Comprehensive study of the chelation and coacervation of alkaline earth metals in the presence of sodium polyphosphate solution.

The effect of chelation of three alkaline earth metals (Ca, Sr, and Ba) by polyphosphates on the pH and viscosity of the solution is examined and correlated to the phosphate glass properties. Also, the impact of the polyphosphate average degree of polymerization (D(p)) as well as the type and amount of chelated divalent cation on the degradation rate of the chains is studied. Subsequently, the number of divalent cations required for polyphosphate chain agglomeration to form a coacervate, and the resulting composition of these coacervates, was investigated. A decrease in polyphosphate solution pH during chelation was routinely obtained, with a sudden shift in the rate of pH drop occurring around a divalent cation/phosphorus molar ratio of 0.18. Longer chains or cations with a smaller ionic radius accelerated the rate of D(p) reduction. The number of divalent cations required for coacervation depends on different variables such as the polyphosphate concentration, the D(p), and the type of divalent cation. The formed coacervate retains the D(p) of polyphosphate originally used for coacervation, and the resulting Ca/P molar ratio depends largely on the amount of calcium being used during coacervation. Overall, this article helps one to understand the coacervation of polyphosphates in order to exploit their potential as a biomaterial.

Impact of trivalent ions on the stability and cohesion of calcium polyphosphate coacervates for embolization applications.

Polyphosphates (PPs) are of interest as temporary in situ setting embolic agents for which cohesive characteristics are vital. Trivalent ions Al3+ and Ga3+ were substituted into calcium PP up to 10 mol % for two PP chain lengths (degree of polymerization, Dp 200 and 9000) and the effect on the dissolution rate of the resulting coacervate was examined. High levels of trivalent ions were found to increase the dissolution rate, especially with aluminum (Al) where the coacervate with the greatest Al content (10 mol %) and larger Dp completely dissolved within the first few hours in tris(hydroxymethyl)aminomethane buffered saline. Conversely, small amounts of trivalent ions slowed the dissolution rate of the coacervates compared to those containing calcium only. The coacervate compositions determined to have the fastest and slowest ion release were evaluated for cohesion upon injection into a simulated blood vessel using a dual lumen needle. PPs with lower trivalent content had a higher coacervate yield overall, with 5% Ga and Dp 200 yielding the smallest proportion of coacervate particulates that could be implicated in unwanted distal embolization. However, further studies are required to evaluate the formation and duration of occlusions in vivo so that the PP composition can best be tailored to meet clinical requirements. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2638-2648, 2019.

Degradation and hemostatic properties of polyphosphate coacervates.

UNLABELLED: Sodium polyphosphate is a linear polymer formed from phosphate units linked together by sharing oxygen atoms. Addition of calcium to a solution of sodium polyphosphate results in phase separation and formation of a polyphosphate coacervate best described as a polymeric rich viscoelastic material. Polyphosphate coacervate is an interesting candidate as a biomaterial based on its ability to bind with different cations and to be loaded with drugs. Here, in vitro degradation and hemostatic properties of polyphosphate coacervates are comprehensively evaluated. We show that polyphosphate coacervates degrade and dissolve at a fast rate, losing half of their original mass in a week and transforming to mainly pyrophosphate after 4weeks. This burst dissolution phase happens earlier for the coacervate prepared from very short chain polyphosphate but overall using longer polyphosphate chains does not increase the coacervate longevity significantly. Substitution of Ca with Sr or Ba does not affect the hydrolysis of coacervates but slows down their dissolution into the media. In a whole blood clotting assay, coacervates profoundly decrease the clotting time especially when very long chain polyphosphates are used. While coacervate chain length and divalent cation type were found to significantly affect prothrombin time and thromboplastin time compared to the control, no discernible trends were observed. Platelets adhere in large numbers to coacervates, especially those containing long chain polyphosphate, but the cell morphology observed suggests that they might not to be fully activated. Overall, the long chain polyphosphate coacervate holds a great potential as a resorbable hemostatic agent. STATEMENT OF SIGNIFICANCE: Divalent cation additions to a sodium polyphosphate solution result in polyphosphate coacervates, or highly viscous gel-like materials, having great potential in bio-applications such as drug delivery and hemostasis. As these coacervates degrade in aqueous environments, we undertook a comprehensive evaluation to better understand the impact of polyphosphate chain length and divalent cation substitution on this hydrolytic response in order to better predict degradation behavior in the body. Furthermore, there is great interest in the role of polyphosphates in hemostasis following recent publications showing that platelets secrete polyphosphates upon thrombin stimulation. In this paper, we evaluate the hemostatic potential of polyphosphate coacervates as bulk constructs, demonstrating that indeed these materials hold great potential as a degradable hemostatic agent.

Developing an in situ forming polyphosphate coacervate as a new liquid embolic agent: From experimental design to pilot animal study.

A radiopaque temporary liquid embolic agent was synthesized from polyphosphate (PP) coacervates and optimized using a design of experiments approach. Variables studied were: strontium substitution (0-15 mol%), barium substitution (0-15 mol%), PP concentration and degree of polymerization of the polyphosphate (Dp). The viscosity, radiopacity and cell viability of the resulting coacervates were measured for 60 formulations and response surface modeling was used to determine the optimum coacervate that maximized radiopacity and cell viability. The optimum coacervate made from PP with a large Dp (9.5 g NaPP/100mL, 2.2 mol% Sr, 9 mol% Ba and 3.8 mol% Ca) was taken forward to a pilot animal trial. In this rabbit model, PP embolic agent successfully occluded the central auricular artery with promising biocompatibility. Further study is required to optimize the cohesiveness and clinical effectiveness of PP as an in situ setting temporary embolic agent. STATEMENT OF SIGNIFICANCE: This article describes the development of a new radiopaque temporary liquid embolic agent from the optimization using design of experiments to a pilot animal study. Embolization is a minimally invasive interventional radiology procedure used to block blood flow in a targeted blood vessel. This procedure is used to treat many conditions including: tumors, aneurysms and arteriovenous malformations. Currently, no inherent radiopaque embolic agents are available in the clinic, which would allow for direct imaging of the material during the procedure and follow up treatment.

The effect of processing on the structural characteristics of vancomycin-loaded amorphous calcium phosphate matrices.

Calcium polyphosphate antibiotic delivery matrices were prepared using a unique processing technique involving the exposure of calcium polyphosphate pastes to high humidity for 0, 5, 24 or 48 h to induce gelling. Subsequently, samples were dried for a minimum of 24 h. The mild conditions associated with matrix fabrication readily allowed for vancomycin incorporation within an environment that did not disrupt antibiotic activity. While reproducible from a processing standpoint, the gelling and drying process did contribute to a decrease in matrix tensile strength and the formation of significant pores near the surface of the matrices. Generally, the core of the gelled matrices appeared to be denser than their non-gelled counterparts. The degree of phosphate chain lysis during the gelling and drying stages was quantified using solution 31P nuclear magnetic resonance (NMR) spectroscopy. Both NMR and Raman spectroscopy indicated that the presence of vancomycin did not appreciably alter the matrix formation process. The ability to incorporate clinically relevant levels of antibiotic within this degradable bone substitute matrix suggests the potential of this approach for creating a localized antibiotic delivery system to treat osteomyelitis infections.

Calcium polyphosphate as an additive to zinc-silicate glass ionomer cements.

Aluminum-free glass ionomer cements (GICs) are under development for orthopedic applications, but are limited by their insufficient handling properties. Here, the addition of calcium polyphosphate (CPP) was investigated as an additive to an experimental zinc-silicate glass ionomer cement. A 50% maximum increase in working time was observed with CPP addition, though this was not clinically significant due to the short working times of the starting zinc-silicate GIC. Surprisingly, CPP also improved the mechanical properties, especially the tensile strength which increased by ∼33% after 30 days in TRIS buffer solution upon CPP addition up to 37.5 wt%. This strengthening may have been due to the formation of ionic crosslinks between the polyphosphate chains and polyacrylic acid. Thus, CPP is a potential additive to future GIC compositions as it has been shown to improve handling and mechanical properties. In addition, CPP may stimulate new bone growth and provide the ability for drug delivery, which are desirable modifications for an orthopedic cement.