Optimization by the Taguchi Method of a Robust Synthesis Protocol of Calcium Carbonate Phosphate

The experimental processes are difficult to model by physical laws, because a multitude of factors can intervene simultaneously and are responsible for their instabilities and their random variations. Two types of factors are to be considered;those that are easy to manipulate according to the objectives, and those that can vary randomly (uncontrollable factors). These could eventually divert the system from the desired target. It is, therefore, important to implement a system that is insensitive to fluctuations in factors that are difficult to control. The aim of this study is to optimize the synthesis of an apatitic calcium carbonate phosphate characterized with a Ca/P ratio equal to 1.61 by using the experimental design method based on the Taguchi method. In this process, five factors are considered and must be configured to achieve the previously defined objective. The temperature is a very important factor in the process, but difficult to control experimentally, so considered to be a problem factor (noise factor), forcing us to build a robust system that is insensitive to the last one. Therefore, a much simpler model to study the robustness of a synthetic solution with respect to temperature is developed. We have tried to parameterize all the factors considered in the process within a wide interval of temperature variation (60˚C - 90˚C). Temperature changes are no longer considered as a problem for apatitic calcium carbonate phosphate synthesis. In this finding, the proposed mathematical model is linear and efficient with very satisfactory statistical indicators. In addition, several simple solutions for the synthesis of carbonate phosphate are proposed with a Ca/P ratio equal to 1.61.

Effects of pore interconnectivity on bone regeneration in carbonate apatite blocks

Porous architecture in bone substitutes,notably the interconnectivity of pores,is a critical factor for bone ingrowth.However,controlling the pore interconnectivity while maintaining the microarchitecture has not yet been achieved using conventional methods,such as sintering.Herein,we fabricated a porous block using the crystal growth of calcium sulfate dihydrate,and controlled the pore interconnectivity by limiting the region of crystal growth.The calcium sulfate dihydrate blocks were transformed to bone apatite,carbonate apatite(CO_(3)Ap)through dissolution–precipitation reactions.Thus,CO_(3)Ap blocks with 15%and 30%interconnected pore volumes were obtained while maintaining the microarchitecture:they were designated as CO_(3)Ap-15 and CO_(3)Ap-30,respectively.At 4 weeks after implantation in a rabbit femur defect,new bone formed throughout CO_(3)Ap-30,whereas little bone was formed in the center region of CO_(3)Ap-15.At 12 weeks after implantation,a large portion of CO_(3)Ap-30 was replaced with new bone and the boundary with the host bone became blurred.In contrast,CO_(3)Ap-15 remained in the defect and the boundary with the host bone was still clear.Thus,the interconnected pores promote bone ingrowth,followed by replacement of the material with new bone.These findings provide a useful guide for designing bone substitutes for rapid bone regeneration.

Growth factor receptors: promising drug targets in cancer

Genetic,epigenetic and somatic changes deregulate the expression of growth factor receptors(GFRs),leading to cancer initiation and progression.Tumor cell growth and survival are orchestrated by clonal expansion and evasion of apoptotic signals in cancer cells.The growth of cells is further supported by angiogenesis and metastasis to distant organs.High expression of GFRs also contributes to the development of resistance.Therefore,therapeutics to target GFRs is a potentially attractive molecular approach to treat cancer more effectively.In this review,we have discussed the contribution of GFRs to cancer development and addressed molecular approaches undertaken to inhibit GFR-mediated pathways.A wide number of monoclonal antibodies(mAbs)and protein kinase inhibitors targeting these GFR-mediated functions are in clinical trials to treat human malignancies.However,most drugs that target GFRs lead to the development of drug resistance and generate adverse effects.Nucleic acid-based therapeutics,e.g.short interfering RNA(siRNA)could be harnessed to selectively silence GFR genes in cancer cells.Different polymer,liposome-based nanocarriers,and the most recently developed pH-sensitive inorganic carbonate apatite nanoparticles have been used in cell culture and preclinical trials for cytoplasmic delivery of the siRNAs targeting different GFR genes.siRNA-based therapeutics have been shown to have signifi cant potential to suppress GFR expression and functions and thus could be developed as molecular therapeutics.Multi-targeting of tumors at different levels by combining various approaches along with chemotherapy would be a promising therapeutic approach to fight the disease.Suitable nanocarriers capable of entrapping siRNA,mAb,GFR inhibitors and classical drugs targeting GFR have potential therapeutic applications.