implantable artificial kidney: from silicon chips to renal
TRANSCRIPT
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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
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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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0.02 0.2 0.5 2
Tran
spor
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uL/c
m2/
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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)
• synthetic glycocalyx
– polysulfobetaine methacrylate (polySBMA)• zwitterionic polymer
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Fg
Ads
orpt
ion,
%PEG
PVAm
polySBMA
First Implanted Silicon NanoporeMembrane HemofilterKensinger et al. ASAIO J 2016
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Ultrafiltrate1 x 1cm SNM
First Implanted Silicon NanoporeMembrane Hemofilter
Adapted from Kensinger et al. ASAIO J 2016
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Device
Filtrate Volume
Titanium Hemofilter PrototypeDimensions: 9.3cm x 5.7cm x 1.4cm
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Ultrafiltrate Ports
Ultrafiltrate Ports
3mm Blood Inlet
3mm Blood Outlet
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Individual Channel
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6.5cm
Blood inlet: 1mm channel height
Blood outlet
3.2cm
NanoporeRegion
Hemofilter Assembly
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Blood Inlet
Seal Plate
Bottom Plate
Top Plate
Assembled Subunits
Blood Outlet
Whole Porcine Blood Bench Top Experiments
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Pump
Blood Reservoir
Inlet
Outlet
Explant: Post-Operative Day 3 (POD3)
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Thrombus
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Device Placed in Retroperitoneum
Arterial Inflow(Dacron Graft)
Venous Outflow(Dacron Graft)
Surgical Considerations for Implantation
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• Housing material and geometry
• Device weight
• Vascular interface
Surgical Considerations for Implantation
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• Housing material and geometry
• Device weight
• Vascular interface
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Device Housing Modification• Housing Redesign
– 40% lighter by using Polyether ether ketone (PEEK)
– Anchoring points incorporated into new PEEK plates
– \
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Titanium PEEK
Anchor points
Surgical Considerations for Implantation
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• Housing material and geometry
• Device weight
• Vascular interface
Vascular Connector Design:
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Graft Connector Modifications• New Synthetic graft
– More rigid material for the tubing with external support rings
• Strain-relieving Sleeve
– External support to provide structural rigidity at the titanium-graft interface
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Intraoperative positioning of modified prototype
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Aorta
External Iliac Vein
Anchors
Modified Vascular Interface
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Anastomosis to Aorta
Strain-relief
Device
Selective angiogram prior to explant on POD3
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Catheter tipIn Inflow graft
Outflow graft 44
Key Phase I Accomplishments
• Cell bioreactor– reliable cell sourcing and expansion
– successful cryopreservation
– active water reabsorption
• Hemofiltration– high hydraulic permeability
– high permselectivity
– multichannel, large scale hemofilter implanted for up to 3 days
• FDA Innovation Pathway 2.0– CDRH program to shorten time-to-market
– goal is to shorten time-to-market without sacrificing safety
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Key Phase 2 Design Targets
• Cell bioreactor– Scale up of bioreactor for macroscopic filtrate reabsorption
• Hemofiltration Longer scale implantation
– Optimization of porosity for increased hemofiltration
• FDA Innovation Pathway 2.0– CDRH program to shorten time-to-market
– goal is to shorten time-to-market without sacrificing safety
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Acknowledgements• Collaborators
– The Kidney Project team
– FDA CDRH
– UCSF Pediatric Device Consortium
– UCSF Surgical Accelerator
– UCSF Clinical Translational Sciences Institute (CTSI)
• Funding – NIH: R01 EB014315; R01 EB008049; R21 EB002285;
K08 EB003468
– DoD: W81XWH-05-2-0010
– NASA: JGBEC
– Rogers Bridging-the-Gap Award
– Hinds Distinguished Professorship II
– Goldman Family Foundation
– Wildwood Foundation
Roy Lab
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