9/29/2016 1 Implantable Artificial Kidney: From Silicon Chips to Renal Clearance *Financial Disclosure Silicon Kidney LLC Shuvo Roy, PhD Professor UCSF Paul Brakeman, MD, PhD Associate Professor UCSF 2 The Implantable Artificial Kidney ESRD Statistics USRDS ADR 2015 3 4 Arrhythmia Care as a Paradigm
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9/29/2016
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Implantable Artificial Kidney: From Silicon Chips to Renal Clearance
*Financial DisclosureSilicon Kidney LLC
Shuvo Roy, PhDProfessorUCSF
Paul Brakeman, MD, PhDAssociate ProfessorUCSF
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The Implantable Artificial Kidney
ESRD Statistics
USRDS ADR 2015
3 4
Arrhythmia Care as a Paradigm
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Application to Renal Replacement
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Application to Renal Replacement
ImplantableArtificialKidney
The Renal Filter Unit: the Nephron
ProximalTubule
Loop of Henle
DistalTubule
CollectingDuct
Glomerulus
The Renal Filter Unit: the Nephron
ProximalTubule
Loop of Henle
DistalTubule
CollectingDuct
Glomerulus
Glomerulus~500,000-1,000,000 per kidneyGenerate ~150L of filtrate per day
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The Renal Filter Unit: the Nephron
ProximalTubule
Loop of Henle
DistalTubule
CollectingDuct
Glomerulus
Renal TubuleSelectively reabsorbs ~99% of most solutesReabsorbs ~99% of filtered waterMost reabsorption occurs in the proximal tubule
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Solution - Implantable Artificial Kidney
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Renal Assist Device
Hemofilter
Bioreactor
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RAD Human Trial Results
• Phase II, multicenter, randomized trial with 58 patients in the ICU
– 50% reduction in mortality for patients treated with the RAD versus conventional therapy
Tumlin J et al. Efficacy and Safety of Renal Tubule Cell Therapy forAcute Renal Failure. JASN 2008 19: 923
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Application to Renal ReplacementKey Target Specifications• Package size no larger than 750 ml
– no pumps
• Solute clearance of 20 ml/min (~20% of normal function)
– membrane hydraulic permeability of 10 ml/min/mmHg/m2
– ~30 liters of filtrate produced per day
• Selective filtration
– Albumin loss of 3-4 G per day (membrane sieving coefficient of 0.025)
• Fluid excretion of about 3-5 liters/day
– Requires reabsorption rate of 3 mmol/min Na+ in bioreactor
– translates to ~25 liters of filtrate reabsorbed per day
The Renal Filter Unit: the Nephron
ProximalTubule
Loop of Henle
DistalTubule
CollectingDuct
Glomerulus
Renal TubuleSelectively reabsorbs ~99% of most solutesReabsorbs ~99% of filtered waterMost reabsorption occurs in the proximal tubule
Optimizing Water Transport
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Optimizing Water Transport – Shear Flow
• Bioreactor features
– Microchannel for controlled shear stress on apical surface of cells
– Corning Snapwell membrane for cell support and transport pathway
– Access to basal surface of cells for sampling
Optimizing Water Transport – Shear Flow
Water Transport (LL-PCK1)
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60
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0.02 0.2 0.5 2
Tran
spor
t in
uL/c
m2/
day
Shear Flow in Dyne/cm2
HRTC on Under Shear Flow
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• Human renal tubule cells (HRTCs)
– reliable isolation and expansion protocols
– 1 gm of biopsy tissue (108-10 cells) for 17 doublings
• Successful cryopreservation and functional longevit y
– 4+ months in liquid nitrogen
– 6+ month cell viability in perfusion circuit
4-month Cell Viability
Cell Growth The Renal Filter Unit: the Nephron
ProximalTubule
Loop of Henle
DistalTubule
CollectingDuct
Glomerulus
Glomerular Filtration~500,000-1,000,000 per kidneyGenerate ~150L of filtrate per day
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Filtration is a Fundamental Barrier to Miniaturization• Current hollow-fiber filtration membranes have majo r
limitations
– thick porous polymer films have non-uniform pore sizes and degrade over time upon exposure to body fluids
SEM – Polymer Membrane TEM – Glomerulus
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Silicon Microfabrication
Precision patterning tools to enable high volume ma nufacturing of semiconductor devices
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Completed Wafer
Each chip contains over 10,000/cm2
rectangular 60 um x 120 um membranes
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Membranes Characteristics
• High hydraulic permeability
– up to 600 ml/hr/mmHg/m2
• no pump needed
• Manufacturing compatibility
– scalable for larger quantities
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Biocompatibility Coatings to Prevent Thrombosis• Evaluation of 3 coatings for protein resistance
– polyethylene glycol (PEG) is widely used– poly(N-vinyldextran aldonamide-co-N-vinylhexanamide) (PVAm)