Engineering Differentiation of Multi-tissue Units

多组织单位的工程分化

基本信息

批准号：
8533775
负责人：
PHIL GORDON CAMPBELL
金额：
$ 51.63万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8533775
关键词：
Address Adsorption Allografting Anatomic Sites Automobile Driving Binding Binding Proteins Biochemical Biomechanics Cell Communication Cell Differentiation process Cells Chemicals Clinical Complex Cues Data Dermal Development Diffusion Direct Costs Discrimination Elements Endocrine Engineering Environment Extracellular Matrix Facilities and Administrative Costs Goals Grant Grouping Growth Factor Heterogeneity Histologic Human Immune response Implant In Situ In Vitro Investigation Lead Mediating Methodology Modeling Mus Muscle Musculoskeletal Musculoskeletal System Outcome Paracrine Communication Pattern Peptide Hydrolases Phase Phenotype Physiological Population Printing Property Protease Inhibitor Proteoglycan Resolution Signaling Molecule Site Solid Source Spatial Distribution Staging Stem cells Stimulus Structure Technology Tendon structure Tissue Engineering Tissues Validation achilles tendon base bone combinatorial design dosage engineering design improved in vitro Model in vivo inhibitor/antagonist injured insight interfacial millimeter mouse model muscle engineering novel public health relevance repaired response scaffold stem cell population subcutaneous wound

项目摘要

DESCRIPTION (provided by applicant): Tissue engineering approaches for driving stem cells toward spatially-organized multi-tissue units of the musculoskeletal system, such as muscle-tendon-bone (MTB), will require spatial control of differentiative cues provided by various components of tissue-engineered constructs, including their: biochemical elements; scaffold material composition and structure; and, biomechanical interactions. Current toolsets to aid in the early stages of discovery, design, and implementation of such complex, multi-variable constructs are either non- existent or severely limited in their capabilities to incorporate spatial control of those biochemical elements provided by exogenous paracrine signaling factors (PSFs). To address this need, we propose a novel PSF biopatterning technology that will enable the creation of persistent, spatially-defined patterns of PSFs organized in multiple neighboring regions of a scaffold, where each region targets a different phenotype to be induced. This capability will be unique because it will enable an exogenous or endogenous stem cell population exposed to a PSF-patterned construct to be driven toward multiple differentiative fates simultaneously in register to these patterns, at sub-millimeter resolution, to form neighboring multi-phenotype groupings within the same construct, both in vitro and in vivo. Pattern designs for an MTB will first be determined with the aid of a systematic design methodology applied to in vitro studies to identify a minimum set of spatially-patterned PSF cues out of a very large number of design possibilities, and then the resulting highest ranking designs will be validated in vivo for driving tissue phenotype formation in an ectopic subcutaneous mouse model. As an additional in vivo validation PSF patterned constructs will be implanted into a mouse Achilles tendon wound model to initiate site-specific host response, and histologically assessed for tissue phenotype expression in register to patterns applied. PUBLIC HEALTH RELEVANCE: New tissue engineering therapies are needed to address the growing demand to repair multi-tissue structures of the musculoskeletal system, such as interconnected bone-tendon-muscle units that are diseased or injured. This becomes an even greater challenge because of the need to spatially control multiple differentiation fates simultaneously, including multi-unit tissue interfaces, within the same intercommunicating pericellular environment. There is an unmet need for new tissue-engineered construct technologies and design methodologies that will enable a stem cell population to be driven toward neighboring regions of different differentiation fates in each region, in vitro and in vivo. We propose to develop and demonstrate a spatial patterning methodology that uses a limited number of exogenous signaling molecules, patterned in scaffolds, to direct stem cells in the musculoskeletal system down multiple neighboring and intercommunicating differentiation fates as a first order model of multi-tissue formation and interaction. Engineered spatial patterning will provide new insights about multi-tissue formation, with the long-term goal to use patterned constructs to improve clinical outcomes of musculoskeletal-related treatments, which represents an estimated annual direct and indirect cost of $510 billion, in terms of 2004 dollars, or 3.1 % of the GDP in the US alone.

描述（由申请人提供）：用于驱动干细胞驱动肌肉骨骼系统的空间多组织单元的组织工程方法，例如肌肉 - 刺孔 - 骨（MTB），需要对由组织启动结构的各种组成部分（包括其：生物生物化学元素）提供的分化性提示提供的空间控制；脚手架材料组成和结构；以及生物力学相互作用。目前的工具集可帮助您在发现，设计和实施这种复杂，多变量构建体的早期阶段，或者在其能力上不存在，或严重限制了对外源性旁分泌信号传导因素（PSFS）提供的生化元素的空间控制的能力。为了满足这一需求，我们提出了一种新颖的PSF生物图案技术，该技术将使在脚手架的多个邻近区域中组织的PSF的持久，空间定义的模式，每个区域都靶向要诱导的不同表型。这种能力将是唯一的，因为它将使暴露于PSF图案构建体的外源或内源性干细胞种群同时在与这些模式的情况下同时朝着多个差异化的命运驱动，以在亚毫米分辨率下，形成相邻的多型型组，包括同一构建体内的同一构建体，包括体外和体内。首先，将首先使用用于体外研究的系统设计方法来确定MTB的模式设计，以确定一组最小的空间图案PSF提示，以大量的设计可能性确定，然后将最高的最高排名设计在体内验证，用于在体内验证用于驱动组织表型的效率下型下型下型下型下型的型。作为附加的体内验证，PSF图案化构建体将植入小鼠跟腱中肌腱伤口模型，以启动特定位点特异性宿主反应，并在组织学评估中，以在登记处的组织表型表达与所应用的模式中表达。公共卫生相关性：需要新的组织工程疗法来解决维修肌肉骨骼系统多组织结构的日益增长的需求，例如患病或受伤的相互联系的骨刺激单元。这成为一个更大的挑战，因为需要在同一间断的细胞周围环境中同时控制多个分化命运，包括多单元组织界面。对新的组织工程构造技术和设计方法的需求未满足，这将使干细胞种群能够驱动到每个区域，体外和体内不同分化命运的邻近区域。我们建议开发和演示一种空间图案方法，该方法使用有限数量的外源信号分子（以脚手架模式模式），将肌肉骨骼系统中的干细胞引导到多个邻近的肌肉骨骼系统中，并将分化分化的命运作为多节奏形成和相互作用和相互作用和相互作用的一级模型。工程的空间图案将提供有关多组织组的新见解，其长期目标是使用图案化的结构来改善与肌肉骨骼相关的治疗的临床结果，这代表了2004年的年度直接和间接成本估计的直接和间接成本为51.11亿美元，或者仅在2004美元中，或仅在美国的GDP中为3.1％。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Crosstalk between substance P and calcitonin gene-related peptide during heterotopic ossification in murine Achilles tendon.

DOI：
10.1002/jor.23833
发表时间：
2018-05
期刊：
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
影响因子：
0
作者：
Tuzmen C;Verdelis K;Weiss L;Campbell P
通讯作者：
Campbell P

An engineered approach to stem cell culture: automating the decision process for real-time adaptive subculture of stem cells.

DOI：
10.1371/journal.pone.0027672
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Ker DF;Weiss LE;Junkers SN;Chen M;Yin Z;Sandbothe MF;Huh SI;Eom S;Bise R;Osuna-Highley E;Kanade T;Campbell PG
通讯作者：
Campbell PG

Phase contrast time-lapse microscopy datasets with automated and manual cell tracking annotations.

DOI：
10.1038/sdata.2018.237
发表时间：
2018-11-13
期刊：
Scientific data
影响因子：
9.8
作者：
Ker DFE;Eom S;Sanami S;Bise R;Pascale C;Yin Z;Huh SI;Osuna-Highley E;Junkers SN;Helfrich CJ;Liang PY;Pan J;Jeong S;Kang SS;Liu J;Nicholson R;Sandbothe MF;Van PT;Liu A;Chen M;Kanade T;Weiss LE;Campbell PG
通讯作者：
Campbell PG

Crosstalk between neuropeptides SP and CGRP in regulation of BMP2-induced bone differentiation.