Calcium phosphate-like bone substitute materials have a long history of successful orthopedic applications such as bone void filling and augmentation. Based on the clinical indications, these materials may be loaded with active agents by adsorption offering a perspective for providing innovative drug-delivery systems. The highly effective bisphosphonate zoledronic acid (ZOL) demonstrated a strong affinity to biominerals and is known to significantly reduce osteoclastic activity. Support of early bone formation and reduction of bone resorption can be promoted after implantation of bioceramics releasing ZOL. The aim of this study was to develop an easy to handle approach to combine ZOL with bone substitutes by use of a dipping technique. The properties of three different materials were investigated by using a number of physicochemical methods such as light microscopy, scanning electron microscopy (SEM), dynamic vapor sorption (DVS), true density, and surface area measurement to evaluate the feasibility of being potential drug carriers. Besides physicochemical characterization, the bone substitutes were evaluated by their ZOL-loading capacity in a time- and concentration-dependent manner. Additionally, the materials were assessed as release systems in an in vitro study. Acontrolled ZOL load in a range of 0.04–1.86 µg/mg material and a release of 0.02–0.18 µg/mg within 30 min is demonstrated. The findings support using the investigated bioceramics as carrier systems to release ZOL. Overall, the results create the base for further development of drug-delivery systems with controlled drug loading and prolonged release and need to be further analyzed in an in vivo study.
FrostHM. The biology of fracture healing. An overview for clinicians. Part II. Clin Orthop Relat Res1989; 248: 294–309.
2.
KurashinaKKuritaHHiranoMKotaniAKleinCPde GrootK. In vivo study of calcium phosphate cements: Implantation of an alpha-tricalcium phosphate/dicalcium phosphate dibasic/tetracalcium phosphate monoxide cement paste. Biomaterials1997; 18(7): 539–543.
3.
ApeltDTheissFEl-WarrakAOZlinszkyKBettschart-WolfisbergerRBohnerM. In vivo behavior of three different injectable hydraulic calcium phosphate cements. Biomaterials2004; 25(7–8): 1439–1451.
4.
FriedmanCDCostantinoPDTakagiSChowLC. BoneSource hydroxyapatite cement: A novel biomaterial for craniofacial skeletal tissue engineering and reconstruction. J Biomed Mater Res1998; 43(4): 428–432.
5.
LarssonSBauerTW. Use of injectable calcium phosphate cement for fracture fixation: A review. Clin Orthop Relat Res2002; 395: 23–32.
6.
OomsEMWolkeJGvan de HeuvelMTJeschkeBJansenJA. Histological evaluation of the bone response to calcium phosphate cement implanted in cortical bone. Biomaterials2003; 24(6): 989–1000.
7.
SchmitzJPHollingerJO. The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res1986; 205: 299–308.
8.
LarssonS. Calcium phosphates: What is the evidence?JOrthop Trauma24(Suppl. 1): S41–S45.
9.
GuoDXuKHanY. The in situ synthesis of biphasic calcium phosphate scaffolds with controllable compositions, structures, and adjustable properties. J Biomed Mater Res2009; 88(1): 43–52.
10.
JoschekSNiesBKrotzRGoferichA. Chemical and physicochemical characterization of porous hydroxyapatite ceramics made of natural bone. Biomaterials2000; 21(16): 1645–1658.
11.
GinebraMPTraykovaTPlanellJA. Calcium phosphate cements as bone drug delivery systems: A review. JControl Release2006; 113(2): 102–110.
12.
PaulWSharmaCP. Ceramic drug delivery: Aperspective. J Biomater Appl2003; 17(4): 253–264.
13.
JosseSFaucheuxCSoueidanAGrimandiGMassiotDAlonsoB. Novel biomaterials for bisphosphonate delivery. Biomaterials2005; 26(14): 2073–2080.
14.
ArkfeldDGRubensteinE. Quest for the Holy Grail to cure arthritis and osteoporosis: Emphasis on bone drugdelivery systems. Adv Drug Deliv Rev2005; 57(7): 939–944.
15.
HjertenSLevinOTiseliusA. Protein chromatography on calcium phosphate columns. Arch Biochem Biophys1956; 65(1): 132–155.
16.
UristMRHuoYKBrownellAGHohlWMBuyskeJLietzeA. Purification of bovine bone morphogenetic protein by hydroxyapatite chromatography. Proc Natl Acad Sci. U S A1984; 81(2): 371–375.
17.
GaoYZouSLiuXBaoCHuJ. The effect of surface immobilized bisphosphonates on the fixation of hydroxyapatite-coated titanium implants in ovariectomized rats. Biomaterials2009; 30(9): 1790–1796.
18.
FleischH. Bisphosphonates: Mechanisms of action. Endocrine Rev1998; 19(1): 80–100.
19.
DenissenHvan BeekELowikCPapapoulosSvan den HooffA. Ceramic hydroxyapatite implants for the release of bisphosphonate. Bone Miner1994; 25(2): 123–134.
20.
ReinholzGGGetzBPedersonLSandersESSubramaniamMIngleJN. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res2000; 60(21): 6001–6007.
21.
GreenJR. Bisphosphonates: Preclinical review. The Oncologist2004; 9(Suppl. 4): 3–13.
22.
GreinerSKadow-RomackerALubberstedtMSchmidmaierGWildemannB. The effect of zoledronic acid incorporated in a poly(D,L-lactide) implant coating on osteoblasts in vitro. J Biomed Mater Res2007; 80(4): 769–775.
23.
MiettinenSSJaatinenJPelttariALappalainenRMonkkonenJVenesmaaPK. Effect of locally administered zoledronic acid on injury-induced intramembranous bone regeneration and osseointegration of a titanium implant in rats. J Orthop Sci2009; 14(4): 431–436.
24.
GreinerSKadow-RomackerAWildemannBSchwabePSchmidmaierG. Bisphosphonates incorporated in a poly(D,L-lactide) implant coating inhibit osteoclast like cells in vitro. J Biomed Mater Res2007; 83(4): 1184–1191.
25.
HnatyszynHJKossovskyNGelmanASponslerE. Drug delivery systems for the future. PDA J Pharm Sci Technol1994; 48(5): 247–254.
26.
SikavitsasVITemenoffJSMikosAG. Biomaterials and bone mechanotransduction. Biomaterials2001; 22(19): 2581–2593.
27.
FrentzenMOsbornJFNoldenR. Use of porous hydroxyapatite in systematic periodontal treatment. A 2-year clinical study. Dtsch Zahnarztl Z1988; 43(6): 713–718.
28.
FrentzenMOsbornJFNoldenR. Clinical example of porous hydroxyapatite ceramic in setting of systematic periodontal treatment (III). Quintessenz1987; 38(11): 1857–1866.
29.
FrentzenMOsbornJFNoldenR. Clinical example of porous hydroxyapatite ceramic in setting of systematic periodontal treatment (II). Quintessenz1987; 38(10): 1671–1679, 1682.
30.
FrentzenMOsbornJFNoldenR. Clinical example of porous hydroxyapatite ceramic in setting of systematic periodontal treatment (I). Quintessenz1987; 38(9): 1509–1519.
31.
MisraDNBowenRLMattamalGJ. Surface area of dental enamel, bone, and hydroxyapatite: Chemisorption from solution. Calcif Tissue Res1978; 26(2): 139–142.
32.
WoodNV. Jr. Specific surfaces of bone, apatite, enamel, and dentine. Science1947; 105(2733): 531–532.
33.
SaalfeldUMeenenNMJuresTTSaalfeldH. Solubility behaviour of synthetic hydroxyapatites in aqueous solution: Influence of amorphous constituents on pH value. Biomaterials1994; 15(11): 905–908.
34.
SharpeJRSammonsRLMarquisPM. Effect of pH on protein adsorption to hydroxyapatite and tricalcium phosphate ceramics. Biomaterials1997; 18(6): 471–476.
35.
AbergJBrohedeUMihranyanAStrommeMEngqvistH. Bisphosphonate incorporation in surgical implant coatings by fast loading and co-precipitation at low drug concentrations. J Mater Sci2009; 20(10): 2053–2061.
36.
PeterBPiolettiDPLaibSBujoliBPiletPJanvierP. Calcium phosphate drug delivery system: Influence of local zoledronate release on bone implant osteointegration. Bone2005; 36(1): 52–60.
37.
AspenbergP. Bisphosphonates and implants: An overview. Acta Orthop2009; 80(1): 119–123.
38.
SeoSWChoSKStorerSKLeeFY. Zoledronate reduces unwanted bone resorption in intercalary bone allografts. Int Orthop2009; 34(4): 599–603.
39.
GreinerSHWildemannBBackDAAlidoustMSchwabePHaasNP. Local application of zoledronic acid incorporated in a poly(D,L-lactide)-coated implant accelerates fracture healing in rats. Acta Orthop2008; 79(5): 717–725.
40.
PanBToLBFarrugiaANFindlayDMGreenJGronthosS. The nitrogen-containing bisphosphonate, zoledronic acid, increases mineralisation of human bone-derived cells in vitro. Bone2004; 34(1): 112–123.
41.
SchindelerALittleDG. Osteoclasts but not osteoblasts are affected by a calcified surface treated with zoledronic acid in vitro. Biochem Biophys Res Commun2005; 338(2): 710–716.
42.
TanzerMKarabaszDKrygierJJCohenRBobynJD. The Otto Aufranc award: Bone augmentation around and within porous implants by local bisphosphonate elution. Clin Orthop Relat Res2005; 441: 30–39.
43.
BobynJDMcKenzieKKarabaszDKrygierJJTanzerM. Locally delivered bisphosphonate for enhancement of bone formation and implant fixation. J Bone Joint Surg2009; 91(Suppl. 6): 23–31.
44.
EspositoMHirschJMLekholmUThomsenP. Biological factors contributing to failures of osseointegrated oral implants. (I). Success criteria and epidemiology. Eur J Oral Sci1998; 106(1): 527–551.
45.
EspositoMHirschJMLekholmUThomsenP. Biological factors contributing to failures of osseointegrated oral implants. (II). Etiopathogenesis. Eur J Oral Sci1998; 106(3): 721–764.
