Regeneration of craniofacial and skeletal bone defects has widely been achieved with bone grafting procedures. The literature suggests that there are more than one million cases of skeletal defects per year that require bone-graft procedures. Autologous bone has been considered the gold standard for such procedures. However, there are several disadvantages associated with this modality of treatment. The ability of stem cells to give rise to multiple specialized cell types along with their extensive distributin in many adult tissues make them an attractive target for application in bone tissue engineering. Dental MSCs such as stem cells from human exfoliated deciduous teeth (SHED) are attractive postnatal stem cells because they possess self-renewal and multilineage differentiation capacity as well as superior osteogenic properties compared to bone marrow mesenchymal stem cells (BMMSCs). The central hypothesis of this proposal is that an RGD-coupled alginate hydrogel scaffold can protect the encapsulated dental MSCs (SHED) from immune cells and cytokines in the early stages of transplantation, providing an appropriate physiochemical microenvironment for enhanced MSC viability and osteo-differentiation. It is hypothesized that these interactions are crucial in the osteogenic lineage commitment of dental MSCs. This proposal addresses a very important unresolved question: what is the role of the microenvironment (biomaterial) in dental MSC-immune cell interplay, fate determination of MSCs and osteogenic differentiation of MSCs. The validity of the central hypothesis will be tested by 1) determining how RGD-coupled alginate hydrogel as an encapsulating scaffold can interfere with the interplay between immune cells and dental MSCs in bone regeneration;2) investigating the detailed mechanism of immune cell-induced MSC apoptosis;3) developing a 3D alginate-based delivery system with anti-inflammatory function in the presence of indomethacin and 4) evaluating the effects of this delivery system on the bone regeneration properties of encapsulated MSCs. Upon successful completion of the Specific Aims, this project will improve our understanding of dental MSC-host immune interactions and introduce a promising MSC-based treatment approach for maxillofacial and skeletal defects. The result will be a novel injectable and biodegradable scaffold, presenting an innovative treatment modality for bone regeneration with therapeutic properties to manage local inflammatory reactions.

Public Health Relevance

There are many disadvantages associated with current bone regeneration therapies (e.g. bone grafts) in reconstructive dentistry and regenerative medicine. In this proposal, an RGD-coupled alginate hydrogel will be formulated to protect MSCs from host immune cells'assault and tuned by local administration of an anti-inflammatory agent to improve the bone regeneration potential of MSCs. This proposal will lay the foundation for a novel therapeutic modality for the repair and regeneration of maxillofacial and skeletal bone defects based on dental mesenchymal stem cells encapsulated in a hydrogel scaffold, with anti-inflammatory therapeutic properties. The long-term goal of this proposal is to provide clinicians with the means to achieve better patient outcomes in dental and orthopedic hard tissue regeneration applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DE023825-01A1
Application #
8764532
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
King, Lynn M
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Ansari, Sahar; Chen, Chider; Xu, Xingtian et al. (2016) Muscle Tissue Engineering Using Gingival Mesenchymal Stem Cells Encapsulated in Alginate Hydrogels Containing Multiple Growth Factors. Ann Biomed Eng 44:1908-20
Ansari, Sahar; Phark, Jin-Ho; Duarte Jr, Sillas et al. (2016) Biomechanical analysis of engineered bone with anti-BMP2 antibody immobilized on different scaffolds. J Biomed Mater Res B Appl Biomater 104:1465-73
Diniz, Ivana M A; Chen, Chider; Ansari, Sahar et al. (2016) Gingival Mesenchymal Stem Cell (GMSC) Delivery System Based on RGD-Coupled Alginate Hydrogel with Antimicrobial Properties: A Novel Treatment Modality for Peri-Implantitis. J Prosthodont 25:105-15
Ansari, Sahar; Freire, Marcelo; Choi, Moon G et al. (2015) Effects of the orientation of anti-BMP2 monoclonal antibody immobilized on scaffold in antibody-mediated osseous regeneration. J Biomater Appl 30:558-67
Diniz, Ivana M A; Chen, Chider; Xu, Xingtian et al. (2015) Pluronic F-127 hydrogel as a promising scaffold for encapsulation of dental-derived mesenchymal stem cells. J Mater Sci Mater Med 26:153
Moshaverinia, Alireza; Chen, Chider; Xu, Xingtian et al. (2015) Regulation of the Stem Cell-Host Immune System Interplay Using Hydrogel Coencapsulation System with an Anti-Inflammatory Drug. Adv Funct Mater 25:2296-2307