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Research Papers

Separation of Solid Stress From Interstitial Fluid Pressure in Pancreas Cancer Correlates With Collagen Area Fraction

[+] Author and Article Information
Michael D. Nieskoski, Kayla Marra, Jason R. Gunn, Stephen C. Kanick, B. Stuart Trembly

Thayer School of Engineering,
Dartmouth College,
Hanover, NH 03755

Marvin M. Doyley

Thayer School of Engineering,
Dartmouth College,
Hanover, NH 03755;
Department of Electrical and
Computer Engineering,
University of Rochester,
Rochester, NY 14627

Tayyaba Hasan

Wellman Center for Photomedicine,
Massachusetts General Hospital,
Harvard Medical School,
Boston, MA 02114

Stephen P. Pereira

Institute for Liver and Digestive Health,
University College London,
London NW3 2QG, UK

Brian W. Pogue

Thayer School of Engineering,
Dartmouth College,
Hanover, NH 03755
e-mail: Brian.W.Pogue@Dartmouth.edu

1Corresponding author.

Manuscript received October 17, 2016; final manuscript received March 3, 2017; published online April 18, 2017. Assoc. Editor: Jeffrey Ruberti.

J Biomech Eng 139(6), 061002 (Apr 18, 2017) (8 pages) Paper No: BIO-16-1409; doi: 10.1115/1.4036392 History: Received October 17, 2016; Revised March 03, 2017

Elevated total tissue pressure (TTP) in pancreatic adenocarcinoma is often associated with stress applied by cellular proliferation and hydrated hyaluronic acid osmotic swelling; however, the causal roles of collagen in total tissue pressure have yet to be clearly measured. This study illustrates one direct correlation between total tissue pressure and increased deposition of collagen within the tissue matrix. This observation comes from a new modification to a conventional piezoelectric pressure catheter, used to independently separate and quantify total tissue pressure, solid stress (SS), and interstitial fluid pressure (IFP) within the same tumor location, thereby clarifying the relationship between these parameters. Additionally, total tissue pressure shows a direct correlation with verteporfin uptake, demonstrating the impediment of systemically delivered molecules with increased tissue hypertension.

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Figures

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Fig. 1

Proposed description of the extracellular matrix component contributions that limit drug distribution in pancreatic cancer. The extracellular matrix component contributions that limit drug distribution and instigate widespread vascular collapse is outlined in (a). Excessive extracellular component deposition coupled with cellular proliferation results in growth-induced solid stress, causing reduced vascular and lymphatic patency and elevated interstitial fluid pressure, thereby, limiting convective transport of large macromolecules into the tumor interstitium (b).

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Fig. 2

Novel technique for measuring individual pressure contributions in pancreatic cancer. A Millar Mikrotip pressure catheter (a) and a modified cover (b) were used to measure total tissue pressure (TTP) as a combination of solid stress (SS) and interstitial fluid pressure (IFP) (c) and IFP only (d). The modified attachment was designed to easily retract, thereby measurement of IFP and TTP were obtained without removing the probe from the tumor location, as illustrated in (e). In this tumor, the modified Millar presser sensor was placed in water from time = 0 to 2 min and placed in the tumor from time = 2 to 12 min. The modified cover was removed at time = 12 min and Millar pressure measurements (no PTFE cover) continued until time = 22 min.

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Fig. 3

Correlation between collagen area fraction and total tissue pressure (TTP). Millar Mikrotip (SPR-671) pressure catheter was used to measure pressure in AsPC-1 tumors and this was compared to collagen area fraction analyzed ex vivo. A strong correlation was observed between collagen area fraction and TTP using a linear regression fit (R2 = 0.799; *p < 0.001). P-value was calculated under the null hypothesis no correlation between TTP and collagen. The y-intercept was 23 mmHg, approximately equal to microvascular pressure (MVP) found in literature [32]. Interstitial fluid pressure (IFP) will not exceed MVP indicating values of TTP > IFP represent solid stress (SS).Comparison between measured values of TTP (mean  = 48.8 mmHg) and IFP (mean = 12.8 mmHg) was made by a Welch t-test (**p < 0.001) for five tumors.

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Fig. 4

Quantitative investigation on drug uptake in pancreatic tumors. Vascular structure and vascular patency were analyzed ex vivo with anti-CD31 immunostain (a) and DiOC7 stain (c), respectively. A statistically significant relationship existed between the orthotopic tumor location (12 tumors included) and subcutaneous tumor location (eight tumors included) for the anti-CD31 (b) stain (p < 0.05) but no apparent correlation with the DiOC7 stain (d); comparison was made by a Welch t-test. A statistically significant correlation between orthotopic location of verteporfin uptake and TTP (e) was determined using linear regression fit (R2 = 0.46, p < 0.04). P-value was computed under the null hypothesis of no correlation between fluorescence signal and TTP. A statistically significant relationship existed between the orthotopic tumor location (f) for verteporfin uptake compared with the subcutaneous tumor location was determined by a Welch t-test (p < 0.01). The p-values were computed against a null-hypothesis that no correlation exists. A zero-slope line indicated no correlation, as illustrated with the subcutaneous tumor location.

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