In vitro setup to study permeability characteristics of contrast agents by MRI

Abstract

An experimental setup consisting of a hollow fiber module (HFM) was developed for the in vitro study of contrast agent (CA) permeability. Controllable flow and known fiber characteristics allowed permeability studies under well-defined conditions with CAs of different molecular weight (MW). In the MRI experiments performed at 4.7 T, the system was perfused at a constant flow rate (5 ml/min) with water and four CA of different MW: Gd-DOTA (MW=0.6 kDa), P846 (3.5 kDa), P792 (6.5 kDa) and P717 (50.5 kDa). R(1) time courses were measured with a saturation-recovery multi-gradient-echo snapshot sequence in the fiber-free HFM input and the fiber-filled center. Concentration time courses were calculated, and CA extravasation was analyzed with a pharmacokinetic model yielding exchange rate constant k(ie). Only Gd-DOTA (k(ie)=2.37+/-0.16 min(-1)) and P846 (k(ie)=0.58+/-0.17 min(-1)) showed quantifiable extravasation. P717 perfusion yielded an intra-capillary volume fraction of 15.6+/-2.7% compared with 12% estimated from the HFM manufacturer's specifications. In conclusion, the experimental setup allowed classification of in vitro permeability characteristics for CAs with different MW and therefore holds potential for systematic comparison of CAs currently under development.

Quantitative analysis of dynamic MRI data obtained with a hollow fibre module

“…This work also shows that we have to correct the qualitative interpretation of the data given in Vautier et al (1) and Heilmann et al (2). In particular, the measured V in_uc cannot be larger than V in as assumed in Heilmann et al (2), where the value of 0.12 given for V in cannot be true.…”

“…All experimental data analysed with our model are cited in Vautier et al (1) and Heilmann et al (2). We recall here briefly these results.…”

“…Owing to the initial gap between the exponential fitting and the calculated DR 1e (t), C a_uc (0) is also larger than the value DR 1e (0)/DR 1max (error of about 10%). This last value, which may be obtained as already described by using impermeable CA (2), is the true estimation of the uncorrected water molecular exchange value V in_uc . V in_uc is thus found to be much smaller than the corrected water molecular exchange V in value.…”

“…For P792 and P717, we did not observe any transport between intra-and extra-fibre volumes of the HFM. We observed only an initial R 1e increase DR 1e (0), corresponding to the filling of the intra-fibre space by CA containing solution (2). Using these CAs, experimental estimations of the intra-fibre volume fraction V in_uc were calculated using the ratio DR 1e (0)/DR 1emax where DR 1emax ¼ r 1 C 0 is the R 1 variation in the perfusate (2).…”

“…In particular, the measured V in_uc cannot be larger than V in as assumed in Heilmann et al (2), where the value of 0.12 given for V in cannot be true. Furthermore, this value corresponds to an inner diameter of the bioreactor of 2.08 cm, which is evidently too big (Fig.…”