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Patent of the Month – Electro-Manipulation of Cells

Patent of the Month –  Electro-Manipulation of Cells

| On 14, Feb 2019

Darrell Mann

Patent of the month this month comes from a sextet of inventors at Old Dominion University in Norfolk, Virginia. US10,070,914 was granted on September 11, and primarily seems to concern the treatment of cancer cells, but it would also seem to have broader application to destroying unwanted bacteria in foodstuffs. Here’s what the background section of the disclosure has to say about the problem being solved:

..the invention relates to apparatus and methods for stimulating death in cells and other biological tissues… Hyperthermia as a method to treat cancer, either by just its thermal effects or in combination with other agents (e.g., radiative cancer treatments) and has been explored for over 30 years. In such treatment methods, the temperature range generally does not exceed 42 C., but studies up to almost 50 C. have been performed. Further, it is known that by increasing the temperature it is possible to reduce the exposure time. For example, it is reported that hyperthermia can be obtained by increasing the local body temperature to about 50 C. Under such conditions, an exposure time on the order of 0.1 hours (6 minutes) was required to provide an effective treatment.

It is also known, that short pulses from milliseconds to nanoseconds can be used to initiate cell death. For example, melanoma tumors in mice have been successfully treated with 300 ns pulsed electrics fields with electric field strengths up to 60 kV/cm. These pulses were delivered to the tumor with needle electrodes, or with plate electrodes surrounding the tumor. In contrast to hyperthermia treatments, such pulse treatments are based on non-thermal effects.

The basic underlying problem is about collateral damage – we wish to destroy ‘bad’ cells, but we don’t want to hazard ‘good’ ones. Here’s how we will usually look to map this problem onto the Contradiction Matrix:

And here’s how the invention solves the problem:

A method for treatment of biological tissues comprising target tissues and other tissues, comprising: causing a temperature of the target tissues to be elevated and maintained at a treatment temperature range which is above a physiological temperature of the biological tissues and at or below about 47.degree. C.; generating, during the causing, an electric field extending through at least a portion of the target tissues using a pre-defined sequence of short duration voltage pulses applied between at least two electrodes; and synchronizing maintain of the treatment temperature range to overlap with applying the sequence of short duration voltage pulses, and wherein the pre-defined sequence is selected such that a magnitude of the electric field is configured to deliver an electrical energy sufficient to induce electromanipulation in the portion of the target tissues at the treatment temperature range and that is lower than a specific electrical energy sufficient to induce electromanipulation in the portion of the target tissues at or below the physiological temperature.

…which is basically a combination of the two previously known strategies… heating cells above a phase-change threshold (Principle 35) and combining this with the short electrical pulses (Principle 19). Except for this finding…

The effect of the decrease in viscosity with temperature… leads to a considerable reduction of the specific electrical energy required to achieve cell death, compared to pulsed electric field effects at (or less than) physiological temperature. In the studies at temperatures below 37degC the specific energy required to achieve a 25% reduction in viability was 2 kJ/cm.sup.3. It was reduced to 49 J/cm.sup.3 for the (very short, pico-second) pulses at elevated temperatures of 47degC. This is all the more surprising since a scaling law for membrane permeabilization predicts that, for shorter pulses, a higher specific energy is required to obtain identical results. This scaling law, which provides a scaling or similarity parameter is based on the assumption that the intensity of an observed bioelectric effect depends on the amount of electrical charges passing through the membrane when a pulse is applied. The effect of pulse number, N, is determined by a statistical (thermal) motion of the cells between pulses: S=S(E.tau. {square root over (N)}) (8) where E is the electric field intensity and .tau. the pulse duration. Bursts of pulses with the product of these three quantities being the same should produce identical results. According to this scaling law, pulses shorter by about a factor of 4, as is the case for 800 and 200 ps pulses, would require a four times higher electric field, or a four times higher specific energy (which scales with E.sup.2.tau.). In our results, we observe the opposite: the specific energy, decreases by a factor 40 when we reduce the pulse duration from 800 ps to 200 ps.

This looks like a fairly staggering example of a 1+1 >> 2 synergy. A closer look at the Old Dominion work and their affiliation with the Association of Bioelectrics reveals a long time fight with the medical profession to prove the merits of electric fields, and particularly pulsed ones. From a TRIZ perspective, both directions are inevitable. Maybe it’s time now this 40x synergy evidence is in, to start believing the TRIZ trends rather more than the medical profession has thus far chosen to do. We sometimes get asked whether TRIZ can help with research type problems. I would say that applying the TRIZ trends to the cancer cell problem a long time ago to give some useful research directions would have saved humanity a lot of time and wasted effort. Good as the US10,070,914 solution is, I’d still like to think that the untapped Evolution Potential left in the current solution would allow the synergy multiplication factor to be upped by at least another order of magnitude. Watch this space…

 

 

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