Peter Andrew Hardy1, Christopher J Norsigian2, Walter Witschey3, and Luke H Bradley2
1Radiology, University of Kentucky, Lexington, KY, United States, 2Anatomy & Neurobiology, University of Kentucky, Lexington, KY, United States, 3Smilow Center for Translational Research, University of Pennsylvania, Philadelphia, PA, United States
Synopsis
Developing tissue mimicking materials can be helpful in reducing the cost and duration of experiments which otherwise require animals. We tested a variety of agarose gels of different gel strength as suitable tissue mimicking material for convection enhanced delivery. The results demonstrate a significant difference in infusion volume and we relate that, through MR measurements, to the mechanical stiffness of the gels. PURPOSE
Convection Enhanced Delivery (CED) is a powerful technique
to deliver drugs locally for the treatment of
degenerative neurological diseases and brain tumors. Testing of CED in large animal
models is time consuming and expensive and to alleviate this burden we sought
to develop a suitable tissue mimic for the putamen (a target for
delivering drugs for the treatment of neurodegenerative diseases)
1. We recognize that the
model might be useful in other applications such as phantoms for MR imaging as
well.
Methods
We tested the mechanical and imaging characteristics of agarose
gels of different composition. Gels were made from agarose powder of varying
strengths {500 g/cm
2, 950 g/cm
2 and 1200 g/cm
2}
by dissolving agarose powder in saline and heating to
90⁰C prior to pouring into receptacles. The strength of the gel is a measure of
its resistance to fracturing. Gels with higher gel strength are stiffer. One liter blocks of gel were used to test the distribution of 0.1% safranin O
dye when infused using CED through a 15 port Codman catheter. One hundred
microliters (Vi) of dye solution was infused at 0.2 μL / min while the infusion
pressure and volume were monitored. From photographs of the infusion cloud taken
at the completion of the infusion we estimated the volume of distribution (Vd). Samples of gels were imaged to
estimate several properties including diffusion coefficient, T1rho, mechanical
stiffness and free volume of water. The diffusion coefficient was estimated
using a standard double echo Echo Planar-spin echo sequence with b-values of 0
and 1000 s/mm
2. To measure
T1rho we imaged samples with a spin-locking spin echo sequence at multiple spin
lock durations
2. Gel samples were placed on a Resoundant™ transducer
and elastographic images were acquired to measure the gel stiffness. To
estimate the volume of free water, we used a MOLLI technique to measure T1 in five
samples of each gel strength to which we added 100 μL of varying concentrations
of Gd-DTPA
3. We then calculated the relaxivity 1/T1/[Gd] per unit of
concentration of Gd.
Results
Figure 1 shows an infusion of 100 μL of 0.1% Safranin O dye into a 500 gm/cm
2 gel sample. Table 1 lists
the measurements performed on the gel samples. From the Vd estimated from photographs of the infusion in each sample we calculated the average ratio Vd:Vi. Measurements of Vd:Vi demonstrate larger ratios for higher gel strengths. The values of Vd:Vi were significantly different between the different gel strengths. There was no obvious trend for the maximum infusion pressure measured during the infusion. From the MOLLI-derived T1 values we estimated the relaxivity of the samples. The measurements of the water diffusion coefficient (ADC), relaxivity (1/T1/[Gd]), and gel density were equivalent
for the three gel strengths demonstrating that the volume for free water was
equivalent for the three gel strengths. Measurements of the shear modulus from the elastographic images demonstrated an increase commensurate with increasing gel strength.
Discussion
The ratio Vd:Vi for the different gel materials increased
with increasing gel strength and the values for different gel strength were
significantly different from one another. This response did not arise from a
difference in the volume accessible to the water as the gels had identical
density and identical relaxivity which could only result from identical free
volume. Additionally, the ADC for the three materials was also similar
indicating that the pore space was large enough that it did not restrict the
free diffusion of water. The variation of Vd:Vi must reflect instead, a
difference in the mechanical properties of the gels and indeed, the
elastographic images indicates a significant difference in the shear modulus of
the materials. We speculate that the difference in Vd:Vi reflects a difference
in the resistance of the material to strain from the infusion pressure leading
to a different rate of progression of the dye through the gel.
Conclusion
These results indicate the ability to select the mechanical
and MRI features of a gel to mimic those of tissue. The Vd:Vi ratio observed in these gels is
similar to that observed in the CED infusion of neurotrophic factors into the putamen
in rhesus monkeys. The difference of Vd:Vi for the different gel strengths
appears to arise primarily from differences in the tensile strength of the gels
rather than from the differences in available free space which appears to be
the same for all gels. These results guide us in the development of suitable
tissue mimics to represent the response of tissue in various surgical
procedures.
Acknowledgements
We thank Walter Witschey, Ph.D. for the use of his T1rho
sequence and Chris Ross for the use of his infusion controller. CJN was
supported by NSF Research Undergraduate Experience grant EEC-0851716. References
1. Hardy PA, Keeley D., Schorn G, et al, “Convection
enhanced delivery of different molecular weight tracers of gadolinium-tagged polylysine.
J Neurosci Methods 2013: 219(1): 169.
2. Witschey WRT, Pilla JJ, Ferrari G, et al,
“Rotating frame spin lattice relaxation in a swine model of chronic, left
ventricular myocardial infarction, Mag Reson Med 2010 64(5): 1453-1460.
3. Kellman P, Arai AE, Xue H, T1 and extracellular
volume mapping in the heart: estimation of error maps and the influence of
noise on precision J Cardio Magn Reson 2013 15:56.