Hello, I am a medical researcher at a leukaemia research unit in London UK. In my spare time, I am trying to put together a device which generates large magnetic pulses. The aim of this project is to magnetically drive superparamagnetic nanoparticles carrying therapeutic agents through a solution containing human lymphocytes and ultimately balistically penetrate them. This is very speculative –I could not easily raise funding through the normal medical research channels, this is why I am largely funding the construction myself. So far I have probably spent several hundred hours of my own time on the project. It’s a little off-topic from the normal Tesla-coil /Railgun/do-my-assignment-for-me stuff but, if I can get the idea to work it might just be something that will be of benefit to people with leukaemia and perhaps other malignant diseases.



I should also say that I have no formal background in electronics and most of what I have done so far has been a learn-as-I-go effort, so I apologise if my questions are naïve……



The prototype device worked quite well; it consisted of a 200uF polypropylene bank rated at 600VDC and a large SCR –I used an MC0 100-16io1 -this is 1600 volt 100A –I have attached the Datasheet- Triggering was achieved quite crudely by discharging a battery-charged 100uf capacitor into a pulse transformer connected to the G-K junction. The energy of the bank is dumped into a low-turns number solenoid which surrounds a test-tube containing the cell/particle suspension. A large fast-freewheel diode was connected in parallel with the solenoid to damp the voltage reversal from the collapsing field

The problem was that with single-shot pulses, there was no evidence that the cells had been penetrated –this was determined by examining the cells in a machine called a flow cytometer which measures colocalisation of cells with the fluorescent particles.

The next phase of the project is to modify the device to produce trains of pulses. The current idea is to charge the bank from one half-cycle of the line input, and discharge into the solenoid whilst the line current swing through the other half-cycle

I have attached the schematic of my first effort.

Before I started construction, I ran a few tests to see if the circuit would work and it immediately became apparent that it was going to be impossible to trigger the SCR in this manner. The zenner diode/resistor in the trigger circuit rapidly heat up trying to drive current through the 1.5 ohm pulse transformer. I guess what I really need is a zero-crossing detector which generates pulses only on one polarity zero cross coupled to a gate driver.

I have found one circuit after much searching on the net –I have attached it. –this generates nice pulses on zero crossing, and by removing D2, I can make it generate pulses that span one half-cycle –this is almost what I want –but not quite, and, I still have to work out how to buffer the circuit to the pulse transformer

After another fruitless weekend hunched over a smoking soldering iron when I should have been spending time with my family, the project has still to get off the ground, and after a year, my long-suffering family would like to see a little more of me at weekends –any help in achieving that aim would be really very much appreciated.

Arn

 

There is a lot there to consider, and I am not sure I understand what exactly is/are your question/s.

1) Firing the SCR with a pulse vs. a half-wave. I don't see any advantage to using the half-wave for firing.
2) At 50 Hz, charging your capacitor in 10 mS will require substantial current (rough guess ~28 A peak from a square wave).
3) Based on your discharge time, force, and viscosity have you done any calculations of the amount of acceleration and movement you might expect (in units of distance) from your nanoparticles?
4) How do your calculations of attainable acceleration compare with what one uses when doing essentially the same experiment with centrifugation?

John

 

Thank you for the quick reply.....

"1) Firing the SCR with a pulse vs. a half-wave. I don't see any advantage to using the half-wave for firing."
The idea is to charge the capacitor bank through a diode on one half-wave and then timing to the zero-transit as a point to discharge through the solenoid, obviously, shorting the solenoid across the bank whilst it was still charging from the line would result in some interesting fireworks

"2) At 50 Hz, charging your capacitor in 10 mS will require substantial current (rough guess ~28 A peak from a square wave)."
Charging the bank from the line is no problem -I have done this, and it works.

"3) Based on your discharge time, force, and viscosity have you done any calculations of the amount of acceleration and movement you might expect (in units of distance) from your nanoparticles?"
It is to my shame that I wouldn't know where to start. But in my defence, I can say that, in a research group of 30 assorted grads, postdocs and professors, I'm miles ahead...it is a sad reflection on the way that science forces specialisation to the exclusion of all else. I WILL say that, there are some precedents; I attended a seminar a few months back where a group were using RF fields to heat nanoparticles that had been targeted to lung tumour cells by antibody recognition of a specific tumour marker. The equipment they were using was modest in size which gives an indication of power density. Also, we routinely separate cells using a permanent magnet system that works very rapidly. I guess you could assume particle size around 100nM and the medium to be water, the cell size will be about 10uM and the cell density can be whatever we choose; probably up to 1exp8/ml is easily achievable .

“4) How do your calculations of attainable acceleration compare with what one uses when doing essentially the same experiment with centrifugation?”
We have ultracentrifuges that can achieve in excess of 600,000 RCF –we use them routinely to concentrate viruses. The problem with centrifugation is the acceleration profile; even one of the flashy new carbon fibre rotors take a good few minutes to crank up to full speed, and in this time, both the particles and cells sediment at essentially the same rate. Of course, eventually the cells reach the bottom of the tube and the particles will be pushed against them…but I suspect that the forces needed to achieve cell penetration by increase in particle effective weight would damage the cells.

The idea is that, by rapidly accelerating particles adjacent to the cells penetration can be achieved with minimal cell damage.

Arn

 

Oh, the question?…..I just want to be able to charge from the line and discharge the bank into a coil..the charging takes place over the half cycle, nice and slow (relatively) whilst the damped discharge is fast and takes place when the charging system is isolated from the line via the charging diode.

 

I can't read the first circuit you posted. Don't know why, but that leaves me in the dark.

Have you considered something like a gate-turn off SCR (see: AAC book or Wikipedia) or another device for which you can control both the on and off of the switch, such as an IGBT or Mosfet. Of course, your pulse current needs to be considered. By analogy, if you look up half-H gate drives for motor control, you will find circuits for synchronizing two pulses such that they are never on at the same time. The bottom side could be your SCR; the top could be your charge circuit.

Back to the biology... One can enhance viral infectivity with slow centrifugation onto a monolayer of cells. It is the so-called shell vial technique. The mechanism is not simply ballistic penetration, but the conditions used might be helpful for comparison. In that method, an rcf of about 700Xg is used for 30 to 45 minutes. Drag from the medium is clearly an important factor. The cells are not noticeably altered in the process. You might consider something like that using centrifugation as a pilot experiment. At least, you could put some limits on the acceleration you will need for cell penetration.

John

 

Hi John..thnks for the reply

Yup...I've used centrifugation to overcome van der waals forces...this works ok...you can also use retronectin, and there IS magnetic transfection, I have a pal who has made a CD marker-expressing plasmid which allows coupling to paramagnetic particles...then pulling down virus this way which also overcomes the repulsive forces at the cell membrane.....all done...I'm trying to achieve balistic penetration in solution...
I have considered the mosfet route...but then it gets into a layer of complexity that's going to take me another year to learn...now, life's a journey and all that I know, but i'd really just like to give this thing a go in the simplest possible way...I guess all I need is:

1) A zero crossing module that generates a pulse on (say) the positive-going half-cycle

2)A driver/buffer stage

The rest I can do myself

I really apreciate the help and the time taken to reply to my (probably overly simplistic questions)

Thank you in advance

 

This is the schematic for the first abortive atept at a generator.....

Arn

 

This is my first try...I have reformated the schematic as a jpg

 

Oh, I just noticed that the freewheel diode is back to front

 

Both of you are way over my head, but I've taken the liberty of redrawing the first schematic. If you'd like me to do the same for future schematics it would be my pleasure. I'm not sure what you're doing with the second print, 1KΩ doesn't conduct much. Are you using it to trigger the SCR?

To be honest, the zener side looks off. You are trying to dump the cap through the coil during the alternate cycle, correct? Let me see if I can touch it up some.

With the addition of another RC network you can shift the phase of the trigger a bit, which would do the same thing I think you were trying to accomplish with the zener circuit. You also had a diode in the wrong place, which probably caused quite a bit of problems.

Better?

 

Thank you so much, this is my first post to the board and I was a little apprehensive that I might be asking some fundamentally stupid questions; but the replies have been very helpful and constructive. The revised schematic looks exactly like the circuit I’m after……my next opportunity to litter the kitchen table with assorted electronic bits ‘n bobs is going to be Tuesday…I will put it together then and we’ll see what happens…I will post the results of the electronic test as soon as I have them, and, if it works, I’ll take it in to the laboratory on Wednesday…hmm, if I get time, I’ll grab some cells and pulse them with fluorescently labelled nanoparticals. And if that works…well, then I guess the next step is to try it with some therapeutic agent….but perhaps I’m getting a little ahead of myself here….I’ll post my progress as it happens.

Thank you all once again.

Arn

 

Please do keep us updated. I sketched an alternative circuit based on conventional gate drives, but don't want to confuse the matter with it now.

I remain a little skeptical that you will be able to get ballistic penetration with magnetopropulsion in liquid. That would be really interesting. However, assuming that that part works, how would it differ from any other non-selective chemotherapeutic assault on the leukemia cells?

John

 

Have you read up on electroporation? That seems as if it would have a great deal more chance of success than a ballistic penetration.

 

Just looking at the design I would allow more cycles to charge the cap, plus use a full wave bridge to increase the charge voltage. Something for the future. I'd like to see Jpanhalt's sketch when it's posted. I love concept circuits, so this is fun.

 

The prototype device worked quite well; it consisted of a 200uF polypropylene bank rated at 600VDC and a large SCR –I used an MC0 100-16io1

To what voltage were you charging the cap bank in the prototype?

 

“Have you read up on electroporation? That seems as if it would have a great deal more chance of success than a ballistic penetration.”

Yup…I’ve been in science for some years –enough time to be around when electroporation was invented!…and I’ve used it many times…along with nucleoporation ….I’ve not searched the patents for nucleoporation n, but I suspect that it uses a composite pulse envelope to achieve nuclear pore opening. Anyway, the downside of these techniques is that they are primarily good at one thing- killing cells- in fact you can get good transfection with both methods with little cell death -but only in cell types that are electroporation friendly –like 293T cells for example. My idea is (I hope) more cell-friendly. Well, I guess that I won’t know until I try it out. The electroporation idea’s not dead in the water though. Of course, there are a whole bunch of things I could do that have more chance of success, and you are probably right- this is totally out there and has little chance of ever working. But if I wasn’t doing this, it would be any one of a whole menagerie of crazy ideas that would be occupying me; like the piezo-electric-standing-wave-cell-manipulator or the high-bandwidth-realtime-single-cell-analyzer (neither of which exist except as wonderful Byzantine
constructs within my head………)

Some of this topic is a little specialised, and I’d like to keep it accessible to everyone, so here’s a quick explanation; electroporation and nucleoporation are techniques whereby a cell surface and/or nuclear membranes are temporarily rendered ‘leaky’ by means of an applied electrical pulse or pulses. The aim of this procedure is to allow researchers to load cells with substances that are otherwise excluded. For example loading a cell with a DNA sequence encoding for a protein to determine its function in disease,in this context, we call this ‘transfection’ or loading cells with a fluorescently tagged antibody to enable visualisation of internal cell structure by microscopy.

It’s probably a hopeless cause that I’m pursuing here, I know; but, you know, it’s the hopeless causes that are worth fighting for -have a nice day everyone, and thank you again.....

 

To what voltage were you charging the cap bank in the prototype?

In the prototype, the bank was charged to a range of voltages from 100-500V, we do have higher rated PSUs in the lab, but the caps are only rated 600VDC and, although the freewheel diode should take care of any nasty voltage reversals, I decided that in this respect 500V was as high as I dared go. Also, my colleges were (with some justification) a little wary about entrusting their shiny £3K supplies to such an obviously deranged project. The prototype was certainly good at one thing –anything ferromagnetic placed within the output solenoid became intensely magnetised after pulsing –it was great fun playing with this aspect of the device –so much so that getting anything out of our knife & fork draw now presents something of a test of strength as the teaspoons want to bring their new-found magnetic friends with them……..

 

200uF at 500V yields 25 Joules. At 230Vac, you'll have a peak of 325V, and so will need approximately 475uF for the same intensity of pulse.

I concur with Bill Marsden about charging over multiple cycles. A voltage doubler would allow charging to higher voltage. A voltage divider could sample the capacitor charge, and this could be compared to a reference level to trigger the SCR.

 

I found some pictures of the original deadly teaspoon magnetiser.

One shows the device sitting on our kitchen table; the four switches select which capacitors are paralleled up, the single switch was for the single-shot gate trigger, and the tube is sitting inside the work coil to the top left.
The other picture shows the interior; not much to it really; just a cap bank, a big SCR and a work coil; note the tiny little freewheel diode across the work coil –on the first firing, it disappeared with an amusing little squeak of distress. Since then, I have substituted a nice hefty 1000V 100A fast diode which has survived thus far….

 

I worked at a university for some years. We had someone come in with a request to build an electroporator. I put in enough capacitance that it was quite possible to blow the contents of the cuvette onto the ceiling. Probably didn't do a lot for cell survival....