Introduction 19 3 17 12 11 15 18 2A 5 6 16 7 2A 20 21 2 4 8 9 22 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. 22 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. Clinical evaluation 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. Surgical technique 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. Rehabilitation 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. Biophysical stimulation 1 Fig. 1 Left Right top bottom  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. Statistical analysis t t 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. 10 P Results 1 Table 1 Characteristics of the groups at baseline  Placebo #29 I-ONE #31 P Mean SE Mean SE Age 29.6 1.6 32.5 1.4 0.17 Weight 72 2 73 3 0.73 Height 175 1 174 2 0.59 VAS 2.4 0.3 3.2 0.5 0.27 SF-36 Health Survey 37 2 37 2 0.95 IKDC Subjective Knee Evaluation Form 48 3 47 3 0.90 P P P P P 2 Fig. 2 P  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. P P P 3 Fig. 3 P  P 2 Table 2 Generalized linear mixed effects models in which the dependent variables considered are: SF-36 Health Survey score, IKDC Subjective Knee Evaluation score and VAS, respectively  Coefficient Std. err. z P SF-36 Health Survey   Group 0.361 2.690 0.13 0.893  Hours of treatment −0.014 0.008 −1.79 0.073  Sex −8.348 4.810 −1.74 0.083  Weight −0.423 0.171 −2.48 0.013  Height 0.220 0.254 0.87 0.386  Age −0.212 0.137 −1.55 0.120  Smoking status 0.768 2.075 0.37 0.711  Use of NSAIDs −4.667 2.726 −1.71 0.087  Time 0.125 0.034 4.58 0.000  Group × Time 0.051 0.014 3.67 0.0001  Constant 37.940 40.302 0.94 0.347 IKDC Subjective Knee Evaluation  Group −1.499 3.417 −0.44 0.661  Hours of treatment −0.007 0.011 −0.62 0.533  Sex −19.390 6.172 −3.14 0.002  Weight −0.578 0.216 −2.68 0.007  Height 0.150 0.322 0.47 0.642  Age −0.754 0.185 −4.08 0.000  Smoking status −2.214 2.783 −0.80 0.426  Use of NSAIDs −2.941 3.805 −0.77 0.440  Time 0.145 0.051 2.89 0.000  Group × Time 0.167 0.031 5.37 0.000  Constant 94.561 51.382 1.84 0.066 VAS   Group 0.799 0.455 1.76 0.079  Hours of treatment −0.000 0.001 −0.22 0.824  Sex 1.583 0.806 1.96 0.050  Weight 0.020 0.029 0.67 0.505  Height 0.027 0.043 0.64 0.524  Age 0.033 0.022 1.5 0.133  Smoking status 0.246 0.337 0.73 0.464  Use of NSAIDs −0.825 0.434 −1.90 0.058  Time −0.441 0.244 3.89 0.000  Group × Time −0.009 0.002 −4.00 0.000  Constant −5.593 6.721 −0.83 0.405 The Group × Time interaction term describes the different trend between the groups 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 P 4 P P P Fig. 4 P  P Discussion 14 13 19 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. 1 2 P 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. 22 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.