title: Scaffold-based delivery of autologous mesenchymal stem cells for mandibular distraction osteogenesis: preliminary studies in a porcine model.
abstract: OBJECTIVE
  Bone regeneration through distraction osteogenesis (DO) is promising but remarkably slow. To accelerate it, autologous mesenchymal stem cells have been directly injected to the distraction site in a few recent studies. Compared to direct injection, a scaffold-based method can provide earlier cell delivery with potentially better controlled cell distribution and retention. This pilot project investigated a scaffold-based cell-delivery approach in a porcine mandibular DO model.
  
  
  METHODS
  Eleven adolescent domestic pigs were used for two major sets of studies. The in-vitro set established methodologies to: aspirate bone marrow from the tibia; isolate, characterize and expand bone marrow-derived mesenchymal stem cells (BM-MSCs); enhance BM-MSC osteogenic differentiation using FGF-2; and confirm cell integration with a gelatin-based Gelfoam scaffold. The in-vivo set transplanted autologous stem cells into the mandibular distraction sites using Gelfoam scaffolds; completed a standard DO-course and assessed bone regeneration by macroscopic, radiographic and histological methods. Repeated-measure ANOVAs and t-tests were used for statistical analyses.
  
  
  RESULTS
  From aspirated bone marrow, multi-potent, heterogeneous BM-MSCs purified from hematopoietic stem cell contamination were obtained. FGF-2 significantly enhanced pig BM-MSC osteogenic differentiation and proliferation, with 5 ng/ml determined as the optimal dosage. Pig BM-MSCs integrated readily with Gelfoam and maintained viability and proliferative ability. After integration with Gelfoam scaffolds, 2.4-5.8×10(7) autologous BM-MSCs (undifferentiated or differentiated) were transplanted to each experimental DO site. Among 8 evaluable DO sites included in the final analyses, the experimental DO sites demonstrated less interfragmentary mobility, more advanced gap obliteration, higher mineral content and faster mineral apposition than the control sites, and all transplanted scaffolds were completely degraded.
  
  
  CONCLUSIONS
  It is technically feasible and biologically sound to deliver autologous BM-MSCs to the distraction site immediately after osteotomy using a Gelfoam scaffold to enhance mandibular DO.
authors.affiliation: Division of Orthodontics, College of Dentistry, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Zongyang
authors.initials: Z
authors.lastname: Sun
authors.forename: Boon Ching
authors.initials: BC
authors.lastname: Tee
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Kennedy
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kennedy
authors.forename: Do-Gyoon
authors.initials: DG
authors.lastname: Kim
authors.forename: Susan R
authors.initials: SR
authors.lastname: Mallery
authors.forename: Henry W
authors.initials: HW
authors.lastname: Fields
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology; D001861:Bone Regeneration; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008334:Mandible / Q000473:pathology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D019857:Osteogenesis, Distraction; D010027:Osteotomy; D013552:Swine; D013977:Tibia / Q000473:pathology; D054457:Tissue Scaffolds / Q000737:chemistry*; D055114:X-Ray Microtomography
chemical_list: D016222:Fibroblast Growth Factor 2; D000469:Alkaline Phosphatase
references.citation: Osteoarthritis Cartilage. 2002 Mar;10(3):199-206
references.pmid: 11869080
references.citation: Bone. 1992;13(1):81-8
references.pmid: 1581112
references.citation: Arch Oral Biol. 2009 Mar;54(3):205-15
references.pmid: 19144324
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 Jul;112(1):50-7
references.pmid: 21194991
references.citation: J Craniofac Surg. 2013 Mar;24(2):e169-75
references.pmid: 23524827
references.citation: Tissue Eng Part A. 2009 Feb;15(2):285-93
references.pmid: 19061430
references.citation: Plast Reconstr Surg. 2003 Dec;112(7):1841-50
references.pmid: 14663228
references.citation: Clin Orthop Relat Res. 1990 Jan;(250):8-26
references.pmid: 2403497
references.citation: Cytokine. 2010 Sep;51(3):305-10
references.pmid: 20580248
references.citation: J Craniofac Surg. 1996 Sep;7(5):347-51
references.pmid: 9133846
references.citation: Circ Cardiovasc Imaging. 2008 Sep;1(2):94-103
references.pmid: 19808526
references.citation: J Pediatr Orthop. 2009 Sep;29(6):643-9
references.pmid: 19700998
references.citation: Clin Oral Investig. 2001 Dec;5(4):214-9
references.pmid: 11800433
references.citation: Plast Reconstr Surg. 1992 Jan;89(1):1-8; discussion 9-10
references.pmid: 1727238
references.citation: Endocrinology. 1997 Oct;138(10):4456-62
references.pmid: 9322963
references.citation: J Tissue Eng Regen Med. 2008 Jul;2(5):253-62
references.pmid: 18537203
references.citation: Clin Orthop Relat Res. 1998 Oct;(355 Suppl):S41-55
references.pmid: 9917625
references.citation: Pediatr Res. 2008 May;63(5):545-51
references.pmid: 18427300
references.citation: J Bone Joint Surg Am. 2006 Jul;88(7):1442-7
references.pmid: 16818968
references.citation: Arthritis Rheum. 2002 Dec;46(12):3349-60
references.pmid: 12483742
references.citation: Cytotherapy. 2013 Jun;15(6):690-702
references.pmid: 23522867
references.citation: Physiol Res. 2011;60(3):559-71
references.pmid: 21401296
references.citation: Plast Reconstr Surg. 2010 Jun;125(6):1771-1780
references.pmid: 20517103
references.citation: Eur J Orthod. 2001 Aug;23(4):349-54
references.pmid: 11544784
references.citation: J Oral Maxillofac Surg. 2010 Jul;68(7):1543-54
references.pmid: 20561467
references.citation: Cell Cycle. 2012 Jan 15;11(2):377-83
references.pmid: 22189711
references.citation: Clin Orthop Relat Res. 1989 Feb;(239):263-85
references.pmid: 2912628
references.citation: Anat Rec (Hoboken). 2011 Jan;294(1):79-87
references.pmid: 21157918
references.citation: Clin Oral Implants Res. 2010 Jul;21(7):709-17
references.pmid: 20636725
references.citation: Transplant Proc. 2008 Mar;40(2):547-50
references.pmid: 18374125
references.citation: J Dent Res. 2008 Feb;87(2):107-18
references.pmid: 18218835
references.citation: J Orthop Res. 2012 Jul;30(7):1019-25
references.pmid: 22570220
references.citation: Arthritis Res Ther. 2003;5(1):32-45
references.pmid: 12716446
references.citation: Biull Eksp Biol Med. 1966 Jul;62(7):120-3
references.pmid: 6005495
references.citation: J Dent Res. 2006 Nov;85(11):966-79
references.pmid: 17062735
references.citation: Iowa Orthop J. 1995;15:118-40
references.pmid: 7634023
references.citation: Stem Cells. 2002;20(3):249-58
references.pmid: 12004083
references.citation: Cytotherapy. 2009;11(2):114-28
references.pmid: 19242838
references.citation: Rev Endocr Metab Disord. 2001 Jan;2(1):81-94
references.pmid: 11704982
references.citation: Oral Dis. 2007 Nov;13(6):530-7
references.pmid: 17944668
references.citation: Arch Oral Biol. 1988;33(8):597-604
references.pmid: 3254129
references.citation: Ann Plast Surg. 2010 Apr;64(4):496-502
references.pmid: 20224349
references.citation: Bone. 2004 Oct;35(4):892-8
references.pmid: 15454096
references.citation: Pediatr Neurosurg. 2008;44(3):216-20
references.pmid: 18354261
references.citation: J Bone Miner Res. 1997 Oct;12(10):1606-14
references.pmid: 9333121
references.citation: J Craniofac Surg. 2010 Sep;21(5):1565-70
references.pmid: 20856049
references.citation: Tissue Eng. 2005 Jan-Feb;11(1-2):41-9
references.pmid: 15738660
references.citation: Clin Orthop Relat Res. 2002 Jun;(399):240-6
references.pmid: 12011715
references.citation: Open Dent J. 2011 Mar 16;5:39-47
references.pmid: 21566691
references.citation: J Oral Maxillofac Surg. 2009 Nov;67(11):2412-7
references.pmid: 19837310
references.citation: Arch Oral Biol. 1976;21(8):473-80
references.pmid: 823928
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Jan;109(1):17-23
references.pmid: 19875317
references.citation: Biophys J. 2006 Oct 15;91(8):3097-112
references.pmid: 16861274
references.citation: Circulation. 2004 Mar 30;109(12):1543-9
references.pmid: 15023891
references.citation: J Orthop Res. 2008 May;26(5):713-20
references.pmid: 18050326
references.citation: J Oral Maxillofac Surg. 2010 Apr;68(4):744-50
references.pmid: 20079961
references.citation: J Bone Miner Res. 1993 Oct;8(10):1173-83
references.pmid: 8256654
references.citation: J Oral Maxillofac Surg. 2010 May;68(5):1112-24
references.pmid: 20223574
references.citation: Cell Tissue Res. 2002 Mar;307(3):321-7
references.pmid: 11904768
references.citation: Methods Enzymol. 2006;419:117-48
references.pmid: 17141054
references.citation: Cytotechnology. 2008 Jan;56(1):1-7
references.pmid: 19002835
references.citation: Neurosurgery. 2002 Mar;50(3):510-6; discussion 516-7
references.pmid: 11841718