Seven million people suffer bone fractures annually in the U.S. Musculoskeletal conditions cost $215 billion/year. These numbers are increasing as the population ages. Calcium phosphate cement (CPC) can be molded and set in-situ to form hydroxyapatite, is osteoconductive, and can be resorbed and replaced by new bone. However, the low strength of CPC limits its use to non-stress locations. In the original five years of this grant, a new group of strong and macroporous CPCs were developed. Scaffolds with long macropores for tissue ingrowth and tailored strength history were generated. Currently, pre-fabricated carriers for stem cell delivery have difficulty in seeding cells deep into the scaffold, and cannot be injected in minimally-invasive procedures. Current injectable carriers are weak and cannot be used in a wide range of load-bearing repairs. Therefore, our objective for the next five years is to develop injectable, strong, tough, and macroporous nano- apatite scaffolds with stem cell and growth factor delivery for dental, craniofacial and orthopedic applications.
In Aim 1, a new class of injectable, strong, tough and macroporous CPCs will be developed. The hypotheses are: (i) CPC composition can be tailored to improve injectability and strength;(ii) Optimizing the reinforcement and macroporosity will yield CPC with high-strain to accommodate for micro-motions within the tissues;(iii) The biomimetic nano-apatite scaffolds will enhance the colonization and differentiation of mesenchymal stem cells (MSCs) derived from rat bone marrow.
Aim 2 will investigate growth factor delivery and test these hypotheses: (i) Fast-setting, strong and macroporous CPC-growth factor carrier can be formulated;(ii) Growth factor release from CPC is proportional to pore volume fraction;(iii) Controlled sequential release of multiple growth factors can be achieved to optimize stem cell function.
Aim 3 will deliver stem cells and test these hypotheses: (i) Stem cells can be encapsulated in hydrogel and incorporated into CPC without decreasing cell viability and differentiation;(ii) Hydrogel beads can dissolve to release the cells and concomitantly create interconnected macropores in CPC;(iii) Stem cells and growth factors can be co-delivered in the same carrier to enhance cell function.
Aim 4 will evaluate bone regeneration in animal models and test these hypotheses: (i) Macroporous CPC delivering stem cells and osteogenic and angiogenic growth factors will be completely resorbed and replaced by new bone across the entire critical-sized cranial defect in rats;(ii) The injectable, strong and macroporous CPCs have much higher resorption and new bone formation rates than traditional CPC;(iii) Optimizing the scaffold composition, macroporosity, and multiple growth factors will greatly enhance bone formation via stem cells. This new generation of injectable, strong and macroporous nano-apatite scaffolds with stem cell and growth factor delivery are expected to have dental, craniofacial and orthopedic applications, with greatly enhanced bone regeneration to improve the health and quality of life for millions of people.

Public Health Relevance

Seven million people suffer bone fractures annually in the U.S. Musculoskeletal conditions cost $215 billion/year. These numbers are increasing as the population ages. This project will develop the first generation of injectable, strong, tough, macroporous, bone mineral-mimicking nano-apatite scaffolds with stem cell and multiple growth factor delivery, and will study bone regeneration in animal models. Potential applications include dental, craniofacial and orthopedic repairs. They include maxillary and mandibular reconstruction and minimally-invasive surgeries such as filling and strengthening osteoporotic bone lesions, with greatly enhanced bone healing and regeneration to improve the health and quality of life for millions of people.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014190-10
Application #
8209173
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Drummond, James
Project Start
2001-07-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
10
Fiscal Year
2012
Total Cost
$277,104
Indirect Cost
$92,368
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Liu, Xian; Wang, Ping; Chen, Wenchuan et al. (2014) Human embryonic stem cells and macroporous calcium phosphate construct for bone regeneration in cranial defects in rats. Acta Biomater 10:4484-93
Chen, Wenchuan; Thein-Han, WahWah; Weir, Michael D et al. (2014) Prevascularization of biofunctional calcium phosphate cement for dental and craniofacial repairs. Dent Mater 30:535-44
Lee, Kangwon; Weir, Michael D; Lippens, Evi et al. (2014) Bone regeneration via novel macroporous CPC scaffolds in critical-sized cranial defects in rats. Dent Mater 30:e199-207
Tang, Minghui; Chen, Wenchuan; Liu, Jun et al. (2014) Human induced pluripotent stem cell-derived mesenchymal stem cell seeding on calcium phosphate scaffold for bone regeneration. Tissue Eng Part A 20:1295-305
Melo, Mary A S; Guedes, Sarah F F; Xu, Hockin H K et al. (2013) Nanotechnology-based restorative materials for dental caries management. Trends Biotechnol 31:459-67
Melo, Mary Anne S; Weir, Michael D; Rodrigues, Lidiany K A et al. (2013) Novel calcium phosphate nanocomposite with caries-inhibition in a human in situ model. Dent Mater 29:231-40
Chen, Wenchuan; Liu, Jun; Manuchehrabadi, Navid et al. (2013) Umbilical cord and bone marrow mesenchymal stem cell seeding on macroporous calcium phosphate for bone regeneration in rat cranial defects. Biomaterials 34:9917-25
Chen, Wenchuan; Zhou, Hongzhi; Weir, Michael D et al. (2013) Human embryonic stem cell-derived mesenchymal stem cell seeding on calcium phosphate cement-chitosan-RGD scaffold for bone repair. Tissue Eng Part A 19:915-27
Liu, Jun; Chen, Wenchuan; Zhao, Zhihe et al. (2013) Reprogramming of mesenchymal stem cells derived from iPSCs seeded on biofunctionalized calcium phosphate scaffold for bone engineering. Biomaterials 34:7862-72
Liu, Jun; Xu, Hockin H K; Zhou, Hongzhi et al. (2013) Human umbilical cord stem cell encapsulation in novel macroporous and injectable fibrin for muscle tissue engineering. Acta Biomater 9:4688-97

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