Characterizing diffusion-controlled release of small-molecules using quantitative MRI: Application to orthopedic infection

Abstract

Calcium sulphate is an established carrier for localized drug delivery, but a means to non-invasively measure drug release, which would improve our understanding of localized delivery, remains an unmet need. We aim to quantitatively estimate the diffusion-controlled release of small-molecules loaded into a calcium sulphate carrier through gadobutrol-based contrast agent, which acts as a surrogate small-molecule. A central cylindrical core made of calcium sulphate, either alone or within a metal scaffold, is loaded with contrast agent that releases into agar. Multi-echo scans are acquired at multiple time-points over 4 weeks and processed into R2* and QSM maps. Mean R2*values are fit to a known drug delivery model, which are then compared to the decrease in core QSM. Fitting R2* measurements of calcium sulphate core while constraining constants to a drug release model results in a R2-value of 0.991, yielding a diffusion constant of 4.59x10-11 m2/s. Incorporating the carrier within a metal scaffold results in a slower release. QSM shows the resulting loss of susceptibility in the non-metal core but is unreliable around metal. R2* characterizes gadobutrol release and QSM detects the resulting decrease in susceptibility. The addition of a porous metal scaffold slows the release of gadobutrol, as expected.