The Development of Tissue Mimicking Gels
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/cm2, 950 g/cm2 and 1200 g/cm2} 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/mm2. To measure T1rho we imaged samples with a spin-locking spin echo sequence at multiple spin lock durations2. 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-DTPA3. 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/cm2 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.

Figures

Figure 1. Photograph of a 100 uL infusion cloud in a 500 gm/cm^2 gel.

Table 1. Infusion and imaging measurements on gels of different gel strength.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
3580