Efficacy of the biomaterials 3wt%-nanostrontium-hydroxyapatite-enhanced calcium phosphate cement (nanoSr-CPC) and nanoSr-CPC-incorporated simvastatin-loaded poly(lactic-co-glycolic-acid) microspheres in osteogenesis improvement: An explorative multi-phase experimental in vitro/vivo study.
OBJECTIVE
The purpose of this multi-phase explorative in vivo animal/surgical and in vitro multi-test experimental study was to (1) create a 3wt%-nanostrontium hydroxyapatite-enhanced calcium phosphate cement (Sr-HA/CPC) for increasing bone formation and (2) creating a simvastatin-loaded poly(lactic-co-glycolic acid) (SIM-loaded PLGA) microspheres plus CPC composite (SIM-loaded PLGA+nanostrontium-CPC). The third goal was the extensive assessment of multiple in vitro and in vivo characteristics of the above experimental explorative products in vitro and in vivo (animal and surgical studies).
Physical and chemical properties of the prepared Sr-HA/CPC were evaluated. MTT assay and alkaline phosphatase activities, and radiological and histological examinations of Sr-HA/CPC, CPC and negative control were compared. X-ray diffraction (XRD) indicated that crystallinity of the prepared cement increased by increasing the powder-to-liquid ratio. Incorporation of Sr-HA into CPC increased MTT assay (biocompatibility) and ALP activity (P<0.05). Histomorphometry showed greater bone formation after 4weeks, after implantation of Sr-HA/CPC in 10 rats compared to implantations of CPC or empty defects in the same rats (n=30, ANOVA P<0.05). METHODS AND RESULTS PERTAINING TO SIM-LOADED PLGA MICROSPHERES+NANOSTRONTIUM-CPC COMPOSITE: After SEM assessment, the produced composite of microspheres and enhanced CPC were implanted for 8weeks in 10 rabbits, along with positive and negative controls, enhanced CPC, and enhanced CPC plus SIM (n=50). In the control group, only a small amount of bone had been regenerated (localized at the boundary of the defect); whereas, other groups showed new bone formation within and around the materials. A significant difference was found in the osteogenesis induced by the groups sham control (16.96±1.01), bone materials (32.28±4.03), nanostrontium-CPC (24.84±2.6), nanostrontium-CPC-simvastatin (40.12±3.29), and SIM-loaded PLGA+nanostrontium-CPC (44.8±6.45) (ANOVA P<0.001). All the pairwise comparisons were significant (Tukey P<0.01), except that of nanostrontium-CPC-simvastatin and SIM-loaded PLGA+nanostrontium-CPC. This confirmed the efficacy of the SIM-loaded PLGA+nanostrontium-CPC composite, and its superiority over all materials except SIM-containing nanostrontium-CPC.
Dental Biomaterials Department, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran.
Reza
R
Masaeli
Dental Biomaterials Department, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran; Iranian Tissue Bank and Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: jafarzat@sina.tums.ac.ir.
Tahereh Sadat
TS
Jafarzadeh Kashi
Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Rassoul
R
Dinarvand
Iranian Tissue Bank and Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Vahid
V
Rakhshan
Department of Oral and Maxillofacial Surgery, School of Dentistry, Shahed University, Tehran, Iran.
Hossein
H
Shahoon
Department of Periodontology, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Behzad
B
Hooshmand
Department of Oral and Maxillofacial Pathology, School of Dentistry, Shahid Beheshti Medical Science University, Tehran, Iran.
Fatemeh
F
Mashhadi Abbas
Biomaterials Group, Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran.
Majid
M
Raz
Biomaterials Group, Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran.
Alireza
A
Rajabnejad
Biomaterials Group, Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran.
Hossein
H
Eslami
Dental Biomaterials Department, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran; Department of Developmental Sciences, School of Dentistry, Marquette University, Milwaukee, WI, USA.
Kimia
K
Khoshroo
Dental Biomaterials Department, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran; Iranian Tissue Bank and Research Center, Tehran University of Medical Sciences, Tehran, Iran; Biomaterials Group, Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran; Department of Developmental Sciences, School of Dentistry, Marquette University, Milwaukee, WI, USA.
Mohammadreza
M
Tahriri
Department of Developmental Sciences, School of Dentistry, Marquette University, Milwaukee, WI, USA; Biomaterials and Advanced Drug Delivery Laboratory, School of Medicine, Stanford University, Palo Alto, CA, USA.
Lobat
L
Tayebi
D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry* / Q000494:pharmacology; D001847:Bone Diseases / Q000188:drug therapy / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002130:Calcium Phosphates / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D006882:Hydroxyapatites / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D008863:Microspheres; D053761:Nanocomposites / Q000737:chemistry*; D010012:Osteogenesis / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000737:chemistry*; D013324:Strontium / Q000737:chemistry
D001672:Biocompatible Materials; D002130:Calcium Phosphates; D004337:Drug Carriers; D006882:Hydroxyapatites; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D019821:Simvastatin; D013324:Strontium
Biomaterials; Bone formation; Brushite; Calcium phosphate cement (CPC); Drug delivery systems; Hydroxyapatite; Poly(lactic-co-glycolic acid) microspheres; Simvastatin; Strontium