The Use of Coacervate Technology as a New Drug Delivery System for Musculoskeleta
使用凝聚技术作为肌肉骨骼的新型药物输送系统
基本信息
- 批准号:8681855
- 负责人:
- 金额:$ 16.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-04 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAgeAngiogenesis InhibitorsAngiogenic FactorAreaArthritisAutologousAutologous TransplantationBMP2 geneBMP4Biomedical EngineeringBiomimeticsBlood CirculationBone RegenerationBone TransplantationCalvariaCell Culture TechniquesCell TherapyChildhoodChondrocytesClinicalDataDefectDegenerative polyarthritisDevelopmentDiseaseDrug Delivery SystemsElderlyEngineered GeneEpidemicEtiologyFractureGene DeliveryGeneticGenetic EngineeringGoalsGoldGrantGrowth FactorHarvestHealedHeparinHumanIn VitroInjection of therapeutic agentInjuryIodoacetatesJointsKnee OsteoarthritisKnowledgeLeadMediatingMethodsModalityModelingModificationMorbidity - disease rateMusMuscleMuscle satellite cellMusculoskeletalNatural regenerationOlder PopulationOutcomePathologicPatientsPopulationProcessProteinsReportingResearch DesignSiteSkeletal MuscleSkeletonStem cellsSupporting CellSurgeonSystemTechnologyTissue EngineeringTissuesTranslatingTranslationsTransplantationUnited StatesVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth FactorsViralWomanWorkangiogenesisarticular cartilagebasebonebone healingbone morphogenetic protein 2bone morphogenetic protein 4cartilage repairclinically relevantcraniofacialdisabilitygene therapyhealinghigh riskimplantationimprovedin vivoinjuredinterestlong bonemennovelnovel therapeuticsoperationosteochondral tissueosteogenicosteogenic proteinpolycationpreventpublic health relevanceregenerativerepairedresearch studysocioeconomicsstandard of carestem cell technologysuccesstherapeutic protein
项目摘要
DESCRIPTION (provided by applicant): Incomplete healing of critical size bone defects, including defects of the craniofacial skeleton, are common. Osteogenic proteins, including bone morphogenetic protein 2 and 4 (BMP2, BMP4), promote bone healing, but the proteins have short half-lives and are rapidly cleared by the bloodstream, which limits their utility. The goals f our previous work were to develop gene therapy and tissue engineering approaches to efficiently deliver osteogenic proteins and improve bone healing using muscle-derived stem cells (MDSCs). We have shown that murine and human MDSCs (hMDSCs) genetically engineered to express BMP2 or 4 could differentiate toward an osteogenic lineage and improve bone healing in calvarial and long bone defects. We also found that concomitant gene delivery of vascular endothelial growth factor (VEGF) improves bone healing after the implantation of BMP2 or 4 expressing MDSCs. Similarly, we have reported that MDSCs isolated from mouse and human skeletal muscle were also capable of chondrogenic differentiation and could be used to promote articular cartilage repair after acute injury (osteochondral defects) and disease (osteoarthritis [OA]), especially when genetically modified to express bone morphogenetic protein 4 (BMP4-MDSC). However, in contrast to bone, our findings also suggested that genetic modification of MDSCs to express both BMP4 and the angiogenic antagonist sFlt-1, could accelerate the AC repair capacity of the cells supporting the fact that blocking angiogenesis is beneficial for AC repair. Although we have made substantial progress in muscle stem cell based therapy for bone and AC healing over the past number of years, most of our previous work involved genetic modification of the stem cells prior to transplantation, a step that limits te clinical translation of the work. We therefore propose a new set of experiments which will aim to circumvent the necessity of using viral transduction via the use of a novel heparin-polycation coacervate delivery system capable of slowly releasing the required therapeutic proteins including BMP2, VEGF and/or sFlt-1 to promote bone and AC repair in conjunction with non- transduced MDSCs. In the first set of experiments we will utilize the heparin-polycation coacervate delivery system to deliver BMP2 and VEGF to enhance hMDSC mediated bone repair. The second set of experiment will aim to promote AC repair after the induction of OA utilizing the heparin-polycation coacervate delivery system to slowly release BMP2 and sFlt-1, in combination with hMDSCs, to enhance AC repair. The efficiency of bone and AC repair with the coacervate-hMDSCs technology will be compared to both hMDSC based gene therapy and hMDSC based free protein therapy (i.e. without the use of the heparin-polycation coacervate). This application outlines a new area of research designed to offer valuable clinically relevant approaches based on novel bioengineering concepts for the treatment of musculoskeletal tissues following injury and disease.
描述(由申请人提供):临界尺寸骨缺损(包括颅面骨骼缺损)的不完全愈合是常见的。成骨蛋白,包括骨形态发生蛋白 2 和 4 (BMP2、BMP4),可促进骨愈合,但这些蛋白的半衰期短,会被血流迅速清除,这限制了它们的用途。我们之前工作的目标是开发基因治疗和组织工程方法,以利用肌肉源性干细胞(MDSC)有效地递送成骨蛋白并改善骨愈合。我们已经证明,经过基因工程改造表达 BMP2 或 4 的小鼠和人类 MDSC (hMDSC) 可以分化为成骨谱系,并改善颅骨和长骨缺损的骨愈合。我们还发现,在植入表达 BMP2 或 4 的 MDSC 后,同时输送血管内皮生长因子 (VEGF) 基因可改善骨愈合。同样,我们报道,从小鼠和人类骨骼肌中分离的 MDSC 也能够进行软骨分化,可用于促进急性损伤(骨软骨缺陷)和疾病(骨关节炎 [OA])后的关节软骨修复,特别是当经过基因改造以表达骨形态发生蛋白 4 (BMP4-MDSC) 时。然而,与骨相比,我们的研究结果还表明,对 MDSC 进行基因修饰以表达 BMP4 和血管生成拮抗剂 sFlt-1,可以加速细胞的 AC 修复能力,支持阻断血管生成有利于 AC 修复的事实。 尽管过去几年我们在基于肌肉干细胞的骨和 AC 愈合治疗方面取得了实质性进展,但我们之前的大部分工作涉及移植前对干细胞进行基因修饰,这一步骤限制了该工作的临床转化。因此,我们提出了一组新的实验,旨在通过使用新型肝素-聚阳离子凝聚层递送系统来避免使用病毒转导的必要性,该系统能够缓慢释放所需的治疗蛋白,包括BMP2、VEGF和/或sFlt-1,以与非转导的MDSC一起促进骨和AC修复。在第一组实验中,我们将利用肝素-聚阳离子凝聚层递送系统来递送BMP2和VEGF以增强hMDSC介导的骨修复。第二组实验旨在利用肝素-聚阳离子凝聚层递送系统缓慢释放BMP2和sFlt-1,与hMDSC结合,诱导OA后促进AC修复,以增强AC修复。将使用凝聚层-hMDSC技术进行骨和AC修复的效率与基于hMDSC的基因疗法和基于hMDSC的游离蛋白疗法(即不使用肝素-聚阳离子凝聚层)进行比较。该申请概述了一个新的研究领域,旨在提供基于新颖的生物工程概念的有价值的临床相关方法,用于治疗损伤和疾病后的肌肉骨骼组织。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Johnny Huard其他文献
Johnny Huard的其他文献
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- 批准号:
10468269 - 财政年份:2020
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The Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis
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