Identifying the superior ossification pathway for tissue engineered approaches to long bone repair
确定组织工程方法修复长骨的最佳骨化途径
基本信息
- 批准号:10591573
- 负责人:
- 金额:$ 37.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccelerationAddressAdhesivesAdsorptionAffectAgeAllogenicAngiogenic FactorApoptosisAutologousBMP2 geneBindingBiological AssayBiomimeticsBone RegenerationBone TransplantationCartilageCell AdhesionCell Differentiation processCell SurvivalCell TherapyCell TransplantationCell physiologyCell secretionCellsChondrogenesisClinicalCuesDataDefectDevelopmentDiseaseExcisionExhibitsExtracellular MatrixFractureGrowth FactorGrowth Factor ReceptorsHealthHistologyImmuneImpairmentImplantIn SituIn VitroIndividualIntegrinsInterventionLongevityMethodsMitogensMusculoskeletalNatural regenerationOsteogenesisOutcomePathway interactionsPatientsPhenotypePhysiologic OssificationPublishingQuality of lifeRecombinant Growth FactorResearchRoleSafetySignal TransductionTestingTherapeuticTissue EngineeringTissuesTransplantationTraumabonebone healingbone repaircartilage implantcartilage transplantationcell growthdisease transmissiondosagehealingimplantationinnovationintramembranous bone formationlong bonemesenchymal stromal cellmorphogensnon-invasive imagingnovelnovel strategiesosteogenicrepair functionrepairedresponseside effectskeletalstem cellssynergismtumor
项目摘要
PROJECT SUMMARY
Musculoskeletal health is a key determinant of mobility and quality of life which affects every individual,
regardless of age. Up to 20% of the 6 million fractures occurring annually in the US will result in nonunion or
slow healing and require intervention for bone regeneration. Mesenchymal stromal cells (MSCs) are one
alternative to bone grafts because of their osteogenic, chondrogenic, and proangiogenic potential. Compared
to monodisperse cells, MSC spheroids better resist apoptosis and secrete 100-fold higher levels of angiogenic
factors while retaining their multipotency. However, MSC spheroids are not yet sufficient to bridge large bone
defects, suggesting the need for effective programming methods to enhance their bone-forming potential.
Furthermore, it is unclear whether bone healing is more effective by jumpstarting cartilage formation or
attempting to induce osteogenic differentiation of resident or transplanted cells. Local delivery of inductive
growth factors such as BMP-2 and TGF-b1 accelerates tissue formation, but the necessary supraphysiological
concentrations and associated complications impair their widespread clinical use. Our data demonstrate that
MSC spheroids loaded with cell-secreted extracellular matrix (ECM) are more responsive to potent mitogens
and exhibit enhanced osteogenic and chondrogenic differentiation while using markedly reduced dosages and
reducing contraindications. Thus, our central hypothesis is that MSC spheroids can be differentiated in situ
toward the osteogenic or chondrogenic lineage by presenting inductive cues adsorbed to incorporated ECM,
which will yield potent cellular building blocks to regenerate large lost bone volumes. Aim 1. Adapt cell-
secreted ECM to locally present inductive factors to MSCs within spheroids to enhance osteogenic or
chondrogenic differentiation. We will test the role of ECM quantity and BMP-2 and TGF-b1 dosage on growth
factor retention and presentation of loaded morphogens and correlating their resulting effect on osteogenesis
and chondrogenesis in vitro. Aim 2. Potentiate MSC osteogenic or chondrogenic differentiation by
manipulating ECM-driven morphogen presentation. We will identify and quantify changes in integrin expression
and growth factor receptor activity in MSC spheroids containing ECM-adsorbed BMP-2 or TGF-b1. We will
then assess changes in MSC differentiation when decoupling the synergy of cell adhesion and growth factor
availability. Aim 3. Establish the therapeutic potential of ECM-adsorbed exogenous morphogens to instruct
MSC spheroids in situ for bone formation. We will determine the capacity of MSC spheroids containing ECM-
adsorbed BMP-2 or TGF-b1 to persist, undergo osteogenic or chondrogenic differentiation in situ, and repair
large bone defects. We will use noninvasive imaging and histology to describe the superior pathway to
promote robust bone formation in long bone defects. The proposed research is innovative because it provides
a novel strategy to reduce the quantity of recombinant growth factors needed to guide cell function, while
establishing whether MSCs directed toward cartilage or bone achieve faster bone repair in long bones.
项目总结
肌肉骨骼健康是影响每个人行动能力和生活质量的关键决定因素,
无论年龄大小。在美国每年发生的600万例骨折中,高达20%将导致骨不连或
愈合缓慢,需要干预以促进骨骼再生。间充质基质细胞(MSCs)是
可替代骨移植,因为它们具有成骨、成软骨和促血管生成的潜能。相比较
对于单分散的细胞,MSC球体更好地抵抗凋亡,并分泌100倍以上的血管生成
因素,同时保持其多功能性。然而,间充质干细胞球体还不足以桥接大块骨。
缺陷,提示需要有效的编程方法来增强其成骨潜力。
此外,目前还不清楚骨愈合是通过启动软骨形成还是通过启动软骨形成更有效。
试图诱导常驻细胞或移植细胞的成骨分化。感应性的本地交付
骨形态发生蛋白-2和转化生长因子-β1等生长因子可加速组织形成,但必要的超生理学
浓度和相关的并发症阻碍了它们的广泛临床应用。我们的数据表明
装载有细胞分泌的细胞外基质(ECM)的MSC球体对强有力的有丝分裂原更敏感
表现出增强的成骨和软骨分化,同时使用显著减少的剂量和
减少禁忌症。因此,我们的中心假设是MSC球体可以在原位分化。
通过提供吸附到被结合的ECM的诱导线索来朝向成骨或成软骨谱系,
这将产生强有力的细胞构建块来再生大量丢失的骨体积。目标1.调整细胞-
分泌ECM在球体内局部向MSCs递送诱导因子,促进成骨或
软骨细胞分化。检测细胞外基质用量和BMP-2、TGF-β1用量对生长的影响。
负载形态因子的保留和呈递及其对成骨的影响
和体外软骨形成。目的2.通过以下方式促进MSC成骨或成软骨分化
操纵ECM驱动的形态生成物呈现。我们将识别和量化整合素表达的变化
以及含有ECM吸附的BMP-2或转化生长因子-β1的MSC球体中的生长因子受体活性。我们会
然后评估去偶联细胞黏附和生长因子协同作用时间充质干细胞分化的变化
可用性。目的3.建立细胞外基质吸附外源形态因子的治疗潜力
MSC球体原位成骨。我们将测定含有ECM-的MSC球体的容量-
吸附BMP-2或转化生长因子-β1持续存在,在原位进行成骨或软骨分化,并修复
大块的骨缺损处。我们将使用非侵入性成像和组织学来描述
促进长骨缺损处强健的骨形成。拟议的研究具有创新性,因为它提供了
一种新的策略,以减少引导细胞功能所需的重组生长因子的数量,同时
确定骨髓间充质干细胞是向软骨还是骨定向,可以更快地修复长骨。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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J. Kent Leach其他文献
Biofabrication of engineered tissues by 3D bioprinting of tissue specific high cell-density bioinks
通过对组织特异性高细胞密度生物墨水进行3D生物打印来进行工程化组织的生物制造
- DOI:
10.1016/j.mattod.2025.03.021 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:22.000
- 作者:
Oju Jeon;Hyoeun Park;J. Kent Leach;Eben Alsberg - 通讯作者:
Eben Alsberg
In Vitro Models for Studying Transport Across Epithelial Tissue Barriers
- DOI:
10.1007/s10439-018-02124-w - 发表时间:
2018-09-14 - 期刊:
- 影响因子:5.400
- 作者:
Navein Arumugasaamy;Javier Navarro;J. Kent Leach;Peter C. W. Kim;John P. Fisher - 通讯作者:
John P. Fisher
Ultrastructure and growth factor content of equine platelet-rich fibrin gels.
马富含血小板的纤维蛋白凝胶的超微结构和生长因子含量。
- DOI:
10.2460/ajvr.75.4.392 - 发表时间:
2014 - 期刊:
- 影响因子:1
- 作者:
J. Textor;K. Murphy;J. Kent Leach;F. Tablin - 通讯作者:
F. Tablin
Macrophage and osteosarcoma cell crosstalk is dependent on oxygen tension and 3D culture
巨噬细胞与骨肉瘤细胞的相互作用依赖于氧张力和三维培养。
- DOI:
10.1016/j.bioadv.2024.214154 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:6.000
- 作者:
Katherine H. Griffin;Isabel S. Sagheb;Thomas P. Coonan;Fernando A. Fierro;R. Lor Randall;J. Kent Leach - 通讯作者:
J. Kent Leach
J. Kent Leach的其他文献
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{{ truncateString('J. Kent Leach', 18)}}的其他基金
MUSCLE: MUsculoSkeletal Clinical Learning Experience Transdisciplinary Musculoskeletal Research Training Program
肌肉:肌肉骨骼临床学习体验跨学科肌肉骨骼研究培训计划
- 批准号:
10410848 - 财政年份:2022
- 资助金额:
$ 37.99万 - 项目类别:
ORS-ISFR 17th International Biennial Meeting
ORS-ISFR第17届国际双年会
- 批准号:
10540642 - 财政年份:2022
- 资助金额:
$ 37.99万 - 项目类别:
MUSCLE: MUsculoSkeletal Clinical Learning Experience Transdisciplinary Musculoskeletal Research Training Program
肌肉:肌肉骨骼临床学习体验跨学科肌肉骨骼研究培训计划
- 批准号:
10612446 - 财政年份:2022
- 资助金额:
$ 37.99万 - 项目类别:
Identifying the superior ossification pathway for tissue engineered approaches to long bone repair
确定组织工程方法修复长骨的最佳骨化途径
- 批准号:
10230915 - 财政年份:2021
- 资助金额:
$ 37.99万 - 项目类别:
Identifying the superior ossification pathway for tissue engineered approaches to long bone repair
确定组织工程方法修复长骨的最佳骨化途径
- 批准号:
10376368 - 财政年份:2021
- 资助金额:
$ 37.99万 - 项目类别:
Dual peptide presentation from bioengineered carriers to potentiate stromal cell function and tissue repair
生物工程载体的双肽呈递可增强基质细胞功能和组织修复
- 批准号:
9320107 - 财政年份:2017
- 资助金额:
$ 37.99万 - 项目类别:
Dual peptide presentation from bioengineered carriers to potentiate stromal cell function and tissue repair
生物工程载体的双肽呈递可增强基质细胞功能和组织修复
- 批准号:
9883782 - 财政年份:2017
- 资助金额:
$ 37.99万 - 项目类别:
Engineering the innate immune response to Staphaureus infection
设计针对葡萄球菌感染的先天免疫反应
- 批准号:
10212940 - 财政年份:2017
- 资助金额:
$ 37.99万 - 项目类别:
Dual peptide presentation from bioengineered carriers to potentiate stromal cell function and tissue repair
生物工程载体的双肽呈递可增强基质细胞功能和组织修复
- 批准号:
9930177 - 财政年份:2017
- 资助金额:
$ 37.99万 - 项目类别:
Engineering the innate immune response to Staphaureus infection
设计针对葡萄球菌感染的先天免疫反应
- 批准号:
9401775 - 财政年份:2017
- 资助金额:
$ 37.99万 - 项目类别:
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