In vitro Total control of confounding variables
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Transcript of In vitro Total control of confounding variables
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In vitro• Total control of confounding variables
– Vasomotion, temperature changes, autoregulation, mean BP• Most accurate because vessel examined directly• Best for detailed information about mechanical properties of vessel material
In vivo (invasive)• Realistic clinical information• Limited by technical problems
– Measurement errors, transitory changes in diam. BP etc
In vivo (non-invasive)• Further technical problems
– Especially pressure
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Measurement of blood pressure
• Invasive– Pressure catheter and transducer
• Non invasive– Sphygmomanometry
• Auscultation (by ear or automatically by microphone)• Oscillometry
– Volume clamp– Tonometry
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• Invasive– Accurate reproduction of central pressure waveforms– Risk of thrombosis and arrhythmias
• Non-invasive– Quick, cheap, widely used– Lack of central pressure measurement– Requires skilled and experienced operators
Advantages/ drawbacks
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Sphygmomanometry
www.fmshk.com.hk/sahk/lecture_noninvasive.pp
Pulse detector(stethoscope or microphone)
Manometer(mercury or capsule type)
Manometer(mercury or capsule type)
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Sphygmomanometry
• 1896 Blood pressure cuff (Riva Rocci)
• 1905 First report of audible detection of heart sounds used with cuff (Korotkov)
• 1968 Microphone used for automatic pressure measurement (Stegall)
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Sphygmomanometry
Capsule manometerReplacing mercury spymomanometerMercury sphygmomanometer
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Korotkov Soundscaused by vibration collapse of the arterial wall??
www.fmshk.com.hk/sahk/lecture_noninvasive.pp
Cuf
f pr
essu
re
Systolic
Diastolic
– Korotkoff IV is a better indication of diastolic pressure according to theory
– However Korotkoff V is the commonly recommended measuring point except in pregnant patients because
• It is associated with less inter-observer variations
• It is easier to detect by most observers
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Errors
• Korotkoff sounds compared to invasive blood pressure measurement– Korotkoff IV is on average 8mm Hg above the invasively
measured diastolic blood pressure– Korotkoff V is on average 2mm Hg above the invasively
measured diastolic blood pressure
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Oscillometry
• Cuff round the arm
• Pressurise cuff (> systolic)
• Allow pressure to drop slowly to zero
• Measure pressure in the cuff during deflation
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Oscillometry: set up
Pressure transducerPressure transducerAir pumpAir pump Bleed valveBleed valve
Micro-processor
Micro-processor DisplayDisplay
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Principle of oscillometry
Variation of cuff pressure as cuff is deflated
Filt
ered
sig
nal
Of
cuff
pre
ssur
e
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Limitations• Inaccurate / unreliable in shock patients• Inaccurate / unreliable in patients with arrhythmias
– The algorithm of measurement assumes a regular pulse, so the reading is unreliable in patients with irregular pulse
Advantages• No skill required• No subjective errors
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Volume clamp
Air
Air
Infra red emitter
Detector
Artery
FingerPressure
Detectedsignal
Change cuffpressure
Measure cuffpressure
To pump
Diameter
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Applanation tonometryDetects pressure of arterial pulsations through the skin
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Problem:
AorticRadial
• Aortic and peripheral pressures are different.• The heart doesn’t care what the pressure is in the radial artery.• It only “sees” aortic pressure.• Aortic pressure is difficult (impossible?) to measure non-
invasively• Can we reconstruct the aortic waveform from the radial?
80
100
120
Systolic
Diastolic
Mean
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Yes we can. At least in principle
• Record radial waveform with tonometry
• Apply inverse transfer function
• “Reconstruct” aortic waveform– What is an inverse transfer function?– How do we reconstruct the waveform?
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Fourier analysis
36027018090
-2
-1
0
1
2
36027018090
-2
-1
0
1
2 H1 + H2H3
36027018090
-2
-1
0
1
2 H1 + H2 + H3H4
36027018090
-2
-1
0
1
2
Mean
H1H2
Measured
H1+H2+H3+H4
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Pa(t) = pa0
+ pa1Cos(t - a1)+ pa2Cos(t - a2)+ pa3Cos(t - a3)+ ...
Pb(t) = pr0
+ pr1Cos(t - r1)+ pr2Cos(t - r 2)+ pr3Cos(t - r 3)+ ...
For each harmonic (n)
Transfer function phase = an - rn
Transfer function amplitude = pan / prn
aortic pressure radial artery pressure
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Amplification of the pulse
AA - CA
CA - RA
AA - RA
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How to derive the central pressure from peripheral measurements
• Compare Fourier series of “typical” aortic pressure waves with Fourier series of the radial pressure computed from tonometric measurements.
• Calculate the amplitude ratio and phase difference for each harmonic
• Apply this ratio and phase difference to each harmonic of the measured radial wave and reconstruct aortic wave that would when transmitted down the arm, produce the measured radial wave
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Question• How well does the typical transfer function
apply to people of different ages and disease states
Answer• Surprisingly well considering the changes that
occur in the arterial system with age and vascular disease
• However, most believe that more work is needed to validate the method
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Pressure transducers(for invasive measurement)
Fluid filled chamber
Stiff diaphragmMeasure its movementelectronically
To pressure to be measured,(via an intra arterial cannula)
Diaphragm manometer
Advantages• Cheap, disposable• easy to use• Accurate mean pressure
Disadvantages• Clotting in cannula, air
bubbles• Therefore errors in pulse
pressure
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Pressure transducers(for invasive measurement - 2)
Cannula tip manometer Semi conducting strain gauge
Diameter may be as small as 0.67 mm
Advantages• High accuracy• Especially in very small
vessels
Disadvantages• No calibration possible when
in position• Expensive• Fragile
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Pressure: comparison of methods
Method Sensitivity Invasive Advantages/ disadvantages
Auscultation + cuff
OK No Subjective, limited to arm or leg. Good in skilled hands
Oscillometry + cuff
OK No As above but less subjective. No mean pressure.
Catheter Good Yes Only direct way to measure in central vessels
Volume clamp Good No Limited to peripheral arteries but can do small ones
Tonometry V. Good No Superficial vessels only, sensitive to movement, good for carotid. No absolute P values. Can be calibrated against cuff methods
PPG V. Good No Superficial vessels only. Used as a pulse detector in conjunction with cuff. PROMISING
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Flow Measurement
• Invasive– Electromagnetic flow velocimetry– Ultrasonic transit time
• Non invasive– Doppler ultrasound– Ultrasonic transit time – Optical (small superficial vessels only)– MRI
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Flow measurement• 1870 Fick principle described
Flow in a given period of time = Amount of substance injected in that time/concentration difference before and after point of entry
• 1886 Fick method first used by Grehart & Quinquardt
• Modern instruments– Optical– Electromagnetic 1936-1937 Kolin– Ultrasonic transit time 1959– Ultrasonic Doppler 1961– MRI 1990’s (not commercial)
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i.d. 0.5 - 26 mm
E = H.d.VInduced voltage
Magnetic field strength
Vessel diameter
Mean blood velocity
Electrode
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Principle of Doppler flow velocimetry
v
c fc
cf
c vf'
cf' (c v)f
cf' cf vf
f' ff
vc
fvfc
c f'
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Flow: comparison of methods
Method Sensitivity Invasive Advantages/disadvantages
Dilution Adequate No Cumbersome, slow,mean values only
Optical Good No Small superficial vessels only
Doppler OK No Absolute flow values difficultto measure
Transit time Good Yes None apart from expense andinvasiveness
E.M OK Yes Electrical noise, hard tocalibrate accurately
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Diameter Measurement
• Mechanical• Optical• Ultrasonic
– Implanted crystals– Pulse echo
• Cine-angiography • MRI
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Invasive Diameter Measurement
• Ultrasound (external transducers)• IVAS• TV• Mechanical• Cine angiography
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Non-invasive diameter measurement
• Pulse echo ultrasound (direct)• PWV (indirect)
– Diameter wave– Flow wave– Pressure wave
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Artery
Differential transformer
Springy stainless steel
Ultrasonic crystals(glued or sutured)Measure time delay
TV camera
Other diameter methods
Transmitter
Receiver
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Measure time delay between transmitted and received pulse
Principle of pulse echo ultrasound
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Diameter: comparison of methods
Method Sensitivity Invasive Advantages/disadvantages
Mechanical OK Yes Cumbersome, but insensitiveto wall movement
Optical Good Yes (no) Non contact but sensitive towall movement. N.I. methodonly measures rel. diam.
Ultrasound(crystals)
Very good Yes Difficult to set up, insensitiveto wall movement
Ultrasound(echo)
Good No Sensitive to wall/patientmovement, but only absolutenon invasive method
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Elasticity measurement
• Direct– Stress
•pressure, tension, area, wall thickness
– Strain•length, diameter
• Indirect– Pulse wave velocity
•detect pressure, diameter or flow pulse
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PWV Methods
• Pressure pulse– Tonometry
• Flow pulse– Doppler
• Diameter Pulse– PPG
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Nature of the PPG Signal
• Commonly regarded as a measure of changes in tissue volume due to arteriolar and capillary blood flow time varying absorption of light or i.r.
• When detected in the vicinity of a large superficial artery, the signal is dominated by changes in the diameter (volume) of the artery.
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SKIN
ARTERYFLOW
Downstreamprobe
MUSCLE/BONE
Upstreamprobe
Infra red emitter Detector
Loukogeorgakis, et al. (2002). Physiological Measurement 23: 581-96.
Optical detection of the diameter wave
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PhotoPlethysmoGraphy (PPG)for pulse wave velocity measurement.How does it work?
• Infra red probes detect transitory change in conduit artery volume due to the passage of the pulse wave
• Measure time delay and distance between the probes
• Pulse wave velocity = d/t
• Pulse wave velocity (compliance)-1/2
t
d
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LED (emitter)Photo-transistor (detector)
20 mm
20 mm
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Validation experiments.
Comparison of PPG with• Echo Tracking.
– Does PPG method really measure large artery diameter?
• Doppler.– How well do PPG derived pulse wave transit times
compare to measurements using an established method?
• Intra-arterial pressure wave.– Do transcutaneous transit time measurements compare
with intra-arterial ones?
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PPG/Echo tracking methods
PPG
Probes on the posterior tibial artery
Probes on the radial artery
PPG
NIUS ultrasoundprobe
NIUS ultrasoundprobe
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PPG
Ultrasound
0 2 4 6 8 10
Frequency (Hz)
Ph
ase
0
100
200
300
400
Ultrasound
Rel
ativ
e am
plit
ud
e
0.01
0.1
1PPG
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PPG/Echo Tracking - Conclusions.
• PPG reproduces the diameter wave with reasonable fidelity, when compared to high precision echo tracking system.
• Timing of the foot is close
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Validation experiments.
Comparison of PPG with• Echo Tracking.
– Does PPG method really measure diameter?
• Doppler.– How well do PPG derived pulse wave transit times
compare to measurements using an established method?
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PPG/Doppler methods
PPGDoppler
Probes on the posterior tibial artery
Probes on the radial artery
PPG
Doppler
ECG
PPG
ECG used as time reference
Doppler
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100
150
200
250
300
350
TT PPG [ms]
100 150 200 250 300 350
TT Doppler [ms]
y = 0.90x + 12.8 r = 0.95
Comparison of PPG and Doppler transit times
Leg
Arm
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Comparison of PPG and Doppler.Difference v mean
-50
-25
0.0
25
50
Doppler - PPG [ms]
0 100 200 300 400
Average [ms]
+ 2SD
- 2SD
Leg
Arm
Mean difference = 8.6 ms
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PPG/Doppler - Conclusions.
• PPG transit times agree satisfactorily with Doppler values recorded at the ‘same’ site.
• The difference plot shows– the transit time estimated by the Doppler instrument is
consistently greater than that derived from the PPG signals (mean difference 8.6 ms)
• The discrepancy is due to the Doppler signal processing
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Validation experiments.
Comparison of PPG with• Echo Tracking.
– Does PPG method really measure diameter?
• Doppler.– How well do PPG derived pulse wave transit times compare to
measurements using an established method?
• Intra-arterial pressure wave.– How well do transcutaneous transit time measurements
compare with intra-arterial ones?
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Subjects
Measurements on 21 volunteers (8 female, age
range 33 to 78 years, mean 57) after elective
coronary angiography, under the approval of
the regional research ethics committee.
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Inguinal ligament
ECG
TP1 Pressuremeasurement pos. 1
Femoral arteriotomy
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Inguinal ligament
Pressuremeasurement pos. 1
ECG
TP1
Pressuremeasurement pos. 2
TP2
PPG measurementpos.
TPPG
TP = TP2-TP1
TPPG = TPPG-TP1
TC
+TC
Femoral arteriotomy
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40
50
60
70
80
90
100
110
PPG transit time [ms]
40 50 60 70 80 90 100 110
Intra arterial transit time [ms]
y = 0.68x + 22, r = 0.66, P < 0.005
Comparison of PPG and intra-arterial transit times
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-30
-20
-10
0.0
10
20
30
I.A. - PPG [ms]
40 50 60 70 80 90 100 110
Mean transit time [ms]
+ 2SD
- 2SD
Comparison of PPG and intra-arterial transit times.Difference v mean
Mean difference = 0.0 ms
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Some limitations.
• Non simultaneous measurement of proximal and distal signals
– Ethical constraint of one catheter
• Proximal signal not transcutaneous
– ‘Hybrid’ measurements will avoid this. i.e. aortic signal from Doppler, distal signal
from PPG.
– Current hardware and software will allow this.
• Effect of errors in distance between measurement sites not investigated
– Careful comparison between I.A. and external distance measurements required.
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PPG/Intra-arterial - Conclusions.• Reasonable correlation between intra-arterial and PPG
transit times and pulse wave velocities.
• Mean difference between the two methods close to zero
• Transcutaneous estimation of pulse wave transit time provides an acceptable estimate of its intra-arterial value.
– Errors in distance measurement must be carefully considered
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Summary of validation results.
Comparison of PPG with• Echo Tracking.
– Does PPG faithfully measure large artery diameter changes and pulse wave timing?
Yes!
• Intra-arterial pressure wave.– Do transcutaneous transit time measurements compare with intra-arterial ones?
Reasonably
• Doppler.– How well do PPG derived pulse wave transit times compare to
measurements using an established method?
Reasonably
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Examples of current usage
• Paediatric PWV studies
– Kawasaki disease
– Twin to twin transfusion syndrome
– Children of diabetic mothers
– Zambian schoolchildren of known birthweight and
nutritional status
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Conclusions
• PPG measurements of PWV in superficial arteries compare well with other methods
• Although we don’t yet know quite what we’re measuring– Capillary and/or large artery volume changes?– More work needed
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Assessment of endothelial function
• Endothelial function– The ability of the vascular endothelium to release vasodilators in
response to reduced mean shear stress• Nitric oxide• PGI2
• EDHF
• Endothelial function is a reliable indicator of vascular “health”– Continuous production of nitric oxide maintains a low basal level of
vascular tone and peripheral resistance– If NO production is impaired:
• Coronary arteries angina• Peripheral arteries mean BP increases • Peripheral endo function closely mirrors that in coronary artery
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Assessment of endothelial function
Impaired endothelial function has prognosticand diagnostic value
• a strong predictor of cardiovascular morbidity and mortality
• associated with a wide range of CV pathology– Angina– Type II diabetes– Smoking– Essential hypertension
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How to assessendothelial function• Direct
– Measure diameter of muscular artery in response to change in shear stress (flow)• Normally induced by reactive hypersaemia after a period of downstream
occlusion• B mode or echo tracking ultrasound (+ doppler)
– Expensive– Highly skilled operators needed– Not in routine clinical use
• Indirect– Venous occlusion plethysmography– Peripheral artery tonometry– Distal temperature changes– Change in arterial compliance
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Principle
• Relaxation of vascular smooth muscle reduction in arterial stiffness
• Reduced stiffness reduced pulsewave velocity
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Protocol
Experiment AEffect of exercise on brachio-radial PWV
• Base line PWV measurement• 5 minutes biceps curl• PWV measurements at 1, 2, 5 and 10 minutes• 47 healthy volunteers
Experiment BEffect of ischaemia on brachio-radial PWV
• Base line PWV measurement• 3 minutes forearm artery occlusion (BP cuff)• PWV measurements at 0.5, 1, 2 and 5 minutes• 36 healthy volunteers
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ResultsExercise test
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0 1 2 3 4 5 6 7 8 9 10 11
Time after exercise [minutes]
Me
an
pu
lse
wa
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loc
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ch
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lati
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ResultsForearm ischaemia
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
1 2 3 4 5 6
Time after cuff deflation [minutes]
Me
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pu
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loc
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Conclusions
• PPG is a reliable, repeatable low cost and robust alternative to the range of methods available for measuring PWV
• It is ideal for paediatric studies
• Changes in PWV may be a simple, low cost method for assesing endothelial function. – Very preliminary study
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Flow-mediated changes in pulse wave velocity: a new clinical measure ofendothelial function.
Naka KK. Tweddel AC. Doshi SN. Goodfellow J. Henderson AH.European Heart Journal. 27:302-9, 2006 Feb.
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Arm
Leg
Hyperaemia increased brachial artery diameter by 8% at this time.
GTN had similar effect
Hyperaemia had negligible effect on brachial artery diameter.
GTN reduced diameter by similar amount to controls
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Sleeve: i.d 4 - 12.5 mm o.d 18 mm
Centralising lid
Ejection screw
Outer Container
Mandrel: diameter 4-10 mm
Artery
Frozen Artery Reaming Trunnion