novel technologies for blood purification
TRANSCRIPT
Novel technologies for blood purification
Prof. Dr. Dimitrios Stamatialis
Biomaterials Science and Technology, MIRA institute, University of Twente
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BST group
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MIRA: Technology
for regeneration
My research focus
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Biomedical membranes & (bio) artificial organs
Bio-separations
• Bio-molecule separations
• Membrane
chromatography
Tissue regeneration
• TE scaffolds - Bioreactors
• Mass transfer-modeling
(Bio)artificial organs
• (Bio)artificial kidney
• (Bio)artificial liver
• (Bio)artificial pancreas
Kidney
Clearance of all uremic solutes:
water soluble small molecular weight
Middle molecules
Protein-bound
- Continuously
Chronic kidney failure
Chronic kidney failure
Build up of waste products
Donor kidney
Artificial kidney
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Artificial kidney – membrane dialyzer
9 Dutch Kidney foundation
Current therapy
Clearance of solutes:
water soluble, small molecular weight
(some) middle molecules
Not - Protein-bound solutes
Not - continuous cleaning
10 Vanholder, Kidney International 2003
Lee, Clinical and Experimental Nephrology 2008
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Wearable kidney
Davenport et al, Lancet 2007
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Wearable artificial kidney program (consortium of Dutch kidney foundation)
Protein-bound solutes
Hippuric acid
Indoxyl sulfate
P-cresyl sulfate
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µM
µM
µM
Meijers et al. CJASN 2009
p-cresol / p-cresyl sulfate
Sorbents
Hemoperfusion columns
Short term: Intoxications
Solute spectrum
Wearable artificial kidneys
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Protein bound - binder in dialysate
Hemodialysis
Hemodialysis with
binder in dialysate
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Patzer et al. Ther Apher Dial, 2006
Dual layer mixed matrix membrane
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Adsorptive particles
Porous matrix
Particle free blood contacting layer
Hollow fiber – flat sheet membranes
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M. S.L. Tijink et al., Acta Biomaterialia 8 (2012) 2279-2287.
MMM
Packed bed
Cu removal from water
Tetala et al. Sep. Pur Tech 2013.
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Flat MMM
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Adsorption from human blood plasma
21 particle
free m
embra
ne
single
laye
r MM
M
dual laye
r MM
M
activa
ted c
arbon
0,0
0,2
0,4
0,6
0,8
1,0
1,2
re
lative c
oncentr
ation relative creatinine concentration
relative PAH concentration
M. S.L. Tijink et al., Acta Biomaterialia 8 (2012) 2279-2287.
Hollow Fiber Spinning
Bore liquid
Polymer solution
for inner layer
Polymer solution for MMM
Triple orifice spinneret
Coagulation bath (H2O)
Pulling wheel
BA
C D
E F
G H
200 µm
200 µm
200 µm
200 µm
100 µm
100 µm
100 µm
100 µm
SL
DL1
DL2
DL3
MMM
PES / PVP – Norit AC
Hollow fiber MMM
24 M. S.L. Tijink et al., Biomaterials (2013) in press.
Clean water permeance : 60 L/m2/h/bar
0.0 0.1 0.2 0.3 0.4 0.50
50
100
150
200
250
300
350
q
(m
g/g
AC
)
C (mg/mL)
creatinine
hippuric acid
indoxyl sulfate
Adsorption isotherms – DL HF
PES/PVP DL3 AC PES/PVP DL3 AC0.0
0.2
0.4
0.6
0.8
1.0
C
t / C
0
1h
4h
Initial PCS:
39.9 mg/LInitial PCS:
115.5 mg/L
p-cresyl sulfate
PES/PVP DL3 AC PES/PVP DL3 AC0.0
0.2
0.4
0.6
0.8
1.0
Ct /
Co
1h
4h
Initial IS:
37.9 mg/L
Initial IS:
106 mg/L
Indoxyl sulfate
PES/PVP DL3 AC PES/PVP DL3 AC0.0
0.2
0.4
0.6
0.8
1.0
Ct /
C0
1h
4h
Initial HA:
76.4 mg/L
Initial HA:
79.8 mg/L
Hippuric acid
Static adsorption from human blood plasma
MMM
PES / PVP – Norit AC
M. S.L. Tijink et al., Biomaterials (2013) in press.
P P
P
scale scale
Pump
Pressure sensorModule
Feed Dialysate
P P
scale
scalePump
Pressure sensorModule
Feed
Permeate Regulatedpressurevalve
Diffusion Convection
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0 1 2 3 4 5 60
20
40
60
80
100
120
diffusion
cre
atinin
e r
em
oval (m
g/g
AC
)
time (h)
total removal
diffusion
adsorption
total removal
adsorption
DL HF
0 1 2 3 4 5 60
2
4
6
8
10
12
14
16
18
20
Rem
oval (m
g/g
me
mbra
ne
)
Time (h)
HA
IS
PCS
Diffusion experiment
0 1 2 3 4 5 60
2
4
6
8
10
12
14
16
18
20
Re
mova
l (m
g/g
mem
bra
ne)
Time (h)
PCS
IS
HA
Convection experiment
MMM
PES / PVP – Norit AC
M. S.L. Tijink et al., Biomaterials (2013) in press.
MMM evaluation
Diffusion
2.3 mg PCS/g membrane and 3.6 mg IS /g membrane in 4h
Convection
2.7 mg/g membrane PCS and 12.9 mg/g membrane IS
Assuming similar removal in vivo:
5-35 gram (0.07-0.5 m2) MMM for daily removal of these toxins
(healthy subjects excrete 78 mg PCS and 69 mg IS in their urine in 24h).
Future work
Inner layer can be optimized (diameter, porosity)
Higher particle loading
Larger modules comparable to:
- hemodialysis concerning surface area / size
- commercial columns concerning particle content
New membrane forming polymer
New particles
Acknowledgements
Dutch Kidney Foundation – PhD Marlon Tijink
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Nephrology dept.
UMC Gent
R. Vanholder
G. Glorieux
MTG
University of Twente
J. Sun
S. Saiful
Z. Borneman
M. Wessling
Nephrology and Hypertension
UMC Utrecht
M. Wester
J. Joles
K. Gerritsen
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BIOART ITN
Kidney and liverdisease treatment
WP1 (P1, P2, P8, P9)
Artificial kidney devices for
prolonged/continuous treatment
WP2 (P1, P3, P8)
Bioartificial kidney device for
removal of uremic toxins
WP3 (P4-P8, P10)
Bioartificial liver devices ensuring viability
and function of hepatic cells
Coordinator – EU BIOART ITN 11 partners - 5 European countries (16 researchers , 3.8 million Euros)
Bioartificial kidney
BioKid project - BMM program
Bioartificial kidney
24/07/2013 36
NanoNext (PhD project, F. Hulshof)
Kidney on Chip
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KNAW grant / BST, TR, BIOS (UT), UMC Nijmegen
100
µm
MDCK
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“See you on the road…”
We're gonna get to that place where we
really want to go…..
But till then, tramps like us….. we were ……..Born to run!
(Born to Run, 1975)
Dual layer HF MMM
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0.0 0.5 1.0 1.5 2.0
0
25
50
75
100
125
150
175
Cle
an
wa
ter
flu
x (
L/m
2/h
)
transmembrane pressure (bar)
clean water permeance: 58 ± 9 L/m2/h/bar
Creatinine adsorption isotherms
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0.00 0.05 0.10 0.150
25
50
75
100q
(m
g/g
AC
)
C (mg/mL)
single layer MMM
dual layer MMM
langmuir fit
Deng et al. Journal of Applied Polymer Science 2007
Creatinine
C4H7N3O
Product of muscle breakdown
Measure for glomerular filtration rate
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Para amino hippuric acid
C9H10N2O3
Albumin bound
Removal in kidney: tubular secretion
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