Gentamicin loading of calcium phosphate implants: implications for cranioplasty.

BACKGROUND: Surgical site infections (SSI) are a significant risk in cranioplasty, with reported rates of around 8-9%. The most common bacteria associated with these nosocomial infections are of the Staphylococcus species, which have the ability to form biofilm. The possibility to deliver antibiotics, such as gentamicin, locally rather than systemically could potentially lower the early postoperative SSI. Various antibiotic dosages are being applied clinically, without any true consensus on the effectiveness. METHODS: Drug release from calcium phosphate (CaP), polyetheretherketone (PEEK), and titanium (Ti) samples was evaluated. Microbiological studies with Staphylococcus aureus (SA) and Staphylococcus epidermidis (SE) including strains from clinical infection were used to establish clinically relevant concentrations. RESULTS: The CaP samples were able to retain and release gentamicin overtime, whereas the Ti and PEEK samples did not show any drug uptake or release. A gentamicin loading concentration of 400 µg/ml was shown to be effective in in vitro microbiological studies with both SA and SE. CONCLUSIONS: Out of the three materials studied, only CaP could be loaded with gentamicin. An initial loading concentration of 400 µg/ml appears to establish an effective gentamicin concentration, possibly translating into a clinical benefit in cranioplasty.

Advanced qualification of pharmaceutical excipient suppliers by multiple analytics and multivariate analysis combined.

Pharmaceutical excipients have different functions within a drug formulation, consequently they can influence the manufacturability and/or performance of medicinal products. Therefore, critical to quality attributes should be kept constant. Sometimes it may be necessary to qualify a second supplier, but its product will not be completely equal to the first supplier product. To minimize risks of not detecting small non-similarities between suppliers and to detect lot-to-lot variability for each supplier, multivariate data analysis (MVA) can be used as a more powerful alternative to classical quality control that uses one-parameter-at-a-time monitoring. Such approach is capable of supporting the requirements of a new guideline by the European Parliament and Council (2015/C-95/02) demanding appropriate quality control strategies for excipients based on their criticality and supplier risks in ensuring quality, safety and function. This study compares calcium hydrogen phosphate from two suppliers. It can be assumed that both suppliers use different manufacturing processes. Therefore, possible chemical and physical differences were investigated by using Raman spectroscopy, laser diffraction and X-ray powder diffraction. Afterwards MVA was used to extract relevant information from each analytical technique. Both CaHPO4 could be discriminated by their supplier. The gained knowledge allowed to specify an enhanced strategy for second supplier qualification.

Evaluation of the osteogenic performance of calcium phosphate-chitosan bone fillers.

There has been recent interest in utilizing calcium phosphates (CaPs) that set in situ for treating bone defects due to the limitations associated with morselized autografts and allografts. However, CaP cements have long setting times, poor mechanical properties, and poor osteoinductivity. This has prompted research toward finding a nonprotein-based compound, such as chitosan, to accelerate setting times and increase osteoinductivity. The purpose of this study was to compare bone growth rates during the early bone healing response achieved using conventionally prepared chitosan-CaP bone filler to an extensively purified chitosan-CaP compound. Both compounds set quickly and stimulated bone formation. Histomorphometry demonstrated a 290% increase in new bone formation when using the conventional chitosan-CaP bone filler and a 172% increase with the highly purified chitosan-CaP compound compared to the increase in bone formation seen with the unfilled control group. The results of this study indicate that a highly purified chitosan-CaP paste stimulated less bone formation than a conventionally prepared chitosan-CaP paste but both pastes have the potential to stimulate bone formation.

Effect of process parameters on the characteristics of porous calcium phosphate ceramics for bone tissue scaffolds.

Porous hydroxyapatite (HA) has already been widely used as a bone substitute due to its similarity with the mineral part of the bone. In this work, cylindrical tablets with micro and macro porosity were produced from stoichiometric and deficient hydroxyapatites by using naphthalene as porosifier agent. The influence of the processing parameters such as Ca/P ratio of start material, calcination temperature, and naphthalene content on the characteristics of porous calcium phosphate tablets was evaluated. Three mineral phases-HA, alpha-TCP (alpha tri-calcium phosphate), and beta-TCP (beta tricalcium phos-phate)-with variable contents were identified by x-ray diffraction (XRD) and Fourier-transformed infrared spectroscopy (FT-IR). Image analysis and density measurements were used to characterize sample porosity. As expected, the total porosity of the calcinated material is not dependent on the stoichiometry of the precursor hydroxyapatite. For calcium-deficient hydroxyapatite, the increase in naphthalene content contributes to stabilize alpha-TCP phase, altering the relative phases content.

[Cellular culture of osteoblasts and fibroblasts on porous calcium-phosphate bone substitutes]. / Culture cellulaire d'ostéoblastes et de fibroblastes sur substituts osseux poreux en phosphate de calcium.

PURPOSE OF THE STUDY: Calcium phosphate ceramics are synthetic bone substitutes able to fill in bone destruction as a support of the bone growth. This work consisted in an in vitro assessment of osteoblasts and fibroblasts cultures on macroporous calcium-phosphate bone substitutes to analyze the interaction between cells and bone substitute. MATERIALS AND METHODS: The macroporous ceramic was composed of 70% hydroxyapatite and 30% tri-calcium phosphate with known mechanical and physico-chemical properties. Three compounds were processed with different size of macropore and with or without microporosity on their surface. Cells were seeded on discs measuring 10 mm in diameter and 2 mm in thickness. Cellular viability was evaluated by the MTT test for every stage of observation. An histological study to observe the invasion in the depth of discs was performed. Scanning electron microscopy was used to analyze the cellular comportment in contact with the surface of substitutes. RESULTS: An exponential cellular growth was effective on each substitute with the two cellular types. Cells spread on the surface of the compounds covering macropores and colonized the depth of the discs. A size of macropore of 300 microm or more seemed to support this invasion. 15 microm sized interconnections appeared to be effective to allow cell migration between macropores. The cell proliferation was similar on substitutes with or without microporosity. CONCLUSION: Biomaterials currently used as bone substitute are more or less osteoconductive but they have no osteoinductive property. A hybrid association of calcium-phosphate ceramic with osteogenic cells should promote the development of a calcium phosphate compound with osteoinductive capacity.

[Tibial valgus osteotomy using a tricalcium phosphate medial wedge: a minimally invasive technique]. / Ostéotomie tibiale de valgisation par addition médiale d'un coin de phosphate tricalcique: technique dite mini invasive.

PURPOSE OF THE STUDY: We present a minimally invasive technique for tibial valgus osteotomy using a medial wedge composed of tricalcium phosphate. MATERIAL AND METHODS: The bone substitute is composed of slowly resorbable tricalcium phosphate material shaped to the desired form and having mechanical properties allowing stable osteotomy via a short incision and staple fixation. Intraoperative fluoroscopy enables a reliable and reproducible technique. A lateral fixation staple is required because there is a risk the lateral hinge could break. This technique was used for 58 knees in 55 patients (mean age 47 years). According to the Ahlback classification of femorotibial degeneration, there were 43 grade I knees, 12 grade II, and 3 grade III. RESULTS: The implant was well tolerated in all cases. Bone healing was achieved in most cases without loss of the osteotomy angle. Complications were: rupture of the lateral hinge in four cases leading to nonunion in one, one low-grade infection. Implant resorption at mid term was significant: among the 22 patients with a follow-up of more than 5 years, the implant was barely visible in 18. DISCUSSION: This technique provides an easy way to achieve tibial valgus osteotomy without compromising future intervention. The technique can be considered to be minimally invasive because of the size of the incision, the minimal fixation required, and the bone sparing effect of the bone substitute.

Preparation and characterization of porous apatite ceramics coated with beta-tricalcium phosphate.

Hydroxyapatite (Ca10(PO4)6(OH)2; HA) is one of the most biocompatible materials with bones, and porous HA is promising bone substitute materials for clinical applications. While there are reports that beta-tricalcium phosphate (Ca3(PO4)2; TCP) has higher resorbability than HA when the material is implanted in a bone defect. In the present study, porous HA coated with beta-TCP was prepared by our unique method. The porous HA of about 60% porosity with interconnecting pore structure was soaked in diammonium hydrogen phosphate solution, and then the HA was sintered at 900 degrees C for 3 h. beta-TCP was revealed by X-ray diffractometry on the surface of porous HA. It was possible to control the content of surface-formed beta-TCP arbitrary by varying the concentration of the solution. The obtained HA coated with 33 wt% beta-TCP (33TCP) had about 60% open porosity with the pore size from 150 to 400 microns. The average compressive strength of this porous ceramics was 17.5 MPa. Surface coated HA with beta-TCP deprived of the brittleness in handling. The weight of HA implanted into muscles was increased obviously at 4 weeks because of formation of carbonate hydroxyapatite on the surface of HA. The weight of 33TCP was scarcely changed up to 12 weeks, but the weight tended to increase at 24 weeks. The carbonate hydroxyapatite was not formed on 33TCP at 4 weeks, but formed on it at 24 weeks. Therefore beta-TCP coated porous HA behaved like beta-TCP initially after implantation, and then behaved like HA.