Bone defects cause functional deficits as well as disfigurement that can severely harm the patients'physical and psychological health. Unlike bone fractures that are usually treated immediately after injury, most cranial-facial bone defects are treated after the initial pathological condition or traumatic injury has been resolved. Thus, methods to heal these defects must promote bone formation at a quiescent site while prohibiting growth of soft tissues into the defect site that stop bone formation. One difficult aspect of bone tissue engineering in the craniofacial and dental areas is complications from soft tissue ingrowth into the active site of new bone formation. Soft tissue ingrowth into a device essentially halts further bone formation. This host response creates a challenge for tissue engineering in that any solution must limit soft tissue interference without impairing bone formation or inducing so much new bone formation that the desired functional or aesthetic morphology of the new bone is not achieved. Our goal is to engineer a device that balances rapid bone formation with limited soft tissue interference that can augment or heal cranial-facial bone defects. Having shown that arachidonic acid metabolism can modulate inflammation related to bone formation, we propose to develop a device that separates cyclooxygenase inhibition (limits soft tissue growth) from 5-lipoxygenase inhibition (promotes osteoblast activity and bone formation). We will use a poly (anhydride-ester) of salicylic acid (PolyAspirin) to inhibit cyclooxygenase and a 5-lipoxygenase inhibitor within a calcium sulfate carrier and calcium phosphate scaffold to promote osteogenesis. The use of small molecule inhibitors as the active ingredients of this device will allow production of low-cost, long shelf-life devices for treating cranial-facial bone defects.

Public Health Relevance

Bony defects of the skull and other cranial-facial bones are common traumatic and pathological injuries. Current methods to treat cranial-facial bone defects are associated with second-site morbidity from autograft harvest, use of potentially infectious allograft bone, poor long-term efficacy, technically challenging procedures, and high costs. Our goal is to develop a low-cost, easy to use and store, tissue engineering device to treat cranial-facial bone defects that accelerates healing by modulating the host inflammatory response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019926-04
Application #
8274327
Study Section
Special Emphasis Panel (ZDE1-RW (11))
Program Officer
Lumelsky, Nadya L
Project Start
2009-06-17
Project End
2013-06-30
Budget Start
2012-06-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$596,991
Indirect Cost
$214,304
Name
University of Medicine & Dentistry of NJ
Department
Biochemistry
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Lin, Hsuan-Ni; O'Connor, J Patrick (2014) Immunohistochemical localization of key arachidonic acid metabolism enzymes during fracture healing in mice. PLoS One 9:e88423
Stebbins, Nicholas D; Ouimet, Michelle A; Uhrich, Kathryn E (2014) Antibiotic-containing polymers for localized, sustained drug delivery. Adv Drug Deliv Rev 78:77-87
Mitchell, Ashley; Kim, Brian; Cottrell, Jessica et al. (2014) Development of a guided bone regeneration device using salicylic acid-poly(anhydride-ester) polymers and osteoconductive scaffolds. J Biomed Mater Res A 102:655-64
Rosario-Melendez, Roselin; Ouimet, Michelle A; Uhrich, Kathryn E (2013) Formulation of salicylate-based poly(anhydride-ester) microspheres for short- and long-term salicylic acid delivery. Polym Bull (Berl) 70:343-351
Ouimet, Michelle A; Stebbins, Nicholas D; Uhrich, Kathryn E (2013) Biodegradable coumaric acid-based poly(anhydride-ester) synthesis and subsequent controlled release. Macromol Rapid Commun 34:1231-6
Su, Bailey; O'Connor, J Patrick (2013) NSAID therapy effects on healing of bone, tendon, and the enthesis. J Appl Physiol (1985) 115:892-9
Rosario-Melendez, Roselin; Yu, Weiling; Uhrich, Kathryn E (2013) Biodegradable polyesters containing ibuprofen and naproxen as pendant groups. Biomacromolecules 14:3542-8
Ouimet, Michelle A; Griffin, Jeremy; Carbone-Howell, Ashley L et al. (2013) Biodegradable ferulic acid-containing poly(anhydride-ester): degradation products with controlled release and sustained antioxidant activity. Biomacromolecules 14:854-61