INTELLECTUAL 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.