Development of 3D Printed Synthetic Bone Graft Containing Small Molecules for Sequential Activation of Hedgehog and Hypoxia Signaling for Treatment of Nonunion Fractures
开发含有小分子的 3D 打印合成骨移植物,用于顺序激活 Hedgehog 和缺氧信号,用于治疗骨不连骨折
基本信息
- 批准号:10413956
- 负责人:
- 金额:--
- 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:2021-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:3D PrintAblationAdultAgonistAnimal ModelAscorbic AcidAutologous TransplantationBindingBlood VesselsBone DevelopmentBone InjuryBone MatrixBone TransplantationBone callusCartilageCell TherapyChondrocytesCombined Modality TherapyDataDefectDevelopmentDiabetic mouseDiphtheria ToxinDisadvantagedDrug TargetingElectromagnetic FieldsEmbryonic DevelopmentErinaceidaeEventExhibitsFailureFibrinFractureFutureGelGenesGeneticGoldGrowth FactorHIF1A geneHealthHealth Care CostsHistologicHypertrophyHypothyroidismHypoxiaImmunohistochemistryImpaired healingImpairmentInvadedLabelLeadMeasurementMechanicsMediatingMesenchymal Stem CellsModelingMolecularMorbidity - disease rateMusOsteoblastsOsteogenesisOxygenPathway interactionsPatientsPhenotypePhysiologic OssificationPhysiologic pulsePhysiologicalPlayPolymersPreparationProcessProcollagen-Proline DioxygenaseProliferatingProteinsRecombinantsRodRoleSHH geneSafetySignal PathwaySignal TransductionSiteSkeletal DevelopmentSourceTestingTherapeuticTherapeutic AgentsTherapeutic EffectThyroid HormonesTimeTissuesTorsionWorkagedbasebonebone epiphysisbone fracture repairbone healingbone massbone repairbone strengthcartilaginousclinically relevantcomparative efficacycost effectivecost effectivenesseffective therapyhealinginhibitorinjury and repairintramembranous bonelong bonemesenchymal stromal cellmicroCTmouse modelnovelnovel therapeuticsrepairedscaffoldsensorside effectskeletalsmall moleculesmall molecule inhibitorsmall molecule therapeuticssmoothened signaling pathwaysubstantia spongiosatherapeutic effectivenesstherapeutic evaluationtransdifferentiationtricalcium phosphateultrasound
项目摘要
ABSTRACT
Bone injuries are a major health problem. There are 7.9 million bone fractures sustained annually in the U.S. Healing
is impaired in about 10% of these fractures with seriously delayed union or non-union, causing morbidity for patients and
enormous healthcare costs. While strategies such as bone grafting, synthetic polymers, low intensity pulsed ultrasound and
electromagnetic fields, growth factors and cell therapy are currently being used or investigated to promote bone healing,
each of these therapies have their own advantages and disadvantages in terms of cost, effectiveness and safety. Thus, there
is a compelling need to find novel effective therapies that promote fracture healing. Vitamin C and thyroid hormone (TH)
are known to play key roles in endochondral bone formation (EBF). Our recent studies on the molecular pathways for TH
and vitamin C actions revealed evidence that sequential activation of hedgehog and hypoxia signaling pathways contribute
to key steps involved in EBF. Our focus in this project is on the therapeutic utility and mechanisms of action of two small
molecules, SAG 21k and IOX2, that activate hedgehog and hypoxia signaling pathways to promote EBF at the fracture site.
In this proof of concept study, we propose to deliver SAG21K and IOX2 locally using 3D printed fibrin gel/β-tricalcium
phosphate (βTCP) scaffolds at the defect site to provide mechanical strength and minimize unwanted side effects on other
tissues. A clinically relevant segmental defect model in the femoral midshaft in which a 2.5-mm defect is stabilized by an
intramedullary threaded rod with attached plastic spacers that does not heal over a prolonged period will be used. Three
aims are proposed. In aim 1, we will 3D print fibrin gel/β-tricalcium phosphate (βTCP) scaffold preparations containing
SAG21k and IOX2 and evaluate the suitability of these preparations for delivery of effective concentrations of SAG21k
and IOX2 at the optimal therapeutic time window for activation of hedgehog and hypoxia signaling at the fracture site by
measurement of downstream signaling targets of these signaling pathways by immunohistochemistry (IHC) and real time
PCR in the fracture callus of mice at different times. In aim 2, we will test the hypothesis that sequential activation of
hedgehog followed by hypoxia signaling will be effective in promoting healing of femoral segmental defects. We will
compare the efficacy of bone healing with SAG21k and IOX2 with that of autografts, a gold standard used for healing of
nonunion defects. We will use validated microCT, bone strength and histological measurements to evaluate the fracture
healing phenotype. Therapeutic effectiveness of SAG21k/IOX2 combination therapy will be studied using aged and
diabetic mice with impaired fracture healing. In aim 3, we will test the hypothesis that sequential activation of sonic
hedgehog and hypoxia signaling induces bone healing by promoting direct conversion of chondrocytes-to-osteoblasts.
Fracture callus chondrocytes will be labeled with TdTomato by genetic inducible fate mapping approaches and the fate of
labeled chondrocytes to form osteoblasts in the bony callus will be evaluated. The role of chondrocytes in bone healing
will be evaluated after chondrocyte ablation with diphtheria toxin in chondrocyte-specific Col10α1-CreER;iDTR mice. In
terms of clinical relevance, we believe that the potential impact of understanding the utility of SAG21k and IOX2 in bone
healing and their mechanisms of action is huge, and therefore the work proposed in this project is significant.
摘要
骨骼损伤是一个主要的健康问题。在美国,每年有790万人骨折。
在这些骨折中,约有10%的骨折严重延迟愈合或不愈合,导致患者发病,
巨大的医疗费用。虽然诸如骨移植、合成聚合物、低强度脉冲超声和
目前正在使用或研究电磁场、生长因子和细胞疗法来促进骨愈合,
这些疗法中的每一种在成本、有效性和安全性方面都有其自身的优点和缺点。因此
迫切需要找到促进骨折愈合的新型有效疗法。维生素C和甲状腺激素(TH)
已知在软骨内骨形成(EBF)中起关键作用。近年来我们对TH的分子途径的研究
和维生素C的作用揭示的证据表明,刺猬和缺氧信号通路的顺序激活有助于
参与EBF的关键步骤。我们在这个项目中的重点是两个小的治疗效用和作用机制,
分子SAG 21 k和IOX 2,激活刺猬和缺氧信号通路,促进骨折部位的EBF。
在这项概念验证研究中,我们建议使用3D打印的纤维蛋白凝胶/β-三钙局部递送SAG 21 K和IOX 2。
磷酸盐(βTCP)支架在缺损部位提供机械强度,并尽量减少对其他不必要的副作用
组织中股骨中段的临床相关节段性缺损模型,其中2.5 mm缺损通过
将使用在长时间内不会愈合的具有附接的塑料间隔物的髓内螺纹杆。三
提出了目标。在目标1中,我们将3D打印纤维蛋白凝胶/β-磷酸三钙(βTCP)支架制剂,
SAG 21 k和IOX 2,并评价这些制剂用于递送有效浓度的SAG 21 k的适用性
和IOX 2在骨折部位激活hedgehog和缺氧信号的最佳治疗时间窗,
通过免疫组织化学(IHC)和真实的时间测量这些信号传导途径的下游信号传导靶标
小鼠骨折后不同时间骨痂中的PCR。在目标2中,我们将检验以下假设:
hedgehog随后缺氧信号传导将有效地促进股骨节段性缺损的愈合。我们将
将SAG 21 k和IOX 2的骨愈合效果与自体移植物的骨愈合效果进行比较,自体移植物是用于骨愈合的金标准,
骨不连缺陷。我们将使用经验证的microCT、骨强度和组织学测量来评估骨折
愈合表型SAG 21 k/IOX 2组合疗法的治疗有效性将使用老年人和
骨折愈合受损的糖尿病小鼠。在目标3中,我们将测试假设,
hedgehog和缺氧信号传导通过促进软骨细胞向成骨细胞的直接转化来诱导骨愈合。
骨折愈伤组织软骨细胞将通过遗传诱导的命运作图方法用TdTomato标记,并且
将评价标记的软骨细胞在骨痂中形成成骨细胞的能力。软骨细胞在骨愈合中的作用
将在软骨细胞特异性Col 10 α1-CreER;iDTR小鼠中用白喉毒素进行软骨细胞消融后进行评价。在
就临床相关性而言,我们认为了解SAG 21 k和IOX 2在骨中的效用的潜在影响
愈合和他们的行动机制是巨大的,因此,在这个项目中提出的工作是重要的。
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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SUBBURAMAN MOHAN其他文献
SUBBURAMAN MOHAN的其他文献
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{{ truncateString('SUBBURAMAN MOHAN', 18)}}的其他基金
Development of 3D Printed Synthetic Bone Graft Containing Small Molecules for Sequential Activation of Hedgehog and Hypoxia Signaling for Treatment of Nonunion Fractures
开发含有小分子的 3D 打印合成骨移植物,用于顺序激活 Hedgehog 和缺氧信号,用于治疗骨不连骨折
- 批准号:
10664885 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Development of 3D Printed Synthetic Bone Graft Containing Small Molecules for Sequential Activation of Hedgehog and Hypoxia Signaling for Treatment of Nonunion Fractures
开发含有小分子的 3D 打印合成骨移植物,用于顺序激活 Hedgehog 和缺氧信号,用于治疗骨不连骨折
- 批准号:
10253962 - 财政年份:2021
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