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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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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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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

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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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