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Lecture 31,Bone Repair April 19,2019. ECEN 5031/4031 Read Chapter 7 Vol 1 You are going to have to go beyond chapter 7 into the review to get detailed information on this topic. Some History.
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Lecture 31,Bone RepairApril 19,2019 ECEN 5031/4031 Read Chapter 7 Vol 1 You are going to have to go beyond chapter 7 into the review to get detailed information on this topic.
Some History • 1. Applications to bone healing grew in part out of the discovery by Yasuda and Satawith the discovery that bones were piezoelectric. • 2. Follow up by medical interest Bassett, Becker, and Pilla are three names to note. • 3. Lots of publications.
Electric and Magnetic Stimulation of Bone and Tissues • 1 Both electric and magnetic fields can modulate growth processes. • 2. The healing of bones that would not regrow is the most widely used application in this area. • 3. Wound healing and soft tissue growth are coming along more slowly.
Background • 1. 5,000,000 bone fractures a year in US and 5% delayed or nonunion. • 2. Multiple Approaches to applying Electric Fields. • A. Pulsed • B. RF Carrier • C. Sine waves • D. Direct E fields or induced E fields with
Background • 1. Acceleration of bone growth up to 150% in rats • 2. Inhibit loss of bone in weightless environment • 3. One study showed best result with a sine wave at 15Hz and 10µV/cm peak E field • 4. Another study showed best results for spinal fusion 10µA/cm2
Background • Get bone regrowth with currents in the range of • i = 5 to 100µA • Voltages of V= 1 to 100mV/cm at the repair site and frequencies in range of 20 to 200kHz • The electric field result in the stimulation of 28% in cell proliferation, a 5 fold increase in growth factor IGFII release ,and increases in osteoblast receptors expression. Also modulation of Ca Calmodulin binding and other changes in the chemistry.
Background • 1. 15 out of 20 randomized studies showed effectiveness of EMF stimulation of bone repair. 5 did not. Most of these studies used PEMF • 2. One study of surgical treatment of 569 ununited tibial bone fractures effective 82% and of 1718 with PEMF 81% • 3. Ultrasound also seems to work.
Some Cell Studies • 1. Stimulation of growth factors IGF II after short EMF trigger by 5x. 28% increase in cell proliferation, • 2. In rats one study increase of 53% and 93% in IGF I and IGFII • 3. Stimulation of TGF-β, mRNA by 3x with PEMF • 4. Up regulation of TGF-β, mRNA and osteocalcin synthesis by 100% another study
Some Cell Studies • 5. Show static magnetic fields modulate Ca+2to Calmodulin by 2 x • (Note Ca does not have a first order magnetic moment so the process starts up stream. Voltage gated channels seem to be involved) • 6. Consistent changes in Ca+2 with pulsed EMF • 7. With PEMF a 14% acceleration of endothelial cell migration for values of B= 2mT peak and a 25Hz repetition rate.
Some Clinical Studies on Soft Tissue. • 1. Double blind treatment of pressure ulcers 84% closure with PRF vs 40% with no treatment. Another study 60% closure vs 0 with no treatment. • 2. Also studies showing reduction in edema by seven fold on ankle sprains and pain decrease by 50%. • 3. Lots of others but also cases of no effects.
Models for Bone Repair. • Background stress 0.1 to 2mV/cm under load. • Less than 1mV/cm to maintain normal state. • 60Hz at 9.6µV/cm inhibits osteoclast cell growth • Rubin et.al.1996 Journal of Bone and Joint Surgery.
PMF Induced Electric Fields • For an air core R, L circuit the current is given by • The wave form for the induced voltage is given by When the time constant τc=(R/L) is small you get constant voltage for a linear increase in current. Make L small so the driving voltage is < 25V
The Induced E Fields • 1. • 2. At RF we get large • 3. For non uniform fields we need
Electrochemical Information Transfer Model • 1. Art’s hypothesis is that the E field must be large enough to effect ion binding and transport. • 2. The signal must be on the same order as those required to trigger a nerve pulse or a few millivolts across the membrane. • 3. The membrane is the site of the interaction and involves Ca binding as the first step in a cascade of events. • 4. It involves voltage dependent binding of ions or ligands and the displacement of water.
Adds in Effects of Chemical Binding to the Relaxation Time • 1. The chemical processes take time. The chemical flow the follows leads to a current 2. Additionally a coupling coefficient is needed from the change in surface charge to a change in the chemical reaction rates.
The Overall Results • 1. The effective impedance is • 2. The overall result is that you need to take into account the chemical binding time constants and the resulting chemical reaction times to calculate what sort of signals and time constants you need for you electrical or magnetic stimulations of the biological processes. • 3. So you have 2 time constants to worry about. τ1= 1-10µs, τ2= 20-200µs for fibroblasts and osteoblasts.
Results Show Bone Growth • 1. Was directly related to the induced E field. • 2. This was checked out in a ring dish. • 3. Other data shows effects of weak magnetic fields including DC or steady state. • 4. Our new data by Julian shows an increase in hyperpolarization by reducing the magnetic field to < 1µT
ICR and Larmor Precession Model • 1. We have talked about the Ion Cyclotron Resonances and the problems with the theory. • 2. Lorentz- Langevin Equation for a bound ion. • 3. The solution is
Larmor Model • 1.For Static magnetic field of 50µT • fL= 18Hz for Ca++ Need small damping to the narrow line widths. Leads to changes Ca – CaM binding. • 2. An alternate theory would be radical pairs where the recombination rate changes with the charge to mass ratio as might be expected for coupling of the electrons to the nucleus more strongly than the external fields.
Experimental Results on Ca-CaMPulsed RF and Static B=2 G on Phosphorylation
Weak Electric Fields and S/N • 1. There is a need to consider the fact that cells can be longer than 10µm. Nerve cells can be centimeters long. • 2. Gap junctions can have low resistance and this resistance can be modulated by repetitive electrical pulses. • 3. This can lead to concentration of the electric fields at the end membrane.
Impedance Values • 1. The voltages at any point along the transmission line are given by • Where Ion Binding Admittance
Transmission Line Characteristics. • 1. Note the voltage decreases with increasing frequency • 2. It increases with length at low frequencies. • 3. Increasing the gap resistance reduces the ending membrane voltage. • 4. This can give tissues different characteristics than cells in culture. • 5. The effects can be different at different times in the cell cycle.
Resonances • 1. If we take into account the time delays associated with the transport of the ions we can get the equivalent of an inductor. • 2. For voltage controlled K+ channels with • and • the time constant is given by • And the admittance is given by
Resonate Frequency for E(ω)=10mV f=16Hz and PEMF=40mV • 1. Note these parameters work for an array of cells and are variable.
Signal to Noise Requirements. • 1. Need a good signal to noise ratio and a large enough voltage to effect the binding energy. • 2. The binding time constant is related to the binding energy and the noise which is in the range of τ=1 to 5ms for Ca-CaM. Need to translate this into an equivlent circuit. • 3.Need pulse signals components in the frequency range 102 to 104 Hz • 4. Pulse length, repetition rate, length of exposures all make a difference.
Estimated Signal to Noise for Two Wave Forms PRF at 27MHz E=10mV/cm and PEMF E=1mV/cm • 1
Lecture 32, April 13,2018Ultrasound • Ultrasound and electric Shocks
Ultra Sound Stimulation • 1. Ultra sound at less than 100mw/cm2 can stimulate bone growth. • 2. Commonly use signals 500µs bursts of 1.5MHz sine waves repeating at 200Hz at 30 to 50mW/cm2 • 3. The vibrations move the charge layers to generate 1 to 10mV in the fluids.
Effects of the Initial State to EMF • 1. Normal bone and tissue do not respond to the same extant as the injured tissue and bone. • 2. Blood flow increase near injury and not much in normal tissue. • 3. • 4.
Membrane Admittance from the HH Equations • 1 Depends on the applied E as well.
Summary • 1. Electric Field Effects on Bone Growth and Mechanical Vibrations are Coupled. • 2. The processes are time, amplitude, and frequency dependent. • 3. There are multiple processes happening in parallel . • 4. These fields work.
