Localized delivery of Sr-doped mesoporous silica nanoparticles embedded in cryogels with adipose-derived stem cells promotes craniofacial bone regeneration in an osteoporotic rat model

Abstract

BackgroundCraniofacial bone defects are considered difficult to treat in osteoporosis individuals. Strontium (Sr) has been proven therapeutically beneficial for osteoporotic patients by multiple studies. Systemically administered, strontium may cause unfavorable adverse effects, but local application is promising. In this study, mesoporous silica nanoparticles (MSN) were used as nanocarriers of strontium, embedded into the hydrogel scaffold along with adipose-derived stem cells under local administration to evaluate its bone regenerating potential in osteoporotic rat model.MethodsMesoporous silica nanoparticles (MSN) and Sr-doped MSN (MSN-Sr) were synthesized using a cetyltrimethylammonium bromide-templated method with tetraethyl orthosilicate. Nanoparticles were characterized by inductively coupled plasma mass spectrometry, transmission electron microscope, dynamic light scattering nano-analyzer, and X-ray photoelectron spectrometer. Gelatin-based cryogels containing these nanoparticles were fabricated through crosslinking and freeze-drying, and evaluated for physicochemical properties, porosity, degradation, thermal stability, and swelling. Rat adipose-derived stem cells (ASCs) were seeded onto cryogels for osteogenic analysis by scanning electron microscope, field emission scanning electron microscope/energy dispersive spectrometer, and quantitative polymerase chain reaction (qPCR). In vivo, ASC-cryogels were implanted in nude mice and osteoporotic rats, with bone regeneration evaluated by micro-CT, histology, and immunohistochemistry.ResultsThe release profile of Sr-doped MSN was verified, and its pore volume and structure were evaluated. After MSNs were embedded into hydrogel, the physiochemistry characteristics including porosity, thermal stability, degradation, and swelling ability showed optimal results. For in vivo study in subdermal layer of nude mice, MSN-Sr cryogel scaffolds cultured with adipose-derived mesenchymal stem cell showed increase expression of osteogenic-related mRNA, including type I collegen, catenin beta 1, and Runx2. MSN-Sr embedded cryogels (G-MSN-Sr) were placed in bone defect of osteoporosis rats. Surface area of the bone defects showed significant decrease in the G-MSN-Sr group compared to pure gelatin gel group and MSN doped cryogel group. Histological analysis of bone formation using H&E, ALP, Masson's Trichrome, and Osteocyte stains further validated the bone regeneration.ConclusionMSN is a feasible nanocarrier for the delivery of Sr ion. Hydrogel scaffolds embedded with strontium doped MSN and mesenchymal stem cells showed promising bone regenerating potential in osteoporotic rat model.