9/29/2016 The Implantable Artificial Kidney Implantable Artificial - - PowerPoint PPT Presentation
9/29/2016 The Implantable Artificial Kidney Implantable Artificial Kidney: From Silicon Chips to Renal Clearance Shuvo Roy, PhD Professor UCSF *Financial Disclosure Silicon Kidney LLC Paul Brakeman, MD, PhD Associate Professor UCSF 2
Shuvo Roy, PhD Professor UCSF Paul Brakeman, MD, PhD Associate Professor UCSF
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USRDS ADR 2015
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Implantable Artificial Kidney
Proximal Tubule Loop of Henle Distal Tubule Collecting Duct Glomerulus
Proximal Tubule Loop of Henle Distal Tubule Collecting Duct Glomerulus Glomerulus ~500,000-1,000,000 per kidney Generate ~150L of filtrate per day
Proximal Tubule Loop of Henle Distal Tubule Collecting Duct Glomerulus Renal Tubule Selectively reabsorbs ~99% of most solutes Reabsorbs ~99% of filtered water Most reabsorption occurs in the proximal tubule
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Hemofilter Bioreactor
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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 for Acute Renal Failure. JASN 2008 19: 923
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– no pumps
function)
– membrane hydraulic permeability of 10 ml/min/mmHg/m2 – ~30 liters of filtrate produced per day
– Albumin loss of 3-4 G per day (membrane sieving coefficient of 0.025)
– Requires reabsorption rate of 3 mmol/min Na+ in bioreactor – translates to ~25 liters of filtrate reabsorbed per day
Proximal Tubule Loop of Henle Distal Tubule Collecting Duct Glomerulus Renal Tubule Selectively reabsorbs ~99% of most solutes Reabsorbs ~99% of filtered water Most reabsorption occurs in the proximal tubule
– Microchannel for controlled shear stress on apical surface
– Corning Snapwell membrane for cell support and transport pathway – Access to basal surface of cells for sampling
Water Transport (LL-PCK1)
20 40 60 80 100 120 140 0.02 0.2 0.5 2
Transport in uL/cm2/day Shear Flow in Dyne/cm2
HRTC on Under Shear Flow
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– reliable isolation and expansion protocols – 1 gm of biopsy tissue (108-10 cells) for 17 doublings
– 4+ months in liquid nitrogen – 6+ month cell viability in perfusion circuit 4-month Cell Viability
Proximal Tubule Loop of Henle Distal Tubule Collecting Duct Glomerulus Glomerular Filtration ~500,000-1,000,000 per kidney Generate ~150L of filtrate per day
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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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Precision patterning tools to enable high volume manufacturing
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Each chip contains
rectangular 60 um x 120 um membranes
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– up to 600 ml/hr/mmHg/m2
– scalable for larger quantities
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– polyethylene glycol (PEG) is widely used – poly(N-vinyldextran aldonamide-co-N-vinylhexanamide) (PVAm)
– polysulfobetaine methacrylate (polySBMA)
10 20 30 40 50 60 Day 1 Day 7 Day 21 Day 28
Fg Adsorption, %
PEG PVAm polySBMA
Kensinger et al. ASAIO J 2016
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Ultrafiltrate 1 x 1cm SNM
Adapted from Kensinger et al. ASAIO J 2016
1 2 3 4 5 6 7 8 1 2 3 4 5
ml/cm2/day Device
Filtrate Volume
Dimensions: 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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6.5cm
Blood inlet: 1mm channel height
3.2cm
Nanopore Region
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Blood Inlet Seal Plate Bottom Plate Top Plate Assembled Subunits Blood Outlet
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Device Placed in Retroperitoneum Arterial Inflow (Dacron Graft) Venous Outflow (Dacron Graft)
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– 40% lighter by using Polyether ether ketone (PEEK) – Anchoring points incorporated into new PEEK plates – \
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– More rigid material for the tubing with external support rings
– External support to provide structural rigidity at the titanium-graft interface
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Catheter tip In Inflow graft
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– reliable cell sourcing and expansion – successful cryopreservation – active water reabsorption
– high hydraulic permeability – high permselectivity – multichannel, large scale hemofilter implanted for up to 3 days
– CDRH program to shorten time-to-market – goal is to shorten time-to-market without sacrificing safety
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– Scale up of bioreactor for macroscopic filtrate reabsorption
– Optimization of porosity for increased hemofiltration
– CDRH program to shorten time-to-market – goal is to shorten time-to-market without sacrificing safety
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– The Kidney Project team – FDA CDRH – UCSF Pediatric Device Consortium – UCSF Surgical Accelerator – UCSF Clinical Translational Sciences Institute (CTSI)
– 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
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