ELECTRICAL EFFECTS IN BIOLOGICAL SYSTEMS Stoke-on-Trent, 9 May 1980; Oxford, 1-2 July 1980,

Two wel1 attended meetings held within seven weeks of each other have served to emphasise the growing importante attached to this subject. That held at Stoke on Trent was the third in a series of symposia on “Methods and Materials for Fracture Fixation” and was organised jointly by the B.E.S., the Biomedical Engineering Unit of the North Staffordshire Polytechnic and the Orthopaedic Department of the North Staffordshire Hospital Centre. It was entitled ‘Electrical stimulation of bone healing’. The second, organised by the Elecrochemical Group of the Royal Society of Chem- istry, was entitled ‘Electrochemistry in the control of biological growth’. Although there was some overlap of subjects and speakers the emphasis of the meetings were differ- ent. At Stoke, the meeting was biased towards clinical work with a supporting content of basic scientific study. The sim was to present the differ- ent methods of using electrical and magnetic stimu- lation for the treatment of non-unions (fractures remaining ununited after, usually, one year but defined also by other radiological and clinical parameters), and to assess these against the use of other methods of treatment. Laboratory studies were included to show that there is an increasing body of scientific knowledge on electrical proper- ties of tissue and the effects of electrical fields upon it, although not necessarily related to clinical studies. In contrast, the Oxford meeting mainly emphasized the effects of electrical energy at cellular level. Clinical papers were included describing the uses of the main systems but the meeting was directed primarily to the fundamental studies.

TREATMENT OF FRACTURE NON-UNIONS

Mr W.J.W. Sherrard, Sheffield spoke at both meet- ings on “The treatment of non-union of fractures by electra magnetic stimulation”. He defined a non-union as failure to heal after more than one year and no change in the radiological appearance over a three month period or more and emphasized that there were two important factors, electrical induction and correct orthopaedic management. He reviewed the reasons why it was preferable to use a non-invasive technique and then presented the characteristics of the stimulation system used; the need for accurate measurement of the coil separa- tion and exact placement of the coils relative to the fracture. Adequate immobilization of the fracture was essential and should be comparable to that used for bone grafts. It should be non-weight- bearing for two months. The method is that devised by Bassett in which two Helmholtz-aiding coils are placed on the outer surface of the plaster tast and fed by a highly specific pulsed current. A magnetic field of about 2 gauss is used. In a range of fractures, treated union was achieved in fifteen out of eighteen un-united

fractures and three out of five pseudarthroses of the tibia with a mean time of union 5.5 months in un-united fractures and 7.75 months in pseudarthro- ses. Clinical and radiographical assessment was used to decide when treatment should end. Typical treatment would be stimulation for 15 hours per day extending over a five and a half month period. Inadequate immobilization of the bone fragments was an important reason for failure. The other factor for failure was the presence of a synovial pseudarthrosis but in one case where the synovial sac was removed, union was subsequently achieved following further electromagnetic treatment. Since this initial series a further ninety cases have been treated and the indications are that similar rates of union wil1 be achieved.

A joint paper by E.M. Downes and J. Watson from Swansea, ‘Treatment of delayed union using pulsed magnetic fields’ was also presented at both. Their system comprises an electronic unit and a.n electro- magnet formed into a G shape. The electromagnet is located on either side of the plaster tast by means of wooden guides. The frequency of the magnetic field is approximately 1 Hz, chosen with regard to body rhythms such as walking and the natural time constants of bone as a piezo electric material.

Downes then presented the results of clinical studies on some 40 patients. The patients are now treated on an out-patient basis. They advise at least 20 hours treatment daily over a six week period. The 66% success rate achieved is lower than that of other centres, but is possibly due to the short treatment time. They now suggest a longer period of treatment, 3 months at least, but possibly less hous per day (12 permitting a normal home life) .

At Stoke, the paper by J.R. Corfield and E.R.L. Jones, Kent and Canterbury Hospital, Canterbury ‘Pulsed magnetic field treatment of delayed union’ was given by Mr. Corfield. Their interest began in 1977 in the need to treat a congenital pseudarthrosis of the tibia in a young child. After surveying the literature on the effects of electric currents on bone growth, they set up a system of extemal pulsed magnetic field treatment. In their system, the frac- ture is sandwiched between a pair of air cored coils, through which is passed a pulse with a fast rise time and a slow fall time, the frequency being 15 Hz. The magnetic field induces a voltage in the region of the fracture during the rise time. Patients are treated on an out-patient basis for twenty-two hours per day over a four to six week period.

At present over twenty patients with several months delayed union, mainly of the tibia have been treated. He emphasized that the series was not a true clinical trial. Of the patients treated results for seventeen were available and eight showed on average clinical union in 2.25 months with X-ray union in 3.6 months from the stcirt of treatment. In the failures was a pseudarthrosis which showed some improvement,

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several atrophic non-unions and several cases of multiple fractures, in which at least one united. They compared the results with altemative farms of treatment and pointed out that union had been achieved for a number of patients purely on an out-patient basis, using low tost equipment. The method is now being tried in a number of hospitals. A method to follow bone healing is now being devised based on acoustic techniques.

Professor Jonathan Black at Oxford presented the work of the University of Pennsylvania group in a paper by Brighton, Black and Friedenberg entitled ‘Treatment of non-union with constant direct current’.He reviewed the early experimental work which had preceeded the clinical studies. DC had been used because this minimized the observed osteopotentials. The system using 4 K-wire cathodes inserted directly into the fracture site each deliver- ing 20pA of constant direct current for twelve weeks. The electrodes and the associated power pack are incorporated into a non-weight bearing tast. In the University of Pennsylvania series 7880% solid union has been achieved. A Te99 bone scan, used to assess synovial pseudarthroses shows that an active result is indicative of ultimate healing following stimulation. Complications were reviewed.

Mr. J.B. King, The London Hospital, spoke at Stoke on ‘Direct current treatment of non-unions using transcuteneous electrodes’. This work was based on the University of Pennsylvania system. He described his own participation in the trial and the results obtained. Fourteen patients have received treatment and current there have been three failures. He is con- vinced that the method works but questions the reasons for failure for which more study is needed in comparison with failures in the control group. A contrast to these methods of treatment was given in the Stoke meeting in a paper by J.K. Webb, Queens Medical Centre, Nottingham entitled ‘The place of internal fixation in non-unions’. The aim of intemal fixation is union with perfect function at the end of it, with the avoidance of joint stiffen- ing. He discussed the role of forces at the fracture site leading to non-union and observed that hyper- trophic non-union was associated with the forma- tion of excess callus and it may be that if callus can not overcome the forces, it wil1 then proceed to non-union. He did not consider that the treatment of hypertrophic non-union presented a problem and it could be repaired satisfactorily by intemal fixation with a good success rate. In fact, results from some centres indicate an almost 100% success rate. Atrophic nomunions, however, have dead bone present and the gap is filled with fibrous tissue. There is no callus. Clinical results were presented and reviewed.

OTHER CLINICAL APPLICATIONS

Two papers in non-orthopaedic areas were presented in Oxford. The first by Dr D.H. Wilson, Leeds Infirmary was “Enhanced recovery of peripheral nerve injuries treated by pulsed

radiofrequency energy”.

The work began following observations made in the treatment of ankle injuries. Trials in rats where the nerve to the flexor muscles of the front limb were divided were reported using a 27.12MHz, 5Omwatt/cm’ pulse having a 65~s pulse width. Arepetition rate of 400 pulses per second was used. After presenting results he concluded that regeneration of the nerves had accelerated.

R.H.C. Bentall, Ealing Hospital spoke on “The use of radiofrequency energy in wound healing and the possible electrophysiological implications” Rat abdominal wall wounds were shown to have enhanced healing with treatment, There is clinical evidente that poorly healing varicose ulcers may be helped. There are many questions which electro- chemists may be able to help to answer.

BASIC SCIENCE

The introductory lecture at Stoke “The nature and origin of the electra-mechanical properties of bone’ bone” by Dr G.W. Hastings reviewed the three main proposals that had been made to account for this phenomena . At Stoke they had attempted to elucidate the mechanism responsible for tehis effect and had come to the conclusion that bone belonged to the group of materials which exhibit ferro-electric properties by consideration of the different classes of crystals; this implies directly --.~ that bone is therefore a piezo-electric material. The consequente of the ferro-electricity is that the charged dipoles in bone are arranged in domains in which they have a definite orientation. This dipole orientation can be changed by the application of mechanical force leading to strain (deformation) or by the application of electrical energy. Experimental results were presented showing the similarity between the behaviour of bone and that of known feryo-elec- tric materials. ;

From these results and from confirmatory evidente from other centres, it bas been proposed that the domain structure is related to the osteonic archi- tecture of bone. The implication of this for bone modelling, growth and healing processes was discussed. Professor A. Pilla, Bio-electra Chemistry Laboratory, Orthopaedic Research Laboratories, College of Physicians and Surgeons, Columbia University, New York lectured at both meetings on ‘Electrical modulation of cel1 surface phenomena and bio- logical regulating processes”. He described experi- ments using weak pulsating currents inductively applied to modulate cel1 and tissue function. This was essentially a study of non-Faradaic electro- chemistry i.e. not involving oxidation or reduction processes. The action of pure current applied to a biological system may perturb interactions at interfaces. Experiments with red blood cel1 systems confirm the existente of non-Faradaic electro- chemical relaxation due to processes such as specific binding and membrane transport.

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The current work has studied calcium uptake in embryonic chick limb explants and radial osteotomy repair in the rat. He described the experimental system to produce the inductively coupled signals and the determination of the most effective signal. A dose amplitude effect has been observed by correlating the signal characteristics with the bio- logical effects. The amount of charge at the surface to be considered defines the leve1 of signal opera- tion. The adaptive response of cell impedance to function, as wel1 as the presence of several regula- tory steps provides the rationale for the existente of several dose amplitude curves and the calcium uptake study provides evidente for this. Results on sodium-loaded human red blood cells show that the activity of the sodium/potassium/ATPase enzyme system can be modified to increase sodium eflux rate. The perturbation ion concentration is affected by the addition of ouabain. The results were interpreted on the basis of ancillary impedance measurements showing the existente of a non- Faradaic electrochemical step dependent upon extra-cellular potassium concentration. The results do not relate to mechanical stresses since he has only been studying cel1 membrane effects. The question was how to compare these results to other processes which disturb cells. It may be highly non- specific in terms of the end result, but for some reason there does appear to be a ‘window’ relating to charge characteristics which permit optimiza- tion of results.

Dr. Sylvia Fitton-Jackson also spoke at both meet- ings with papers entitled ‘The response of skeletal tissues grown in organ culture to pulsed magnetic lïelds’ and ‘Biological responses to pulsed magnetic fields in chondrogenic and osteogenic tissues’.

In the experiments reported, organ cultures of tibiae taken from 13.5 day old embryonic chickens were used as model systems. The experimental tibiae were exposed to magnetic fields of the same sort used for patients under three different regimes of alternating on-off periods. The measurement of 3 H-thymidine uptake was used and showed that mitosis was inhibited in both osteogenic and chondrogenic tissues by prolonged treatment. Additionally, levels of cyclic adenosine monophosphate were also supp- ressed. Levels of this cAMP in the shafts however, responded rapidly to six hour altemating periods of treatment, being elevated as high as 5% in com- parison with controls, but they were usually supp- ressed up to 400% in cartilage, the fluctuations depending on the type of pulse and age of culture. Further measurements showed that while treat- ment with pulsed magnetic field suppressed the synthesis of the sugar-containing materials in carti- lage in comparison with controls the fibrous collagen significantly increased in amount with length of treatment. Osteogenic cells were generally more responsive than chondrogenic cells, there being a differente with the type of signal used. Rudiments were exposed to radio-active calcium during the last 24 h of cultivation to see if there was a change in rate of mineralization, meauring only tightly bound labelled calcium. Levels of incorpora-

tion were extremely small in the cartilaginous moieties compared with the uptake of the shafts. Rate of uptake of bound calcium in the shafts was found to be related with the phased on-off periods of treatment, and under some conditions where treatment was for altemating six hour periods, the amount of calcium uptake was nearly doubled. Results from different experiments emphasize that the responses to pulsed magnetic fields are time- dependent and vary with the type of tissue and signal. Whether the different responses between chondrogenic and osteongenic tissues are related to the varied nature of the extra-cellular materials is questionable. The chondrogenic cell is surrounded by macromolecules and interstitial fluids which would react to electrical currents differently from the drier collagen/mineral rich osteogenic tissues.

Dr L.W.M. Janssen presented a paper to the Oxford meeting comparing the effects of direct current (DC) and pulsed current (PC) on embryonic bone tissues.Embryonic rate calvaria were used and direct current was applied. Various parameters related to bone cel1 activity were determined. Bone cel1 activity was found to be increased by DC electrical fields. By comparison of PC effect on alkaline phosphatase release and lactate production, they proposed cer- tain mechanisms for the processes occurring. It was assumed that the mechanism was an electro- phoretic effect of the electrical stimulus. Results in unirlirectional PC experiments suggest a more efficient type of stimulation. There was discussion following the paper relating to the possibility of electrolytic reactions and the change produced in cel1 environment.

Dr D. Bellamy then spoke on ‘Electrochemistry and tumour growth’. Continuous recording was made of interstitial pH and temperature of subcutaneous Walker carcinoma in the rat. A passive platinum electrode linking the tumour environment to a nor- mal part of the body through a connective tissue bridge appears to produce inhibition of the tumour. It was proposed that a change of redox environment is produced, the electrode functioning as a redox couple and providing an alternative path for elec- trons arising from oxidation processes in the tumour.

Dr L.A. Norton presented the paper ‘Biomolecular changes in hard tissue cells in response to capaci- tative coupled proliferative signals’. Previous studies showing the enhancement of bone growth by electrical stimuli led them to investigate the postu- late that the phenomenon is mediated by ,the cel1 membrane. Various elements of cel1 function may be studied for example DNA synthesis. Experimen- tal methods in tissue culture and problems encoun- tered were described. Results presented included 3 H thymidine incorporation into cartilage and bone cells. There was a significant differente from con- trols, after 6 hours exposure to electric perturba- tion (EP). Ion flux modulation by chemical methods was used to study the role played by ion flux in EP phenomena. They considered their results to have demonstrated that EP signals are transduced at the cel1 membrane which is then taking part in cel1

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proliferation control. Dr Black presented a second paper at Oxford: ‘Physical mechanisms in DC stimulation of osteo- genesis’. Reviewing earlier observations which had led them to the understanding that for electrodes inserted at a fracture site, bone forms when the electrode is cathodic. He developed the concept that the cathode is an oxygen “getter”. This pro- duces local oxygen deficiency and increased pH. The experimental conditions required to achieve stimu- lation were described. Determination of oxygen tension in healing fractures shows that it is low for the first 25 h post-operatively. Effects of current density and electrode position were discussed. Thus an intermediate physico-chemical effect produces bone stimulation. C.D. Stem spoke at Oxford on ‘Electrical control of early development (non-neural) in the young chick embryo’. A vibrating electrode probe was used in this study. They detected strong extra cellular electrical currents associated with an early stage of embryo development. Relationship of current flow to migration of the germ layers was discussed. Implications of these observations in terms of an information system for embryo development were discussed.

The Stoke symposium contained a series of three papers from the Laboratory for Experimental Surgery of the Swiss Research Institute in Davos. The first given by Dr H. Gerber dealt with studies carried out on electrical stimulation of 18 day embryonic rat femora. The field used was 30 gauss at a frequency of 20 Herz using the method of Kraus-Lechner. Where temperature control was used, there were no differences in growth between the stimulated femur and the control. An experiment in which an injury was present, again showed no detectable differente. In the second paper, Dr S. Perren, reported on experiments carried out by Blumlein. They had carried out in vivo experiments using beagle dogs. X-ray evaluation did not give conclusive results. Micro-radiography was used with special attention being paid to the vascularity of the space. A pure magnetic field was used with a coil and also implan- ted inductors. A segment of bone was dissected. NO correlation was obtained. In a series of experimen- tally produced hypertrophic non-unions, using plate fixation, these were treated with the coil with a 250 mV inductor. In several series no significant correlations could be obtained between the non- unions and the control group, in which no stimu- lation was used. The final paper from Davos given by Dr M. Enzler reported on work in dogs in which a segment of the ulna had been recected in a series of twelve dogs in which an osteotomy of the ulna wasgerformed. NO effect on the healing of the osteotomy was observed using Bassett equipment. Evalüation was by means of mechanical testing, radiography and histology. There was no differente between active and passive treatment. A similar result was found in a second series.

HS. Dobbs reported on ‘The release of metal ions from orthopaedic implants’. This was a report of post mortem studies carried out on one patient who had a metal-metal hip prosthesis in Co-Cr-Mo alloy. The other hip had a metal-plastic prosthesis. He emphasized the need for reports of systematic effects. Ion release and metal sensitivity may be more important than is realized. There appears to be an increase with post-op time of Co and Cr retained in the tissues. (See Biomaterials 1980 1 (4) )* Prof. R.J.P. Williams in the concluding paper at Ox- ford summarized the physical characteristics of stimulation. It affects al1 types of cells, influences cel1 growth, and despite its being an electrical process, has nothing to do with electrons but rather is ionic. Studies of slow and fast muscle show that exposure of the former to pulses converts it to the latter. Al1 ion gradients are pum ed and he stated that all effects are due to Ca 2! movements. Ca’+ being divalent is particularly active in terms of binding proteins. Decrease in oxygen leve1 wil1 de- crease the efficiency of the calcium pump. The in- put Channel for calcium in vivo is triggered by electrical pulses. Inside the cel1 there may be a high calcium flux and the multiple membrane systems% the cel1 and high storage capacity for Ca” contribute to an automatie amplifier system.

A great deal of interest was produced as a result of these meetings and it was one of the first occasions when it had been possible to hear both the clinical results and the scientific experiments which were attempting to underpin them. It is stil1 undoubtedly a controversial area, as the negative results of the Swiss group with magnetic stimulation show. There is little question that bone does show electrical characteristics and also that there is an effect on biological systems when studied in the laboratory. However, the clinical picture is not quite so certain. The fact that many of the patients for whom the treatment has been successful have in the past received a variety of treatments does not always mean that these have always been the most effective for that particular case. The clinicians who spoke have al1 emphasized the need for correct orthopaedic treatment for their patients and the need for com- plete immobilization of the fractures. It may be that this was the determining factor.

It should be noted that in discussion a word of warning was entered regarding observation on the adverse effects on major organs remote from the site of magnetic stimulation when prolonged treat- ment is given. There is a differente in mechanism between DC

stimulation with electrodes and magnetic effects and more work is clearly needed. The involvement of the electrochemical group of the Royal Society of Chemistry is an encouraging sign for the advance- ment of the scientific studies.

G.W. Hastings

Copies of the abstract booklet are available from DI G.W. Hastings, Bio-Medical Engineering Unit, c/o Medical Institute, Hartshill, Stok+on-Trent, Staffordshire, UK.

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