Accurate Therapeutic Response Assessment of Pancreatic Ductal Adenocarcinoma Using Quantitative Dynamic Contrast-Enhanced Magnetic Resonance Imaging With a Point-of-Care Perfusion Phantom: A Pilot Study.

OBJECTIVES: The aim of this study was to test the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with concurrent perfusion phantom for monitoring therapeutic response in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: A prospective pilot study was conducted with 8 patients (7 men and 1 woman) aged 46 to 78 years (mean age, 66 years). Participants had either locally advanced (n = 7) or metastatic (n = 1) PDAC, and had 2 DCE-MRI examinations: one before and one 8 ± 1 weeks after starting first-line chemotherapy. A small triplicate perfusion phantom was imaged with each patient, serving as an internal reference for accurate quantitative image analysis. Tumor perfusion was measured with K using extended Tofts model before and after phantom-based data correction. Results are presented as mean ± SD and 95% confidence intervals (CIs). Statistical difference was evaluated with 1-way analysis of variance. RESULTS: Tumor-size change of responding group (n = 4) was -12% ± 4% at 8 weeks of therapy, while that of nonresponding group (n = 4) was 18% ± 15% (P = 0.0100). Before phantom-based data correction, the K change of responding tumors was 69% ± 23% (95% CI, 32% to 106%) at 8 weeks, whereas that of nonresponding tumors was -1% ± 41% (95% CI, -65% to 64%) (P = 0.0247). After correction, the data variation in each group was significantly reduced; the K change of responding tumors was 73% ± 6% (95% CI, 64% to 82%) compared with nonresponding tumors of -0% ± 5% (95% CI, -7% to 8%) (P < 0.0001). CONCLUSIONS: Quantitative DCE-MRI measured the significant perfusion increase of PDAC tumors responding favorably to chemotherapy, with decreased variability after correction using a perfusion phantom.

Portable perfusion phantom for quantitative DCE-MRI of the abdomen.

PURPOSE: The aim of this study was to develop a portable perfusion phantom and validate its utility in quantitative dynamic contrast-enhanced magnetic resonance imaging of the abdomen. METHODS: A portable perfusion phantom yielding a reproducible contrast enhancement curve (CEC) was developed. A phantom package including perfusion and static phantoms were imaged simultaneously with each of three healthy human volunteers in two different 3T MR scanners. Look-up tables correlating reference (known) contrast concentrations with measured ones were created using either the static or perfusion phantom. Contrast maps of image slices showing four organs (liver, spleen, pancreas, and paravertebral muscle) were generated before and after data correction using the look-up tables. The contrast concentrations at 4.5 min after dosing in each of the four organs were averaged for each volunteer. The mean contrast concentrations (4 organs × 3 volunteers = 12) were compared for the two scanners, and the intra-class correlation coefficient (ICC) was calculated. Also, the ICC of the mean Ktrans values between the two scanners was calculated before and after data correction. RESULTS: The repeatability coefficient of CECs of perfusion phantom was higher than 0.997 in all measurements. The ICC of the tissue contrast concentrations between the two scanners was 0.693 before correction, but increased to 0.974 after correction using the look-up tables (LUTs) of perfusion phantom. However, the ICC was not increased after correction using static phantom (ICC: 0.617). Similarly, the ICC of the Ktrans values was 0.899 before correction, but increased to 0.996 after correction using perfusion phantom LUTs. The ICC of the Ktrans values, however, was not increased when static phantom LUTs were used (ICC: 0.866). CONCLUSIONS: The perfusion phantom reduced variability in quantitating contrast concentration and Ktrans values of human abdominal tissues across different MR units, but static phantom did not. The perfusion phantom has the potential to facilitate multi-institutional clinical trials employing quantitative DCE-MRI to evaluate various abdominal malignancies.

Highly extensible bio-nanocomposite fibers.

Here, we show that a poly(ethylene oxide) polymer can be physically cross-linked with silicate nanoparticles (Laponite) to yield highly extensible, bio-nanocomposite fibers that, upon pulling, stretch to extreme lengths and crystallize polymer chains. We find that both, nanometer structures and mechanical properties of the fibers respond to mechanical deformation by exhibiting strain-induced crystallization and high elongation. We explore the structural characteristics using X-ray scattering and the mechanical properties of the dried fibers made from hydrogels in order to determine feasibility for eventual biomedical use and to map out directions for further materials development.

Assessment of using laponite cross-linked poly(ethylene oxide) for controlled cell adhesion and mineralization.

The in vitro cytocompatibility of silicate (Laponite clay) cross-linked poly(ethylene oxide) (PEO) nanocomposite films using MC3T3-E1 mouse preosteoblast cells was investigated while cell adhesion, spreading, proliferation and mineralization were assessed as a function of film composition. By combining the advantageous characteristics of PEO polymer (hydrophilic, prevents protein and cell adhesion) with those of a synthetic and layered silicate (charged, degradable and potentially bioactive) some of the physical and chemical properties of the resulting polymer nanocomposites could be controlled. Hydration, dissolution and mechanical properties were examined and related to cell adhesion. Overall, this feasibility study demonstrates the ability of using model Laponite cross-linked PEO nanocomposites to create bioactive scaffolds.

Addition of chitosan to silicate cross-linked PEO for tuning osteoblast cell adhesion and mineralization.

The addition of chitosan to silicate (Laponite) cross-linked poly(ethylene oxide) (PEO) is used for tuning nanocomposite material properties and tailoring cellular adhesion and bioactivity. By combining the characteristics of chitosan (which promotes cell adhesion and growth, antimicrobial) with properties of PEO (prevents protein and cell adhesion) and those of Laponite (bioactive), the resulting material properties can be used to tune cellular adhesion and control biomineralization. Here, we present the hydration, dissolution, degradation, and mechanical properties of multiphase bio-nanocomposites and relate these to the cell growth of MC3T3-E1 mouse preosteoblast cells. We find that the structural integrity of these bio-nanocomposites is improved by the addition of chitosan, but the release of entrapped proteins is suppressed. Overall, this study shows how chitosan can be used to tune properties in Laponite cross-linked PEO for creating bioactive scaffolds to be considered for bone repair.

Tuning cell adhesion by incorporation of charged silicate nanoparticles as cross-linkers to polyethylene oxide.

Controlling cell adhesion on a biomaterial surface is associated with the long-term efficacy of an implanted material. Here we connect the material properties of nanocomposite films made from PEO physically cross-linked with layered silicate nanoparticles (Laponite) to cellular adhesion. Fibroblast cells do not adhere to pure PEO, but they attach to silicate containing nanocomposites. Under aqueous conditions, the films swell and the degree of swelling depends on the nanocomposite composition and film structure. Higher PEO compositions do not support cell proliferation due to little exposed silicate surfaces. Higher silicate compositions do allow significant cell proliferation and spreading. These bio-nanocomposites have potential for the development of biomedical materials that can control cellular adhesion.

Silicate cross-linked bio-nanocomposite hydrogels from PEO and chitosan.

The compositions and the multi phase structures of bio-nanocomposite hydrogels made from silicate cross-linked PEO and chitosan are related to some of their physical and biological properties. The gels are injectable and self-healing because the cross-linking is physical and reversible under deformation. The presence of chitosan aggregates affects the viscoelastic properties and reinforces the hydrogel network. The chitosan adds advantageous properties to the hydrogel such as enhanced cell spreading and adhesion. In vitro biocompatibility data indicate that NIH 3T3 fibroblasts grow and proliferate on the bio-nanocomposite hydrogel as well as on hydrogel films.

Heterogeneity in nanocomposite hydrogels from poly(ethylene oxide) cross-linked with silicate nanoparticles.

We investigate the influence of ionic strength on the structural heterogeneity and viscoelastic properties of nanocomposite hydrogels. We use small-angle scattering and rheology to monitor structural changes as a function of ionic strength. Increasing ionic strength makes the nanocomposite gels macroscopically heterogeneous, stiffer and more turbid. At high shear rates, nanometre structures rearrange within aggregates and orient in the flow direction. The changing structural properties that develop with ionic strength are due to increased heterogeneity of nanoparticle distribution and polymer-nanoparticle interactions as well as to the formation of PEO [poly(ethylene oxide)] aggregates interacting with sodium cations, which reinforce the overall hydrogel network.