Substituted calcium phosphates (CaPs) are vital materials for the treatment of bone diseases and repairing and replacement of defects in human hard tissues. In this paper, we present some applications of the rarely used pulsed electron paramagnetic resonance (EPR) and hyperfine interaction spectroscopy approaches [namely, electron spin-echo envelope modulation (ESEEM) and electron–electron double-resonance detected nuclear magnetic resonance (EDNMR)] to investigate synthetic CaPs (hydroxyapatite, tricalcium, and octacalcium phosphate) doped with various cations (Li+, Na+, Mn2+, Cu2+, Fe3+, and Ba2+). These resonance techniques provide reliable tools to obtain unique information about the presence and localization of impurity centers and values of hyperfine and quadrupole tensors. We show that revealed in CaPs by EPR techniques, radiation-induced stable nitrogen-containing species and carbonate radicals can serve as sensitive paramagnetic probes to follow CaPs’ structural changes caused by cation doping. The most pulsed EPR, ESEEM, and EDNMR spectra can be detected at room temperature, reducing the costs of the measurements and facilitating the usage of pulsed EPR techniques for CaP characterization.
Octacalcium phosphate (OCP), a new-generation bone substitute material, is a considered precursor of the biological bone apatite. The two-layered structure of OCP contains the apatitic and hydrated layers and is intensively involved in ion-exchange surface reactions, which results in OCP hydrolysis to hydroxyapatite and adsorption of ions or molecular groups presented in the environment. During various in vitro procedures, such as biomaterial solubility, additive release studies, or the functionalization technique, several model solutions are applied. The composition of the environmental solution affects the degree and rate of OCP hydrolysis, its surface reactivity, and further in vitro and in vivo properties. The performed study was aimed to track the structural changes of OCP-based materials while treating in the most popular model solutions of pH values 7.2−7.4: simulated body fluid (SBF), Dulbecco's phosphate-buffered saline (DPBS), supersaturated calcification solution (SCS), normal saline (NS), and Dulbecco's modified Eagle's medium (DMEM). Various degrees of OCP hydrolysis and/or precipitate formation were achieved through soaking initial OCP granules in the model solutions. Detailed data of X-ray diffraction, Fourier-transform infrared spectroscopy, atomic emission spectrometry with inductively coupled plasma, and scanning electron microscopy are presented. Cultivation of osteosarcoma cells was implemented on OCP pre-treated in DMEM for 1−28 days. It was shown that NS mostly degraded the OCP structure. DPBS slightly changed the OCP structure during the first treatment term, and during further terms, the crystals got thinner and OCP hydrolysis took place. Treatment in SBF and SCS caused the precipitate formation along with OCP hydrolysis, with a larger contribution of SCS solution to precipitation. Pre-treating in DMEM enhanced the cytocompatibility of materials. As a result, on performing the in vitro procedures, careful selection of the contact solution should be made to avoid the changes in materials structure and properties and get adequate results.
Bones are the fourth most frequent site of metastasis from malignant tumors, including breast cancer, prostate cancer, melanoma, etc. The bioavailability of bone tissue for chemotherapy drugs is extremely low. This requires a search for new approaches of targeted drug delivery to the tumor growth zone after surgery treatment. The aim of this work was to develop a method for octacalcium phosphate (OCP) bone graft functionalization with the cytostatic drug cisplatin to provide the local release of its therapeutic concentrations into the bone defect. OCP porous ceramic granules (OCP ceramics) were used as a platform for functionalization, and bisphosphonate zoledronic acid was used to mediate the interaction between cisplatin and OCP and enhance their binding strength. The obtained OCP materials were studied using scanning electron and light microscopy, high-performance liquid chromatography, atomic emission spectroscopy, and real-time PCR. In vitro and in vivo studies were performed on normal and tumor cell lines and small laboratory animals. The bioactivity of initial OCP ceramics was explored and the efficiency of OCP functionalization with cisplatin, zoledronic acid, and their combination was evaluated. The kinetics of drug release and changes in ceramics properties after functionalization were studied. It was established that zoledronic acid changed the physicochemical and bioactive properties of OCP ceramics and prolonged cisplatin release from the ceramics. In vitro and in vivo experiments confirmed the biocompatibility, osteoconductivity, and osteoinductivity, as well as cytostatic and antitumor properties of the obtained materials. The use of OCP ceramics functionalized with a cytostatic via the described method seems to be promising in clinics when primary or metastatic tumors of the bone tissue are removed.
Recent approaches to the calcium phosphate (CaP) materials functionalization with drugs and biomolecules have been actively developed for bone defect reconstruction. However, the current techniques are low efficient in context of drug incorporation and non-controlled release from the materials. Eventually, continuous therapeutic effect in bone defect area couldn’t be achieved. The aim of this work was to develop an effective method for biologically active molecules incorporation onto the surface of CаP materials, and to study the dynamics of its release. Octacalcium phosphate (OCP), β-tricalcium phosphate (β-TCP) and β-tricalcium phosphate with biomimetic calcium phosphate layer (β-TCPmod.) were used as ceramic bioactive carriers. Bovine serum albumin (BSA) was used as a model compounds. BSA incorporation on the ceramics surface was performed by biomimetic co-precipitation from several buffer solutions containing the incorporated compound. The efficiency of biomolecules incorporation was evaluated by measuring BSA concentrations in solutions before and after materials incubation. The release of the incorporated molecules from the materials was investigated for 6 days. The structure and composition of the obtained materials were studied by application of XRD, FTIR, SEM, BET methods. It was shown that the OCP specific surface (surface area, (SBET)) was almost in 12 times higher than SBET of β-TCP. By using biomimetic approach the increase of β-TCP surface area in 1.6 times was achieved; this enhanced protein incorporation more than 3 times. The BSA biomimetic co-precipitation together with CaP on the OCP surface proved to be more effective than its adsorption from salt free solutions. The study of BSA release revealed that only 45% of loaded albumin released during 6 days of observation. Therefore, the effective method of CaP functionalization was developed. Based on biomolecules incorporation by biomimetic co-precipitation from CaP solutions, it provided a low rate of its release.
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