; morphogens; mouse model; response; scaffold; tissue support frame

DESCRIPTION (provided by applicant): The overall goal of this REVISED proposal is to design and fabricate biomimetic scaffolds that mimic how certain embryonic tissues induce whole organ formation in the embryo, and ultimately, to use these developmentally-inspired materials to engineer artificial tissues and organs in adult animals. As a proof-of- principle, we propose to fabricate multifunctional scaffolds that induce formation of differentiated tooth starting with adult mesenchymal stem cells (aMSCs) and adult oral epithelial cells (aOECs). Our approach is based our past work which shows that during embryogenesis, the dental epithelium transfers its inductive capabilities to undifferentiated dental mesenchyme by stimulating a mesenchymal condensation response, and that the resulting physical compaction of cells is sufficient to trigger this developmental switch in vitro as well as subsequent tooth differentiatio in vivo. In addition, we now include new preliminary results that show we can fabricate thermosensitive polymer scaffolds that shrink and artificially induce mesenchymal condensation when placed at body temperature, and that tooth differentiation can be stimulated both by warming in vitro and by combining these materials with embryonic dental mesenchymal cells and implanting them under the kidney capsule in mice in vivo. Based on analysis of the embryonic tooth induction process, we believe that we can enhance the efficiency of this artificial induction process by including other key extracellular matrix (ECM) molecules and morphogens in these scaffolds that contribute to normal tooth development; we also plan to optimize the design and fabrication of the mechano-inductive scaffolds. Thus, the long-term goal of this proposal is to fabricate biomimetic polymer scaffolds that can reprogram aMSCs to differentiate into inductive mesenchyme that instructs normal aOECs to form a differentiated tooth in vivo. The Specific Aims of this proposal include: 1) to fabricate a mechanically actuatable biomimetic polymer scaffold that induces aMSCs to undergo odontogenic differentiation in vitro by producing cell compaction, 2) to identify molecules that mediate tooth formation during embryogenesis that can enhance compaction-induced tooth differentiation in vitro, and 3) to bioengineer a differentiated tooth in vivo using an optimized biomimetic scaffold in combination with aMSCs and aOECs in a mouse model.

描述（由申请人提供）：本修订提案的总体目标是设计和制造仿生支架，模拟某些胚胎组织如何诱导胚胎中的整个器官形成，并最终使用这些开发灵感材料在成年动物中设计人工组织和器官。作为原理证明，我们建议制造多功能支架，诱导分化牙齿的形成与成人间充质干细胞（aMSC）和成人口腔上皮细胞（aOECs）开始。我们的方法是基于我们过去的工作，这表明在胚胎发生过程中，牙齿上皮细胞通过刺激间充质凝聚反应将其诱导能力转移到未分化的牙齿间充质，并且由此产生的细胞物理压实足以触发体外发育开关以及随后的体内牙齿分化。此外，我们现在包括新的初步结果，表明我们可以制造热敏聚合物支架，当放置在体温下时收缩并人工诱导间充质冷凝，并且牙齿分化可以通过体外加热和将这些材料与胚胎牙齿间充质细胞结合并将其植入小鼠体内的肾包膜下来刺激。基于对胚胎牙齿诱导过程的分析，我们相信我们可以通过在这些支架中加入其他关键的细胞外基质（ECM）分子和形态发生素来提高这种人工诱导过程的效率，这些分子和形态发生素有助于正常的牙齿发育;我们还计划优化机械诱导支架的设计和制造。因此，该提案的长期目标是制造仿生聚合物支架，其可以重编程aMSC以分化成诱导间充质，该诱导间充质指导正常aOECs在体内形成分化的牙齿。该提案的具体目标包括：1）制造可机械致动的仿生聚合物支架，其通过产生细胞压实来诱导aMSC在体外经历牙源性分化，2）鉴定在胚胎发生期间介导牙齿形成的分子，其可以增强牙源性诱导的牙齿体外分化，和3）在小鼠模型中使用优化的仿生支架与aMSC和aOEC组合来体内生物工程化分化的牙齿。