Inhibition of calcification in biomaterials
Creators: name: Hsu, Carolyn Hwei-Chuen
Publisher: name: University of Utah
Year: 2012

description: Calcification occurs during long term implantation of biomaterials. The purpose of this research is to develop inhibitors (diphosphonates and surfactants) of calcification and incorporate them into biomaterials (Biomer^ and p-HEMA coated Biomer^). These inhibitors (surfactant: octadecanyl phosphonic acid, OPA; diphosphonates: 1-hydroxylbenzyl 1,1-diphosphonic acid, HBDP and 1-hydroxyl 10-undecanoyl 1,1-diphosphonic acid, HUDP) are synthesized and characterized, then evaluated for their ability to control calcification on biomaterials. In addition, commercially available compounds (surfactant: sodium dodecyl sulfate, SDS; diphosphonate: 1-hydroxylethyl 1,1-diphosphonic acid, HEDP) were incorporated into biomaterials and tested under both static and dynamic in_ vitro experimental conditions.  Among the inhibitors used in these calcification experiments, the diphosphonate compounds show the most promise as calcification inhibitors when incorporated into the polymer. Surfactants, however, resulted in the enhancement of calcification when they were incorporated into polymer. When the inhibitors are added to solution the concentration (diphosphonates or surfactant) has to be greater than lxlO~° M to observe inhibition of calcification.  In addition to inhibitors, calcification was affected by physical factors such as temperature and pH.   It was found that when temperature and pH were increased the calcification also increased. At 25°C less calcific deposits were found than at 37°C. Significantly less calcification was found at pH 6.4 than at pH's 7 and 7.8. When inhibitors were incorporated into biomaterials, it was found that sodium dodecyl sulfate (SDS) and OPA incorporated into Biomer^ caused extensive calcification under static conditions. When SDS was incorporated into Biomer* and the samples were calcified in the dynamic experiment, extensive calcification was also seen. However, when HBDP and HUDP were incorporated into Biomer^ and then coated with p-HEMA, both showed significant inhibition of calcification compared with control samples under both static and dynamic conditions. A comparison of HBDP and HUDP revealed that HBDP showed a greater degree of inhibition than HUDP. This was due to the larger amount of HBDP released from the polymer.  Also, a significant difference between static and dynamic experimental results were found. A comparison between the static and dynamic in_ vitro experiments revealed that more calcification occurs on biomaterials in the static system than in the dynamic system. Two hypotheses which prove reasonable to explain these discrepancies are 1) a temperature difference between the systems, and 2) changes in the polymer surface caused by flexing in the dynamic system.  The experimentally supported hypothesis for the mechanism of inhibition of calcification by surfactants is the formation of a monolayer of surfactant on the polymer surface. However, the mechanism of calcification inhibition by diphosphonates is different. The diphosphonate compounds are hypothesized to act as crystal poisons and, therefore, inhibit crystal proliferation.  It can be concluded from these studies that the diphosphonate (HBDP and HUDP) effectively inhibit calcium phosphate deposition in short term ill vitro experiments.