Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures. Current therapy involves extensive surgical intervention including fronto-orbital advancement and radical calvarial bone repositioning. Although the current techniques often successfully restore normal brain growth vectors, increase intracranial volume, and decrease intracranial pressure, the surgical intervention is extensive and the outcomes are variable. Furthermore, the calvarial bone regenerates quickly and can refuse shortly after surgery. When refusion occurs, secondary surgeries are required which increases patient morbidity and mortality. Our group has set out to radically improve the treatment of craniosynostosis by minimizing the extent of surgical intervention, improving outcomes, and inhibiting the occurrence of refusion. We are in a unique position to design a novel therapy that could be tailored to improve the treatment of children who present with craniosynostosis, regardless of the molecular or genetic etiology. To determine the proper growth factor cues, doses, and cell fraction, we will employ stem cell characterization using a novel inkjet printing technology to assess the osteogenic potential of skeletal muscle-derived and adipose-derived cells isolated from a rabbit model of human nonsyndromic coronal suture synostosis (Aim #1A). Based on our findings from Aim #1A, we will create a suture replacement scaffold using our inkjet printing to create spatially-defined patterns of immobilized growth factors that will reproducibly form two regions of bone separated by an interdigitating non- bone region in vitro (Aim #1B). We will then test the effectiveness of our suture replacement scaffolds to improve the surgical treatment of rabbits with craniosynostosis in vivo (Aim #2). To demonstrate the clinical relevance of this approach in humans, we will employ similar progenitor cell characterization as in Aim #1 on cells derived from skeletal muscle and adipose of children with craniosynostosis and assess these cells'responsiveness to our suture replacement scaffolds in vitro (Aim #3). By completing these Aims, we will make significant progress in improving the surgical treatment of craniosynostosis. Furthermore, the development of technologies that can be used to both characterize stem cell differentiation potential and to spatially control the differentiation of multipotent cells will have broad impact in the field of tissue engineering. Public Health Relevance Statement (Provided by Applicant): Project Narrative Craniosynostosis is the term given to the premature fusion of one or more of the calvarial sutures. Fusion of a suture results from a failure of correct pattern formation between bone and non-bone tissues. We have set out to improve the surgical management of children with craniosynostosis through tissue engineering. We will develop emergent inkjet printing technology to characterize progenitor cells and to reproducibly pattern tissue formation in vivo. By patterning cell differentiation, it may be possible to create tissues that function similarly to normal, unfused sutures. The technology that will be developed in performing the proposed work will have broad impact on the field of stem cell biology, the application of tissue engineering, and on the treatment of children with craniosynostosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019430-05
Application #
8268322
Study Section
Special Emphasis Panel (ZEB1-OSR-D (M1))
Program Officer
Drummond, James
Project Start
2008-08-15
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$360,846
Indirect Cost
$86,388
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Cray Jr, James; Cooper, Gregory M (2013) Regression modeling to inform cell incorporation into therapies for craniosynostosis. J Craniofac Surg 24:226-31
Cooper, Gregory M; Durham, Emily L; Cray Jr, James J et al. (2011) Direct comparison of progenitor cells derived from adipose, muscle, and bone marrow from wild-type or craniosynostotic rabbits. Plast Reconstr Surg 127:88-97
Cray Jr, James J; Gallo, Phillip H; Durham, Emily L et al. (2011) Molecular analysis of coronal perisutural tissues in a craniosynostotic rabbit model using polymerase chain reaction suppression subtractive hybridization. Plast Reconstr Surg 128:95-103
DeCesare, Gary E; Cooper, Gregory M; Smith, Darren M et al. (2011) Novel animal model of calvarial defect in an infected unfavorable wound: reconstruction with rhBMP-2. Plast Reconstr Surg 127:588-94
Cooper, Gregory M; Mooney, Mark P; Gosain, Arun K et al. (2010) Testing the critical size in calvarial bone defects: revisiting the concept of a critical-size defect. Plast Reconstr Surg 125:1685-92
Cooper, Gregory M; Miller, Eric D; Decesare, Gary E et al. (2010) Inkjet-based biopatterning of bone morphogenetic protein-2 to spatially control calvarial bone formation. Tissue Eng Part A 16:1749-59