Multi-doped apatite: Strontium, magnesium, gallium and zinc ions synergistically affect osteogenic stimulation in human mesenchymal cells important for bone tissue engineering.

Functional calcium phosphate biomaterials can be designed as carriers of a balanced mixture of biologically relevant ions able to target critical processes in bone regeneration. They hold the potential to use mechanisms very similar to growth factors naturally produced during fracture healing, while circumventing some of their drawbacks. Here we present a novel phase of carbonated-apatite containing Mg2+, Sr2+, Zn2+ and Ga3+ ions (HApMgSrZnGa). While all dopants decrease the crystallinity, Ga3+ limits crystal growth and enables the formation of a nanosized apatite phase with enhanced specific surface area. Coexistence of the ions enhances degradability and controls solubility of low crystalline, distorted, multi-doped apatite structure, controlled by Ga3+ ions accumulated at the surface. Consequently, HApMgSrZnGa supports the viability of human mesenchymal stromal cells (MSCs) and induces their stimulation along the osteogenic lineage. In addition, the co-released ions has a synergistic antimicrobial effect, particularly within the HApMgSrZnGa-Au(arg) composite with Au(arg) as contact-based antimicrobial. The activity is stable up to two months in vitro. Osteogenic nature and antimicrobial activity, combined in a single biomaterial, are suggesting a well-balanced, multi-doped apatite design applicable as future option in bone regeneration and tissue engineering.

Antimicrobial Polymeric Composites with Embedded Nanotextured Magnesium Oxide.

Nanotextured magnesium oxide (MgO) can exhibit both antibacterial and tissue regeneration activity, which makes it very useful for implant protection. To successfully combine these two properties, MgO needs to be processed within an appropriate carrier system that can keep MgO surface available for interactions with cells, slow down the conversion of MgO to the less active hydroxide and control MgO solubility. Here we present new composites with nanotextured MgO microrods embedded in different biodegradable polymer matrixes: poly-lactide-co-glycolide (PLGA), poly-lactide (PLA) and polycaprolactone (PCL). Relative to their hydrophilicity, polarity and degradability, the matrices were able to affect and control the structural and functional properties of the resulting composites in different manners. We found PLGA matrix the most effective in performing this task. The application of the nanotextured 1D morphology and the appropriate balancing of MgO/PLGA interphase interactions with optimal polymer degradation kinetics resulted in superior bactericidal activity of the composites against either planktonic E. coli or sessile S. epidermidis, S. aureus (multidrug resistant-MRSA) and three clinical strains isolated from implant-associated infections (S. aureus, E. coli and P. aeruginosa), while ensuring controllable release of magnesium ions and showing no harmful effects on red blood cells.

Applicability of image analysis to support QbD driven development of pellets.

OBJECTIVE: The stages of preparing high drug loaded pellets were investigated using static and dynamic imaging techniques to provide a greater understanding and ease the scale up process. SIGNIFICANCE: An example of a real case laboratory and production scale quality by design (QbD) based development of pellets is demonstrated. Potential process analytical technology (PAT) approaches by dynamic image analysis (DIA) are presented in various process phases. METHODS: Pellets were prepared at laboratory and production scale (high shear granulation, extrusion/spheronization, drying, and coating). The influence of process parameters on pellet properties (aspect ratio (AR), yield, pellet size, and their distribution) was investigated using static and DIA. During coating, we focused on the coating thickness and identification of potential agglomeration. RESULTS AND CONCLUSION: The effects of kneading time, amount of water, extrusion screen plate (ESP) opening diameter and thickness on pellet properties were confirmed in accordance with literature. In terms of screw speed, spheronization speed and time, no considerable influence on pellet properties was observed in the range of studied process parameters, thereby confirming the design space. In addition to the ESP thickness and opening diameter, quality of the ESP impacts the pellet properties. Lastly, coating thickness measurements with dynamic and static image analysis were comparable and an exemplary case of in-line agglomeration detection was presented. Real-time evaluation with PATVIS APA is an effective PAT tool for the evaluation of spheronization (pellet size distribution, AR, and yield) and coating (coating thickness, agglomeration detection).