Bone morphogenetic protein-2 delivered by hyaluronan-based hydrogel induces massive bone formation and healing of cranial defects in minipigs.
BACKGROUND
Reconstruction of large craniofacial bone defects is a challenge using bone transplants or alloplastic materials. The use of bone morphogenetic protein (BMP)-2 together with a suitable carrier is an attractive option that may facilitate new bone formation. The authors have developed a hydrogel that is formed in situ by the cross-linking of multifunctional hyaluronic acid and polyvinyl alcohol derivatives mixed with hydroxyapatite nanoparticles, in the presence of BMP-2. The aim of this study was to evaluate the suitability of the hydrogel as a carrier for BMP-2 in repairing critical size cranial defects in a minipig model.


METHODS
Cranial defects (2 x 4 cm) were created in 14 minipigs. The experimental groups were as follows: group 1, craniotomy and application of 5 ml of hydrogel with 1.25 mg of BMP-2 (n = 6); group 2, craniotomy and application of 5 ml of hydrogel without BMP-2 (n = 6); and group 3, craniotomy with no further treatment (n = 2).


RESULTS
After 3 months, computed tomographic and histologic examinations were performed. There was spontaneous ossification in the untreated group, but the healing was incomplete. The hydrogel alone demonstrated no further effects. The addition of 1.25 mg of BMP-2 to the hydrogel induced a greater than 100 percent increase in bone volume (p = 0.003) and complete healing of the defects. Histologic examination revealed compact lamellar bone in the BMP group without intertrabecular fibrous tissue, as was seen in the other groups. The hydrogel was resorbed completely within 3 months and, importantly, caused no inflammatory reaction.


CONCLUSIONS
The injectable hydrogel may be favorable as a BMP-2 carrier for bone reconstruction.
Docherty-Skogh
Ann-Charlott
AC
Stockholm and Uppsala, Sweden From the Stockholm Craniofacial Center, Department of Reconstructive Plastic Surgery, Karolinska University Hospital; the Departments of Molecular Medicine and Surgery and Laboratory Medicine, Karolinska Institute; the Polymer Chemistry Division, Department of Materials Chemistry, Uppsala University; and the Departments of Clinical Sciences and Biomedicine and Veterinary Public Health, Swedish University of Agricultural Sciences.
Bergman
Kristoffer
K
Waern
Marianne Jensen
MJ
Ekman
Stina
S
Hultenby
Kjell
K
Ossipov
Dimitri
D
Hilborn
Jöns
J
Bowden
Tim
T
Engstrand
Thomas
T
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage*; D003399:Craniotomy; D017886:Durapatite; D006820:Hyaluronic Acid; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D008297:Male; D008853:Microscopy; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D010012:Osteogenesis / Q000187:drug effects*; D011142:Polyvinyl Alcohol; D012886:Skull / Q000166:cytology; D013552:Swine; D013556:Swine, Miniature; D023822:Tissue Engineering / Q000379:methods*; D014057:Tomography, X-Ray Computed
D055396:Bone Morphogenetic Protein 2; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011142:Polyvinyl Alcohol; D006820:Hyaluronic Acid; D017886:Durapatite