A biphasic calcium phosphate ceramic scaffold loaded with oxidized cellulose nanofiber-gelatin hydrogel with immobilized simvastatin drug for osteogenic differentiation.

A novel bone scaffold containing bioceramic and biopolymer materials with an osteoinductive simvastatin molecule was developed to enhance bone regeneration. An oxidized cellulose nanofiber (OCNF)-Gelatin (Gel) hydrogel was loaded into a biphasic calcium phosphate (BCP) ceramic in which simvastatin was entrapped, resulting in a scaffold with both osteoconductive and osteoinductive properties. The fabricated scaffold showed interconnected porosity with micro- and macroporous orientation. After loading the OCNF-Gel (HG), the mechanical stability of the ceramic BCP scaffold was increased suitable for the application of hard tissue regeneration. Fourier-transform infrared spectroscopy showed that simvastatin was successfully coated on the BCPHG scaffolds. OCNF, with its slower degradation, may contribute to the sustained release of drug from the scaffold. Initially simvastatin was released from the scaffold at high levels, then was constantly and gradually released for up to 4 weeks. Pre-osteoblast MC3T3E1 cells were seeded on the scaffolds to investigate cell viability, morphology, and differentiation. The simvastatin-loaded BCPHG-S scaffolds showed better cell proliferation and spreading compared to other scaffolds. Immunostaining assays showed the expression of proteins responsible for osteogenic differentiation. Alkaline phosphatase and osteopontin were more highly expressed in the BCPHG-S scaffold than in other scaffolds. These results suggest that simvastatin-loaded BCPHG scaffolds provided physiological environments suitable for better osteogenic differentiation.

Osteoinductive porous biphasic calcium phosphate ceramic as an alternative to autogenous bone grafting in the treatment of mandibular bone critical-size defects.

The bone-induction capacity of a porous biphasic calcium phosphate (pBCP) using heterotopic implantation in mouse (mHI-model) and its efficacy as substitute for autograft in mandibular critical-size defect in rabbit (rabMCSD-model) was investigated. In mHI-model, pBCP was implanted into the thigh muscles and bone formation was histomorphometrically and immunohistochemically evaluated. In rabMCSD-model, 13 mm bone defects were treated with pBCP or autograft and bone repair comparatively evaluated by radiographic and histomorphometric methods. In mHI-model, formed bone and immunolabeling for bone morphogenetic protein-2 and osteopontin were observed in 90% of pBCP implanted samples after 12 weeks. In rabMCSD-model neither statistically significant difference was found in newly formed bone between pBCP and autograft groups at 4 weeks (18.8 ± 5.5% vs 27.1 ± 5.6%), 8 weeks (22.3 ± 2.7% vs 26.2 ± 5.1), and 12 weeks (19.6 ± 4.7% vs 19.6 ± 2.3%). At 12 weeks, the stability and contour of the mandible were restored in both treatments. Near tooth remaining, pBCP particles were covered by small amount of mineralized tissue exhibiting perpendicular attachments of collagen fiber bundles with histological characteristic of acellular cementum. Within the limitations of this study, it was concluded that pBCP is osteoinductive and able to stimulate the new formation of bone and cementum-like tissues in rabMCSD-model, suggesting that it may be an alternative to treatment of large bone defect and in periodontal regenerative therapy. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1546-1557, 2018.

Novel strategy for f-HAp/PVP/Ag nanocomposite synthesis from fluoro based ionic liquid assistance: Systematic investigations on its antibacterial and cytotoxicity behaviors.

A novel biomimetic f-HAp/PVP/Ag nanocomposite was synthesized under the ionic liquid medium, which was composed of inorganic and organic nanofillers like fluor-hydroxyapatite, silver nanoparticles and polyvinyl pyrrolidone. In composite synthesis, the first time we were used fluorine based ionic liquid for the fluorine contents on the fluor-hydroxyapatite nanoparticles which were resulting in very good crosslinking and interfacial bonding with the PVP and Ag nanoparticles. Ionic liquid has assisted good morphological structure of both inorganic materials. The chemical interaction and crystallinity changes of the nanocomposite were evaluated by FTIR and XRD studies. The surface morphology and composition of the samples were observed by FE-SEM, HR-TEM and EDS analyses. This report reveals that the greener approach for synthesis of fluor-hydroxyapatite nanocomposite and sustained delivery of silver and fluorine ions from the fluor-hydroxyapatite surface to the bacterial surface have been reducing the bacterial growth rate which was evaluated by different pathogenic bacterial strains via different methods and it also favourable cytotoxicity effect with human osteosarcoma (MG-63) cells.

Preparation, evaluation, and first clinical use of 177Lu-labeled hydroxyapatite (HA) particles in the treatment of rheumatoid arthritis: utility of cold kits for convenient dose formulation at hospital radiopharmacy.

While radiation synovectomy (RSV) constitutes a successful paradigm for the treatment of arthritis, a major cornerstone of its success resides in the selection of appropriate radiolabeled agent. Among the radionuclide used for RSV, the scope of using (177)Lu [T1/2 = 6.65 d, Eß(max) = 497 keV, Eγ = 113 KeV (6.4%), 208 KeV (11%)] seemed to be attractive owing to its suitable decay characteristics, easy availability, and cost-effective production route. The present article describes a formulation of (177)Lu-labeled hydroxyapatite (HA) using ready-to-use kits of HA particles of 1-10 µm size range. The developed kits enable convenient one-step preparation of (177)Lu-HA (400 ± 30 MBq doses) in high radiochemical purity (>99%) and stability at hospital radiopharmacy. The preparation showed promising results in pre-clinical studies carried out in Wistar rats bearing arthritis in knee joints. In preliminary clinical investigation, significant improvement in the disease conditions was reported in 10 patients with rheumatoid arthritis of knee joints treated with 333 ± 46 MBq doses of (177)Lu-HA. The studies reveal that while (177)Lu labeled HA particles holds considerable promise as a cost-effective agent for RSV, the adopted strategy of using HA kits could be a potential step toward wider clinical utilization of radiolanthanide-labeled HA particles.

The use of 185 MBq and 740 MBq of 153-samarium hydroxyapatite for knee synovectomy in haemophilia.

The penetration of beta energy of 153-samarium ((153) Sm) (0.8 MeV) is not only appropriate for synovectomy of median articulations but is possible to improve the radiobiological effect using increased activities. The aim of this study was to assess the effectiveness of 185 MBq and 740 MBq of 153-samarium hydroxyapatite ((153) Sm-HA) in knees of haemophilic patients. Thirty-one patients--36 knees, 30 males, were divided into two groups without coinjection of corticosteroid: A - 14 patients (17 knees) treated with intra-articular dose of 185 MBq of (153) Sm-HA, average age 23 years; B--17 patients (19 knees) with 740 MBq of (153) Sm-HA, average age 21.3 years. The evaluation before and after 1 year of synovectomy used the following criteria: reduction in the number of haemarthroses and use of the coagulation factor and improvement in articular motility. Adverse-effects occurrence was considered too. Early and late scintigraphic studies were performed after synoviorthesis and no joint immobilization was recommended. The reduction in haemarthrosis and use of coagulation factor were: group 1--31.3% and 25%; group 2--81.5% and 79% with P < 0.001 respectively; no significant improvement in knees motility was noted for both groups. Four cases of mild reactional synovitis were observed in each group. The scintigraphic control showed homogenous distribution of the radiopharmaceuticals with no articular escape; the material was considered safe by its permanence in the articulation. We have significant improvement in the synovectomy of haemophilic knees with 740 MBq of (153) Sm-HA; the less penetration of its beta radiation was compensated by the increased biological effect with the higher used activity.

A sugar-based phase-transitioning delivery system for bone tissue engineering.

Bone tissue engineering approaches commonly involve the delivery of recombinant human bone morphogenetic proteins (rhBMPs). However, there are limitations associated with the currently used carriers, including the need for surgical implantation and the associated increase in infection risk. As an alternative to traditional porous collagen sponge, we have adopted a solution of the injectable sucrose acetate isobutyrate (SAIB) as a carrier for rhBMP-2. The ability to deliver rhBMP-2 and other agents by injection reduces the infection risk and lesion size whilst in surgery, with the potential to avoid open surgery altogether in some indications. The primary methodology used for this in vivo study was a C57BL6/J mouse ectopic bone formation model. Specimens were examined by x-ray, microCT, and histology at 3 weeks. SAIB was delivered non-invasively and produced up to 3-fold greater bone volume compared to collagen. To further refine and improve upon the formulation, SAIB containing rhBMP-2 was admixed with candidate compounds including ceramic microparticles, anti-resorptives, and cell signalling inhibitors and further tested in vivo. The formulation combining SAIB/rhBMP-2, the bisphosphonate zoledronic acid (ZA), and hydroxyapatite (HA) microparticles yielded a 10-fold greater bone volume than SAIB/rhBMP-2 alone. To investigate the mechanism underlying the synergy between ZA and HA, we used in vitro binding assays and in vivo fluorescent biodistribution studies to demonstrate that ceramic particles could bind and sequester the bisphosphonate. These data show the utility of SAIB as a non-invasive rhBMP delivery system as well as describing an optimised formulation for bone tissue engineering.

Does bone marrow affect the radiological outcome when added to biphasic ceramic graft in treatment of benign bone lesions?

PURPOSE: The aim of this study is to describe the role of bone marrow aspirate in treatment of the benign bone lesions by comparing two groups of patients (16 patients in each group) with benign bone lesions treated with surgical curettage and filling the defect with either composite ceramic graft hydrated with bone marrow aspirate "group 1" or composite ceramic graft alone without a bone marrow aspirate "group 2". MATERIALS AND METHODS: The mean age was 19.7 years (group 1) and 18.5 years (group 2). The mean size of the cavitary bone lesions was 29.2 cm(2) (group 1) and 25.9 cm(2) (group 2). The mean follow-up period was 47 months. RESULTS: The percentage of ceraform resorption had increased from 31.3% at 6 months to 75.4% at 36 months for group 1 patients and from 20.9% at 6 months to 60.3% at 36 months for group 2 patients. The percentage of bone trabeculation through the cavitary defects had increased from 30.3% at 6 months to 85.5% at 36 months for group 1 patients and from 18.9% at 6 months to 72.0% at 36 months for group 2 patients. The mean of the percentage of ceraform persistence at 36 months after its implantation was 24.6% for group 1 patients and 39.7% for group 2 patients. CONCLUSION: Adding bone marrow aspirate to ceraform biphasic ceramic had hastened the rate of its resorption and had decreased the rate of its persistence.

In vivo stability of hydroxyapatite nanoparticles coated on titanium implant surfaces.

PURPOSE: Nanotechnology has been employed in attempts to enhance bone incorporation of dental implants. Often, nanoparticles are applied to the implant surface as particle coatings. However, the same properties that may increase the functionality may also lead to undiscovered negative effects, such as instability of the nanocoating. The aim of this study was to investigate the stability/instability of the nanoparticles using a radiolabeling technique. MATERIALS AND METHODS: Twenty threaded and turned titanium microimplants were inserted in 10 rats. All 20 implants were coated with nanometer-sized hydroxyapatite (HA) particles. In order to trace the HA nanoparticles, the particles for 16 implants were labeled with calcium 45 (45Ca). After 1, 2, 4, and 8 weeks, the implants and surrounding bone were retrieved and analyzed using autoradiography with respect to particle migration from the implant surface. Samples from the brain, liver, thymus, kidney, and blood, as well as wooden shavings from the rats' cages, were also retrieved and analyzed using liquid scintillation counting. RESULTS: The radioactivity representing the localization of 45Ca decreased over time from the vicinity of the implant. The amounts of 45Ca found in the blood and in the rats' excretions decreased with time and corresponded well to each other. After 8 weeks, the only trace of 45Ca was found in the liver. CONCLUSION: The results indicated that released particles leave the body through the natural cleaning system, and the probability that the nanocoating will assemble in vital organs and thus become a potential biologic risk factor is unlikely.

Mechanisms of action of fluoride for caries control.

Fluoride was introduced into dentistry over 70 years ago, and it is now recognized as the main factor responsible for the dramatic decline in caries prevalence that has been observed worldwide. However, excessive fluoride intake during the period of tooth development can cause dental fluorosis. In order that the maximum benefits of fluoride for caries control can be achieved with the minimum risk of side effects, it is necessary to have a profound understanding of the mechanisms by which fluoride promotes caries control. In the 1980s, it was established that fluoride controls caries mainly through its topical effect. Fluoride present in low, sustained concentrations (sub-ppm range) in the oral fluids during an acidic challenge is able to absorb to the surface of the apatite crystals, inhibiting demineralization. When the pH is re-established, traces of fluoride in solution will make it highly supersaturated with respect to fluorhydroxyapatite, which will speed up the process of remineralization. The mineral formed under the nucleating action of the partially dissolved minerals will then preferentially include fluoride and exclude carbonate, rendering the enamel more resistant to future acidic challenges. Topical fluoride can also provide antimicrobial action. Fluoride concentrations as found in dental plaque have biological activity on critical virulence factors of S. mutans in vitro, such as acid production and glucan synthesis, but the in vivo implications of this are still not clear. Evidence also supports fluoride's systemic mechanism of caries inhibition in pit and fissure surfaces of permanent first molars when it is incorporated into these teeth pre-eruptively.

The effect of calcium phosphate nanoparticles on hormone production and apoptosis in human granulosa cells.

OBJECTIVES: Although many nanomaterials are being used in academia, industry and daily life, there is little understanding about the effects of nanoparticles on the reproductive health of vertebral animals, including human beings. An experimental study was therefore performed here to explore the effect of calcium phosphate nanoparticles on both steroid hormone production and apoptosis in human ovarian granulosa cells. METHODS: Calcium phosphate nanoparticles uptaking was evaluated by transmission electron microscopy (TEM). The cell cycle was assessed with propidium iodide-stained cells (distribution of cells in G0/G1, S, and G2/M phases) by flow cytometry. The pattern of cell death (necrosis and apoptosis) was analyzed by flow cytometry with annexin V-FITC/PI staining. The expression of mRNAs encoding P450scc, P450arom and StAR were determined by RT-PCR. Progesterone and estradiol levels were measured by radioimmunoassay. RESULTS: TEM results confirmed that calcium phosphate nanoparticles could enter into granulosa cells, and distributed in the membranate compartments, including lysosome and mitochondria and intracellular vesicles. The increased percentage of cells in S phase when cultured with nanoparticles indicated that there was an arrest at the checkpoint from phase S-to-G2/M (from 6.28 +/- 1.55% to 11.18 +/- 1.73%, p < 0.05). The increased ratio of S/(G2/M) implied the inhibition of DNA synthesis and/or impairment in the transition of the S progression stage. The apoptosis rate of normal granulosa cells was 7.83 +/- 2.67%, the apoptotic rate increased to 16.53 +/- 5.56% (P < 0.05) after the cells were treated with 100 microM calcium phosphate nanoparticles for 48 hours. Treatment with calcium phosphate nanoparticles at concentrations of 10-100 microM didn't significantly change either the progesterone or estradiol levels in culture fluid, and the expression levels of mRNAs encoding P450scc, P450arom and StAR after 48 h and 72 h period of treatment. CONCLUSION: Calcium phosphate nanoparticles interfered with cell cycle of cultured human ovarian granulosa cells thus increasing cell apoptosis. This pilot study suggested that effects of nanoparticles on ovarian function should be extensively investigated.

Clinical evaluation after 1 year of 153-samarium hydroxyapatite synovectomy in patients with haemophilic arthropathy.

The aim is to evaluate the efficiency of the treatment with 153-samarium hydroxyapatite (153-Sm-HA) in haemophilic arthropathy. Thirty-one patients (30 males) with ages ranging from 8 to 34 years (average age = 20.6 years) were treated with fixed intra-articular dose of 185 MBq (5 mCi) and divided into two groups: infantile-juvenile (13 patients with up to 18 years of age, an average age of 12.7 years and arthropathy evolution of 7.8 years), and adult (18 patients older than 18 years, an average age of 24 years and arthropathy evolution of 18.7 years). The clinical evaluation before and after 1 year of synovectomy used the following criteria: subjective (pain through visual scale, articulation inspection), objective (articular movement through flexion level, sensitivity to palpation and leakage through joint circumference), reduction on the use of the coagulation factor, number of haemarthrosis, and the occurrence of adverse effects. The results were classified as: 1, good (remission from 70% to 100% of manifestations); 2, moderate (remission from 40% to 69%); and 3, poor (remission from 0% to 39%). Seventy-eight joints were tested: 15 knees, 36 elbows, 24 ankles, 1 shoulder and 2 hips. Early scintigraphic (1-2 h) and late scintigraphic (24-72 h) studies were performed after synoviorthesis. The cost of the procedure per joint was also estimated. No significant difference in the synoviorthesis result between groups was observed. The results were good for 75% of elbows, 87.5% of ankles and 40% of knees; the reduction in haemarthrosis and use of the coagulation factor was respectively 78% and 80% for elbows, 82% and 85% for ankles and 30% and 35% for knees. Four cases of reactional synovitis were observed in the 31 patients. The scintigraphic control showed homogeneous distribution of the material with no articular escape. The use of 153 Sm-HA in the treatment of the haemophilic arthropathy is effective for intermediate-size joints (elbows and ankles), but less effective for knees. Moreover, this treatment presents an excellent safety profile and accessible cost.

Measurement of extent of bone ongrowth and hydroxyapatite absorption in retrieved acetabular cups.

BACKGROUND: To understand why hydroxyapatite (HA)-coated acetabular cups did not produce satisfactory results, we measured the extent of bone ongrowth and HA absorption of the retrieved cups. METHODS: Between March 1992 and June 1998, a total of 289 patients underwent total hip arthroplasty with an HA-coated ABG (Anatomical Benoist Giraud) prosthesis in our hospital. We revised 71 cups in our hospital, 43 of which were included in this study. The cups were in situ for an average of 80.4 months. We revised 21 cups for polyethylene wear and osteolysis, 20 for loosening, and 2 for recurrent dislocation. The outer surfaces of the cups were subdivided by two circular grooves into three areas: central, middle, peripheral. Bone ongrowth and HA absorption was measured in terms of area and thickness. The areas were graphically calculated using a computer imaging analysis system. The thickness of the HA coating remaining on the retrieved cup was measured by an x-ray coating thickness measurement instrument. RESULTS: Of the 43 cups, 37 had bone ongrowth. Bone ongrowth was observed on the central surface in 23 cups, on the middle surface in 27 cups, and on the peripheral surface in 15 cups; 6 of the 37 cups had bone ongrowth only in the groove. Altogether, 37 cups showed bone ongrowth on 6.43% of the outer acetabular surface. HA absorption appeared in all 43 cups, and an average 63.21% of the HA coating area was absorbed. there was a proportional relation between the rate of HA absorption and implantation duration, but there was no consistent trend between the thickness of the HA coating and implantation duration. CONCLUSIONS: We suggest that progressive HA absorption and minimal bone ongrowth are related to the failure of HA-coated acetabular cups at long-term follow-up after total hip arthroplasty.

Histologic study of incorporation and resorption of a bone cement-collagen composite: an in vivo study in the minipig.

OBJECTIVE: Calcium phosphates are clinically established as bone defect fillers. They have the capability of osseoconduction and are characterized by a slow resorption process. The present study evaluated the suitability of a newly developed calcium phosphate cement modified with collagen type I. STUDY DESIGN: The modified cement paste was inserted in differently designed defects of 10 minipigs. Further, an alveolar ridge augmentation was performed, applying the cement paste. The cement hardened in situ during the operation, forming a hydroxyapatite collagen composite. Animals were sacrificed after 1, 3, 6, 12, and 18 months. The tissue integration and resorption process was then evaluated using nondecalcified microsections. All animals were evaluated for histology. RESULTS: The implanted material showed osseoconductive characteristics. Resorption started from the edge of the defect zone, and bone substitution followed rapidly. Twelve months after placement of the cement, complete remodeling was observed. CONCLUSION: It can be concluded that the applied hydroxyapatite-collagen cement composite shows good resorption and bone integration.

Biodegradation and bioabsorption innovation of the functionally graded bovine bone-originated apatite with blood permeability.

Bioabsorbable and functionally graded apatite (fg-HAp) ceramics were designed using bovine bone by the calcination and partial dissolution-precipitation methods. The fg-HAp ceramics that were developed had gradual distributions of the degree of crystallinity and the grain size of single-phase hydroxyapatite from the surface layer of the pore wall to the bulk structure region. Calcination at 1073 K gave a specific surface area of 30 m2 x g-1 and porosities of 60-80%. The pore structure of the fg-HAp was classified into two regions: a macro-pore region (100-600 microm) originating from spongy bone and a micro-pore region (10-160 nm) related to body fluid permeation and blood permeability. By implantation in subcutaneous tissue of rat, it was confirmed that body fluid permeated the bulk region of the fg-HAp ceramics through the micro-pores. The volumetric populations occupied by body fluid were 60% at 4 weeks and 68% at 8 weeks in the ceramics explants, indicating drastic bioabsorption, although the body fluid was found to be immunopositive for an albumin as the main serum protein in blood. On the fg-HAp ceramics developed here, the bioabsorption rate could be controlled by careful selection of the calcination temperature. These ceramics can be applied as new biomimetic ceramics exhibiting surface and bulk degradations and cellular absorption by giant cells.

Dissolution kinetics of iron-, manganese-, and copper-containing synthetic hydroxyapatites.

Micronutrient-substituted synthetic hydroxyapatite (SHA) is being evaluated by the National Aeronautics and Space Administration's (NASA) Advanced Life Support (ALS) Program for crop production on long-duration human missions to the International Space Station or for future Lunar or Martian outposts. The stirred-flow technique was utilized to characterize Ca, P, Fe, Mn, and Cu release characteristics from Fe-, Mn-, and Cu-containing SHA in deionized (DI) water, citric acid, and diethylene-triamine-pentaacetic acid (DTPA). Initially, Ca and P release rates decreased rapidly with time and were controlled by a non-SHA calcium phosphate phase(s) with low Ca/P solution molar ratios (0.91-1.51) relative to solid SHA ratios (1.56-1.64). At later times, Ca/P solution molar ratios (1.47-1.79) were near solid SHA ratios and release rates decreased slowly indicating that SHA controlled Ca and P release. Substituted SHA materials had faster dissolution rates relative to unsubstituted SHA. The initial metal release rate order was Mn >> Cu > Fe which followed metal-oxide/phosphate solubility suggesting that poorly crystalline metal-oxides/phosphates were dominating metal release. Similar metal release rates for all substituted SHA (approximately 0.01 cmol kg-1 min-1) at the end of the DTPA experiment indicated that SHA dissolution was supplying the metals into solution and that poorly crystalline metal-oxide/phosphates were not controlling metal release. Results indicate that non-SHA Ca-phosphate phases and poorly crystalline metal-oxide/phosphates will contribute Ca, P, and metals. After these phases have dissolved, substituted SHA will be the source of Ca, P, and metals for plants.

Hydroxylapatite with substituted magnesium, zinc, cadmium, and yttrium. II. Mechanisms of osteoblast adhesion.

The present in vitro study investigated osteoblast adhesion on hydroxylapatite (HA) doped with either cadmium (Cd), zinc (Zn), magnesium (Mg), or yttrium (Y). Compared with any other dopant tested in the present study, osteoblast adhesion was significantly (p < 0.05) greater on HA doped with Y after 4 h; in addition, osteoblast adhesion increased with concentration (2-7 mol%) of Y in HA. The findings that HA doped with greater amounts of Y adsorbed higher concentrations of calcium and, subsequently, of vitronectin and collagen (proteins known to mediate osteoblast adhesion), but not of albumin, laminin, and fibronectin, may explain the observed enhanced adhesion of osteoblasts on these substrates. Interactions (i.e., adsorption and configuration/bioactivity) of vitronectin and collagen may have been promoted by increased porosity of doped HA. Through doping with Y, the present study provided the first evidence that HA can be synthesized and processed with improved cytocompatibility properties for osteoblast adhesion, and thus offered essential information for the design of novel proactive bioceramics. Proactive bioceramics which elicit specific, timely, and desired responses from surrounding cells and tissues are necessary for improving bonding of orthopaedic/dental implants to juxtaposed bone; such osseointegration will, undoubtedly, enhance implant efficacy.

Formulation of calcium phosphates/poly (d,l-lactide) blends containing gentamicin for bone implantation.

Implants to prevent or treat osteomyelitis are described, composed of phosphate/poly(d,l-lactide) blends containing the antibiotic gentamicin. Seven formulations of implants containing 3% gentamicin sulfate (GS) were prepared at 433 MPa and 693 MPa of compression pressure. The blends contained phosphates (25% hydroxyapatite (HAP), 75% tricalcium phosphate (TCP)) and 20% dl-PLA (weight average molecular weight, M(w): 30 kD). To prolong GS release, implants were coated with PLGA (M(w):100 kD) or dl-PLA (M(w): 200 kD). Various durations of GS release from these devices were demonstrated as feasible. Release times of more than 10 weeks were attained with implants coated with dl-PLA (M(w): 200 kD), greatly exceeding the performance of the commercial formulation.

[Intraperitoneal and intrathoracic administration of hydroxyapatite-carboplatin (HAp-CBDCA)].

We have investigated the efficacy of intraperitoneal or intrathoracic administration of hydroxyapatite particles (HAp) loaded carboplatin (CBDCA). HAp-CBDCA (HAp; 200 mg, CBDCA; 4 mg) was administered intraperitoneally to rats with peritoneal carcinomatosis. The area under the curve of the ascitic platinum (Pt) increased significantly with rats given HAp-CBDCA, and the omental Pt levels in the HAp-CBDCA group remained higher and longer. Additionally, the HAp-CBDCA group showed a trend toward longer survival when compared with the CBDCA alone group. In clinical use, HAp-CBDCA (HAp; 5 g, CBDCA; 150 mg) was administered intrathoracically to a patient who had undergone esophagectomy. The Pt in serum was detected until 7 days after administration of HAp-CBDCA.

The effect of locally implanted complexes of adriamycin-hydroxyapatite complexes on tumor--study of a new alternative treatment for hepatic cancer.

A new targeting anticancer system was prepared by using hydroxyapatite particles (2 mm in diameter) as carrier material and adriamycin as anticancer agent. The adsorption and release properties of the complexes were assayed by fluorometry in vivo and in vitro and the curative effect on W-256 sarcoma of rat was observed. The results showed that one particle of hydroxyapatite could adsorb approximately 0.08 mg adriamycin and they can maintain a steady and slow release of adriamycin from hydroxyapatite for one month. When hydroxyapatite-adriamycin complexes were implanted into the liver of rat, liver adriamycin concentration at the implanted region was obviously higher than that achieved by injection of adriamycin solution. The locally implanted complexes obviously inhibited the growth of subcutaneous implanted tumor of rat, and increased the survival rate of rat with implanted liver tumor.

Preliminary evaluation of a polyethyleneglycol-stabilized manganese-substituted hydroxylapatite as an intravascular contrast agent for MR angiography.

A blood-persistent particulate paramagnetic contrast agent has been formulated via size stabilization of manganese-substituted hydroxylapatite by a polyethylene glycol (PEG) bearing a terminal diphosphonate. At high PEG surface densities (35-40 mol%), particles with mean diameter 8 +/- 2 nm were obtained. Relaxivities of autoclaved samples (at 20 MHz proton Lamor frequency) were R1 = 18.7 +/- .8 mM-1 sec-1 and R2 = 22.3 +/- .7 mM-1 sec-1. The formulation persisted in rabbit blood with a biphasic clearance profile. Half-lives (with amplitudes in parenthesis) were 4 +/- 1 minutes (55%), and 49 +/- 3 minutes (45%), respectively, for the two phases. A dose of 40 mumol Mn/kg body weight enhanced the signal from rabbit vasculature for more than 45 minutes on MR angiograms. Thus, PEG-modified MnHA particles may find use as T1 agents for MR angiography.