DEVELOPING AN INJECTABLE IN-SITU-FORMING CALCIUM POLYPHOSPHATE SYSTEM AS A HEMOSTATIC AGENT

Abstract

Sodium Polyphosphate (NaPP) is a linear inorganic polymer formed from PO4 structural units. NaPP glass is soluble in water, but addition of multivalent cations to its solutions results in a precipitate and formation of a polyphosphate coacervate. These coacervates are comprised of hydrated chains of polyphosphates that are immiscible with water. It has been shown that polyphosphate chains released from platelets after activation may play a significant role in the coagulation cascade. This observation alludes to the great potential especially for these polyphosphate coacervates in hemostasis applications. In this thesis, detailed studies of a polyphosphate coacervate system derived from NaPP and divalent cations, namely calcium, strontium and barium, are described together with the potential of an in situ forming coacervate as an embolic agent. NaPPs with degrees of polymerization (Dp)<500 were successfully achieved by fractionation of NaPP glass that was prepared from NaH2PO4.H2O. NaPPs with Dp>500 were produced successfully by ion-exchange of potassium Kurrol salt that was prepared from KH2PO4. The effects of divalent cation (Ca, Sr and Ba) addition to NaPP solutions were comprehensively studied, and it is shown that the number of divalent cations required for coacervation depends on different variables such as the NaPP concentration, the Dp, and the type of divalent cation. Polyphosphate coacervates prepared from different NaPPs and cations were found to degrade at a fast rate, limiting them to short-term bio-applications. Additional rheological studies revealed that viscoelastic properties of these coacervates depend profoundly on the cation type and NaPP Dp, allowing one to tweak their composition to achieve a desired physical property. Polyphosphate coacervates were found to be an excellent candidate for hemostasis applications, decreasing clotting time significantly especially when very long chain polyphosphates were used. Lastly a polyphosphate liquid embolic system with optimum radiopacity, injectability and cyto-compatibility was developed and tested in vivo with promising results. The ability of a polyphosphate coacervate to be loaded with an anticancer drug, with a subsequent slow rate of release, was also demonstrated. Overall this thesis establishes the potential of a polyphosphate in situ forming system and polyphosphate coacervates in general as a unique platform for bio-applications.