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Bioinspired Citrate-based Metabonegenic Biomaterials for Bone Regenerative Engineering

Author:
Ma, Chuying
Additional Titles:
Bioinspired Citrate based Metabonegenic Biomaterials for Bone Regenerative Engineering
Published:
[University Park, Pennsylvania] : Pennsylvania State University, 2019.
Physical Description:
1 electronic document
Additional Creators:
Yang, Jian
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Open Access.
Summary:
Although significant progress has been made in the development of bone regenerative engineering, the currently available materials are limited by their inabilities to mimic the native bone composition, lacking a defined organic-inorganic interface and limited functionalities to encourage cell-materials interaction. In the project, we sought to meet the increasing clinical needs for novel bone synthetic grafts by taking advantage of the citrate chemistry and biology to develop bioinspired metabonegenic citrate-based biomaterials for facilitated bone regeneration. First, given insufficient information is available regarding the biocompatibility of citrate and 1,8-octanediol, the monomers that used in citrate-based materials synthesis, the present project started with a systemic investigation of the cytocompatibility of 1,8-octanediol and citrate in vitro in terms of acute cytotoxicity, immune response, and long-term functionality evaluation. A diffusion model and a risk assessment model of the released citrate and 1,8-octanediol from cylindrical composites during degradation were established with an attempt to estimate the in vivo biocompatibility of the two monomers. Further, in light of the indispensable structural role of citrate in natural bone while with its biological role inevitably overlooked, we moved forward to identify soluble citrate as an osteo-promotive factor for hMSCs with an optimal concentration at 200 M, and a stage-specific response favoring supplementation during pre- and early stage differentiation. A previously unexplored link between citrate metabolism and its downstream effects on osteogenic differentiation of hMSCs, named metabonegenic regulation, has been revealed. Our studies showed that extracellular citrate uptake through solute carrier family 13, member 5 (SLC13a5) supported osteogenic differentiation via regulation of energy-producing metabolic pathways, which led to elevated cell energy status to fuel osteo-differentiation of hMSCs with high metabolic demands. We next identified citrate and phosphoserine (PSer) as a synergistic pair in polymeric design, exhibiting concerted action not only in metabonegenic potential for orthopedic regeneration, but also in facile reactivity into a fluorescent system for materials tracking and imaging. We herein designed a novel, citrate/phosphoserine-based photoluminescent biodegradable polymer (BPLP-PSer), which was lastly fabricated into BPLP-PSer/hydroxyapatite composite microparticulate scaffolds, demonstrating significant improvements in bone regeneration and tissue response in rat femoral condyle and cranial defect models. It is our belief that the present study may inspire the development of new generations of bioinspired biomaterials that better recapitulate the metabolic microenvironments of stem cells to meet the dynamic needs of cellular growth, differentiation and maturation, so as to tissue engineering.
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Dissertation Note:
Ph.D. Pennsylvania State University 2019.
Reproduction Note:
Microfilm (positive). 1 reel ; 35 mm. (University Microfilms 29267301)
Technical Details:
The full text of the dissertation is available as an Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
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