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Research Update

Research Update. Sukhi Basati PhD Candidate Laboratory for Product and Process Design Director: Prof. Andreas Linninger 5/12/2011. Spring 2011 research aims. Initiate HC experiments on west campus Priority: High

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Research Update

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  1. Research Update Sukhi Basati PhD Candidate Laboratory for Product and Process Design Director: Prof. Andreas Linninger 5/12/2011

  2. Spring 2011 research aims • Initiate HC experiments on west campus • Priority: High • Induce HC in weanling rats experiments should not last longer than end of February • 2nd surgery involves implanting sensor into hydrocephalic ventricles and CSF removal • Submit acute volume measurement paper • Priority: High • JNS - pediatrics • Design and fabricate long term electronics consisting of surface mount components (microcontroller + wireless transmitter) • Priority: Medium • Write draft of HC simulation in weanling rats • Priority: Medium

  3. History of HC • Study of this disease was limited to cadaver dissection. • Claudius Galen (200 AD) – animal dissections • Al Zahrawi (1013 AD) – removal of CSF • Vesalius (1551) – questioned outflow of CSF, and wrote 1st scientific description of HC – 2 year old girl who had 9 lbs. of ecxess water. • Noted that base of skull and extension of nerves were intact. (she had full use of her senses) • Kelly-Monroe Doctrine (1783) – increase in volume of blood, brain, or CSF causes rise in ICP. • Francois Magendie (1855) – occluded CSF pathways lead to HC • Key and Retzius (1875) – their work proved CSF is secreted from choroid plexus, flows through ventricles, and is absorbed in pachhionan granulations. • Dandy and Blackfan (1913) – created first animal model of HC • Bering (1955) – Dog experiments, removed choroid plexus and produced cHC – ventricle with CP induced ventriculomegaly. • HC defined as mechanical, hydraulic disorder (Leonardo Da Vinci, 1510) (Key and Retzius 1875) (Dandy and Blackfan, 1913)

  4. History of HC Hakim 1976  proposed an important model of the brain as a sponge, postulating that large transmural pressure differences between the SAS and ventricles cause ventricular enlargement by squeezing water out of the brain parenchyma. Clinical Intracranial Pressure Amplitude- Measure of Compliance Di Rocco 1978  Injected balloons into brains of lambs to obtain CSF dynamic parameters. DelBigio and Bruni1988  observed collapse of capillaries following hydrocephalus, and found a decrease in cerebral blood flow following long term hydrocephalus. Greitz1993  Observed timing of CSF pulse with arterial systolic pulse. Pickard and Pena 2004  quantified decrease in cerebral blood flow via PET scans in patients with communicating hydrocephalus. Per Eide 2005  proposes that compliance of brain tissue should be used as diagnostic P. K. Eide, A new method for processing of continuous intracranial pressure signals. Med. Engr. And Physics, 28: 579-587, 2006.

  5. Animal Models What tools are available to understand the progression of the disease? MRI Evaluation of Treatment in Hydrocephalic Rats • Clinical • Intracranial pressure amplitude • Tissue compliance • Animal • Dog ICP monitor • Imaging • MRI / DTI / Histology Histology of Extracellular Space in Hydrocephalic Rats Penn 2005 MR Del Bigio, Effect of hydrocephalus on rat brain extracellular compartment. Cerebrospinal Fluid Research, 5:12, 2008. MR Del Bigio, Magnetic Resonance Imaging and Behavioral Analysis of Immature Rats with Kaolin-Induced Hydrocephalus: Pre- and Postshunting Observatinos. Experimental Neurology, 148: 256-264, 1997.

  6. Investigation into chronic HC CSF bulk flow vs. capillary reabsorption Also need decreased intracranial compliance  chronic hydrocephalus (Greitz 2004)

  7. HC Device History • 1893, Mikulicz implanted glass wool shunt into lateral ventricle of 6 month old infant, extending through SAS and into subgaleal compartment. – 1st permanent shunt. (followed patient over 2 years) • 1898, he developed gold plated metal tube. (patient died 2 months later) • Interventriculostomy III/IV – Leksell 1949 used stereotactic coordinates • Ventriculocisternography – Torkildsen (1938) developed valveless drain from ventricle – cisterna magna • Kausch 1905 implanted shunt from ventricle to peritoneal cavity (VP shunt) • VP shunts used more often after 1950 due to better materials • Luyendijk 1959 – petticoat shunt with expanding diameter drain intended to prevent obstruction. (Mikulicz, 1895) Luyendijk 1959 (Leksell 1949)

  8. HC Device History • 1949 – Nulsen invented valve with 2 balls and 2 springs in series. Spitz implanted it and followed up over 2.5 years. • “If adequate absorption of • cerebrospinal fluid can be secured more uniformly by • this procedure in the future, it would seem to be a method • which most closely reestablishes normal physiology.” • 1955 Pudenz and engineer Heyer – distal teflon valve which functioned for 2 years • 1956 John Holter – father of HC son, developed most widely used valve system today - a double silicone slit valve mounted on a helix spring • 1958 – Schulte (watchmaker) joined Pudenz and Heyer and improved distal slit valve. Engelsman and Sikkens 1956 Drawing of Holter and HC son Nulsen and Spitz 1949 Pudenz and Heyer 1955

  9. HC Treatment Development • Kuffer, 1969 – adjustable valve by screwdriver • 1973 – Hakim valve (external magnet) • programmable medos-hakim valve has 18 different positions. • ranging from 30 – 200 mm H20. • appeared on market 1989 • flow regulating valves • idea tested by hakim in 1973 and hildebrand 1976 • Anti-siphon device • conceived by portnoy and patented by schulte in 1973. • Unfortunately, the external switching diaphragm is highly susceptible to any kind of increased external tissue pressure • (doubtful on clinical performance, clinical trials inconclusive) • Gravitational valve – proposed by Hakim 1975 • Active shunts – conceptually proposed Kuffer 1969 S. Hakim 1973 Cordis Orbis-Sigma valve Aschoff A., et. al, “The scientific history of hydrocephalus and its treatment”. Neurosurg Rev, 22:67-93, 1999.

  10. HC Treatment Options Chabrerie A., and Black P. “Ventricular Shunts”. J Intensive Care Med. 17: 218, 2002.

  11. Limitations of existing treatment • Infection • Infection occurs in 8-10% of cases and is also a significant concern because of increased morbidity, high re-infection rates, and other severe complications. • A single shunt infection costs US$30,000 • Obstruction • Tissue coagulation • hydraulic mismanagement • Over/Under drainage Costs associated with treatment of hydrocephalus (Patwardhan 2001) • Despite the amount of research over the years, much of the disease remains a mystery including : • Why do the ventricles dilate? • What is the role of cerebrovenous pressure? • What causes normal-pressure hydrocephalus? • How is the brain of a child with hydrocephalus • different from that of a young or elderly adult? (Jong 2000) (Bergsneider 2006)

  12. Different approaches • “Smart Shunt” • Still in testing phase • Measures pressure and flow through shunt and transmits info wirelessly to surgeon. • ISSYS, numerous other companies are “developing” (Ko, 1988) (Chung 2005)

  13. Our approach An Implantable System for Intracranial Volume Measurements in Hydrocephalus • Different approach to continuously monitor volume • Measurement Technique • Methodology for an Implantable System • Prototype Design • Sensor Fabrication • Instrumentation Design and Fabrication • Validation • Bench-Top Analysis • Acute Measurements in Hydrocephalic Animal

  14. B Sensor Prototype Fabrication • Systematic approach to sensor fabrication • started big  small • Cost effective approach • Polyimide catheters • Preliminary studies • industrial collaboration? Future work: • Silicone catheter Microautomation Dicing Saw C

  15. RMS to DC converter Voltage to Current Converter Howland current source Sine Wave Generator 1 Khz 10 μA peak-peak 1 DC to DC converter Power 4 8 mV Sine wave voltage generator µC (PIC12F683) RMS  DC converter Datalogger /Labview Sampling Rate = 1000 Hz 2 Differential Amplifier Gain = 68 (0.4 * 68) mV 19.2 mV 3 7.6 mV VI converter Instrumentation amplifier RF Transmitter E1 E2 E3 E4 Instrumentation Design • Requirements • AC signal excitation • Constant current • High SNR • Data acquisition 1.95 • Advantages • Adjustable current source • Adjustable frequency • Adjustable gain • Modifiable design • Future MCU incorporation 1.15 Front • Current Work: • Microcontroller integration. • RF transmitter using RS-232 protocol • On-off power control for periodic measurements Back

  16. 1.95 1.15 Front Back

  17. Hospital care for children with hydrocephalus in the United States: utilization, charges, comorbidies, and deaths Simon et. al 2008. J. Neurosurg Pediatrics Randomized trial of cerebrospinal fluid shunt valve design in pediatric hydrocephalus • For each year in 1997, 2000, 2003 there were 38,000-40,000 admissions, ~400,000 hospital days, and total hospital charges of $1.4 – 2.0 billion • accounts for 3.1% of all pediatric hospital charges J. M. Drake et. Al. Neurosurgery, 1998. • Patients received one of 3 valves: • Standard differential pressure valve • Delta valve (Medtronic) includes siphon-control • Orbis-Sigma valve (Cordis) with a variable resistance component One hundred-fifty patients reached an endpoint; shunt obstruction occurred in 108 (31.4%), overdrainage in 12 (3.5%), loculated ventricles in 2(0.6%), and infection in 28 (8.1%). Sixty-one percent were shunt failure-free at 1 year and 47% at 2 years, with a median shunt failure-free duration of 656 days. Cerebrospinal fluid shunt failure, predominantly from shunt obstruction and infection, remains a persistent problem in pediatric hydrocephalus. Two new valve designs did not significantly affect shunt failure rates. Results: Limitations of existing treatment Conclusions:

  18. Acute Volume Measurements – Sensor Implant What happens when we insert sensor into brain tissue? • Is sensor too stiff? • Why do we need live animals? • MRI validation of sensor insertion • 7T MRIS UofC • Artifact (1.5 mm dia) • durability • Observations during surgery • CSF pulsations • real-time measurements • stable • Additional experiments to be performed: • contralateral measurement • pulsatile volume measuremenet

  19. Acute Volume Measurements – HC induction Gross Dissection • How do we assess proper induction of HC? • Specific indicators • Weight (Del Bigio 1997) • Gait • Ask them

  20. Rat Brains

  21. Summer Plans • Rat sensor in silicone brain phantom • Rat sensor in brain tissue • obtain HC rats from outside collaborator • assess whether acute shunting can be performed on kaolin induced HC rats via imaging • develop wireless unit and test on bench-top brain phantom • REU Plans • test wireless unit in silicone brain phantom • obtain x-section with brain tissue to observe ventricular enlargement • create cavities in brain tissue and test rat sensor • improve bench-top dynamic model used in angiography studies • perform reconstruction with images from angiography

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