Collaborative Research: Regulators of cellular microenvironment and multiscale osteointegration

ID: MPS/DMR/BMAT(7623) 1106165 PI：瓦格纳约翰逊，艾米ORG：伊利诺伊大学ID: MPS/DMR/BMAT(7623) 1105591 PI：墨菲，威廉ORG：威斯康星大学标题：合作研究：细胞微环境和多尺度骨整合的调节因子磷酸钙（CaP）被广泛应用于种植体涂层和骨再生/修复，因为它们的许多特性使它们成为与骨结合的理想材料。然而，调控CaPs骨整合的机制尚不清楚。由于缺乏适当的工具和方法，既可以隔离关键监管机构，又可以以受控和系统的方式将它们结合起来，因此进展停滞不前。三个因素对CaP系统特别重要：微孔隙度、BMP-2和生物磷灰石。与骨整合相关的潜在主导机制被假设为BMP-2的隔离和微孔存在下生物磷灰石的增强形成。目标是量化这些因素在骨形成不同阶段的相对重要性和潜在相互作用，并了解其影响背后的机制，使用cap作为生物材料平台和一套独特的工具。与仅具有大孔隙度的cap相比，具有大孔隙度（100um）和微孔隙度（50um）的cap大大增强了骨整合。虽然微孔隙主要用于促进大孔的生长，但现在有证据表明微孔隙也是骨的空间，其在CaP支架中的包含可以导致多尺度骨整合(MSO)-骨在宏观和微孔中的生长。这是任何其他系统都无法做到的。这套独特的工具将用于研究关键调节因子、微孔隙、BMP-2和生物磷灰石的作用，以及它们对骨整合影响背后的机制。这些工具允许(1)控制微孔隙度，这使得系统地探索微孔隙度和相关特征成为可能；(2)以不同程度的亲和力将BMP-2附着在cap上，这为研究隔离和释放BMP-2的效果提供了独特的机会；(3)在cap表面生长生物磷灰石的能力，这使得研究生物磷灰石对细胞反应的影响成为可能。此外，这些参数中的每一个都可以独立控制。具体目标是：(1)确定在有效的趋化和骨诱导刺激（BMP-2）作用下细胞迁移的最小孔径。这对于建立MSO的孔隙特征界限至关重要。(2)确定刺激对吸引间充质干细胞到基质的影响。(3)确定刺激对基质生成和矿化的影响。更广泛的影响：总的来说，这里使用的系统方法将所描述的因素和提出的分析结合起来，将为与骨骼界面的生物材料的合理设计提供新的见解。潜在的进展将导致对骨/材料相互作用的新理解，可能对那些受骨质流失或关节衰竭（例如涂层植入物）影响的人有巨大的好处，并可能减轻与这些手术相关的一些经济负担。主要的教育活动与开发一个教学模块有关，该模块使用基于探究的方法，并使校园女中（CMSG, Urbana， IL）的科学教师参与研究活动。与CMSG合作的目标是积极影响女孩对STEM的看法，这可能会导致她们在该领域的坚持。与CMSG的合作是与现有的NSF NSEC合作进行的，学习模块将成为NSF中心现有教育项目的一部分，用于针对代表性不足群体的项目。

ID: MPS/DMR/BMAT(7623) 1106165 PI: Wagoner Johnson, Amy ORG: University of IllinoisID: MPS/DMR/BMAT(7623) 1105591 PI: Murphy, William ORG: University of WisconsinTitle: Collaborative Research: Regulators of cellular microenvironment and multiscale osteointegrationINTELLECTUAL MERIT: Calcium Phosphates (CaP) are utilized in a wide range of applications including implant coatings and in bone regeneration/repair because of their many attributes that make them ideal to interface with bone. However, the mechanisms regulating osteointegration of CaPs have yet to be understood. Progress has stalled because of a lack of appropriate tools and methodologies that can isolate key regulators as well as combine them in a controlled and systematic way. Three factors stand out as particularly important for the CaP system: microporosity, BMP-2, and biologic apatite. The potential dominating mechanisms relating to osteointegration are hypothesized to be sequestration of BMP-2 and enhanced formation of biologic apatite in the presence of micropores. The goal is to quantify the relative importance of and potential interactions between these factors at different stages of bone formation and to understand the mechanisms behind their influence, using CaPs as a biomaterial platform and a unique set of tools. CaPs with macro (100um) and microporosity (50um) have greatly enhanced osteointegration as compared to those with only macroporosity. While microporosity has been used primarily to enhance growth into macropores, there is now evidence that microporosity is also a space for bone and its inclusion in CaP scaffolds can result in multiscale ostointegration (MSO)- bone growth throughout both macro and micropores. This has not been achieved with any other system. The unique suite of tools will be used to examine the role of key regulators, microporosity, BMP-2, and bioapatite, and the mechanisms behind their influence on osteointegration. The tools allow for (1) control of microporosity, which uniquely enables systematic exploration of microporosity and related characteristics, (2) attaching BMP-2 to CaPs with varying levels of affinity, which provides the unique opportunity to study the effects of both sequestered and releasing BMP-2, and (3) the capability to grow biological apatite on the surface of CaPs, which enables investigation of the influence of biological apatite on cell response. Further, each of these parameters can be independently controlled. The specific objectives are: (1) Determine the minimum pore size through which cells will migrate given a potent chemotactic and osteoinductive stimulus, BMP-2. This is critical for establishing bounds on pore characteristics for MSO. (2) Determine the influence of the stimuli in attracting mesenchymal stem cells to the substrate. (3) Determine the influence of the stimuli in matrix production and mineralization.BROADER IMPACTS: Taken together, the systematic approach used here to combine the factors described and the proposed analysis will provide new insight into the rational design of biomaterials that interface with bone. The potential advances will lead to new understanding of bone/material interactions, could have huge benefit for those affected by bone loss or joint failure (e.g. coated implants), and could relieve some of the economic burden associated with these procedures. The main educational activities are related to developing an instructional module that uses an inquiry-based approach and engages science teachers at the Campus Middle School for Girls (CMSG, Urbana, IL) in research activities. The objective in working with CMSG is to positively influence girls' perceptions of STEM, which may lead to their persistence in the field. The work with CMSG is in partnership with an existing NSF NSEC, and the learning module will become part of the existing educational programs in the NSF Center for use in programs that target underrepresented groups.