Novel technologies for blood purification Prof. Dr. Dimitrios Stamatialis Biomaterials Science and Technology, MIRA institute, University of Twente 1
BST group MIRA: Technology for regeneration 5
My research focus Biomedical membranes & (bio) artificial organs Tissue regeneration TE scaffolds - Bioreactors Mass transfer-modeling (Bio)artificial organs (Bio)artificial kidney (Bio)artificial liver (Bio)artificial pancreas Bio-separations Bio-molecule separations Membrane chromatography 6
Clearance of all uremic solutes: Kidney 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 8
Artificial kidney membrane dialyzer Dutch Kidney foundation 9
Current therapy Clearance of solutes: water soluble, small molecular weight (some) middle molecules Not - Protein-bound solutes Not - continuous cleaning Vanholder, Kidney International 2003 Lee, Clinical and Experimental Nephrology 2008 10
Wearable kidney Davenport et al, Lancet 2007 11
Wearable artificial kidney program (consortium of Dutch kidney foundation) 12
Protein-bound solutes Hippuric acid Indoxyl sulfate P-cresyl sulfate 13
p-cresol / p-cresyl sulfate µm µm µm Meijers et al. CJASN 2009
Sorbents Hemoperfusion columns Short term: Intoxications Solute spectrum Wearable artificial kidneys 15
Protein bound - binder in dialysate Hemodialysis Patzer et al. Ther Apher Dial, 2006 Hemodialysis with binder in dialysate 16
Dual layer mixed matrix membrane Adsorptive particles Porous matrix 0 Particle free blood contacting layer Hollow fiber flat sheet membranes M. S.L. Tijink et al., Acta Biomaterialia 8 (2012) 2279-2287. 17
Cu removal from water Packed bed MMM Tetala et al. Sep. Pur Tech 2013.
19
Flat MMM 20
relative concentration Adsorption from human blood plasma 1,2 relative creatinine concentration relative PAH concentration 1,0 0,8 0,6 0,4 0,2 0,0 particle free membrane single layer MMM dual layer MMM activated carbon M. S.L. Tijink et al., Acta Biomaterialia 8 (2012) 2279-2287. 21
Hollow Fiber Spinning Polymer solution for MMM Bore liquid Polymer solution for inner layer Triple orifice spinneret Pulling wheel Coagulation bath (H2O)
A B SL 200 µm 100 µm MMM PES / PVP Norit AC DL1 DL2 C E 200 µm D F 100 µm DL3 G 200 µm H 100 µm 200 µm 100 µm
Hollow fiber MMM Clean water permeance : 60 L/m 2 /h/bar M. S.L. Tijink et al., Biomaterials (2013) in press. 24
q (mg/g AC) Adsorption isotherms DL HF 350 300 indoxyl sulfate 250 200 150 creatinine 100 hippuric acid 50 0 0.0 0.1 0.2 0.3 0.4 0.5 C (mg/ml)
p-cresyl sulfate Indoxyl sulfate 1.0 1h 4h 1.0 1h 4h C t / C 0 0.8 0.6 0.4 Initial PCS: 39.9 mg/l Initial PCS: 115.5 mg/l C t / C o 0.8 0.6 0.4 Initial IS: 37.9 mg/l Initial IS: 106 mg/l 0.2 0.2 0.0 PES/PVP DL3 AC PES/PVP DL3 AC 0.0 PES/PVP DL3 AC PES/PVP DL3 AC Static adsorption from human blood plasma MMM PES / PVP Norit AC 1.0 Hippuric acid 1h 4h C t / C 0 0.8 0.6 0.4 Initial HA: 76.4 mg/l Initial HA: 79.8 mg/l 0.2 0.0 PES/PVP DL3 AC PES/PVP DL3 AC M. S.L. Tijink et al., Biomaterials (2013) in press.
Pressure sensor P Module P Pressure sensor P Module P P Pump Pump Permeate scale Regulated pressure valve Feed scale Dialysate scale Feed scale Diffusion Convection
creatinine removal (mg/g AC) DL HF 120 100 80 60 40 20 total removal diffusion adsorption total removal adsorption diffusion 0 0 1 2 3 4 5 6 time (h) 28
Removal (mg/g membrane) Removal (mg/g membrane) 20 18 16 14 12 10 8 6 4 Diffusion experiment HA 2 PCS 0 0 1 2 3 4 5 6 Time (h) MMM PES / PVP Norit AC IS Convection experiment 20 18 HA 16 14 12 10 IS 8 6 4 PCS 2 0 0 1 2 3 4 5 6 Time (h) 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 m 2 ) 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 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 32
WP2 (P1, P3, P8) Bioartificial kidney device for removal of uremic toxins BIOART ITN WP1 (P1, P2, P8, P9) Artificial kidney devices for prolonged/continuous treatment WP3 (P4-P8, P10) Bioartificial liver devices ensuring viability and function of hepatic cells Kidney and liver disease treatment Coordinator EU BIOART ITN 11 partners - 5 European countries (16 researchers, 3.8 million Euros) 33
Bioartificial kidney BioKid project - BMM program
Bioartificial kidney
NanoNext (PhD project, F. Hulshof) 24/07/2013 36
Kidney on Chip MDCK 100 µm KNAW grant / BST, TR, BIOS (UT), UMC Nijmegen 38
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) 39
Clean water flux (L/m 2 /h) Dual layer HF MMM 175 150 clean water permeance: 58 ± 9 L/m 2 /h/bar 125 100 75 50 25 0 0.0 0.5 1.0 1.5 2.0 transmembrane pressure (bar) 41
q (mg/g AC) Creatinine adsorption isotherms 100 75 single layer MMM dual layer MMM langmuir fit 50 25 0 0.00 0.05 0.10 0.15 C (mg/ml) Deng et al. Journal of Applied Polymer Science 2007 42
Creatinine C 4 H 7 N 3 O Product of muscle breakdown Measure for glomerular filtration rate 43
Para amino hippuric acid C 9 H 10 N 2 O 3 Albumin bound Removal in kidney: tubular secretion 44