Construction Of Porous Magnesium Phosphate Based Bone Cement Drug Sustained Delivery System

Thanks to favorable self-setting and plasticity,bone cement has been widely used in the bone repair fields.Among various kinds of bone cements,calcium phosphate cement and magnesium phosphate cement have attracted considerable attention because of its great cytocompatibility and biodegradability.However,some drawbacks such as low strength,lacking of macropores and no drug treatment effect restrict its using in clinical practice.In order to solve these problems,a drug sustained delivery system with high strength,good cytocompatibility and ability of self-formation of inner pores,based on a kind of magnesium phosphate based bone cement（MPBC）,is proposed in this paper.The research works are concluded as follows:To solve the too fast setting rate and poor cytocompatibility brought from high pH,Ca（H₂PO₄）₂·H₂O and citric acid were additionally introduced when preparing the MPBC.Characterizations of the physicochemical and biological properties of the prepared MPBC were performed in detail.Results show that the setting time increases with the addition of Ca（H₂PO₄）₂·H₂O and the raise of citric acid concentration.The addition of Ca（H₂PO₄）₂·H₂O and citric acid has almost no influence on the degradation rate of bone cement,but obvious effect on pH.MPBC has weaker alkalinity so that exhibits better suitability for cell proliferation and adhesion.Because the gelatin microspheres crosslinked by glutaraldehyde have cytotoxicity,we replaced glutaraldehyde with carbodiimide as the crosslinking agent.Gelatin microspheres with suitable particle size and different cross-linking degrees were obtained by controlling the stirring speed and EDC concentration.The cross-linking degree,swelling,degradation and biocompatibility of gelatin microspheres before and after crosslinking were studied.Results show that the gelatin microspheres with higher degree of crosslinking have smaller swelling degree,slower degradation rate and better cell compatibility.In view of the lacking of macropores in MPBC,a porous MPBC system was fabricated by compounding the degradable gelatin microspheres with MPBC.The influences of the addition amount and crosslinking degree of gelatin microspheres on the physical and chemical properties of bone cement were analyzed.The formation of porous in the degradation process was researched.The cytocompatibility was investigated.Results show that the setting time is shortened and the compressive strength decreases with the increase of the microsphere amount,but the cross-linking degree of microspheres has no obvious effect on the compressive strength.The time of microspheres degraded into pores slow down with the increase of cross-linking degree.The cell experiment shows that proliferation of osteoblasts can be promoted on the composite bone cement,indicating the good biocompatibility。Finally,aiming at the scarce drug treatment effect of the bone cement,a drug sustained-release carrier was constructed on the MPBC by compounding it with drug loaded gelatin microspheres.Diclofenac sodium was selected as the drug model and loaded inside gelatin microspheres.The encapsulation,drug-loading and drug-release properties of the microspheres were analyzed.The influences of drug loaded microspheres and drugs on the setting time and compressive strength was analyzed.The release conditions of 4 kinds of drug delivery system in vitro were analyzed and their release curves were fitted.Results show that with the increase of the concentration of the crosslinking agent,the drug loading rate and the entrapment efficiency decrease slightly,while the release time of the microspheres increases correspondingly,and obvious abrupt release phase appears in the prophase stage.When the microspheres were embedded into bone cement,the release process lasts for more than 2 months.This is mainly because the MPBC itself has good adhesive properties and can encapsulate the drug and drug loaded microspheres tightly in the matrix.The drug must be released through two layers of media,and thereby to drug release for a long time can be realized.This drug sustained delivery system based on porous MPBC forms a porous structure through the degradation of microspheres,which can provide channels for the growth of blood vessels and tissues,and thus promote the growth of new bone.At the same time,long-term sustained release of drug can be achieved.