Low-frequency pulsed electromagnetic fields significantly improve time of closure and proliferation of human tendon fibroblasts
The promotion of the healing process following musculoskeletal injuries comprises growth factor signalling, migration, proliferation and apoptosis of cells. If these processes could be modulated, the healing of tendon tissue may be markedly enhanced. Here, we report the use of the Somagen™ device, which is certified for medical use according to European laws. It generates low-frequency pulsed electromagnetic fields that trigger effects of a nature that are yet to be determined.
A 1.5-cm wide, linear scrape was introduced into patellar tendon fibroblast cultures (N?=?5 donors). Treatment was carried out every second day. The regimen was applied three times in total with 30 minutes comprising pulsed electromagnetic field packages with two fundamental frequencies (10 minutes of 33 Hz, 20 minutes of 7.8 Hz). Control cells remained untreated. All samples were analyzed for gap closure time, proliferation and apoptosis one week after induction of the scrape wound.
The mean time for bridging the gap in the nontreated cells was 5.05?±?0.33 days, and in treated cells, it took 3.35?±?0.38 days (P <0.001). For cell cultures with scrape wounds, a mean value for BrdU incorporation of OD?=?0.70?±?0.16 was found. Whereas low-frequency pulsed electromagnetic fields treated samples showed OD?=?1.58?±?0.24 (P <0.001). However, the percentage of apoptotic cells did not differ between the two groups.
Our data demonstrate that low-frequency pulsed electromagnetic fields emitted by the Somagen™ device influences the in vitro wound healing of patellar tendon fibroblasts and, therefore, possibly increases wound healing potential.
One of the most important advances in promotion of the healing process following musculoskeletal injuries has evolved from the insight that treatment of these injuries with prolonged immobilization may delay recovery and adversely affect normal tissues. Conversely, controlled early resumption of activity can promote restoration of function. Experimental studies in the several past decades confirm and help explain the deleterious effects of prolonged immobilization and the beneficial effects of activity on the musculoskeletal tissues [1,2]. At the beginning of the healing process, controlled motion and loading of tendon and ligament repair tissue help align the regeneration of cells and collagen fibers, stimulate collagen synthesis and increase strength [3–6]. Early or excessive strain, however, can increase the inflammatory reaction and may damage repair tissue, leading to failure of the healing process .
However, not only mechanical loading or growth factor signalling is important for healing processes. DNA activity concerning transcription and translation, as well as cell cycle mechanisms, plays a pivotal role. Those activities comprise proliferation, migration and apoptosis of cells. If these processes could be modulated, the healing of tendon tissue may be enhanced markedly. This modulation could prevent the occurrence of excessive strain by accelerating tendon healing.
In order to study such processes in vitro, wound-healing assays have been carried out in tissue cultures for many years. These assays monitored cell behavior, including appraising the migration and proliferative capacities of different cells under various culture conditions. They generally involve growing cells to a confluent monolayer as a first step. The layer is ‘wounded’ by a scraping device (razor-blade, pipette tip, needle or cell-scraper). This penning in the cell layer gets repopulated because the cells on the wound edge are no longer contact-inhibited. At the cellular level, healing involves the cells’ detachment from and attachment to the matrix adjacent to the wound area, migration, and proliferation. This repopulation is microscopically observed over a time course to assess the gap closure time, the occupied area over time, or the rate of migration [8–10]. Moreover, proliferation and apoptosis are investigated regularly. Depending on the cell type, the growth factors present, and the extent of the wounded region, wound repair ranges from several hours to days.
Until the 1980s it was believed that biological information within cell systems was being transferred not only chemically but also physically via electromagnetic waves. Information of this nature activates or inhibits biochemical processes [11,12].
Led by these findings in the early 1990s, Sachtleben GmbH, Hamburg, Germany developed the Somagen™ device, which supposedly stimulates the communication mechanisms of cells (Figure 1). The low-frequency pulsed electromagnetic fields (PEMF) electromagnetic signals have been described as affecting enzymes, cells, tissues and whole organisms. Even though the effects exerted by PEMF could be measured, the reasons for the reactions of the biological systems remain unidentified. However, several theories exist to explain these effects, for example the Larmor precession [13,14], the hypothesis of Gartzke and Lange  or radical pair mechanism [16–18] (for review see ). The application of the PEMF induces changes in cellular processes, among others, differentiation , apoptosis , DNA synthesis , protein expression , protein phosphorylation , anti-inflammatory effects  and hormone production .
PEMF instruments like the Somagen™ device generate low-frequency electromagnetic signals in order to accelerate, among others, wound healing response. This enhances the regeneration potential of the destroyed tissue, especially the stimulation of new formation of connective tissue, something for which the vasodilatation and increased cell division are likely responsible . Furthermore, growth factor signalling, which is important for healing processes, can be influenced by low-frequency electromagnetic signals. Zhao et al. could demonstrate a stimulation of the VEGF receptor signaling pathway by applying an electric field on vascular endothelial cells . Another study demonstrated an increased type I collagen expression in fibroblasts after exposure to pulsing electric fields . Zhao et al. summarized that electric fields polarize the activation of multiple signalling pathways, including the PI3 kinases/Pten, membrane growth factor receptors and integrins, both key players in the wound healing processes .
However, the effect of low-frequency PEMF emitted by the Somagen™ device on fibroblasts as key players in wound healing remains to be investigated. Therefore, this study focuses on the effects of PEMF on the healing process of tendon fibroblasts in an in vitro wound healing model. Our findings may be helpful in the field of ligament tissue engineering and may support the development of new strategies for ligament repair.
Fibroblasts were isolated from five patients undergoing surgical treatment of the knee joint. The study protocol is in accordance with the standards of the Declaration of Helsinki. Following approval by the ethical committee of Hannover Medical School, written informed consent was obtained from the patients. The specimens of approximately 4?×?2 mm were aseptically collected from the patellar tendon. The obtained patellar tendon specimen was divided into 0.5 mm2 pieces and transferred into petri dishes with a roughened bottom. Dulbecco’s Modified Eagle’s Medium (DMEM) was used as culture medium containing 10% fetal calf serum, 1% gentamicin and 1% amphotericin B (Biochrom, Berlin, Germany). Tissue specimens were cultured in a humidified environment with 5% CO2 at 37°C. Medium was replenished every second day. After six to eight days, fibroblasts started to grow out of the patellar tendon specimens. After another three to four weeks, the cells reached 80 to 90% confluence. The cells were trypsinized and subcultured in 75 cm2 flasks (13?×?103 cells/cm2). Concomitantly, they were counted and an overall viability of more than 90% was observed using the trypan blue exclusion test. This procedure was repeated once. Cells in the second passage were harvested and 1.5?×?105 fibroblasts were transferred into six-well tissue culture plates (Corning, Vienna, Austria).
Induction of the scrape wound
Scrape wounds were performed in confluent monolayer cultures of the patellar tendon fibroblasts. A 1.5 cm wide, linear scrape was introduced with a cell scraper over the entire diameter of the well. The wound area was marked with three black ink dots on each side of the wound for reference. Cultures were rinsed with culture medium to remove floating cellular debris, and fresh culture medium was added.
Low-frequency pulsed electromagnetic fields treatment protocol
Cell cultures were treated every second day, three times in total, with a registered and certified Somagen™ device, according to company’s protocol (Sachtleben GmbH, Hamburg) In this work, a specific “wound healing” program was used. The applied program consisted of two PEMF signal packages of 10 minutes at a fundamental frequency of 33 Hz and 20 minutes at 7.8 Hz. This ‘wound healing’ program was developed by Sachtleben GmbH in cooperation with different dermatology clinics and has been successfully used before in a clinical setting . The signals have the shape of spike pulses with varying send/pause intervals. Thereby, a magnetic flux density of 0.25 ?T up to 3.16 ?T emerged. At a 5-mm distance from the applicator, electric field strength up to 6.3 mV/cm was measurable (Additional file 1). Applicators attached to the Somagen™ device were placed in the incubator. The six-well tissue culture dishes were put directly on top of the applicators, thereby having a distance to the fibroblast monolayer of approximately 1 to 2 mm. Control cells were also put on the applicator without starting the program and were cultivated in a separate incubator to avoid interactions between the stimulated and nonstimulated cells.
In order to measure any deviation between the treated versus the control cell cultures, time to closure of the gap, proliferation and apoptosis were determined.
Time to closure
The wound was microscopically examined daily for repopulation of the wound area (Figure 2A). The end point of observation was the complete bridging of the scrape wound. Therefore, before the scratch was initiated, a photograph as control with a 20× magnification was captured with the microscope (Zeiss). Afterwards, a photograph with the same magnification was made every day. For quantification, the free area was highlighted, calculated and compared to the control with the software ImageJ 1.42q (National Institute of Health, Maryland, USA). Three independent calculations of each donor were made.
The analysis of cell proliferation was performed one week after induction of the scrape wound using a standard BrdU kit for spectrophotometry (Roche, Mannheim, Germany). BrdU is a thymidine analog that is incorporated into the DNA during the synthesis phase (S1) of the cell cycle. At 0, 6 and 12 hours after application of BrdU, the amount of inserted BrdU was analyzed according to a modified protocol for the larger dishes. To remove non-incorporated BrdU, cells were washed twice with DMEM. Washed cells were fixed with 70% ethanol in 0.5 M HCl at -20°C for 30 min and washed three more times with DMEM. Nucleases were added to the cells at 37°C for 30 min to increase the accessibility of the incorporated BrdU for detection by anti-BrdU Fab-fragment. This incubation was performed in a buffer containing 66 mM Tris, 0.66 mM MgCl2, and 1 mM 2-mercaptoethanol to permeate the cells and disintegrate disulphide bonds. After washing the cells three times with DMEM, a mouse monoclonal Fab-fragment against BrdU conjugated with horse-radish peroxidase was added to the cells together with 10 mg/ml BSA in phosphate-buffered saline. The cells were incubated at 37°C for 30 min and subsequently washed three times with DMEM. The bound conjugate was visualized using 1 mg/ml of the soluble chromogenic substrate 2,2′-Acinobis [3-ethylbenzthiazoline-sulfonic acid] (ABTS). The signal was increased by adding 1 mg/ml of ABTS-substrate enhancer. The optical density of each sample was measured at 405 nm and 490 nm.
Analysis of apoptosis was performed one week after induction of the scrape wound according to the protocol provided by the manufacturer (Bender Med systems, Vienna, Austria). Briefly, adherent cells were detached from the cell culture dishes by carefully scratching with a cell scraper. The cells were centrifuged at 1500?×?g and 4°C; afterwards, the pellet was carefully resuspended in 100 ?l binding buffer (10 mM HEPES, pH 7.4; 140 mM NaCl; 5 mM CaCl2) and stained with 6 ?l recombinant human annexin-V-FITC and 6 ?l of propidium iodide for discrimination of living, apoptotic and necrotic cells (Bender Med Systems, Vienna, Austria). After incubation for 20 min at 4°C in darkness, the cells were centrifuged and resuspended in 100 ?l binding buffer. Flow cytometry was carried out on a FACS-calibur (Becton-Dickinson, Heidelberg, Germany). The software Cellquest-pro V1.1 from Becton-Dickinson was used for data analysis.
All experiments were performed in duplicates for each of the five patients. Furthermore, cells of each donor were divided into two groups: treated and nontreated. Data are presented as mean?±?standard deviation. Differences between the treated and nontreated patellar tendon fibroblasts were analyzed using Student’s t-test. A P value of less than 0.05 was considered statistically significant.
Characterization of the patellar tendon fibroblasts
Patellar tendon fibroblasts were used for cell culture. Characterization of the cells was carried out as described before .
Time to closure
A uniform 1.5-cm-wide scrape wound was observed in every well of the six-well tissue culture plates. The edges of the wounds were sharply delineated. Damaged cells were observed in the edges that still adhered to the bottom of the well. On the consecutive days, the wound area was occupied by fibroblasts. The mean time for bridging the gap in the nontreated cells was 5.05?±?0.33 days (Figure 2B). Treatment with the specific ‘wound healing’ program emitted by Somagen™ device significantly accelerated the bridging time to 3.35?±?0.38 days (P <0.001).
The percentage of Annexin-V positive cells did not differ between the two groups (nontreated 38.5?±?6.5% versus Somagen™ device-treated 38.7?±?7.7%) as depicted in Figure 3A.
Proliferation was determined by BrdU incorporation. The obtained values are optical density values corrected for unspecific backgrounds (Figure 3B). Untreated cell cultures with scrape wounds showed a mean value of 0.70?±?0.16. A significant increase was observed after application of the specific ‘wound healing’ program emitted by Somagen™ device (1.58?±?0.24, P <0.001).
We investigated that certain low-frequency PEMF sequences influence in vitro wound healing of patellar tendon fibroblasts possibly via increasing the proliferation rate. In a similar model of scrape wounding of human foreskin fibroblasts, the 0.8-mm-wide gap was closed within 36 hours due to a preassembled matrix-containing fibrinogen. Moreover, this accelerated closure of the gap was associated with an 8-fold increase in 3H-thymidine incorporation, indicating a high proliferation rate . Rodemann et al., who treated skin fibroblasts with electromagnetic fields, could detect a significant increase of the collagen synthesis and the protein content . The proliferation capacity of the cells probably plays a role in the secondary wound healing phase. As noted in similar models using intestinal epithelial cells or endothelial cells, the rate of cell proliferation, determined by BrdU incorporation, did not differ between migrating and stationary cells over the initial 24-h period [34–36]. This indicates that early epithelial and endothelial restitution is independent of proliferation. After the migration phase that allows cells to go beyond the wound edges, cells have to proliferate in order to repopulate the wound area.
These processes are modulated by signal transduction pathways. The second messenger Ca2+ seems to be involved, as brief treatment with increased extracellular Ca2+ during scrape wounding accelerated wound area closure rates by 50% [37,38]. In our study, the tendon fibroblasts display 30% better wound area closure rates by low-frequency PEMF treatment. The differences may be due to the different cell origin, namely skin fibroblasts in the literature and tendon fibroblasts in our study. Furthermore, the multi-functional signal transducer NF-?B was activated as soon as 30 minutes after scrape wounding . Especially at the wound edges, the subunit p65 was found. Within 5 minutes after wounding, ERK activation was evident. Again, this activation was particularly prominent in cells residing at the scrape edge . These signal transduction molecules are important during adaptation and healing processes of tendon fibroblasts. This has been observed using cyclic, longitudinal strain in patellar tendon fibroblasts. Fifteen minutes of strain elicit NF-?B binding to DNA and is associated with increased proliferation [39,40]. c-fos and JNK are also activated . Therefore, low-frequency PEMF may activate these signal transduction pathways.
These signal transduction pathways are not only involved in proliferation but also in apoptosis. In our model, 30 to 40% apoptosis of patellar tendon fibroblasts was observed. This is in concert with earlier observations using the same type of cells . Treatment with the specific ‘wound healing’ low-frequency PEMF program did not result in any changes in apoptosis rates. Epithelial cells showed induction of apoptosis originating at the wound edges, but this apoptotic effect subsequently spread over a 24-hour period to encompass areas not originally damaged .
Our study included only five replicates; therefore, more studies are necessary to further investigate the positive effect of low-frequency PEMF in a larger cohort of samples. Additionally, in vivo studies should confirm these results in a whole organism with tendon pathology.
Nevertheless, the treatment with low-frequency PEMF enhances the wound healing potential of patellar tendon fibroblasts in vitro. The incidence of tendon and ligament injuries grows due to the increasingly sports-oriented society. Treatment of such injuries is still a challenge to orthopedic trauma surgeons as a restitutio ad integrim can hardly be achieved. Therefore, new modes of treatment are investigated to improve the outcome of such pathologies. Low-frequency PEMF seems to have no adverse effects when applied in the human situation . Furthermore, it is non-invasive, easy to handle, and has a short application time.
These results may be extrapolated to wound-healing phenomena in other soft tissues, for example skin and muscle. Wound healing is a complex process involving many different cell types and coordinated signalling responses, but fibroblasts, as a part of this complexity, support the healing process and in our study show an improved wound area closure rate under the influence of low-frequency PEMF. Thus, low-frequency electromagnetic signals could be an interesting new treatment option for wound-healing processes in vivo by accelerating closure of the wounds. Based on the positive results, further in vivo studies using low-frequency PEMF generated by the Somagen™ device for modulating wound healing
ABTS 2: 2′-Acinobis [3-ethylbenzthiazoline-sulfonic acid]; BrdU: Bromodesoxyuridin; DMEM: Dulbecco’s Modified Eagle’s Medium; FITC: fluorescein isothiocyanate; OD: optical density; PEMF: pulsed electromagnetic fields.
The authors declare that they have no competing interests. Sachtleben GmbH provided the Somagen™ device for this project free of charge. Jens Sachtleben and Karsten Falldorf are both managing directors of Sachtleben GmbH.
CS and MvG conceived and designed the study. CS and MvG performed the experiments and analyzed the data. KF and JS provided data on the device and reviewed the manuscript. All authors read and approved the final manuscript.
Additional file 1:
Somagen™ measured field data.
The authors would sincerely like to thank Sachtleben GmbH for providing the Somagen™ device for this project. We would also like to thank Fritz Seidl, M.A. Interpreting and Translating, for proofreading this paper.
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Low frequency pulsed electromagnetic field affects proliferation, tissue-specific gene expression, and cytokines release of human tendon cells.
- 1Orthopaedic Biotechnologies Laboratory, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy. email@example.com
Low frequency pulsed electromagnetic field (PEMF) has proven to be effective in the modulation of bone and cartilage tissue functional responsiveness, but its effect on tendon tissue and tendon cells (TCs) is still underinvestigated. PEMF treatment (1.5 mT, 75 Hz) was assessed on primary TCs, harvested from semitendinosus and gracilis tendons of eight patients, under different experimental conditions (4, 8, 12 h). Quantitative PCR analyses were conducted to identify the possible effect of PEMF on tendon-specific gene transcription (scleraxis, SCX and type I collagen, COL1A1); the release of pro- and anti-inflammatory cytokines and of vascular endothelial growth factor (VEGF) was also assessed. Our findings show that PEMF exposure is not cytotoxic and is able to stimulate TCs’ proliferation. The increase of SCX and COL1A1 in PEMF-treated cells was positively correlated to the treatment length. The release of anti-inflammatory cytokines in TCs treated with PEMF for 8 and 12 h was significantly higher in comparison with untreated cells, while the production of pro-inflammatory cytokines was not affected. A dramatically higher increase of VEGF-A mRNA transcription and of its related protein was observed after PEMF exposure. Our data demonstrated that PEMF positively influence, in a dose-dependent manner, the proliferation, tendon-specific marker expression, and release of anti-inflammatory cytokines and angiogenic factor in a healthy human TCs culture model.
Effects of biophysical stimulation in patients undergoing arthroscopic reconstruction of anterior cruciate ligament: prospective, randomized and double blind study
Pre-clinical studies have shown that treatment by pulsed electromagnetic fields (PEMFs) can limit the catabolic effects of pro-inflammatory cytokines on articular cartilage and favour the anabolic activity of the chondrocytes. Anterior cruciate ligament (ACL) reconstruction is usually performed by arthroscopic procedure that, even if minimally invasive, may elicit an inflammatory joint reaction detrimental to articular cartilage. In this study the effect of I-ONE PEMFs treatment in patients undergoing ACL reconstruction was investigated. The study end-points were (1) evaluation of patients’ functional recovery by International Knee Documentation Committee (IKDC) Form; (2) use of non-steroidal anti-inflammatory drugs (NSAIDs), necessary to control joint pain and inflammation. The study design was prospective, randomized and double blind. Sixty-nine patients were included in the study at baseline. Follow-up visits were scheduled at 30, 60 and 180 days, followed by 2-year follow-up interview. Patients were evaluated by IKDC Form and were asked to report on the use of NSAIDs. Patients were randomized to active or placebo treatments; active device generated a magnetic field of 1.5 mT at 75 Hz. Patients were instructed to use the stimulator (I-ONE) for 4 h per day for 60 days. All patients underwent ACL reconstruction with use of quadruple hamstrings semitendinosus and gracilis technique. At baseline there were no differences in the IKDC scores between the two groups. At follow-up visits the SF-36 Health Survey score showed a statistically significant faster recovery in the group of patients treated with I-ONE stimulator (P < 0.05). NSAIDs use was less frequent among active patients than controls (P < 0.05). Joint swelling resolution and return to normal range of motion occurred faster in the active treated group (P < 0.05) too. The 2-year follow-up did not shown statistically significant difference between the two groups. Furthermore for longitudinal analysis the generalized linear mixed effects model was applied to calculate the group × time interaction coefficient; this interaction showed a significant difference (P < 0.0001) between the active and placebo groups for all investigated variables: SF-36 Health Survey, IKDC Subjective Knee Evaluation and VAS. Twenty-nine patients (15 in the active group; 14 in the placebo group) underwent both ACL reconstruction and meniscectomy; when they were analysed separately the differences in SF-36 Health Survey scores between the two groups were larger then what observed in the whole study group (P < 0.05). The results of this study show that patient’s functional recovery occurs earlier in the active group. No side effects were observed and the treatment was well tolerated. The use of I-ONE should always be considered after ACL reconstruction, particularly in professional athletes, to shorten the recovery time, to limit joint inflammatory reaction and its catabolic effects on articular cartilage and ultimately for joint preservation.
Articular cartilage performs mechanical functions absorbing the different loads applied to a joint in the course of daily activity . Homeostasis and mechanical competence of cartilage are regulated by the activity of the chondrocytes that maintain the function and the integrity of the extracellular matrix, proteoglycans and collagen.
In consideration of the scant repairability of the cartilage, even modest damages resulting from trauma or inflammation may be the starting point for cartilage degeneration leading over time to extensive lesions that deepen into the thickness of the cartilage itself, ultimately exposing the subchondral bone tissue [3, 17].
Joint injury may involve synovial tissue, cartilage and subchondral bone leading to joint inflammation, swelling and pain. Surgical interventions must certainly be included among the triggers of inflammatory reaction in a joint . The development of arthroscopic procedures has undoubtedly limited joint damage associated to surgery for reconstruction of ligaments; nevertheless, it does not avoid the inflammatory response. Thus, while arthroscopic procedures make surgery less invasive, the inflammatory response at the joint remains and the release of pro-inflammatory cytokines in the synovial fluid is associated with an increase in the aggrecanase activities that lead to a degradation of the cartilage matrix, and also inhibit proteoglycan synthesis [11, 15, 18]. To prevent cartilage damage, current pharmacological therapies aim to control the catabolic effects of the pro-inflammatory cytokines and enhance anabolic activity, proteoglycan synthesis and proliferation of chondrocytes. Drugs that combine the above effects are called chondroprotectors; in this category should be included drugs with A2A adenosine receptor agonist activity, able to stimulate the physiological pathways that control inflammation and promote chondrocyte anabolic activities. Nevertheless, these drugs are in early stages of clinical testing .
Pre-clinical studies have shown that pulsed electromagnetic fields (PEMFs) in vitro favour the proliferation of chondrocytes [6, 16], stimulate proteoglycan synthesis  and demonstrate an A2A adenosine receptor agonist activity [20, 21]. Electromagnetic fields in vivo prevent degeneration of articular cartilage and down-regulate the synthesis and release of pro-inflammatory cytokines in the synovial fluid [2, 4, 8, 9]. These findings suggest that electromagnetic fields may be used to control joint inflammation and to stimulate cartilage anabolic activities, finally resulting in chondroprotection.
A clinical study performed in patients undergoing arthroscopic treatment for cartilage lesions showed that biophysical treatment with PEMFs was well tolerated by the patients and led to a decrease in the use of non-steroidal anti-inflammatory drugs (NSAIDs) and to an early functional recovery; the positive effect of the treatment was maintained at a 3-year follow-up .
Arthroscopic reconstruction is the treatment of choice following anterior cruciate ligament (ACL) rupture; although minimally invasive, the procedure is associated with joint reaction involving the synovia and it is expected to lead to an increase of pro-inflammatory cytokines in the synovial fluid with catabolic effect on articular cartilage. In this study, we evaluated whether the treatment with PEMFs could be used to control joint inflammatory response in patients undergoing ACL reconstruction. The end points of the study were: (1) patients’ functional recovery evaluated by International Knee Documentation Committee (IKDC) form; (2) use of NSAIDs, necessary to control joint pain and inflammation.
Materials and methods
Patients and study design
In 2004–2005, 84 patients undergoing ACL reconstruction were evaluated for inclusion in the study at five clinical centres. Of these, 69 gave their informed consent to participate in the study. The prospective randomized and double-blind study was approved by the local ethical committees. Inclusion criteria were the following: age between 18 and 45 years, ACL complete lesion following acute trauma or consequence of ligament chronic degeneration. All lesions were documented by MRI and confirmed during the intervention. The following were the exclusion criteria: osteonecrosis of the femoral condyle, rheumatoid arthritis, autoimmune disease, systemic disease and patients requiring meniscus repair.
The patients were assigned to the active or placebo group according to the following randomization criteria: age (18–30 or 31–45), sex, smoking status, origin of ACL rupture (traumatic or degenerative). For randomization of patients, a computer-generated schedule was prepared by a biostatistician. In this process, a random number seed was entered into the computer to generate a list that assigned equal numbers of active and placebo stimulators. The minimum number of patients per group required was calculated by power analysis taking into account the results of a previous study .
Of the 69 patients included, two never started the therapy, two dropped out within 2 weeks of therapy, and five did not return at follow-up visits; a total of 60 patients were therefore available for subsequent analysis. The ACL rupture occurred during sports activity in 49 patients (24 active and 25 placebo), daily activity in eight patients (four active and four placebo) and traffic accident in three patients (three active). At the time of ACL reconstruction 29 patients underwent also meniscectomy: 15 in the active group and 14 in the placebo.
The patients were evaluated by IKDC Form before the intervention and at 30, 60 and 180 days afterwards. The different parts of the questionnaire, IKDC Current Health Assessment Form (SF-36 Health Survey), IKDC Subjective Knee Evaluation Form and IKDC Knee Examination Form were analysed separately. As regards the scores of the questionnaires, for each subject we considered the changes at follow-up visits with respect to the values recorded at baseline, before surgery.
Pain intensity was evaluated by visual analogue scale (VAS) of 10-cm length: 0 cm no pain, 10 cm maximum pain. The patients were allowed to use NSAIDs to control knee pain when present and had to report doing so.
A 2-year follow-up telephone interview was conducted and the patients were asked: (a) if they had undergone further surgery at the knee, (b) if they had pain at the knee, (c) if they had functional limitation in daily activity, (d) if they returned to previous sport activity level.
ACL arthroscopic repair was performed by quadruple hamstrings semitendinosus and gracilis technique. Tendons were harvested with the tendons stripper through a 2–3 cm vertical incision on the antero-medial tibial area. Diameter of the quadruple hamstrings semitendinosus and gracilis tendons was measured, while the tibial tunnel and same size femoral tunnel (30 mm length) were prepared. The graft was pulled up through the tibial tunnel with the knee at 90° of flexion and suspended on the external femoral cortex (Endobutton, Smith and Nephew, London, UK). Distally, the graft was fixed with an interference absorbable screw at the tibia at 10° of flexion.
All the patients underwent standard rehabilitation using passive knee flexion daily. Exercises started within the third post-operative day with isometric quadriceps contractions and then progressed to active closed-chain exercises by 4–6 weeks postoperatively. During the first 20 days patients were instructed to use two crutches and then progressive weight bearing until the end of the second month.
The patients were treated with active or placebo devices. The active stimulators (I-ONE; IGEA, Carpi, Italy) generated a magnetic field of peak intensity of 1.5 mT at a frequency of 75 Hz; no heat or vibration was felt by the patient during treatment (Fig. 1).
The patients were instructed to use the stimulator for 4 h per day, not necessarily consecutively, for 60 days. Treatment started within 7 days from the surgery. Each device contained a clock to monitor the hours of use.
The results were analysed with SPSS 13.0 (Statistical Packages for Social Sciences Inc, Chicago, IL, USA). Comparison among the continuous variables in the two groups was performed with Student’s heteroschedastic t test; comparison of continuous variables within each group during follow-up was performed with Student’s paired t test.
Binomial and categorical variables were compared by contingency tables applying the chi-square test for 2 × 2 tables and the Cochran Mantel Haenszel test for larger size tables.
Generalized linear mixed effects model was applied to the SF-36 Health Survey, IKDC Subjective Knee Evaluation and VAS data to test if a different trend between the two groups was present during follow-up by correcting for the following covariates: sex, age, weight, height, hours of treatment, smoking status, use of NSAIDs. In this analysis, a mathematical model is built which takes into account the trend over time of individual patients belonging to each group (Group × Time interaction) and determines if a statistical difference exists between the groups during the follow-up .
The minimum significance level for all the statistical tests was set at P < 0.05.
At baseline, the two groups of study were homogeneous for age, weight, height, VAS, SF-36 Health Survey and IKDC Subjective Knee Evaluation score (Table 1).
Average daily treatment was the same in both groups: 3.92 ± 0.5 h/die versus 3.13 ± 0.3 h/die in the I-ONE group and the placebo group, respectively (P = n.s.).
The average pain was modest and almost absent at 6 months’ follow-up: 0.7 ± 0.2 cm among placebo and 0.9 ± 0.2 cm among active. At 30 days, less patients in the active group used NSAIDs: 8% in the I-ONE group versus 27% in the placebo group (P < 0.05).
The SF-36 Health Survey score decreased significantly at 30 days, in both groups (P < 0.0005). At 60 days the mean SF-36 Health Survey score in the I-ONE patients already exceeded the initial value (by 3.2 points), whereas in the patients of the placebo group SF-36 Health Survey score was slightly below the initial mean value (by ?0.7 units). At 6 months a significant (P < 0.005) increase was observed for SF-36 Health Survey average values in both groups; the patients of the I-ONE group were above the initial values by 10.1 units, while the placebo group exceeds the baseline value by 7.2 units. The mean changes of SF-36 Health Survey score in the I-ONE group are systematically higher with respect to placebo during follow-up, P < 0.05 (Fig. 2).
The IKDC Subjective Knee Evaluation score increased over 6 months and did not show significant differences between the two groups at any follow-up visit.
The IKDC Knee Examination Form outlined both groups including subjects with joint swelling before surgery (one in placebo and two in I-ONE group, P = n.s.) and at 30 days’ follow-up (five in placebo and six in I-ONE group, P = n.s.). On day 60, joint swelling was observed in the placebo group (two patients) only. Joint swelling was not observed any more at 6 months’ follow-up. Limitation in the passive range of motion of the knee was more frequent in the placebo group than in the I-ONE group (P < 0.05) (Fig. 3).
Finally, the generalized linear mixed effects analysis revealed a significantly different trend (group × time interaction, P < 0.0001) between the two groups for SF-36 Health Survey score, IKDC Subjective Knee Evaluation score and for VAS, showing a positive effect of I-ONE treatment. The estimate coefficients and significance of independent variables for three models are displayed in Table 2.
At the 2-year follow-up interview 86% of the patients in the I-ONE group and 75% in the placebo group reported complete functional recovery, no knee pain and return to sport activity.
ACL reconstruction and meniscectomy
When the cohort of patients, undergoing both ACL reconstruction and meniscectomy, was analysed separately, the SF-36 Health Survey score confirmed the faster recovery trend among I-ONE treated patients compared to placebo, P < 0.05 (Fig. 4). At 6 months, SF-36 Health Survey average score increase was 11.4 in the I-ONE group (P < 0.005 vs. baseline) and 7.1 in placebo group (P = ns vs. baseline). Further, the average values of SF-36 Health Survey were significantly higher in the I-ONE group compared to the placebo (45.2 ± 1.5 vs. 37 ± 2.7, P < 0.05).
The percent of patients with limitation in the passive range of motion was lower in the I-ONE group compared to the placebo one (34% I-ONE vs. 50% placebo at day 30 and 4% I-ONE vs. 17% placebo at day 60, P < 0.05).
Arthroscopic surgery has gained a large success and led to a significant increase in its use: about 650,000 procedures are performed in the USA each year . However, the access into the joint space is always associated to an inflammatory reaction that may jeopardize the benefits expected from surgery. Joint inflammation has a catabolic effect on extracellular matrix and inhibits chondrocyte activity; thus, all means capable of locally controlling the inflammation should be adopted to prevent the onset and limit the progression of cartilage damage. Furthermore, unlike bone tissue after damage, the cartilage will not completely recover its competence: once lost, the articular cartilage does not reform .
Many efforts are made to develop strategies able to control joint inflammation and to favour the anabolic activities of chondrocytes; these are challenging objectives, and up to now the pharmacological approaches based on the use of drugs, whether by systemic or by local route, have not yet been able to demonstrate a genuine chondroprotective effect in humans .
Pre-clinical studies have shown PEMFs to have a chondroprotective effect, mediated by the control of inflammation and by the stimulation of chondrocyte activity; thus, we hypothesized that after arthroscopic surgery PEMFs treatment can be used for articular cartilage protection and ultimately joint preservation.
This prospective, randomized and double-blind study investigated whether and to what extent the employment of I-ONE, by controlling joint reaction to arthroscopy, could accelerate functional recovery in patients undergoing ACL reconstruction. The I-ONE treatment was well tolerated by the patients and no adverse side effects were observed. The results show that, at 30 days after surgery, in I-ONE group significantly fewer patients used NSAIDs to control pain, compared to patients in the placebo group; afterwards, the use of NSAIDs was not necessary in either group.
When IKDC Subjective Knee Evaluation average scores were analysed, we found no statistically significant difference between the I-ONE and placebo group; this is in agreement with the findings of other authors who reported that this parameter does not correlate with the other clinical information collected using the SF-36 Health Survey form . However, when the results of the two groups were analysed by generalized linear mixed effects model, which takes into account the trend of each patient in both groups and the effect of confounding factors, we could evidence a positive significant effect of I-ONE treatment also in the Subjective Knee Evaluation (Table 2).
The SF-36 Health Survey average scores at baseline were the same in the I-ONE and placebo groups; however, the high standard deviation testify the large distribution of initial score values. To monitor patient’s recovery after ACL reconstruction, we considered the SF-36 Health Survey score changes with respect to baseline for each individual subject. At 2 and 6 months SF-36 Health Survey increase is undoubtedly higher in I-ONE group than in the placebo group. This result indicates a faster recovery in the treated patients. This positive effect of I-ONE treatment is confirmed by the generalized linear mixed effects analysis. Further, when the cohort of patients who underwent both ACL reconstruction and meniscectomy was analysed, we observed that the average increase of SF-36 Health Survey at 60 days in the I-ONE group was the same as that of placebo group at 6 months (6.0 vs. 7.1, P = n.s.).
The IKDC Knee Examination Form showed how in the placebo group the resolution of joint swelling and the recovery of complete range of motion occur later compared to the I-ONE group; no significant difference in scoring was observed among centres.
The study end-points were thus demonstrated: fewer patients in the I-ONE group required the use of NSAIDs and their functional recovery was faster.
At 2-year follow-up no statistically significant difference was observed between two groups, although the percent of patients with complete recovery was slightly higher in the I-ONE group.
In this study we applied a statistical analysis specifically developed for longitudinal studies that allows to calculate the group × time interaction. This test, that considers individual patient’s score at different time points and the possible influence of confounding factors, supports the positive effect of I-ONE treatment on the recovery of patients undergoing ACL reconstruction.
Our data confirm the results reported by Zorzi et al.  in a group of patients treated with I-ONE following an arthroscopic treatment for cartilage lesions. To the authors’ knowledge, there are no other reports of use of biophysical stimulation after surgical procedures of the knee.
Biophysical stimulation allows treating individual joints, permeating the whole cartilage surface and thickness, the synovia and the subchondral bone. The effectiveness of biophysical stimulation is not limited by considerations such as diffusion ability and concentration gradient, which are present and important in the dynamic of a pharmacological intervention; joint tissues are paramagnetic, they do not attenuate the biophysical signal and thus are all homogenously exposed to the treatment efficacy. Biophysical stimulation is an effective therapeutic intervention to control the detrimental consequences of the inflammation over articular cartilage in the absence of negative side effects.
I-ONE should always be considered after ACL reconstruction, particularly in professional athletes, to shorten the recovery time, to limit joint inflammatory reaction and ultimately for joint preservation.
Supported by Igea through a grant of Research funding of Regione Emilia Romagna. Setti is Igea employ; the other authors have no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2008 Nov;22(11):1318-22.
Effects of decimeter wave and sodium hyaluronate product on postoperative adhesions in flexor tendon.
[Article in Chinese]
Tian D, Luo J, Zhang Q, Zhang Y, Liu K, Yu K, Han J, Han J.
Department of Hand Surgery, Third Hospital of Hebei Medical University, Shijiazhuang Hebei 050051, PR China.
OBJECTIVE: To compare the effect of decimeter wave with sodium hyaluronate product (SHP) on preventing and treating peritendinous adhesion and promoting tendon healing.
METHODS: Totally 96 healthy male white 6-month-old Leghorn chickens weighing (2.24 +/- 0.07) kg were randomized into group A (decimeter wave therapy group, n = 32), in which decimeter wave therapy was applied 1 to 21 days after operation at a frequency of 915 MHz, a power of 8 W, radiation distance of 10 cm, for 10 minutes once per day; group B (SHP group, n = 32), in which 5 mL and 1.2% SHP was applied; and group C (control group, n = 32), in which injury received no treatment. The III and IV toes of left feet of all chickens were made into tendon injury model. The general condition of animal was observed after operation; gross and histological observations were made 7, 10, 14, 18, 21 and 28 days after operation, and the biomechanical analysis was done 14 and 28 days after operation.
RESULTS: Operative incision healed well, no infection and death occurred. Peritendinous adhesions in groups A, B were looser, and tendon healing was better than that of group C 14 and 28 days after operation. More fibroblasts with active metabolism and more collagen formation in groups A, B than that in group C. The Pmax of group A was better than that of group B 14 and 28 days after operation (P < 0.05); the delta max of group A was better than that of group B 18 and 21 days after operation (P < 0.05), and the W0 of group A was better than that of group B 18, 21 and 28 days after operation (P < 0.05). There was no significant difference between group A and group B at the other time points.
CONCLUSION: Topical decimeter wave therapy and application of SHP after flexor tendon repair can promote intrinsic healing, meanwhile they can prevent the adhesion of tendon and reduce extrinsic healing. Decimeter wave therapy can improve the qualities of tendon’s wound healing.
J Hand Surg Am. 2006 Sep;31(7):1131-5.
Pulsed magnetic field therapy increases tensile strength in a rat Achilles’ tendon repair model.
Strauch B, Patel MK, Rosen DJ, Mahadevia S, Brindzei N, Pilla AA.
Department of Plastic and Reconstructive Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA. firstname.lastname@example.org
PURPOSE: To examine the effect of pulsing electromagnetic fields on the biomechanic strength of rat Achilles’ tendons at 3 weeks after transection and repair.
METHODS: This noninvasive modality was tested in a prospective, randomized, double-blinded, placebo-controlled study to evaluate the effect of a specific noninvasive radiofrequency pulsed electromagnetic field signal on tendon tensile strength at 21 days post transection in a rat model.
RESULTS: In the animals receiving PMF exposure, an increase in tensile strength of up to 69% was noted at the repair site of the rat Achilles’ tendon at 3 weeks after transection and repair compared with nonstimulated control animals.
CONCLUSIONS: The application of electromagnetic fields, configured to enhance Ca(2+) binding in the growth factor cascades involved in tissue healing, achieved a marked increase of tensile strength at the repair site in this animal model. If similar effects occur in humans, rehabilitation could begin earlier and the risk of developing adhesions or rupturing the tendon in the early postoperative period could be reduced.
Radiologe. 2004 Jun;44(6):597-603.
Conservative treatment and rehabilitation of shoulder problems.
[Article in German]
Paternostro-Sluga T, Zöch C.
Klinik für Physikalische Medizin und Rehabilitation, Allgemeines Krankenhaus der Medizinischen Universität Wien. email@example.com
The shoulder joint has an important influence on arm- and hand function. Therefore, activities of daily living, working and leisure time can be negatively influenced by diseases of the shoulder joint. Problems of the shoulder joint can be induced by muscular dysbalance and poor body posture. There is a strong relationship between shoulder function and body posture. Conservative treatment and rehabilitation of the shoulder joint aims at improving the local dysfunction of the shoulder joint as well as at improving function and social participation. Antiinflammatory and pain medication, exercise, occupational, electro-, ultrasound and shock wave therapy, massage, thermotherapy and pulsed electromagnetic fields are used as conservative treatments. Exercise therapy aims at improving muscular performance, joint mobility and body posture. Occupational therapy aims at improving functional movements for daily living and work. Electrotherapy is primarily used to relieve pain. Shock wave and ultrasound therapy proved to be an effective treatment for patients with calcific tendinitis. The subacromial impingement syndrome can be effectively treated by conservative therapy.
Biomed Sci Instrum. 2002;38:157-62.
Quantitative characterization of rat tendinitis to evaluate the efficacy of therapeutic interventions.
Wetzel BJ, Nindl G, Swez JA, Johnson MT.
Terre Haute Center for Medical Education, Indiana University School of Medicine, Indiana State University, Terre Haute, IN 47809, USA.
Tendinitis is a painful soft tissue pathology that accounts for almost half of all occupational injuries in the United States. It is often caused by repeated movements and may result in loss of work and income. Current treatments for tendinitis are aimed at reducing inflammation, the major cause of the pain. Although anti-inflammatory drugs and various alternative therapies are capable of improving tendinitis, there are no quantitative scientific data available regarding their impact on inflammation. The objective of this study is to determine the time course for healing of rat tendinitis without intervention to be able to assess the efficacy of tendinitis treatments. We are interested in evaluating the therapeutic use of pulsed electromagnetic fields (PEMFs), a therapeutic modality that has been found to be beneficial for healing soft tissue injuries. Tendinitis was induced in Harlan Sprague Dawley rats by collagenase injections into the Achilles tendon, and tendons were collected for four weeks post-injury. To determine the amount of edema, we used caliper measurements of the rat ankles and quantified the tendon water content. To determine the extent of inflammation, we estimated the number of inflammatory cells on histological sections applying stereological methods. The data reveal that edema is maximal 24 hours after injury accompanied by a massive infiltration of inflammatory cells. Inflammatory cells are then gradually replaced by fibroblasts, which are responsible for correcting damage to the extracellular matrix. This natural time course of tendon healing will be used to evaluate the use of PEMFs as a possible therapeutic modality.
|Arch Phys Med Rehabil. 1997 Apr;78(4):399-404.|
Pulsed magnetic and electromagnetic fields in experimental achilles tendonitis in the rat: a prospective randomized study.
Lee EW, Maffulli N, Li CK, Chan KM.
Department of Orthopaedics and Traumatology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
OBJECTIVE: To investigate the effects of pulsed magnetic fields (PMF) and pulsed electromagnetic fields (PEMF) on healing in experimental Achilles tendon inflammation in the rat.
DESIGN: Prospective randomized trial.
SETTING: University medical school.
METHODS: Exposure of the Achilles tendon and injury by a weight of 98.24 g falling from a height of 35cm in 180 male Sprague-Dawley rats.
INTERVENTION: A daily 15-minute session with PMF of 17Hz or 50Hz, or PEMF of 15Hz or 46Hz, or a sham session.
OUTCOME MEASURES: Random sacrifice 2 hours after the operation, and at 1, 3, 7, 14, or 28 days. Assessment of water content, weight, and histological appearance of the tendons.
RESULTS: The time from injury and the various treatment modalities exerted a significant influence on the water content of the tendon after the injury (two-way ANOVA, p = .02). At day 3, the water content of the PEMF 46Hz group was significantly higher than in the other groups, decreasing sharply by day 7, and being similar to the other groups thereafter. By the end of the experiment, the PEMF 15Hz group was not significantly different from the control group. At day 7, the PMF 50Hz group showed significantly lower water content than the control group (p = .03), but at 14 days the PMF 50Hz group was not significantly different from the control group. PMF 50Hz suppressed the extravascular edema during early inflammation. PMF 17Hz showed a similar initial trend, producing a consistent lower water content throughout the experiment, reaching statistical significance by the end of treatment. By the end of the experiment, the collagen fibers had nearly regained their normal alignment in all groups, with a more physiological alignment seen in the PEMF 17Hz group.
CONCLUSIONS: The tendon returned to histological normality in all groups, but the PMF 17Hz group showed better collagen alignment by the end of the study. PMF 17Hz resulted in a greater reduction of inflammation, with a better return of the tendon to histological normality. Different PMF and PEMF could be applied according to when treatment is started after the injury. If there is no delay between injury and beginning of pulsed magnetic treatment, PMF 17 should be used.
|Lancet. 1984 Mar 31;1(8379):695-8.|
Pulsed electromagnetic field therapy of persistent rotator cuff tendinitis. A double-blind controlled assessment.
Binder A, Parr G, Hazleman B, Fitton-Jackson S.
The value of pulsed electromagnetic fields (PEMF) for the treatment of persistent rotator cuff tendinitis was tested in a double-blind controlled study in 29 patients whose symptoms were refractory to steroid injection and other conventional conservative measures. The treated group (15 patients) had a significant benefit compared with the control group (14 patients) during the first 4 weeks of the study, when the control group received a placebo. In the second 4 weeks, when all patients were on active coils, no significant differences were noted between the groups. This lack of difference persisted over the third phase, when neither group received any treatment for 8 weeks. At the end of the study 19 (65%) of the 29 patients were symptomless and 5 others much improved. PEMF therapy may thus be useful in the treatment of severe and persistent rotator cuff and possibly other chronic tendon lesions.