title: Effect of cell origin and timing of delivery for stem cell-based bone tissue engineering using biologically functionalized hydrogels.
abstract: Despite progress in bone tissue engineering, the healing of critically sized diaphyseal defects remains a clinical challenge. A stem cell-based approach is an attractive alternative to current treatment techniques. The objective of this study was to examine the ability of adult stem cells to enhance bone formation when co-delivered with the osteoinductive factor bone morphogenetic protein-2 (BMP-2) in a biologically functionalized hydrogel. First, adipose and bone marrow-derived mesenchymal stem cells (ADSCs and BMMSCs) were screened for their potential to form bone when delivered in an RGD functionalized alginate hydrogel using a subcutaneous implant model. BMMSCs co-delivered with BMP-2 produced significantly more mineralized tissue compared with either ADSCs co-delivered with BMP-2 or acellular hydrogels containing BMP-2. Next, the ability of BMMSCs to heal a critically sized diaphyseal defect with a nonhealing dose of BMP-2 was tested using the alginate hydrogel as an injectable cell carrier. The effect of timing of therapeutic delivery on bone regeneration was also tested in the diaphyseal model. A 7 day delayed injection of the hydrogel into the defect site resulted in less mineralized tissue formation than immediate delivery of the hydrogel. By 12 weeks, BMMSC-loaded hydrogels produced significantly more bone than acellular constructs regardless of immediate or delayed treatment. For immediate delivery, bridging of defects treated with BMMSC-loaded hydrogels occurred at a rate of 75% compared with a 33% bridging rate for acellular-treated defects. No bridging was observed in any of the delayed delivery samples for any of the groups. Therefore, for this cell-based bone tissue engineering approach, immediate delivery of constructs leads to an overall enhanced healing response compared with delayed delivery techniques. Further, these studies demonstrate that co-delivery of adult stem cells, specifically BMMSCs, with BMP-2 enhances bone regeneration in a critically sized femoral segmental defect compared with acellular hydrogels containing BMP-2.
authors.affiliation: 1 Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology , Atlanta, Georgia .
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Dosier
authors.forename: Brent A
authors.initials: BA
authors.lastname: Uhrig
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Willett
authors.forename: Laxminarayanan
authors.initials: L
authors.lastname: Krishnan
authors.forename: Mon-Tzu Alice
authors.initials: MT
authors.lastname: Li
authors.forename: Hazel Y
authors.initials: HY
authors.lastname: Stevens
authors.forename: Zvi
authors.initials: Z
authors.lastname: Schwartz
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Boyan
authors.forename: Robert E
authors.initials: RE
authors.lastname: Guldberg
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000464:Alginates / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects / Q000502:physiology*; D002113:Calcification, Physiologic / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018483:Diaphyses / Q000187:drug effects / Q000473:pathology; D020723:Glucuronic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006603:Hexuronic Acids / Q000494:pharmacology; D020100:Hydrogels / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020007:Implants, Experimental; D007211:Indoles / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D040521:Subcutaneous Tissue / Q000187:drug effects; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*; D055114:X-Ray Microtomography; D000097382:CD68 Molecule
chemical_list: D000464:Alginates; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D020723:Glucuronic Acid; D049452:Green Fluorescent Proteins; D006603:Hexuronic Acids; D020100:Hydrogels; D007211:Indoles; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C007293:DAPI