Preparation And Performance Of Porous Calcium Phosphate Cement Granules With Macro/Micro Pores

Bone defects, which are always caused by tumor, trauma, osteomyelitis, aging and disease, leading to the gradually increasing bone patients all over the world. Hence, the needs for bone regenterationincreasingly each year. Autogenous and allogeneic were widely used traditionally, but their drawbacks were also difficult to be solved. Along with the development of biomedical materials, artificial bone substitutes have been focused and explored widely for their excellent advantages. Calcium phosphate with granular shape is considered to be filled in complex bone defects and easy to handle in clinic. Three dimensional interconnected pores would be produced by packing granules, whichwas proved to bebenefit for bone tissues and vascular formation. The content, sizes and distribution of pores are proved to be important for osteogeneration and angiogenesis. Therefore, porous structure in bone substitute has a great value to research.Bone defects often occurred with disease, assisting with the treatment of drugs. Calcium phosphate ceramic fabricated through high temperature, which is not suitable for loading drugs. To solve the aforementioned problems, we selected calcium phosphate cement(CPC) to prepare porous granules by using freeze-dripping method in this study. Additionally, biodegradable polymer microspheres and air bubbles were applied as pores agents to produce macropores both in surface and interior of CPC granules.Poly(lactic-co-glycolic) acid(PLGA) microspheres with pore size ranging in 50-100 nm were fabricated by emulsion method. PLGA/CPC granules with microspheres-in-granule structure were produced by freeze-dripping method. PLGA/CPC granules behaved a good anti-disintegration ability and the sizes of PLGA/CPC granules are in a range of 0.3 to 3 mm.The compressive stress of CPC granules were increased accompanied with the addition of PLGA microspheres. The ―sea-island‖ structure was clearly observed on the surface of PLGA/CPC granules contributing to amounts of exposed PLGA microspheres. However, blood perfusion ability of PLGA/CPC granules was proved bad with the mass ratio of PLGA microspheres to CPC at 40 w.t.%, which was contributed to the hydrophobic PLGA microspheres distributing on CPC granules’ surface.As the prolongation of in vitrodegradation, the in situ macro-pores were generated after PLGA microspheres degradation. PLGA/CPC granules with microspheres-in-granule structure were proved to be favor for cell adhesion and proliferation. Vancomycin and methotrexate were used as model drugs adding in PLGA/CPC granules by evaluating the effect of loading ways and drug types on the in vitro release behavior. Burst release within 24 h was inevitable when drugs were loaded in CPC matrixwhile the sustainable release profile at least 49 days was achieved by loading drugs in PLGA microspheres. Furthermore, multi-release behaviors from PLGA/CPC granules were detected by loading methotrexate and vancomycin separately.Air bubbles were used as pore agents by increasing the viscosity of CPC slurry and the addition of surfactant in CPC. Porous CPC granules behaved good anti-disintegration by incubating in phosphate buffer solutions. Apart from the intrinsic micro-pores in CPC, macro-pores were generated both in the surface and interior of CPC granules. During the fabrication process, the lifetime of air bubbles were prolonged via the increment of slurry viscosity. The porosity of porous CPC granules was 72.68±2.03%. Porous CPC granules were proved better for cell adhesion, proliferation and differentiation. Moreover, CPC slurry with lots of bubbles was produced by using surfactant. Pores inside CPC granules were interconnected andthe porosity of porous CPC granules was 81.99±2.31 %. P Porous CPC granules were treated by PLGA to maintainthe mechanical property. Multy-layerswerecovered on the surface of porous CPC granules after being treated with PLGA,which was proved to be favor for hindering burst release of vancomycin from CPC matrix. Granules-scaffold with three dimensional interconnected pores was constructedby packing porous CPC granules treated with PLGA.