building a bioartificial kidney: from silicon chips to .... paul brakeman.pdf · paul brakeman, md,...
TRANSCRIPT
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Building a Bioartificial Kidney: From Silicon Chips to
Renal Clearance
Paul Brakeman, MD, PhDMedical Director, Pediatric Dialysis Unit
Assistant ProfessorDepartment of Pediatrics
UCSF
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Currently There Are > 540,000 Patients with End Stage Renal Disease in the United States
USRDS Annual Report, 2009
Surv
ival
Pro
babi
lity
Months
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Currently There Are > 540,000 Patients with End Stage Renal Disease in the United States
USRDS Annual Report, 2009
Surv
ival
Pro
babi
lity
> 350,000 patients receive dialysis
Months
![Page 4: Building a Bioartificial Kidney: From Silicon Chips to .... Paul Brakeman.pdf · Paul Brakeman, MD, PhD ... USRDS Annual Report, 2009 Survival Probability ... Urea Urea Waste H 2O](https://reader031.vdocuments.net/reader031/viewer/2022022009/5af3324b7f8b9a154c8c8974/html5/thumbnails/4.jpg)
Currently There Are > 540,000 Patients with End Stage Renal Disease in the United States
USRDS Annual Report, 2009
Surv
ival
Pro
babi
lity
> 350,000 patients receive dialysis
> 70,000 patients waiting for a renal transplant
Months
![Page 5: Building a Bioartificial Kidney: From Silicon Chips to .... Paul Brakeman.pdf · Paul Brakeman, MD, PhD ... USRDS Annual Report, 2009 Survival Probability ... Urea Urea Waste H 2O](https://reader031.vdocuments.net/reader031/viewer/2022022009/5af3324b7f8b9a154c8c8974/html5/thumbnails/5.jpg)
Currently There Are > 540,000 Patients with End Stage Renal Disease in the United States
USRDS Annual Report, 2009
Surv
ival
Pro
babi
lity
> 350,000 patients receive dialysis
> 70,000 patients waiting for a renal transplant
Only 18,000 transplants per yearMonths
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Strategies to Increase Numbers of Available Organs
• Publicity campaigns to increase organ donation• Extended criteria for identifying usable organs (Audard Trans Int 2007)
• Desensitized patients so they are more likely to be able to find a compatible kidney (Montgomery NEJM 2011)
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Strategies to Increase Numbers of Available Organs
• Publicity campaigns to increase organ donation• Extended criteria for identifying usable organs (Audard Trans Int 2007)
• Desensitized patients so they are more likely to be able to find a compatible kidney (Montgomery NEJM 2011)
• Engineer replacement organs
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Strategies for Engineering Replacement Organs
• Generate humanized animals and use them as a source for organs
• Grow an organ using stem cells• Use human kidney cells to reconstitute renal tissue
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Strategies for Engineering Replacement Organs
• Generate humanized animals and use them as a source for organs
• Grow an organ using stem cells• Use human kidney cells to reconstitute renal tissue • Engineer a bioartificial organ using novel technology for hemofiltration and renal cells to provide cellular function
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The Bioartificial Kidney Project
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The Bioartificial Kidney Project
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Frank Partridge 2009 Johnson Research
The Bioartificial Kidney Project
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The Renal Filter Unit: the Nephron
Peritubular Capillary
ProximalTubule
Loop of Henle
DistalTubule
CollectingDuct
Glomerulus
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Peritubular Capillary
ProximalTubule
Loop of Henle
DistalTubule
CollectingDuct
Glomerulus~500,000-1,000,000 per kidneyGenerate ~150L of filtrate per day
The Renal Filter Unit: the Nephron
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Peritubular Capillary
Loop of Henle
DistalTubule
CollectingDuct
GlomerulusProximal TubuleSelectively reabsorbs ~80% of most solutesReabsorbs ~80% of filtered water1,25-(OH)2-Vit D3 activation
The Renal Filter Unit: the Nephron
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Peritubular Capillary
ProximalTubule
Loop of Henle
Distal TubuleFine tunes solute excretionFurther water excretion
CollectingDuct
Glomerulus
The Renal Filter Unit: the Nephron
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H2O
Schematic of the Bioartificial Kidney
Blood
Filtrate
H2O Na+
Na+
Urea
Urea
Waste
H2O Na+ Urea
H2O Na+ Urea
H2O
Blood H2O Na+
Na+ Urea
H2O Na+
H2O Na+ Urea
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H2O
Blood
Filtrate
H2O Na+
Na+
Urea
Urea
WasteHemofilter
H2O Na+ Urea
H2O Na+ Urea
H2O
Blood H2O Na+
Na+ Urea
H2O Na+
H2O Na+ Urea
Schematic of the Bioartificial Kidney
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H2O
Blood
Filtrate
H2O Na+
Na+
Urea
Urea
Waste
H2O Na+ Urea
H2O Na+ Urea
H2O
Blood H2O Na+
Na+ Urea
H2O Na+
H2O Na+ Urea
o Based on hemofiltration to eliminate need for dialysateo Implantable to allow for continuous blood cleansing o Incorporate of renal cells to reabsorb solutes and exclude toxinso Renal cells provide some metabolic and hormonal functions
Bioreactor - Human renal tubular cells
Schematic of the Bioartificial Kidney
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Innovations Required for Implantation of the RAD
Humes et al., Univ. of Michigan
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Innovations Required for Implantation of the RAD
Humes et al., Univ. of Michigan
o Elimination of high pressure pumps
o Miniaturization of the hemofilter
o Better biocompatibility of the filter and blood path
o Intrinsic feedback to monitor patient‘s homeostasis
o Stable function for months to years
o Adequate reabsorptionof salt and water
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• Targets– Hemofiltration‐
• 30 liters per day of filtrate produced
Design Targets for the Bioartificial Kidney
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• Targets– Hemofiltration‐
• 30 liters per day of filtrate produced – why?
Design Targets for the Bioartificial Kidney
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Improvement in Survival with Intensive Daily Dialysis
Johansen K, Kidney Int, 2009
Conventional hemodialysis
Nocturnal hemodialysis
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• Targets– Hemofiltration‐
• 30 liters per day of filtrate produced – how?
Design Targets for the Bioartificial Kidney
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Improved Membrane Technology is Critical for Miniaturizing the Bioartificial Kidney
Standard dialysis membrane Silicon nanopore membrane
William Fissell and Shuvo Roy, J Memb Sci, 2010
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• Very consistent pore sizes create highly selective pores and allow for exclusion of antibodies and medium to large size proteins for better biocompatibility
• High hydraulic permeability• Smooth surface allows for coating
the membranes to allow for low bioreactivity
Silicon nanopore membrane after 48 hours of in vitroexposure to whole blood
Fissell, J Memb Sci, 2010
Improved Membrane Technology is Critical for Miniaturizing the Bioartificial Kidney
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• Very consistent pore sizes create highly selective pores and allow for exclusion of antibodies and medium to large size proteins for better biocompatibility
• High hydraulic permeability• Smooth surface allows for coating
the membranes to allow for low bioreactivity
Silicon nanopore membrane after 48 hours of in vitroexposure to whole blood
Fissell, J Memb Sci, 2010
Improved Membrane Technology is Critical for Miniaturizing the Bioartificial Kidney
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3‐Dimensional CAD Rendering of the Bioartificial Kidney
Hemofilterblood in blood out
ultrafiltrate
Membrane chips bondedback-to-back
}
ultrafiltrateblood
membranesilicon substratebonding layer
Bioreactor Current hydraulic
permeability of the silicon membrane is 10 l/cm2/min/PSI.
At this porosity the hemofilter requires 380 cm2 of filter area to generate 30L per day of filtrate – About the size of two decks of cards
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Ex‐vivo Hemofilter Design Testing
Computer Assisted Design
ManufacturingPrototype
TestingPrototype
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• Targets– Hemofiltration‐
• 30 liters per day of filtrate produced• Biocompatibility of the filter and blood path
– Bioreactor‐• Barrier function to prevent reabsorption of toxins• 25 liters of water reabsorption• 3500 mM of sodium reabsorption• Metabolic function
Design Targets for the Bioartificial Kidney
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Properties of an Ideal Renal Cell for the Bioreactor
o Barrier to reabsorption of toxinso Adequate reabsorption of sodium, potassium,
phosphorus and watero Provides metabolic function including 1,25 OH
Vitamin D productiono Stable for 3-4 monthso Non-immunogenic
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Analysis of Cells in a LaminarFlow Bioreactor
Standard Tissue Culture Tissue Culture Under Flow Conditions
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0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
OK LLC-PK1
CreatinineRetention
Urea Retention
Barrier Function of Commercially Available Proximal Tubule Cell Lines
n = 6 n = 6 n = 6 n = 6
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Water Transport of Proximal Tubule Cell Lines
Tran
sport R
ate L
/cm
2 /day
Ferrell et al. 2011, submitted
0
10
20
30
40
50
60
OK LLC-PK1 HCTC
n = 4 n = 4
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Immortalized Human Proximal Tubule Cells ‐ RPTEC/TERT1 Cells
Primary human proximal tubule cells were transfected with human telomerase and clones were selected and characterized
Green = Acetylated Tubulin Green = -catenin
Wieser, Grillari, AJPR, 2008
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Barrier Function of RPTEC/TERT1 Cells
n = 6 n = 6 n = 6 n = 697.0%
97.5%
98.0%
98.5%
99.0%
One Month Two Months Three Months
Perc
ent r
etai
ned
crea
tinin
e
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Salt Reabsorption of RPTEC/TERT1 CellsTran
sport R
ate
mEq
/cm
2 /day
n = 6 n = 6
20181614121086420
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Salt Reabsorption of RPTEC/TERT1 Cells
n = 6
25 kD
20 kD
-tubulin
ZO-1
10uM
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Water Transport of Other Immortalized Human Renal Proximal Tubule Cells
n = 4 n = 4
Sanechika, NDT, 2011
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Water Transport of Other Immortalized Human Renal Proximal Tubule Cells
n = 4 n = 4
** Actual reabsorption 17 uL/cm2/day
Sanechika, NDT, 2011
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Salt and Water Transport in Renal Proximal Tubule Cells
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Bioartificial Kidney Project
Silicon Nanofabrication Cell Engineering
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UCSF Bioartificial Kidney Team
• UCSF Team memberso Brakeman Lab
o Chao‐Zong Leeo Natalie Spivako Daniel Kaplan
o Shuvo Roy Labo Rishi Kanto Alex Hellero Peter Solero Torin Yeager
o Mark Wilson Labo Steven Hettso Loi Doo Mathem Saeedo Jeremy Durack
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Bioartificial Kidney
• Non‐UCSF Team memberso William Fissell Lab (Vanderbilt School of Medicine)
o Nicholas Ferrell, PhDo David Humes, MD (University of Michigan)
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Project Team
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Bioartificial Kidney Project
Silicon Nanofabrication Cell Engineering