Pulsed microamperage stimulation: a controlled study of healing of surgically induced wounds in Yucatan pigs.

[Byl NN, McKenzie AL, West JM, et al. Pulsed microamperage stimulation: a controlled study of healing of surgically induced wounds in Yucatan pigs. Phys Ther. 1994,74:201-219.]

Key Words: Electrical stimulation, Microamperage current, Wound healing. Controlling growth and differentiation of tissues is one of biology's most intriguing challenges. Because the body can be viewed as a bioelectric system, electrocurrents have been applied for therapeutic purposes for many years.[1] In the last few years, microamperage electrical current has become popular.[2] Despite a paucity of controlled experimental studies, these microamperage currents (<1 mA intensity)[3] are now also being promoted to accelerate soft tissue wound repair.

Although a variety of types of electrical current are used in wound healing, the greatest attention has been given to galvanic current because predictable electric fields are known to form around the electrodes, attracting specific types of ions near the different poles. The electrical field creates stable secondary magnetic fields around direct currents and alternating or reversing polarity around faradic currents.[4] The electrostatic field, the electromagnetic field, and the polarity of the treating electrode have been associated with tissue stress that increases collagen deposition, as defined by Wolff's Law.[5,6] Further, under the anode (positive polarity), enhanced ion transport, fibroblast migration, and protein synthesis and decreased vascular congestion[7,8] have been reported, whereas under the cathode (negative polarity), increased migration of epidermal cells, macrophages, and leukocytes has been documented in addition to decreased bacterial counts.[9-14] Under both the anode and cathode, increased transcutaneous oxygen, an important element for healing,[15] has also been measured.[16]

One of the underlying assumptions in electrical stimulation with exogenous microcurrents is that the applied therapeutic current should facilitate the injury current, or the reversal of the natural resting electrical field that occurs after tissue injury.[17] Thus, the type of tissue to be stimulated and the status of the tissue (healthy or injured) determine the polarity of the treating electrode. In bone, a positive resting current has been measured around the healthy bone shaft. This current changes to negative following a fracture.[2] A negative current is measured in normal skin,[18] but following an injury, this current becomes positive.[19]

There is substantial evidence that continuous, cathodal microamperage stimulation applied throughout the day significantly accelerates bone healing,[20-27] but the evidence that direct microamperage stimulation predictably accelerates dermal and tendon repair is less convincing. Although the majority of studies report positive results, many have had a small number of subjects or no controls and the variables selected for stimulation were varied. Of the frequently cited studies, some reported success with cathodal stimulation.28,29 Assimacopoulous[28] surgically induced full-thickness wounds in rabbit ears and used stainless steel electrodes embedded in surgical gauze to continuously deliver a 100-[mu]A current at a density of 18 [mu]A/[cm.sup.2] for 18 to 19 days. Unfortunately, there were only four wounds in the treatment group and four wounds in the control group, Konikoff[29] continuously delivered 10-[mu]A current for 7 days with a cathodal electrode to full-thickness, 2-cm incisions via 1.0- X 2.5-cm platinum gauze. The wounds were surgically induced to midline from T-7 to T-10 on New Zealand albino rabbits. The tensile strength was twice as high in the treated wounds than in the untreated wounds that were uninfected after 7 days and in which the stimulators were intact.

Other researchers[30,31] reported positive findings with anodal stimulation. in a large, controlled study, Alvarez et al[30] induced 0.3-mm deep wounds (7x10 mm) in pig skin. There were three groups of lesions: (1) untreated wounds; (2) wounds in which 50- to 300-[mu]A current was delivered with a silver-impregnated nylon electrode embedded in the wound bed, which was covered with an occlusive dressing; and (3) wounds in which electrodes were embedded but the current was not turned on. The current was continuously delivered for 7 days, with the wounds assessed each day. In this study, the epithelization of the wounds supplied with current was significantly more rapid at days 2, 3, and 4 than either the placebo or the controls, with 50% of the current-treated wounds healed by 2.9 days.

Carley and Wainapel[31] reported success with alternating polarity. In 30 human subjects with indolent ulcers, the cathode was initially placed on the wound to clean the wound, with the current 200 to 4,000 [mu]A below the setting that provokes bleeding. The size of the electrodes was approximately 25 [cm.sup.2], and current density was 16 [mu]A/[cm.sup.2]. Current was supplied in cycles of 2 hours on and 4 hours off, three times a day, unless the ulcer was infected. If the ulcer was infected, the cathodal stimulation was continued until there was a plateau in healing, and then the polarity was reversed. in controlled rabbit studies, Rowley and collegues[32-34] demonstrated that negative stimulation frees the wound of infection (as much as a 40% decrease in the growth rate of Escherichia coli with 20 mA/[cm.sup.2] current). When the current was more physiological (28 [mu]A/[cm.sup.2]), there was only a 4% reduction in the rate of bacterial growth. Antibiotic treatment, however, was far more effective than current passage.

This same diversity of findings and treatment protocols was also found in tendon healing research. For example, Owoeye et al[35] found that tenotomized Achilles tendons of rats were significantly stronger than the non-tenotomized tendons of control animals following anodal stimulation (75 [mu]A, 10 pps, for 15 minutes a day for 14 days) but significantly weaker following cathodal stimulation. Nessler and Mass,[36] however, reported accelerated tendon healing with cathodal stimulation (9 [mu]A) but discoloration and necrosis near the anode.

Only three studies demonstrated negative results from applied exogenous microcurrents. Carey and Lepley[37] applied a current of 200 to 300 [mu]A for 2, 3, and 5 days over 4-cm full-thickness wounds in rabbits. One wound in each rabbit was treated with the cathode of a 24-gauge stainless steel electrode, and a second wound was treated with the anode. This protocol produced a high current density of 320 to 475 [mu]A/[cm.sup.2]. No significant wound healing was promoted at either the anode or the cathode. Necrosis was observed at the anode, and a scarcity of inflammatory cells was noted at the cathode. These negative findings could be explained by either the high-density current or the possible side effects of the steel electrode.

Wu et al[38] carried out a more extensive study with healing of the rectus abdominis muscle and the parietal peritoneum. They passed 40, 80, or 400 [mu]A of current for 7 days through bilateral, surgically induced laparotomy wounds. There were no significant differences in the tensile strength of the wounds stimulated with the anode or the cathode, but no significant necrosis was observed. Unfortunately, there were no controls in this study, and the researchers did not study the effect of the current on the skin itself. In another study of wound healing in horse skin,[39] full-thickness skin wounds (1.5 or 2 [cm.sup.2]) were surgically produced and currents of 10 to 20 [mu]A were supplied via stainless steel electrodes or metal sutures with the anode threaded in the subcutaneous tissues under the wound and the cathode embedded in the subcutaneous tissues in the center of the wound. The wounds were not bandaged. After supplying the currents for 4 weeks, the wounds with the embedded electrodes healed more slowly, with or without current, than did the wounds of control animals with no electrodes. In the wounds with electrodes, there was no difference in healing between those with the current on and those that did not receive current. Infection, however, was a problem in all the series. These negative results could have stemmed from placement of the steel electrode directly in the wound site for an extended period of time or the fact that the wounds were uncovered and unprotected, leaving them exposed to infection while also allowing them to dry. Either of these conditions could have interfered with healing.

Additional controlled studies are needed to clarify the benefits of microamperage electrical simulation for normal healing and repair as well as for treatment of wounds in which healing is a problem. The optimal polarity, current intensity, density, and treatment time required for maximum effect on healing need to be clarified for all of the common lesions referred to physical therapists (eg, pressure sores, acute traumatic lesions such as abrasions and lacerations). The purpose of this double-blind randomized study was to determine whether microamperage stimulation (at 100 [mu]A, 0.1 Hz, pulsed, 1 hour per day with a large electrode fully covering the wounds) could measurably accelerate healing of acute, superficial, deep, and incisional wounds. We hypothesized that the electrically stimulated wounds would close faster, would be stronger, and would look more completely healed after 1 week of daily microamperage stimulation.

Method

Subjects

Ten Yucatan mini pigs(*) (age 4 months) served as the subjects for the study. The swine were selected as the research animal because the skin is considered physiologically similar to human skin.[40,41] In addition, the swine can be socialized, handled, and treated without anesthesia. An animal model also permits better control of the environment; nutrition; exercise; and wound acuity, severity, depth, and location.

Procedure

The surgical procedures and the methods of measurement for subcutaneous oxygen ([PsqO.sub.2]), wound quality, analysis of collagen (hydroxyprolene), breaking strength, wound size, and histological analysis have been described previously by Byl et al.[42] The Appendix gives a summary of the detailed procedures.[43-48] Table 1 outlines the scale used to evaluate the quality of healing, and Table 2 outlines the ordinal scale that was used to code the histological analysis. Figures 1 and 2 provide a visual reference for the wounds and a visual model of the tonometer used to measure oxygen and temperature, respectively. Figure 3 shows the device used to measure tensile strength, and Figure 4 depicts the electrical stimulation unit and the arrangement of electrodes.

Wound Type

Four sets of surgical wounds were induced on each animal. Each set consisted of three lesions: (1) a partial-thickness lesion (1 [cm.sup.2]), (2) a full-thickness lesion (1 [cm.sup.2]), and (3) an incisional wound (4 cm). These surgical wounds simulated acute superficial wounds (eg, abrasions, full-thickness pressure sores, ulcers) and postsurgical incisions or lacerations. Using a model with multiple types of acute

Tabble 1. Visual Observation Scale for Quality of Healing

                                              Yes (0)   No (1)

Infection
Pus present                                   0         1
Swelling present                              0         1
Odor present                                  0         1
Exudate present                               0         1
Epithelium
Presence of new growth                        0         1
Healthy color (pink) of epithelium            0         1
Maturity of healing
Hair follicles in epithelium                  0         1
Vascularization apparent                      0         1
Approximation of wound
(good closure of incision)                    0         1
Granulation tissue healthy
(tissue in full-thickness lesion beefy red)
Before cleaning                               0         1
After cleaning                                0         1
Soft tissue status around lesion

Soft                                          0         1
Mobile                                        0         1

Total score

wounds provided the opportunity to create matched pairs of lesions for analysis of differences and allowed us to control factors such as nutrition and exercise. The lesions selected were similar to the types of acute wounds referred to physical therapists. In addition, by including a full-thickness lesion as well as a sutured incision, this model permitted the opportunity to determine whether there was a more measurable effect of the current when the stratum corneum (the rate-limiting barrier of the skin) was removed with the epithelium.

Treatment

The Myomatic i microamperage pulsed galvanic stimulator([dagger]) was used for treatment. This is a constant-current machine (60 V) with a 50% duty cycle (Fig. 4). At a pulse rate of 1 pps and a current intensity of 100 [mu]A, 5OX[10.sup.-6] coulombs (C) were delivered to the tissue. (This was calculated according to the following formula: Q=I t/2, where Q=coulombs, I=current intensity, and t=seconds, with the time divided by 2 based on the 50% duty cycle.) For the study, 0.3 pps was selected as the pulse rate. One cycle consisted of 3 seconds on and 3 seconds off. Thus, for the time on (3 seconds), 300X[10.sup.-6] C Was delivered to the tissue. With an electrode measuring 4 x 13 cm covering both wound sets on the treatment side, the density of the current delivered was 5.8 x [10.sup.-6] C/[cm.sup.2] (coulombs delivered divided by the area of the electrode). Each wound set was covered with a sterile electrode and kept covered for 7 days, thus preserving the moistness of the wound and decreasing the risk of infection. The sham-treated wounds were also kept similarly covered, but the electrodes were never activated. The treatment electrodes were connected to a two-channel machine and stimulated simultaneously.

The treatment protocol was designed to simulate the treatment protocol used by Alvarez et al[31] and was modified for an outpatient treatment practice, in which patients usually come in for treatment for 1 hour several times a week. The current was selected at the midrange of current intensities administered by Alvarez et al[31] (100 [mu]A) and the same intensity selected by Assimacopoulous.[29] The treatment electrode was defined as positive to facilitate the injury current and to enhance protein synthesis.[19] All the animals received treatment for 1 hour a day for 5 days starting 24 hours after surgery. The animals were sacrificed on day 7. The pigs were treated while resting in a sling. Socks and blankets were used to keep the pigs warm during the treatment, and they were housed in temperature-controlled quarters.

The four wound sets were randomly assigned to receive either treatment or sham treatment, with the two wound sets on each side assigned as a single set. The treatment electrodes (positive) were placed directly over the wound on the dorsal surface of the trunk, and the negative electrode was placed on the ventral surface of the trunk (Fig. 4). A frequency of 0.3 Hz was selected to ensure that the pulsed current was on for more than 1 second (meeting the criteria for the pulsed monophasic current to be classified as direct current).[3] During one electrical stimulation session for each pig, [PsqO.sub.2] and subcutaneous temperature (Tsq) were measured on the first and second postoperative days.

Research Design and Data Analysis

This was a controlled, posttreatment experimental design with random assignment to treatment and control groups. Given the complexity of healing and repair, multiple healing variables were selected for analysis, with

Table 2. Scales for Histologic Analysis of Quality of Healing for Incisional and
Full-Thickness Lesions

Incisional wounds
 Fibroblast proliferation
  O=no active proliferation
  1=very few fibroblasts
  2=mostly fibroblasts
  3=equal number of fibroblasts and fibrocytes
  4=mature fibrocytes dominate
 Collagen organization
  1=disorganized, no apparent fibers
  2=somewhat organized, immature (fibers apparent)
  3=organized, almost normal
  4=normal organization
 Collagen density
  1=thin deposition, large vacuoles
  2=some areas dense, some loose, thin
  3=almost normal density
  4=normal density
Full-thickness lesions
 Granulation tissue
  1=granulation tissue unhealthy, infected
  2=granulation tissue partially unhealthy
  3=granulation tissue healthy, but not fully even with epidermis
  4=granulation tissue healthy, even with epidermis
 Wound demarcation
  1=wound tissue area distinctly marked from healthy tissue
  2=wound tissue healthy, but immature and easily distinguished
  3=wound tissue well integrated into normal tissue

collagen deposition (as measured by hydroxyproline), cellular activity (DNA), collagen histology (ordinal scale), tensile strength (in grams), quality of healing (ordinal scale), mast cell degranulation, and wound size percentage of change in area) as the primary dependent variables.

To control for the small sample size, the variability among pigs, and the use of ordinal scales, the analysis of differences was carried out on paired difference scores using a paired Wilcoxon test for all of the variables. This test is equivalent to asking whether there is a significant difference in healing between the matched pairs of lesions on each pig.[49] The final analysis is then carried out on all of the difference scores. This procedure controls for the variability within each pig while permitting analysis across all possible paired differences. All tests were two-tailed. The critical values were set at the .05 level of probability. Each dependent variable was considered a separate family and analyzed independently.

Results

Tables 3 and 4 [Tabular Data Omitted] 5 summarize the components of healing for the sham-treatment and treatment groups. All wounds healed within a week, and none of the wounds became infected. Comparing the control and treatment lesions, there were no statistically significant differences among any of the lesions on any of the wound healing variables selected for this study. In general, all of the incisions were well approximated and epithelialized within a week. The partial-thickness lesions had noticeable hair growth and visible blood vessels, but they were not fully integrated into the surrounding tissue. The full-thickness lesions showed epithelialization around all the edges, with good granulation and good wound contraction. The area of the full-thickness lesions decreased between 5 and 7 [mm.sup.2] in both the control and the experimental groups, and the area of the partial-thickness lesions decreased by an average of 20 [MM.sup.2] after a week of healing.

Table 6 summarizes the analysis of the degranulation of the mast cells. After 7 days of healing, there were no significant differences in mast cell degranulation between the tissues from the control or experimental lesions or between either the control or the experimental lesions and normal intact tissue.

Table 7 [Tabular Data Omitted] summarizes the information on [PsqO.sub.2] and Tsq measurements during and after microamperage stimulation in the Yucatan mini pigs breathing room air. There were no significant changes in [PsqO.sub.2] or Tsq during or after stimulation.

Discussion

In this study, pulsed direct anodal microcurrent (100 [mu]A) administered 1 hour daily for 5 days did not measurably accelerate the healing of acute surgically induced incisional, full-thickness, or partial-thickness lesions in Yucatan mini pigs. Because this finding differs from what was expected based on other research studies, it is important to analyze what variables might account for the observed outcome.

Most studies reporting positive findings were carried out with humans who were inpatients or on animals where it was possible to deliver continuous electrical stimulation. In the studies dealing with patients with chronic, nonhealing wounds, other traditional wound care was provided (eg, debridement, wound dressings, medication). Thus, without adequate controls, it is not possible to determine whether the wounds healed because of the current or because of the other care provided, including keeping the wounds clean and protected. In our study, the wounds were protected and covered to maintain cleanliness and moistness, but they were not otherwise treated with anything except microcurrent. It is not clear which of these variables might have made the significant difference. It is possible that a healthy wound heals quickly and that little can be done to accelerate the healing process within a week. This, however, was not the case in the study by Alvarez et al.[30] It is also possible that 1 hour of exogenous current is insufficient to ensure that the polarity or the mechanical benefits of the current could be realized in such a short time.

In another study similar to ours, significant reductions in wound size were measured in surgically induced full-thickness lesions in swine (SC Davis and colleagues, personal communication, and conference presentation[50]). In that study, the wounds were treated with wire electrodes resting in saline-soaked gauze over the wound. The positive electrode was placed over the wound site, and a 30-mA current was applied for 0.5 hour, twice a day for 5 days. There were two main differences between the Davis et al study[50] and our study: (1) the amplitude of the current was 300 times higher, and (2) the current was denser (delivered through wire electrodes through sterile gauze within the 1-[cm.sup.2] area of each full-thickness lesion) compared with the electrode area of 52 [cm.sup.2] used in our study. If pulsed galvanic stimulation with milliamperage current could accelerate the rate of healing in otherwise healthy animals with surgically induced full-thickness wounds, it may be that microamperage current could only be similarly effective if the density of the current was higher or the treatment time was longer so that the total amount of current administered to the wound was similar to that of the other studies.

Other researchers have demonstrated the critical nature of current density, separate from intensity, and its effect on healing. Schauble et al[51] and Humphrey and Seal52 were able to destroy tumors using microamperage stimulation (500 and 960 [mu]A respectively) delivered at a high density through the point of a steel needle electrode. Yet, other researchers[23-34] report accelerated wound healing with currents of a similar intensity, but a lower density (delivered through saline-soaked gauze).

Another possible explanation for the lack of accelerated wound healing could have been the size of the electrodes. The electrodes covered the entire wound area for both the treatment and sham-treatment wounds. This type of coverage has two possible effects: (1) It decreases the density of the current, as discussed, and (2) it does not enhance the lateral field differential between the middle and lateral edges of the wound. A natural lateral electrical field (100 mV) is created between the wound edge, the area around the wound edge and the center of the wound. The wound has a stronger positive charge in the center compared with the wound edge and the area immediately around the wound edge.[53] The wound must be kept moist, or this current will not be maintained.[53] Epithelial cells have been shown to migrate to the lateral edge of a wound. Barker et al53 Suggest that a small positive electrode placed in the middle of the lesion would heighten the lateral field and consequently increase cell migration. It is possible that a large electrode interferes with the lateral field and brings the polarity of the lateral field to neutral. Clinical research studies are needed to verify this finding in controlled wounds.

The study protocol administered only anodal stimulation. No preliminary cathodal stimulation was given in the early phases of treatment, although it has been shown that the leukocytes and macrophages are attracted to a cathodal electrode.[9-14] Some researchers[32-34] have suggested that wounds should be treated preliminarily with cathodal current to aid in cleanup prior to beginning anodal stimulation, particularly in an infected wound. On the other hand, other researchers[28-36] have shown acceleration of healing with anodal, cathodal, or alternating polarity. Thus, it is unlikely that failing to provide cathodal stimulation prior to anodal stimulation can sufficiently explain the lack of significant findings. However, it may be possible that the intensity or the total current received was not adequate to facilitate the polarity effects required to accelerate healing.

In this study, no significant changes were measured in [PsqO.sub.2] during anodal pulsed microcurrent stimulation, even though research studies in the literature have documented increased in [PsqO.sub.2] under both the cathode and the anode.[16] In an unpublished pilot study with human subjects by Byl et al,5 significant increases in [PsqO.sub.2] were measured in well-perfused human subjects during and after anodal (but not cathodal) microamperage electrical stimulation delivered with the same stimulation characteristics as those used in this wound study. However, the sensitivity of measurement for these subjects was enhanced by having them breathe oxygen-enriched air to maintain 100% perfusion. It was difficult to achieve 100% oxygen perfusion with the swine because they did not like to be masked to breathe the oxygen and it was difficult to keep the swine warm during treatment. Despite covering the animals with blankets and putting on socks, the body temperature of the swine was lower than normal during the treatment session. This drop in temperature could have decreased the blood flow and the oxygen available to the tissue. Hopf et al[55] and Knighton et al[56] have shown that even a small increase in blood flow can increase [PsqO.sub.2]. If microamperage pulsed direct stimulation had the potential to increase oxygen delivery, then it should be correlated with enhanced tissue healing. Further research is needed to determine the association between anodal/cathodal stimulation and tissue oxygen.

Recently, well-controlled studies have been reported on the effectiveness of high-voltage pulsed biphasic twin-peaked electrical current for healing dermal pressure ulcers.5-59 In two of the studies,[57,58] the wounds were stimulated with a negative electrode over the wound until debridement, and then the treatment electrode was changed to positive. The polarity of the treatment electrode was then reversed every 3 days until the ulcer reached stage Il and then was reversed daily until healing was complete. In the third study,[59] the treatment electrode was negative and remained negative for the 20 days of treatment. For the majority of the treatment period, the frequency was either 105 or 128 pps. The intensity of current for these studies was reported as 29.2 mA,[57] 35 mA,[58] and 200 V.[59] Treatment was administered for 1 hour a day, with the wounds covered with saline-soaked gauze. The electrode was fabricated of heavy-duty aluminum foil that attached to the leads with alligator clips. Although these studies limited treatment to once daily for an hour, the primary differences between these studies and our study was the use of milliamperage

Table 5. Ordinal scale Histology Results for Controls Compared With Electrically
Stimulated Incisions(a)

                          Control          Experimental
                          (Scale Scores)   (Scale Scores)


Full-thickness wounds
  Granulation
   Median                    3.0              3.0
   Range                     2-4              2-4
  Demarcation
   Median                    2.0              2.0
   Range                     1-3              1-3
Incisional wounds
  Fibroblast proliferation
   Median                    3.0               3.0
   Range                     2-4               2-4
  Collagen organization
   Median                    3.0               3.0
   Range                     2-4               2-4
  Collagen density
   Median                    3.0               3.0
   Range                     2-4               2-4

(a)There were no significant differences between the control and treatment group
s on any of the
histological variables using the paired Wilcoxon test.

current delivered for a minimum of 3 weeks. Thus, the total amount of current received in the high-voltage studies was greater than that received in our microamperage study, and the treatment period was 3 weeks compared with 1 week. in addition, the polarity of the treatment electrode was changed when the rate of healing slowed in these studies, whereas the polarity of the electrode remained consistent in our study. Interestingly, with the twin-peak monophasic wave form, there was probably minimal polarity effect under the treatment electrode. Thus, the increased collagen deposition leading to wound closure in the high-voltage studies was more likely related to the mechanical effects of the current (eg, piezoelectric or change in cell permeability) than to the polarity effects.

The issue of reliability and sensitivity of measurement also warrants discussion. If the instruments were not sensitive or did not yield reliable measurements, changes could have been overlooked. We previously used the same wound-healing model to evaluate the effects of ultrasound on wound repair.[42] In that study, a significant 30% increase in tensile strength and hydroxyproline deposition was measured in the wounds of a treatment group compared with those of a control group. To further maximize the sensitivity of the analysis in this electrical stimulation study, a paired Wilcoxon test was used to preserve the ability to measure paired differences within each animal as well as to analyze the paired differences across all animals.49 In both studies, the measurements of the control groups were similar except for the measurement of DNA. It is possible that the additional coverage of the electrode altered the cellular activity. Thus, given the commonality of subjects and types of wounds, if there were objective differences in healing, these scales should have been sensitive enough to measure the differences.

Despite the physiological similarities of pig skin and human skin, there are some differences that could have altered the effectiveness of low-voltage microamperage stimulation in the swine compared with humans. For example, swine dermis is considerably thicker than human dermis.[40,41] The thickness of the dermis could have created a high skin resistance, interfering with current transmission. On the other hand, because the stratum corneum (which provides the greatest resistance and protection for the underlying dermis) was removed in both full- and partial-thickness lesions, there was no barrier to the current. Thus, dermis thickness does not provide an adequate explanation for the differences in effectivenvess.

One other difference between swine skin and human skin is that the primary control of circulation is based on a thermal mechanism that is highly dependent on ambient temperature. Human subjects have better internal mechanisms to maintain body temperature compared with swine. Thus, during any wound-healing study, researchers must maintain both hydration and body warmth; otherwise, vasoconstriction can occur, interfering with healing by decreasing the oxygen available to the wound.[56] This concern for thermoregulation was addressed in our study. Because the pigs were treated while lying still in a sling, socks were placed on the feet and the pigs were covered with blankets to maintain normal body temperature. Despite this protocol, the swine body temperature remained lower than normal.

More research is needed to clarify whether the intensity, density, polarity, and duration of pulsed galvanic microcurrent stimulation has a significant effect on the acceleration of wound repair. How long does microcurrent need to be delivered before the polarity of the tissue under the treatment electrode is altered? Studies are also needed that control the total current delivered to comparable wounds, particularly when pulsed low-voltage monophasic microcurrent stimulation is applied compared with

Table 6. microamperage Compared With Sham Stimulation of Surgically Induced
Wounds and Normal Tissue for Degranulation of Mast Cells (Expressed as Percentag
e)(a)

                        Mast Cells(b)
                        Type I         Type II   TypeIII

Control incision
  X[bar]                 26.6          40.8        13.9
  S                      14.7          21.0         5.6
  Range                  12.5-45.5     25.1-60.1    5.1-21.3
Experimental incision
  X[bar]                29.1          34.9        19.2
  SD                    11.9          16.8         7.4
  Range                 17.1-46.5     17.4-55.2    4.1-25.2
Normal intact skin(c)
  X[bar]                 36.7          44.3         18.9
  SD                     12.2          13.7         17.2
  Range                   2.1-52.3     30.2-58 2     2.2-26.3

(a) There were no significant differences in mast cell degranulation between the
 control or electric
stimulated lesions,
(b) Type I=intact dark blue cells; type II=cells from which some granules have b
een extruded, but
the cell outline is largely intact and metachromasia is observed; type III=cells
 in which degranulat
is extensive and widespread (with complete or partial disintegration of the orig
inal cell out-line)
and the granules show a purple-red metachromasia.
(c) Data taken from previous studies of 10 Yucatan mini pigs.

twin-peak pulsed high-voltage monophasic current. Controlled studies are also needed that compare the differences in healing when microcurrent stimulation is applied to wounds with a small electrode placed in the center of a wound compared with a large electrode placed over the entire wound.

Summary

No significant differences in wound healing were measured in acute partial-thickness, full-thickness, and incisional wounds treated with sham stimulation compared with low-voltage pulsed anodal galvanic microamperage stimulation (100 [mu]A) for 1 hour a day over 5 consecutive days. The results of this well-controlled study differ from the findings reported by some other researchers. More research is needed to determine whether this type of treatment can be used by clinicians to accelerate wound repair. (*) Charles River Laboratories, WAshington, MA 01887. ([dagger]) Monad Corp, 908 E Holt Ave, Pomana, CA 91767.

References

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Med J Osaka Univ. 1953;4:195-208. [14] Dodgen PW, Johnson BW, Baker LL, Chambers RB. The effects of electrical stimulation on cutaneous oxygen supply in diabetic older adults. Phys Ther. 1987;67:793. Abstract. [15] Knighton DR, Halliday B, Hunt TK. Oxygen as an antibiotic: the effect of inspired oxygen on infection, Arch Surg. 1987;23:221-226. [16] Gagnier KA, Manix NL, Baker LL, Rubayi S. The effects of electrical stimulation on cutaneous oxygen supply in paraplegics. Phys Ther. 1988;68:835. Abstract. [17] Borgens RB. What is the role of naturally produced electric current in vertebrate regeneration and healing? Int Rev Cytol. 1982;76: 245-298. [18] Foulds IS, Barker AT, Human skin battery potentials and their possible role in wound healing. Br J Dermatol. 1983;19:515-522. [19] Illingworth CM, Barker AT. Measurement of electrical currents emerging during the regeneration of amputated finger tips in children. Clin Phys Physiol Meas. 1980;1:87-89. [20] Friedenberg ZB, Andrews T, Smolenski BJ, et al, Bone reaction to varying amounts of direct current. Surg Gynecol Obstet. 1970;151: 894-899. [21] Friedenberg ZB, Roberts PG, Didizian NH, Brighton CT. Stimulation of fracture healing by direct current in the rabbit fibula. J Bone Joint Surg [Am]. 1971;53:1400-1408. [22] Lavine LS, Lustrin I, Shamos MH. Experimental model for studying the effect of electric current on bone healing. Nature. 1969;224; 1112-1113. [23] Lavine LS, Lustrin I, Shamos MH, et al. Electric enhancement of bone healing. Science. 1971;175:1118-1121. [24] Goh JC, Bose K, Kang YK, Nugroho T. Effects of electrical stimulation on the biomechanical properties of fracture healing in rabbits, Clin Orthop. 1988;233:268-273. [25] Bassett GA, Pawluk RJ, Pilla AA. Augmentation of bone repair by inducively coupled electromagnetic fields. Science. 1974;184:575-577. [26] Sharrard WJW. Double-blind trial of pulsed electromagnetic fields for delayed union of tibial fractures. J Bone Joint Surg [Br]. 1990;72: 347-355. [27] Ieran M, Zaffuto S, Bagnacani M, et al. Effect of low frequency pulsing electromagnetic fields on skin ulcers of venous origin in humans: a double blind study. J Orthop Res. 1990;8:276-282. [28] Assimacopoulous D. Wound healing promotion by the use of negative electrical current. Am J Surg. 1968;34:423-431. [29] Konikoff JJ. Electrical promotion of soft tissue repairs. Ann Biomed Eng. 1976;4 1-5. [30] Alvarez OM, Mertz PM, Smerbeck RV, Eaglstein WH. The healing of superficial skin wounds is stimulated by external electric current. Invest Dermatol. 1983;81:144-148. [31] Carley PJ, Wainapel SF. Electrotherapy for acceleration of wound healing: low intensity direct current. Arch Phys Med Rehabil. 1985;68: 443-445. [32] Rowley BA. Electrical current effects on E coli growth rates. Proc Soc Exp Biol Med. 1972; 139 929-934 [33] Rowley BA The influence of electrical current on an infecting microorganism in wounds. Ann NY Acad Sci. 1974;238:543-551. [34] Rowley BA, McKenna JM, Chase GR. The influence of electrical current for enhancement of tissue healing. Biomed Sci Instrum. 1974; 10: 111-114. [35] Owoeye I, Spielholz NJ, Nelson AJ. Low intensity pulsed galvanic current and the healing of tenotomized rat Achilles tendons: preliminary report using load to breaking measurements. Arch Phys Med Rehabil. 1987;68: 415-418. [36] Nessler JP, Mass DP. Direct current electrical stimulation of tendon healing in vitro. Clin Orthop 1987;217:303-312. [37] Carey LC, Lepley D. Effect of continuous direct current on healing wounds. Surg Forum 1962:13:33-35 [38] Wu DT, Go N, Dennis C, et al. Effects of electrical currents and interfacial potentials on wound healing. J Surg Res 1967;7:122-128. [39] Steckel RR, Page EH, Geddes LA, Van Vleet RA. Electrical stimulation on skin wound healing in the horse: preliminary studies. Am J Vet Res. 1984;45:800-803. [40] Monteiro-Riviere NA. Ultrastructural evaluation of the porcine integument. In Tumbleson E, ed. Swine in Biomedical Research. New York, NY; Plenum Press; 1986;2:641, [41] Kerrigan CL, Zelt RG, Thomson JG, Diano E. The pig as an experimental animal in plastic surgery research for the study of skin flaps, myocutaneous flaps and fasciocutaneous flaps. Lab Anim Sci. 1986;36:408-412. [42] Byl NN, McKenzie AM, West J, et al. Effects of low dose ultrasound on acceleration of wound healing in mini Yucatan pigs. Arch Phys Wed Rehabil. 1992;73:656-664. [43] Burton KA. A study of the conditions and mechanism of the diphenylamine reaction the colorimetric estimation of deoxyribonucleic-acid. Biochemistry. 1956;62:315-321. [44] Woesner JF. The determination of hydroxyproline in tissue and protein samples containing small proportions of this amino acid. Arch Biochem Biophys. 1961;93:440-447. [45] Grant RA. Estimation of hydroxyproline by the AutoAnalyser. J Clin Pathol. 196417:685-686. [46] Charney J, Williamson MB, Bernhart FW. An apparatus of the determination of the tensile strength of healing wounds. Science. 1947; 105:396-397. [47] Dyson M, Suckling J. Stimulation of tissue repair by ultrasound: a survey of the mechanisms involved, Physiotherapy. 1978;64:105-108. [48] Gray P, ed. The Encylopedia of microscopy and Microtechnique. New York, NY: Van Nostrand Reinhold; 1973:289-291. [49] Marascuilo LA, McSweeney M. Nonpara-metric Distribution-Free Methods for the Social Sciences Monterey, Calif: Brooks/Cole Publishing Co; 1977:325-350 [50] Davis SC, Cassaniga AL, Reich JD, Mertz PM. Pulsed electrical stimulation: effect of varying polarity. In: Proceedings of the University of miami School of medicine Wound Healing Annual Meeting, San Francisco, CA; 1991, Abstract. [51] Schauble MK, Habal MB, Gullick HD. Inhibition of experimental tumor growth in hamsters by small direct currents, Arch Pathol Lab Med. 1977;101:294-297. [52] Humphrey CE, Seal EH. Biophysical approach toward tumor regression in mice. Science. 1959;130:388-389. [53] Barker AT, Jaffe IF, Vanable JW. The glabrous epidermis of cavies contains a powerful battery. Am J Physiol. 1982;242:R358-R366. [54] Byl NN, McKenzie A. The effect of microcurrent stimulation on wound healing. In: Proceedings of the Annual Meeting of the California Chapter of the American Physical Therapy Association, October 1991. Abstract. [55] Hopf HA, Jensen JA, Hunt TK. Calculation of subcutaneous tissue blood flow, Surg Forum. 1988:39:33-36. [56] Knighton DR, Hunt TK, Scheuenstuhl H, et al. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science. 1983:221 1283-1285. [57] Feeder JA, Kloth LC, Gentzkow DG. Chronic dermal ulcer healing enhanced with monophasic pulsed electrical stimulation. Phys Ther. 1991;71;639-649. [58] Gentzkow GD, Pollack SV, Kloth LC, Stubbs HA. Improved healing of pressure ulcers using Dermapulse a new electrical stimulation device. Wounds. 1991;3:158-170. [59] Griffin JW, Tooms RE, Mendius RA, et al. Efficacy of high voltage pulsed current for healing of pressure ulcers in patients with spinal cord injury. Phys Ther. 1991;71:433-444. Appendix. Detailed Study Methodology and Procedures

Surgery

Each pig arrived 5 days before surgery and was housed in the Animal Care Facility at the Universit Socialization included introduction to the Pantopento sling that would be used during treatment and

Anesthesia was induced with 2.5% to 4.0% halothane. After endotracheal intubation, anesthesia was air. The skin of the swine was shaved and prepared with Betadine(*) before the trunk was draped for on the dorsum with a sterile marker. Each of the four wound sets consisted of a 6-cm incision suture nonabsorbable nylon monofilament(+)), a full-thickness wound (1 [cm.sup.2]), and a partial-thickness the wounds, rotating responsibilities by side (right versus left) for each animal (see Fig 1).

Hydroxyproline (collagen) deposition was measured in two 5-cm lengths of expanded polytetrafluoroe size). The ePTFE tubes were tunneled subcutaneously 0.5 cm from the soft tissue wounds using a Keith

During anesthesia, the tonometer([parallel]) that was to be used for measuring subcutaneous oxygen treatment incisions. The tonometer (see Fig. 2) consisted of a 7-cm length of oxygen-permeable Silas (1.25-in) intravenous catheter.(**) The tonometer was passed through the subcutaneous tissue with a end of the Silastic tubing. The spinal needle was then cut off (see Fig. 2).

All wounds were photographed; traced to size on a flexible, clear plastic sheet for planimetry mea flexible carbon electrodes (4x 13 cm). The wounds and the electrodes were then covered with Tegaderm accessible for treatment. The covering kept the wound clean and moist for the 7 days of the study. A wounds, and the pig was dressed in a vest to protect the implants. The animal was kept in the animal

Subcutaneous Oxygen and Temperature Measurements

For [PsqO.sub.2] and subcutaneous temperature (Tsq) measurements, an optical oxygen electrode([par inserted into the Silastic tonometer after calibration in room air. The optode and thermistor were t record and save the measurement data. The tonometer was then flushed with hypoxic saline. Because th tonometer/optode assembly was covered with heavy-duty aluminum foil. Baseline [PsqO.sub.2] and Tsq w equilibration (when two consecutive reading, taken 5 minutes apart, differed by less than 2 mm Hg). optode is 5%. Variability between different sites on the same animal is due to local variations in p site, however, has been found to be extremely stable and reliable in the UCSF Wound Healing Laborato tolerant of the electrical current, pulsed microamperage current was delivered with the Monad stimul and Tsq were measured following the delivery of current with the anode and then the cathode over the The current intensity varied from 10 to 800 [mu]A, and the frequency varied from 0.1 to 999 Hz. No d

The [PsqO.sub.2] and Tsq were monitored continually on all pigs during and 15 to 30 minutes after Subcutaneous oxygen and Tsq were also measured in two of the pigs while they were breathing suppleme flowing at 10 L/min). Research conducted on humans has shown that the sensitivity of measuring [PsqO oxygen saturated prior to the treatment.(55,56) measurements were continuously monitored and recorde oxygen challenge for 20 minutes for purposes of measurement was not considered a confounding variabl after stimulation could provide insight into understanding the physiological contributions of electr

Necropsy

At 7 days, the wounds were exposed, photographed, traced onto a flexible plastic sheet for planime for quality of healing, The pig was then euthanized with pentobarbital (150-200 mg/kg of ketamine an and the wounds were carefully dissected with 1-cm margins and prepared for histological and tensile were then performed.

Visual Appearance

A nominal scale for visual analysis was design for the study. Intrarater reliability was .97, as m (ICC), and .94, as measured with the Pearson Product-Moment Correlation Coefficient. Interrater reli as measured by the Pearson correlation coefficient. Table 1 summarizes the visual analysis items. At blinded to control and treatment sides), with the mean scores used for data analysis. The photograph

Analysis of Collagen Deposition

The ePTFE tubes were removed on postoperative day 7 and frozen at -20[degrees]C until prepared for determined (in micrograms per centimeter) using the methods outlined by Burton.[43] Hydroxyproline, according to the methods outlined by Woesner(44) and Grant(45) and reported in micrograms per centim blinded to the treatment group.

Breaking Strength

The incisional tissue was used to measure tensile strength according to a modification of the Char hour postnecropsy, and the measurement of all tissues required up to 4 hours. Three samples of the i cm in length). The variance of the thickness of the samples was 0.5 mm within subjects and 0.7 mm be tested was 18,850 g, which was insufficient to pull apart normal skin.

The sequence of testing tissue samples was varied to minimize effects of time and order on the str titrated through plastic tubing into a water-collection bag. The force was transmitted to the tissue milliliters) of water required to separate the incisional tissue was recorded and converted to a wei "tensile strength." Gross weight of the water bag and the time to tissue separation were both record

Histology

Mast cell degranulation was analyzed in tissue biopsy samples (1 [cm.sup.2]) excised from the woun degranulation was included in this study to determine whether microamperage stimulation had a simila ultrasound.(47) Normal-sucrose fixed specimens were paraffin-embedded(##) and sectioned (10 Km at 20 sample and then mounted on slides. Sections were then deparaffinized and hydrated in 60% ethanol pri blue 0 in a sodium acetate buffer (pH 5.6. 2,-3 minutes each), blotte, and placed in n-butanol (30-6 Permount.(47) Staining quality was compared by a standard toluidine protocol to ensure consistency. degranulation(47) were applied to 10 randomly selected fields from each tissue sample and examined a classified as types I, II, and III. The total number of each type of cell was averaged across sample falling into each of the three categories was determined to compare differences.

Full-thickness samples from each incision and full-thickness lesions were fixed in 10% buffered fo hydrated to 70% ethanol, and stained with a routine hematoxylin and eosin stain before light microsc randomly selected fields from sections of the tissue samples were qualitatively evaluated and rated fibroblast proliferation according to a defined scale (see Tab. 2). No attempts were made to type th was used as the standard for comparison.

Wound Size

The area of the full-and partial-thickness lesions \vas measured to the nearest square milliliter between the perimeter measurement from the wound site and the perimeter measurement from the tracing coefficient). Five area measurements were taken for each lesion. These measurements were averaged fo measured each lesion until there was 90% agreement on five measurements. Then one investigator assum measurements. The changes in the initial area measurements compared with those taken after 1 week we score and averaged for data analysis. A negative percentage indicated that the wound was smaller com measurement, and a positive percentage indicated that the wound size was larger than the original me

(*) The Purdue Frederick Co, 100 Connecticut Ave, Norwalk, CT 06856.

([dagger]) Davis Geck Inc, America Cynamic, Danbury, CT 06810.

([double dagger]) Gore-Tex, WL Gore and Associates, Flagstaff, AZ 86004.

([sections]) Richard-Allan Medical, Richland, MI 49083.

([parallel]) TOPS Software, Inner Space Medical, 1923 SE Main St, Irvine, CA 92713.

(#) Dow Corning, Midland, MI 48640.

(**) Terumo Medical Corp, Elkton, MD 21921.

([daggers]) 3M Medical-Surgical Div, St Paul, MI 55101

([double daggers]) Model EWL, 183-93, Zenith Portable Laptop Computer.

([Subsections]) Monad Corp, 908 E Holt Ave, Pomona, CA 91767.

([double parallels]) 118075 Tamaya Technics Inc, 9111 Barton, Overland Park, KS 66202.

(##) Tissue Tek II, Miles Lab Inc, Diagnostic Div, Elkhart, IN 46515.

Invited Commentaries

Following are two commentaries on "Effect of Microamperage Stimulation on the Rate of Wound Healing in Rats: A Histological Study" and "Pulsed Microamperage Stimulation: A Controlled Study of Healing of Surgically Induced Wounds in Yucatan Pigs."

Electrical stimulation using low-amperage currents is not new to the practice of physical therapy, yet relatively little is really known regardingthe proven clinical or physiologic effects of such stimulation in humans. In recent years, a number of commercial manufacturers have stimulated interest in the clinical use of low-amperage currents with the development of devices designed to produce either monophasic or biphasic pulsed currents (also known as interrupted direct and alternating currents, respectively). This new class of stimulators are designed so that current amplitudes are kept very low and electrically excitable tissues, nerve, and muscle are not stimulated as they are in most common electrotherapeutic applications. Devices in this commercial class are referred to as "MENS" (the acronym for microcurrent or microamperage electrical nerve stimulation) units.

The authors of the two reports to which this commentary is addressed are to be applauded for their efforts. These reports represent a long-overdue examination of the efficacy of MENS therapy in wound management. In general, each study appears to be well designed and carefully executed. A superficial examination suggests that the studies were very similar. Both used animal models, skin wounds were surgically produced, the same commercial stimulator was used in treatment, anodes were the primary treatment electrode, and a number of dependent measures were used to assess the effects of the treatment. Even the conclusions of both reports were the same (ie, microcurrent stimulation does not accelerate dermal wound healing).

Upon closer examination, however, the two studies were in many ways quite different and therefore represent a greater contribution to the body of knowledge regarding micro-current efficacy in wound care. The differences between the two studies are emphasized in the Table. One key difference between the two studies was the wound coverage between electrical treatments. Leffmann et al left wounds uncovered between treatments and suggested that this factor may have "inhibited current penetration" with MENS. In the study by Byl et al, wound coverage was maintained throughout the study, possibly improving the conductive properties in and around the wound.

The most marked difference between the two studies was related to the stimulation characteristics used. Each study used peak currents at amplitudes of 100 [mu]A with 50% duty cycles. This essentially means that current was induced for one half of each treatment session. The duration of treatment, however, was twice as long in the study by Leffmann et al compared with the study by Byl and col leagues. The total current delivered each day in the Leffman et al study was at least twice that of the Byl et al study, and treatment was continued for nearly three times as long. In spite of these treatment duration differences, the outcome was the same--no evidence of enhancement of healing.

Possibly the most important difference between the stimulation variables used in each study was the current density beneath the treatment electrodes. By my calculations and given that 4-x 13-cm electrodes were used, average currrent density in the Byl et al study was 0.92 [mu]A/[cm.sup.2] (50[mu]A/52 cm.sup.2) (note: the authors present charge density). In contrast, 0.41 X 0.41 -cm electrodes were used in the Leffmann et al study and resulted in applied average current densities of 297 [mu]A/[cm.sup.2](50 [mu]A/0,1682 [cm.sup.2]). The use of much smaller treatment electrodes resulted in much higher current densities approximately 300 times higher). Leffmann and colleagues then applied this much higher current density for twice as long than did Byl et al. In spite of this fact, no effect on wound healing-dependent measures was observed. The lack of significant findings between the very low current density treatment (Byl et al study) and the higher current density treatment (Leffmann et al study) does not suggest that current densities falling between these two levels will enhance the rate of dermal wound healing. Although the possibility does exist that one study used too little current and the other study used too much current to promote healing, it is equally likely that both studies used so little current that the stimulation had no physiologic effect. Because each group of authors indicated that stimulation variables were selected based on manufacturers' recommendations, one must ask, "What was the scientific basis for the establishment of these recommendations?"

Aside from the specific research design and results, the "Discussion" sections of the two reports appeared to be written in contrasting tones. Leffmann et al addressed several factors that may have affected the study's results, and they presented arguments that dismissed each factor as being the significant reason why MENS did not augment healing. Byl et al also identified factors that may account for the lack of MENS' effects on dermal wounds. In contrast to Leffmann et al, Byl and co-authors suggested that MENS failed to augment healing because the "polarity or ... mechanical benefits" that exist were not "realized" with the particular stimulation variables that were used. With the lack of other published scientific studies to the contrary, one must question whether the type of stimulation provided by the particular stimulator used has any beneficial effects on wound healing. Byl and colleagues argue that microamperage amplitude currents could be as effective as other higher-amplitude currents, such as high-voltage pulsed galvanic stimulation (HVPGS) currents, if treatment time were extended. If further research proves this to indeed be true, why would a clinician choose a more extended treatment over an equally effective, shorter-duration electrical stimulation program? Another explanation suggested to account for the lack of MENS' effects on wound healing was associated with Becker and Selden's[1] hypothesized injury currents. I cannot debate that a voltage difference may exist between the center of an open wound and the surrounding normal tissue. However, measurement of a voltage difference related possibly to a differential distribution of electrically charged particles does not mean that electrical currents will actually be produced between the two regions, nor that an augmentation of currents between these regions will enhance healing. Becker and Selden's theories on a bioelectric system have not been thoroughly examined in humans and do not provide valuable insight into the contemporary understanding of wound healing.

After reading each of these reports, one important question keeps returning to my mind: Why is MENS currently being used by physical therapists in the treatment of not only wounds but a variety of other clinical problems?

Four main factors have led to the rise in clinical interest in the uses of these instruments. First, physical therapists and other health care practitioners are continuously searching for new means to manage stubborn clinical problems such as pain or open wounds that often do not respond to more traditional forms of treatment. Second, early results from studies using low-amperage continuous direct currents or twin-spike monophasic pulsed currents (known commercially as HVPGS, or simply "high-volt," currents) for management of these problems have been encouraging. Third, theories have been proposed regarding a heretofore unrecognized body control system based on minute currents in and around cells that influence not only normal functions but also the body's responses to injury. Fourth, health care workers have been subjected to vigorous marketing campaigns by manufacturers who have used testimonials and articles in nonrefereed publications attesting to the beneficial effects of this form of electrotherapy.

From my perspective, MENS treatment has not been developed and validated according to established scientific procedures. Rather, MENS exhibits nearly all of the characteristics of an unorthodox, controversial therapy as presented by Golden[2] and summarized by Harris in a presentation at the 1993 Annual Conference of the American Physical Therapy Association.[3] These characteristics include

1. Treatment based on theory outside the boundaries of existing knowledge or scientific fact.

2. Use of the therapy after only uncontrolled empirical reports.

3. Treatment proposed to be effective for a broad range of problems often chronic problems in which standard medical or surgical treatment produces limited success).

4. Promotion of treatment through non-peer-reviewed publications and testimonials from patients and practitioners.

5. Claims of no harmful side effects of treatment.

As indicated by the authors of both reports, virtually no evidence exists on the clinical efficacy of MENS therapy. Research results from studies demonstrating the efficacy of other forms of stimulation (DC or HVPGS) in wound care do not validate the use of MENS approaches to wound care.

With all of the identified shortcomings associated with MENS, I believe that at this time the use of MENS should be recognized as experimental. Clinicians should not feel compelled to purchase and learn how to use these devices. Academicians should not feel a need to provide detailed instruction to students in the use and applications of this form of stimulation. On the other hand, proponents of MENS therapy should take on the responsibility of performing the research needed to establish the scientific basis and clinical validity of this proposed form of electrotherapy. Andrew J Robinson, PhD, PT Associate Professor Department of Physical Therapy Ithaca College Ithaca, Ny 14850

References

[1] Becker RO, Selden G. The Body Electric: Electromagnetism and the Foundation of Life. New York, NY: William Morrow & Co Inc; 1985. [2] Golden GS. Controversial therapies in developmental disabilities. In: Gottlieb MI, Willians JE, eds. Developmental Behavioral Disorders, Volume 3: Selected Topics. New York, NY: Plenum Press; 1991. [3] Harris SR. How is a new treatment approach critiqued for scientific merit? Platform presentation at First Annual Catherine Worthingham Fellows Forum, Annual conference of the American Physical Therapy Association; June 12-16,1993; Cincinnati, Ohio.

Both Byl et al and Leffmann et al have used surgically induced wounds in mammals to test the effectiveness of "microcurrent stimulation" on the healing of these wounds directly and on various markers of tissue healing and inflammation. In all cases, they found no effect compared with sham stimulation. This is a powerful indictment of sub-sensory-level stimulation both for the treatment of open wounds and further, I would argue, for acute inflammation.

The purveyors of "microcurrent" stimulators have claimed effectiveness for the treatment of "pain, swelling, inflammation, atrophy, and wound healing" with sub-sensory-level stimulation.1 Although such stimulators have been commercially available since the mid-1980s, to my knowledge, there has not been a single prospective study of the effects of these devices that has shown a positive effect over placebo stimulation. Leffmann and colleagues' definition of "microcurrent stimulation" is critical to this understanding and actually captures the essence of the "microcurrent" stimulators that are currently on the market. The description of a type of stimulator by a single electrical characteristic (in this case, current intensity) is inadequate, and Leffmann and colleagues' definition clarifies the essential characteristics of the type of stimulation produced by devices sold as "microcurrent" stimulators.

Both Byl et al and Leffmann et al reviewed other studies that have demonstrated a positive effect of electrical stimulation on wound healing.(2-11) The electrical stimulation examined in those studies differs from the "microcurrent" stimulation used in Byl and colleagues'and Leffmann and colleagues' studies and in clinical application in one of two critical ways: (1) The stimulation is above sensory threshold, or (2) it has a higher current density and clearly polar effects. The use of these previous studies that used very different stimulation characteristics as justification for the use of "microcurrent stimulation" is unacceptable. One could analogously argue that if three sets of 10 exercises, at 80% of a person's one-repetition maximum, three times per week can increase muscle strength over a period of time, then performing the same exercise regimen at one thousandth of the load should similarly affect strength. All electrical stimulation is not the same. There is no evidence for the effectiveness of "microcurrent stimulation," and the studies of Byl and Leffmann and their colleagues undescore this.

I expect that there will be criticism of Byl and colleagues' and Leffmann and colleagues' studies based on the fact that animal models were used, and that the wounds were surgically induced and acute rather than chronic. Both groups of authors make convincing arguments for the use of animal models. Byl and colleagues had previously used the same experimental model to demonstrate that ultrasound can accelerate healing of wounds, which demonstrates the sensitivity, of the model to therapeutic intervention. maintain that these models represent the best-case scenarios for testing of the modality. With respect to acute versus chronic wounds, a similar argument applies. if there were a differentially better effect under the conditions of these studies, perhaps the data could be extrapolated to the case of chronic open wounds. Because no positive effects were noted, however, even under very controlled conditions in acute wounds, there is little likelihood that there would be an effect on chronic open wounds.

In addition, acute, surgically induced wounds are a very good model of acute inflammation. Both studies tested markers of tissue healing (oxygen perfusion, mast cell degranulation, fibroblast density, capillarization) and found no effects of the stimulation on any of these variables. The implications of these results for the use of "microcurrent stimulation" to treat inflammatory conditions such as acute tendinitis are portentous.

Both research teams used commercially available stimulators and treatment settings recommended by the manufacturers. These were well-controlled studies, and no positive (or negative) effects were noted. We can conclude that under the conditions used in these studies, "microcurrent stimulation" is ineffective. I disagree with the conclusions of Byl et al. The results of their study (and that of Leffmann and colleagues) do not conflict with those in the literature; they studied different phenomena. The theoretical constructs do not support the use of "microcurrent stimulation" to accelerate healing. The stimulation characteristics of the cited studies evoke predictable physiological responses; the purported responses to "microcurrent stimulation" are speculative. Lynn Snyder-Mackler, ScD. PT SCS Assistant Professor Department of Physical Therapy University) of Delaware 315 Mckinly Laboratory Newark, DE 19716

References

[1] Picker RI, Current trends: low-volt pulsed microamp stimulation, part II, Clinical Management in Physical Therapy, 1989:9(3):28-33. [2] Alvarez OM, Mertz PM, Smerbeck RV, et al. The healing of superficial skin wounds is stimulated by external electrical current. J Invest Dermatol. 1983;81:144-148. [3] Picker RI. Current trends: low-volt pulsed microamp stimulation, part 1. Clinical Management in Physical Therapy. 1988;9(2):10-14. [4] Carley PJ, Wainapel SF. Electrotherapy for acceleration of wound healing: low intensity direct current. Arch Phys Med Rehabil 1985;66: 43 46. [5] Gault WR, Gatens PF. Use of low intensity direct current in management of ischemic skin ulcers. Phys Ther. 1976;56:265-269. [6] Wolcott LE, Wheeler PC, Hardwicke HM, et al Accelerated healing of skin ulcers by electrotherapy: preliminary clinical results. South Med J. 1969;62:795-801. [7] Brown M, Gogia PP. Effects of high voltage stimulation on cutaneous wound healing in rabbits. Phys Ther. 1987;67:662-667. [8] Brown M, McDonnell MK, Menton DN. Polarity effects on wound healing using electrical stimulation in rabbits. Arch Phys Med Rehabil, 1989;70:624-628, [9] Cupshan M. High-voltage galvanic stimulation: an aid to post-operative healing. Current Pod May 1981:110-114. [10] Cruz N, Bayron F. Suarez A. Accelerated healing of full-thickness burns by the use of high-voltage pulsed galvanic stimulation in the pig. Ann Plast Surg. 1989;28:49-55 [11] Deuland R, Hoffer RE, Seleen WA, et al. The effects of low voltage current on healing of thermal third-degree wounds. Cornell Vet. 19-7;68:51-59. [12] Byl NN, McKenzie AM, West J, et al. Effects of low dose ultrasound on acceleration of wound healing in mini Yucatan pigs, Arcb Phys Med Rehabil. 1992;73:656-664.

Author Responses

We would like to thank the Editor for the opportunity to make a statement concerning the commentaries by Dr Snyder-Mackler and Dr Robinson. Until recently, we were not familiar with the protocol and complete results of Byl et al (see article by Byl et al in this issue). Their conclusions have reinforced our feelings about the future course of "microamperage" stimulation in physical therapy practice. We agree with the conclusions of the commentators that it is time for health practitioners in general and physical therapists specifically to abandon the use of "microamperage" stimulation for wound healing. The literature review from our study as well as that of Byl et al indicate that there are established, tested, and viable electrical stimulation treatment protocols for wound healing, and it is not necessary to spend additional resources of time and money trying to validate a treatment technique that does not work. As Dr Snyder-Mackler mentioned, the lack of positive findings with tissue healing and repair places a black cloud over "microamperage" stimulation in general. This does not preclude the possibility that "microamperage". stimulation may yet prove useful in other conditions commonly treated by physical therapists such as the modulation of pain, but it does indicate prudent clinical judgment is warranted. David J Leffmann, PT David A A all, PhD, PT Paul R Holmgren, PhD Mark W Cornwall, PhD, PT

We appreciate the careful review of the commentators regarding our study and the study by Leffmann and colleagues, both studying the effects of pulsed, direct microcurrent stimulation on the acceleration of normal wound healing. Both Dr Snyder-Mackler and Dr Robinson recognized the degree of control applied to both of these studies, and both commentators carefully articulated the similarities and differences between the procedures followed in the two studies. Based on the findings from these two controlled studies using two different sets of characteristics for microcurrent stimulation with two different animal models and two different wound models, both commentators concluded that there was no evidence of accelerated wound healing in healthy, surgically induced soft tissue lesions treated with pulsed, direct microamperage current. The similarities in healing between the sham-treated and experimental lesions were found whether the treatment time was 1 or 2 hours daily, whether the treatment was carried out over a duration of 1 or 2 weeks, or whether the lesions were treated with a very low current density (0.96 A/[cm.sup.2]/1/2 s) or a relatively high current density (297 A/[cm.sup.2]/1/2 s).

The findings from these studies have clinical implications for physical therapists. When referred a healthy patient, immediately postsurgery and possibly immediately postinjury, it is unlikely that microcurrent stimulation at 100 [mu]A, 1 to 2 hours a day for 1 to 2 weeks, with electrodes that are large enough to cover the wounded area would significantly accelerate normal healing, However, whether these same current characteristics would accelerate repair in a patient with a nonhealing wound, an ischemic ulcer, or an infected wound cannot be inferred from these studies.

In our study, the incisional and partial-thickness lesions were well healed 7 days after the wounds were induced. In the Leffmann et al study, after 2 weeks, the full-thickness lesions were virtually 100% healed. It has been difficult by any means to improve normal wound repair. This time frame is a significant contrast to studies of patients with problem wounds in which wound closure requires months to years despite comprehensive treatment that may or may not include electrical stimulation.[1-4] We agree that these studies need to be taken to a more chronic model, but which kind: ischemic, inflamed, autoimmune, or infected?

Although there are studies that confirm the enhancement of healing of normal wounds with the application of specific modalities (eg, administration of oxygen,[5,6] hydration,[7] ultra-sound[8]), the amount of acceleration is relatively small (usually 20%-30%). With a small effect size, a greater number of subjects are needed, as discussed in the Leffmann et al study. Leffmann and colleagues point out that if they had increased the number of subjects one-hundredfold, the differences between the sham-treated lesions and the experimental lesions might have been statistically significant, but, under normal circumstances, a 10% difference is not clinically useful. Interestingly, what the authors do not point out is that the control wounds would have been better healed than the stimulated wounds (see Tab. 2). In our study, the differences were generally less than 5% between the sham-treated and stimulated lesions; on some variables, the wounds in the experimental group were better healed than those in the control group, whereas on other variables, the control wounds were better healed.

Density of microcurrent is clearly an important variable in these and other electrical stimulation studies. Current density is the amount of current flow per unit of area and is the measure of the quantity of charged ions moving through a cross-sectional area of tissue.9 It is usually expressed in units of milliamperes per square centimeter. When time is considered, density is usually reported as coulombs. Many of the studies on electrical stimulation fail to provide details about current density. if the calculation of current density is based on the intensity of the current and the area of the treatment electrode assuming a frequency of 1 pulse per second), then calculations of coulombs as a measure) of density can be confusing. Dr Robinson summarized the differences in current densities for the two studies in the Fable. Based on a time frame of 1 pulse per second with a 50% duty cycle (the equivalent of the current being on for 1/2 second), he noted a substantial difference in current density between the two studies (0.96 A/[cm.sup.2] versus 297 A/[cm.sup.2). In our article, we report the current density in coulombs, which incorporates the frequency and the duty cycle into the calculations. These two calculations arc similar if one takes time out of the equation.

Most importantly, the fact that neither low-density nor high-density current was associated with either significant acceleration of healing or significant tissue destruction is a powerful finding. In two studies using microcurrent,[10,11] the same low-intensity direct current (100 [mu]A) was applied in a continuous mode with a small needle electrode for the purpose of destroying tumors. If this continuous current had been applied with a 2-mm needle electrode, then the estimated density of the current applied would have been approximately 500 A/[cm.sup.2].

Determining the appropriate characteristics for effective use of electrical stimulation for soft tissue repair may be very difficult, as the experience with bone healing suggests. Although there has been significant interest in the biomechanical and bioelectrical principles of bone growth and repair since the 1800s with the definition of Wolff's law,[12] it has taken nearly 90 years of debate and research for physicians and surgeons to finally accept that electrical stimulation facilitates bone healing. The same issues of stimulation characteristics were critical in the bone-healing studies, as they certainly will be in soft tissue wound studies.

Current intensity and density have been critical variables.[13-19] In the bone healing studies, needle electrodes are commonly placed directly into the fracture site. In these studies, the greatest healing generally occurred around the cathode.15 The greatest enhancement of bone deposition was associated with continuous, direct currents with an intensity between 2 and 10 [mu]A.[16] If the needle electrodes had been 2 mm in diameter, the current density would have been 10 to 50 A/[cm.sup.2]. Destructive effects were measured when the current was between > 20 and 100 [mu]A.[16] This amount of current would be equivalent to a density of 100 to 500 A/[cm.sup.2].

The treatment time and the duration of treatment have also been important in bone-healing studies.[17-22] Most Of the bone-healing studies applied continuous, direct current of between 2 and 100 [mu]A for 8 to 24 hours a day for weeks or months at a time.[17] Acceleration of bone formation in otherwise normal bone with a fracture occurs in the first 8 weeks of electrical stimulation, with no differences noted between control and stimulated fractures after 12 weeks of healing.[18] However, in studies of patients with nonhealing fractures, the duration of electrical stimulation varied from 3 to 4 months to over a year.[19-22] These studies in bone healing reinforce the conclusion that electrode polarity, current density, treatment time, and duration of treatment are all important characteristics of microcurrent stimulation.

Further microcurrent studies are needed of patients and animals with healthy as well as problem wounds. Under controlled conditions, these studies need to modify the density of the current, the treatment time, and the treatment duration and then examine the interactions among these variables. Clearly, if a high-intensity current administered for a short period of time can measurably accelerate healing similar to a low-intensity current administered for a long period of time, then, even if both are equally effective, one would choose the more efficient treatment. On the other hand, it is well known that direct current can be irritating to the skin, particularly at a high intensity.[9] Thus, it may be necessary to moderate the intensity of the current.

Electrical current has been commonly used in the practice of medicine for centuries. However, the use of electrical current for soft tissue healing is still in its infancy. Until the theoretical underpinnings are elucidated, defining the stimulation characteristics for the most effective clinical applications for soft tissue repair is going to be a search for the proverbial needle in a haystack. We hope, nonetheless, that physical therapists are challenged by the findings from these two studies and will be committed to set up controlled clinical studies to continue to try and identify the appropriate characteristics of current for the acceleration of healing and repair of normal as well as problem wounds. Nancy N Byl, Phd, PT Alison L Mckenzie, Phd, PT Thomas K Hunt, MD Harriet Williams Hopf, MD

References

[1] Carey LC, Lepley D. Effect of continuous direct current on healing wounds. Surg Forum. 1962:13:33-35. [2] Assimacopoulous D. Wound healing promotion by, the use of negative electrical current Am J Surg. 1968;34423-431 [3] Feedar JA, Kloth LC, Gentzkow DG. Chronic dermal ulcer healing enhanced with monophasic pulsed electrical stimulation, Phys Ther. 1991;72 639-649. [4] Griffin JW, Tooms RE, Mendius RA, et al. Efficacy of high voltage pulsed current for healing of pressure ulcers in patients with spinal cord injury. Phys Ther. 1991;72:433 44. [5] Davis JC, Hunt TK. Problem Wounds: The Role of Oxygen, New York, NY: Elsevier Science Publishing Co Inc; 1988. [6] Knighton DR, Hunt TK, Scheuenstuhl H, et al. Oxygen tension regulates the expression of angiogenesis factor by macrophages. 1983;221: 1283-1285. [7] Hopf HA, Jensen JA, Hunt TK. Calculation of subcutaneous tissue blood flow. Surg Forum. 1988;39:33-36. [8] Byl NN, McKenzie AM, West J, et al. Effects of low dose ultrasound on acceleration of wound healing in mini Yucatan pigs. Arch Phys Med Rehabil. 1992:73:656-664. [9] Nelson RM, Currier DP. Clinical Electrotherapy. Mateo, Calif: Appleton & Lange; 1991. [10] Schauble MK, Habal MB, Gullick HD. Inhibition of experimental tumor growth in hamsters by small direct currents. Arch Pathol Lab Med. 1977;202:294-297. [11] Humphrey CE, Seal EH. Biophysical approach toward tumor regression in mice. Science. 1959;130:388-389, [12] Forrester JC, Zederfeldt BH, Hayes TL, Hunt TK. Wolff's Law in relation to the healing skin wound. J Trauma. 1967;10:770-779. [13] Yasuda I. Fundamental aspects of fracture treatment [in Japanese]. J Kyoto Med Soc. 1953; 4:395-406. Reprinted, in English, in: Clin Orthop. 1977;124:5-8. [14] Lavine LS, Lustrin I, Shamos MH, et al. Electric enhancement of bone healing. Science. 1970;175:1118-1121. [15] Friedenberg ZA. Stimulation of fracture healing by direct current in the rabbit fibula. 1 Bone Joint Surg [Am]. 1971;53:1400-1408. [16] Friedenberg ZA, Andrews T, Smolenski BI, et al. Bone reaction to varying amounts of current. Surg Gyncol Obstet. 1970;151:894-899. [17] GOH JCH, Bose K, Do MA. Precision programmable constant direct current electrical stimulator for fracture healing. J Biomed Eng. 1986;8:365-368. [18] Goh JCH, Bose K, Kang YK, Nugroho B. Effects of electrical stimulation on the biomechanical properties of fracture healing in rabbits Clin Orthop. 1989;233:268-273. [19] Lavine LS, Grodzinsky AJ. Current concepts review: electrical stimulation of repair of bone. J Bone Joint Surg [Am]. 1987;69:626-630. [20] Lavine LS, Shamos MH, Rinaldi RA, Liboff AR. Electric enhancement of bone healing. Science. 19-2;175:118-121. [21] Brighton CT, Black J, Friedenberg ZB, et al. A multicentre study of the treatment of nonunion with constant direct current. J Bone Joint Surg [Am], 1981;63:2-13. [22] Brighton CT. The semi-invasive method of treating nonunion with direct current. Orthop Clin North Am. 1984;15:33-45.

NN Byl, PhD, PT, is Associate Professor and Director, Graduate Program in Physical Therapy, Univer of California School of Medicine, 374 Parnassus Ave, Room 301, San Francisco, CA 94143-0736 (USA). Address all correspondence to Dr Byl.

Al McKenzie, PhD, PT, is Assistant Professor, Graduate Program in Physical Therapy, University of California School of Medicine.

JM West, RN, MN, is Research Coordinator, Wound Healing Laboratory, Department of Surgery, University of California School of Medicine.

JD Whitney, RN, PhD, is Assistant Professor, Department of Physiological Nursing, University of Washington, Seattle, WA 98195. At the time of this study, Dr Whitney was a doctoral student, School of Nursing, University of California at San Francisco.

TK Hunt, MD, is Professor and Director, Would Healing Laboratory, Department of Surgery, Universit of California School of Medicine.

HW Hopf, MD, is Assistant Professor, Department of Anesthesia, University of California School of Medicine.

H Scheuenstuhl, is Specialist, Wound Healing Laboratory, Department of Surgery, University of California School of Medicine.

The swine protocol for this study was approved by the Animal Research Committee, University of California School of Medicine.

This study was funded, in part, by the Research Evaluation and Allocation Committee, University of California at San Francisco. The electrical stimulator was donated for the study by Monad Corp. The optodes were funded by NIH grant GM 27345. The tissue oxygen monitoring equipment was donated by Inner Space Medical. Davis and Geck donated the suture material.

This article was submitted January 25, 1993, and was accepted September 13, 1993.