title: Injectable dual-gelling cell-laden composite hydrogels for bone tissue engineering.
abstract: The present work investigated the osteogenic potential of injectable, dual thermally and chemically gelable composite hydrogels for mesenchymal stem cell (MSC) delivery in vitro and in vivo. Composite hydrogels comprising copolymer macromers of N-isopropylacrylamide were fabricated through the incorporation of gelatin microparticles (GMPs) as enzymatically digestible porogens and sites for cellular attachment. High and low polymer content hydrogels with and without GMP loading were shown to successfully encapsulate viable MSCs and maintain their survival over 28 days in vitro. GMP incorporation was also shown to modulate alkaline phosphatase production, but enhanced hydrogel mineralization along with higher polymer content even in the absence of cells. Moreover, the regenerative capacity of 2 mm thick hydrogels with GMPs only, MSCs only, or GMPs and MSCs was evaluated in vivo in an 8 mm rat critical size cranial defect for 4 and 12 weeks. GMP incorporation led to enhanced bony bridging and mineralization within the defect at each timepoint, and direct bone-implant contact as determined by microcomputed tomography and histological scoring, respectively. Encapsulation of both GMPs and MSCs enabled hydrogel degradation leading to significant tissue infiltration and osteoid formation. The results suggest that these injectable, dual-gelling cell-laden composite hydrogels can facilitate bone ingrowth and integration, warranting further investigation for bone tissue engineering.
authors.affiliation: Department of Bioengineering, Rice University, P.O. Box 1892, MS 142, Houston, TX, 77251-1892, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Vo
authors.affiliation: Department of Bioengineering, Rice University, P.O. Box 1892, MS 142, Houston, TX, 77251-1892, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Shah
authors.affiliation: Department of Bioengineering, Rice University, P.O. Box 1892, MS 142, Houston, TX, 77251-1892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Bioengineering, Rice University, P.O. Box 1892, MS 142, Houston, TX, 77251-1892, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Tatara
authors.affiliation: Department of Bioengineering, Rice University, P.O. Box 1892, MS 142, Houston, TX, 77251-1892, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, Rice University, P.O. Box 1892, MS 142, Houston, TX, 77251-1892, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Roh
authors.affiliation: Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Department of Bioengineering, Rice University, P.O. Box 1892, MS 142, Houston, TX, 77251-1892, USA; Department of Chemical and Biomolecular Engineering, Rice University, P.O. Box 1892, MS 362, Houston, TX, 77251-1892, USA. Electronic address: mikos@rice.edu.
authors.forename: A G
authors.initials: AG
authors.lastname: Mikos
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology*; D018914:Cells, Immobilized / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005780:Gelatin / Q000494:pharmacology; D020100:Hydrogels / Q000494:pharmacology*; D007267:Injections; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D008863:Microspheres; D011916:Rats, Inbred F344; D023822:Tissue Engineering / Q000379:methods*; D055114:X-Ray Microtomography
chemical_list: D020100:Hydrogels; D005780:Gelatin; D000469:Alkaline Phosphatase
keywords: Critical size cranial defect; Gelatin microparticles; Mesenchymal stem cells; Mineralization; N-isopropylacrylamide