Abstract

Adipose tissue is a very important biologic component to nutrient storage and transport as well as a commonly used medium for drug delivery. Continuous insulin infusion using pump therapy for the treatment of Type 1 Diabetes is one of the most notable of these drug delivery cases. Though the adipose subspace is used for insulin delivery, the flow mechanics of the fluid and drug within the extracellular space is not currently well understood, and difficult to study by experimentation. This study therefore was completed to develop a three-dimensional computational fluid dynamics (CFD) model that incorporated adipose region interstitial flow that would be induced in the adipose region by oncotic pressure driven fluid flow from the capillaries to consider trends in the deposition and dispersion of insulin in relation to current market cannulas used in insulin pump. The study was able to show that the CFD model developed could obtain results very similar to ex vivo experimentation found in literature. Further, the results indicated that cannula geometry likely does not have a drastic effect on insulin deposition size. The study was able to indicate that cannula geometry could have a large effect on insulin dispersion within the adipose region which has implication for insulin therapy success in regard to drug absorption into the capillaries of the adipose subspace.

References

1.
Yao
,
W.
,
Shen
,
Z.
, and
Ding
,
G.
,
2013
, “
Simulation of Interstitial Fluid Flow in Ligaments: Comparison Among Stokes, Brinkman and Darcy Models
,”
Int. J. Biol. Sci.
,
9
(
10
), pp.
1050
1056
.10.7150/ijbs.7242
2.
Grodzinsky
,
A. J.
,
Levenston
,
M. E.
,
Jin
,
M.
, and
Frank
,
E. H.
,
2000
, “
Cartilage Tissue Remodeling in Response to Mechanical Forces
,”
Annu. Rev. Biomed. Eng.
,
2
(
1
), pp.
691
713
.10.1146/annurev.bioeng.2.1.691
3.
Swartz
,
M. A.
, and
Fleury
,
M. E.
,
2007
, “
Interstitial Flow and Its Effects in Soft Tissues
,”
Annu. Rev. Biomed. Eng.
,
9
(
1
), pp.
229
256
.10.1146/annurev.bioeng.9.060906.151850
4.
Tarbell
,
J. M.
,
Weinbaum
,
S.
, and
Kamm
,
R. D.
,
2005
, “
Cellular Fluid Mechanics and Mechanotransduction
,”
Ann. Biomed. Eng.
,
33
(
12
), pp.
1719
1723
.10.1007/s10439-005-8775-z
5.
Ng
,
C. P.
, and
Swartz
,
M. A.
,
2003
, “
Fibroblast Alignment Under Interstitial Fluid Flow Using a Novel 3-D Tissue Culture Model
,”
Am. J. Physiol.
,
284
(
5
), pp.
H1771
H1777
.10.1152/ajpheart.01008.2002
6.
Bhave
,
G.
, and
Neilson
,
E. G.
,
2011
, “
Body Fluid Dynamics: Back to the Future
,”
J. Am. Soc. Nephrol.
,
22
(
12
), pp.
2166
2181
.10.1681/ASN.2011080865
7.
McLennan
,
D. N.
,
Porter
,
C. J. H.
, and
Charman
,
S. A.
,
2005
, “
Subcutaneous Drug Delivery and the Role of Lymphatics
,”
Drug Discovery Today: Technol.
,
2
(
1
), pp.
89
96
.10.1016/j.ddtec.2005.05.006
8.
Yao
,
W.
,
Li
,
Y.-B.
, and
Chen
,
N.
,
2013
, “
Analytic Solutions of the Interstitial Fluid Flow Models
,”
J. Hydrodyn., Ser. B
,
25
(
5
), pp.
683
694
.10.1016/S1001-6058(13)60413-8
9.
Yao
,
W.
, and
Ding
,
G.-H.
,
2011
, “
Interstitial Fluid Flow: Simulation of Mechanical Environment of Cells in the Interosseous Membrane
,”
Acta Mech. Sin.
,
27
(
4
), pp.
602
610
.10.1007/s10409-011-0439-7
10.
Mokhtar
,
W.
, and
Lubbers
,
R.
,
2022
, “
CFD Modeling of Interstitial Fluid Flow in Subcutaneous Adipose Tissue
,”
ASME
Paper No. IMECE2022-90593.10.1115/IMECE2022-90593
11.
Jockel
,
J. P. L.
,
Roebrock
,
P.
, and
Shergold
,
O. A.
,
2013
, “
Insulin Depot Formation in Subcutaneous Tissue
,”
J. Diabetes Sci. Technol.
,
7
(
1
), pp.
227
237
.10.1177/193229681300700128
12.
Zedelmair
,
M.
,
2016
, “
Numerical Simulation of Insulin Depot Formation and Absorption in Subcutaneous Tissue Modeled as a Porous Media
,”
Master's thesis
,
California State University
,
Northridge, CA
.https://scholarworks.calstate.edu/concern/theses/1j92gb64c
13.
Heinemann
,
L.
,
2008
, “
Variability of Insulin Action: Does It Matter?
,”
Insulin
,
3
(
1
), pp.
37
45
.10.1016/S1557-0843(08)80010-3
14.
Heinemann
,
L.
,
Walsh
,
J.
, and
Roberts
,
R.
,
2014
, “
We Need More Research and Better Designs for Insulin Infusion Sets
,”
J. Diabetes Sci. Technol.
,
8
(
2
), pp.
199
202
.10.1177/1932296814523882
15.
Störchile
,
P.
,
Müller
,
W.
,
Sengeis
,
M.
,
Ahammer
,
H.
,
Fürhapter-Rieger
,
A.
,
Bachl
,
N.
,
Lackner
,
S.
,
Mörkl
,
S.
, and
Holasek
,
S.
,
2017
, “
Standardized Ultrasound Measurement of Subcutaneous Fat Patterning: High Reliability and Accuracy in Groups Ranging From Lean to Obese
,”
Ultrasound Med. Biol.
,
43
(
2
), pp.
427
438
.10.1016/j.ultrasmedbio.2016.09.014
16.
Wei
,
J. C. J.
,
Edwards
,
G. A.
,
Martin
,
D. J.
,
Huang
,
H.
,
Crichton
,
M. L.
, and
Kendall
,
M. A. F.
,
2017
, “
Allometric Scaling of Skin Thickness, Elasticity, Viscoelasticity to Mass for Micro-Medical Device Translation: From Mice, Rats, Rabbits, Pigs to Humans
,”
Sci. Rep.
,
7
(
1
), p.
15885
.10.1038/s41598-017-15830-7
17.
Heinemann
,
L.
, and
Krinelke
,
L.
,
2012
, “
Insulin Infusion Set: The Achilles Heel of Continuous Subcutaneous Insulin Infusion
,”
J. Diabetes Sci. Technol.
,
6
(
4
), pp.
954
964
.10.1177/193229681200600429
18.
Lv
,
Y.-G.
,
Liu
,
J.
,
Gao
,
Y.-H.
, and
Xu
,
B.
,
2006
, “
Modeling of Transdermal Drug Delivery With a Micro Needle Array
,”
J. Micromech. Microeng.
,
16
(
11
), pp.
2492
2501
.10.1088/0960-1317/16/11/034
19.
Farvid
,
M. S.
,
Ng
,
T. W. K.
,
Chan
,
D. C.
,
Barrett
,
P. H. R.
, and
Watts
,
G. F.
,
2005
, “
Association of Adiponectin and Resistin With Adipose Tissue Compartments, Insulin Resistance and Dyslipidaemia
,”
Diabetes, Obes. Metab.
,
7
(
4
), pp.
406
413
.10.1111/j.1463-1326.2004.00410.x
20.
Baumgartner
,
C.
,
Hasgall
,
P. A.
,
Di
Gennaro
,
F.
,
Neufeld
,
E.
,
Lloyd
,
B.
,
Gosselin
,
M. C.
,
Payne
,
D.
,
Klingenböck
,
A.
, and
Kuster
,
N.
,
2018
, “
IT'IS Database for Thermal and Electromagnetic Parameters of Biological Tissues, Version 4.0
,” IT'IS Foundation, Zurich, Switzerland, accessed June 10, 2020, https://itis.swiss/virtual-population/tissue-properties/overview/
21.
Burren
,
D.
,
2019
, “
Bolus Speeds—How Fast Is Your Pump?
,” BionicWookiee, Melbourne, Victoria, Australia, accessed July 1, 2020, https://bionicwookiee.com/2019/07/30/bolus-speeds-how-fast-is-your-pump/
22.
Scallan
,
J.
,
Huxley
,
V. H.
, and
Korthuis
,
R. J.
,
2010
,
Capillary Fluid Exchange: Regulation, Functions, and Pathology
,
Morgan and Claypool Life Science
,
San Rafael, CA
.
23.
Hansen
,
K. C.
,
D'Alessandro
,
A.
,
Clement
,
C. C.
, and
Santambrogio
,
L.
,
2015
, “
Lymph Formation, Composition, and Circulation: A Protein Perspective
,”
Int. Immunol.
,
27
(
5
), pp.
219
227
.10.1093/intimm/dxv012
24.
Fox
,
S.
, and
Rompolski
,
K.
,
2022
, Human Physiology,
16th ed.
,
McGraw-Hill LLC, New York
.
25.
Peurichard
,
D.
,
Delebecque
,
F.
,
Lorsignol
,
A.
,
Barreau
,
C.
,
Rouquette
,
J.
,
Descombes
,
X.
,
Casteilla
,
L.
, and
Degond
,
P.
,
2017
, “
Simple Mechanical Cues Could Explain Adipose Tissue Morphology
,”
J. Theor. Biol.
,
429
, pp.
61
81
.10.1016/j.jtbi.2017.06.030
26.
Yao
,
W.
,
Li
,
Y.
, and
Ding
,
G.
,
2012
, “
Interstitial Fluid Flow: The Mechanical Environment of Cells and Foundation of Meridians
,”
Evidence-Based Complementary Altern. Med.
,
2012
, pp.
1
9
.10.1155/2012/853516
27.
Mihai
,
L. A.
,
Chin
,
L.
,
Janmey
,
P. A.
, and
Goriely
,
A.
,
2015
, “
A Comparison of Hyperelastic Constitutive Models Applicable to Brain and Fat Tissues
,”
J. R. Soc. Interface
,
12
(
110
), p.
20150486
.10.1098/rsif.2015.0486
28.
Thomsen
,
M.
,
Hernandez-Garcia
,
A.
,
Mathiesen
,
J.
,
Poulsen
,
M.
,
Sørensen
,
D. N.
,
Tarnow
,
L.
, and
Feidenhans'l
,
R.
,
2014
, “
Model Study of the Pressure Build-Up During Subcutaneous Injection
,”
PLoS One
,
9
(
8
), p.
e104054
.10.1371/journal.pone.0104054
29.
Versteeg
,
H. K.
, and
Malalasekera
,
W.
,
2010
,
An Introduction to Computational Fluid Dynamics: The Finite Volume Method
, 2nd ed.,
Pearson/Prentice Hall
,
Harlow
, UK.
30.
Tu
,
J.
,
Yeoh
,
G. H.
, and
Liu
,
C.
,
2018
,
Computational Fluid Dynamics
, 3rd ed.,
Butterworth-Heinemann
,
Cambridge
, UK.
31.
Frost
,
G. I.
,
2007
, “
Recombinant Human Hyaluronidase (rHuPH20): An Enabling Platform for Subcutaneous Drug and Fluid Administration
,”
Expert Opin. Drug Delivery
,
4
(
4
), pp.
427
440
.10.1517/17425247.4.4.427
32.
Kim
,
H.
,
Park
,
H.
, and
Lee
,
S. J.
,
2017
, “
Effective Method for Drug Injection Into Subcutaneous Tissue
,”
Sci. Rep.
,
7
(
1
), pp.
1
11
.10.1038/s41598-017-10110-w
33.
McDonald
,
T. A.
,
Zepeda
,
M. L.
,
Tomlinson
,
M. J.
,
Bee
,
W. H.
, and
Ivens
,
I. A.
,
2010
, “
Subcutaneous Administration of Biotherapeutics: Current Experience in Animal Models
,”
Curr. Opin. Mol. Ther.
,
12
(
4
), pp.
461
470
.https://pubmed.ncbi.nlm.nih.gov/20677097/
34.
Ritcher
,
W. F.
, and
Jacobsen
,
B.
,
2014
, “
Subcutaneous Absorption of Biotherapeutics: Knowns and Unknowns
,”
Drug Metab. Dispos.
,
42
(
11
), pp.
1881
1889
.10.1124/dmd.114.059238
35.
Chen
,
W.
,
Yung
,
B. C.
,
Qian
,
Z.
, and
Chen
,
X.
,
2018
, “
Improving Long-Term Subcutaneous Drug Delivery by Regulating Material-Bioenvironment Interaction
,”
Adv. Drug Delivery Rev.
,
127
(
1
), pp.
20
34
.10.1016/j.addr.2018.01.016
36.
Frayn
,
K. N.
, and
Karpe
,
F.
,
2014
, “
Regulation of Human Subcutaneous Adipose Tissue Blood Flow
,”
Int. J. Obes.
,
38
(
8
), pp.
1019
1026
.10.1038/ijo.2013.200
37.
Polacheck
,
W. J.
,
Charest
,
J. L.
, and
Kamm
,
R. D.
,
2011
, “
Interstitial Flow Influences Direction of Tumor Cell Migration Through Competing Mechanisms
,”
Proc. Natl. Acad. Sci. U. S. A.
,
108
(
27
), pp.
11115
11120
.10.1073/pnas.1103581108
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