Pulsed Electromagnetic Field Therapy and Direct Current Electric Field Modulation Promote the Migration of Fibroblast-like Synoviocytes to Accelerate Cartilage Repair In Vitro.

Articular cartilage injuries are a common source of joint pain and dysfunction. As articular cartilage is avascular, it exhibits a poor intrinsic healing capacity for self-repair. Clinically, osteochondral grafts are used to surgically restore the articular surface following injury. A significant challenge remains with the repair properties at the graft-host tissue interface as proper integration is critical toward restoring normal load distribution across the joint. A key to addressing poor tissue integration may involve optimizing mobilization of fibroblast-like synoviocytes (FLS) that exhibit chondrogenic potential and are derived from the adjacent synovium, the specialized connective tissue membrane that envelops the diarthrodial joint. Synovium-derived cells have been directly implicated in the native repair response of articular cartilage. Electrotherapeutics hold potential as low-cost, low-risk, non-invasive adjunctive therapies for promoting cartilage healing via cell-mediated repair. Pulsed electromagnetic fields (PEMFs) and applied direct current (DC) electric fields (EFs) via galvanotaxis are two potential therapeutic strategies to promote cartilage repair by stimulating the migration of FLS within a wound or defect site. PEMF chambers were calibrated to recapitulate clinical standards (1.5 ± 0.2 mT, 75 Hz, 1.3 ms duration). PEMF stimulation promoted bovine FLS migration using a 2D in vitro scratch assay to assess the rate of wound closure following cruciform injury. Galvanotaxis DC EF stimulation assisted FLS migration within a collagen hydrogel matrix in order to promote cartilage repair. A novel tissue-scale bioreactor capable of applying DC EFs in sterile culture conditions to 3D constructs was designed in order to track the increased recruitment of synovial repair cells via galvanotaxis from intact bovine synovium explants to the site of a cartilage wound injury. PEMF stimulation further modulated FLS migration into the bovine cartilage defect region. Biochemical composition, histological analysis, and gene expression revealed elevated GAG and collagen levels following PEMF treatment, indicative of its pro-anabolic effect. Together, PEMF and galvanotaxis DC EF modulation are electrotherapeutic strategies with complementary repair properties. Both procedures may enable direct migration or selective homing of target cells to defect sites, thus augmenting natural repair processes for improving cartilage repair and healing.

Biophysical stimulation of bone and cartilage: state of the art and future perspectives.

INTRODUCTION: Biophysical stimulation is a non-invasive therapy used in orthopaedic practice to increase and enhance reparative and anabolic activities of tissue. METHODS: A sistematic web-based search for papers was conducted using the following titles: (1) pulsed electromagnetic field (PEMF), capacitively coupled electrical field (CCEF), low intensity pulsed ultrasound system (LIPUS) and biophysical stimulation; (2) bone cells, bone tissue, fracture, non-union, prosthesis and vertebral fracture; and (3) chondrocyte, synoviocytes, joint chondroprotection, arthroscopy and knee arthroplasty. RESULTS: Pre-clinical studies have shown that the site of interaction of biophysical stimuli is the cell membrane. Its effect on bone tissue is to increase proliferation, synthesis and release of growth factors. On articular cells, it creates a strong A2A and A3 adenosine-agonist effect inducing an anti-inflammatory and chondroprotective result. In treated animals, it has been shown that the mineralisation rate of newly formed bone is almost doubled, the progression of the osteoarthritic cartilage degeneration is inhibited and quality of cartilage is preserved. Biophysical stimulation has been used in the clinical setting to promote the healing of fractures and non-unions. It has been successfully used on joint pathologies for its beneficial effect on improving function in early OA and after knee surgery to limit the inflammation of periarticular tissues. DISCUSSION: The pooled result of the studies in this review revealed the efficacy of biophysical stimulation for bone healing and joint chondroprotection based on proven methodological quality. CONCLUSION: The orthopaedic community has played a central role in the development and understanding of the importance of the physical stimuli. Biophysical stimulation requires care and precision in use if it is to ensure the success expected of it by physicians and patients.

An open-label, one-arm, dose-escalation study to evaluate safety and tolerability of extremely low frequency magnetic fields in acute ischemic stroke.

Extremely low frequency magnetic fields (ELF-MF) could be an alternative neuroprotective approach for ischemic stroke because preclinical studies have demonstrated their effects on the mechanisms underlying ischemic damage. The purpose of this open-label, one arm, dose-escalation, exploratory study is to evaluate the safety and tolerability of ELF-MF in patients with acute ischemic stroke. Within 48 hours from the stroke onset, patients started ELF-MF treatment, daily for 5 consecutive days. Clinical follow-up lasted 12 months. Brain MRI was performed before and 1 month after the treatment. The distribution of ELF-MF in the ischemic lesion was estimated by dosimetry. Six patients were stimulated, three for 45 min/day and three for 120 min/day. None of them reported adverse events. Clinical conditions improved in all the patients. Lesion size was reduced in one patient stimulated for 45 minutes and in all the patients stimulated for 120 minutes. Magnetic field intensity within the ischemic lesion was above 1 mT, the minimum value able to trigger a biological effect in preclinical studies. Our pilot study demonstrates that ELF-MF are safe and tolerable in acute stroke patients. A prospective, randomized, placebo-controlled, double-blind study will clarify whether ELF-MFs could represent a potential therapeutic approach.

Experimentally induced cartilage degeneration treated by pulsed electromagnetic field stimulation; an in vitro study on bovine cartilage.

BACKGROUND: Osteoarthritis (OA) is the final result of progressive alterations to articular cartilage structure, composition and cellularity, followed by an increase in the concentration of pro-inflammatory cytokines in joint synovial fluid. Even though the effect of pulsed electromagnetic field (PEMF) stimulation in counteracting OA progression and inflammation is of increasing interest, because of its anabolic and anti-inflammatory properties, the present study aimed to improve the knowledge on cartilage extracellular matrix (ECM) and chondrocyte changes related to the exposure of PEMF, from a histological and histomorphometric point of view. METHODS: An in vitro OA model was realized, culturing bovine cartilage explants with a high dose of interleukin 1ß (IL1ß, 50 ng/ml) at different experimental times (24 h, and 7 and 21 days). The effects of PEMFs (75 Hz, 1.5 mT) were evaluated in cartilage explants treated with IL1ß or not (control), in terms of cartilage structure, cellularity and proteoglycans, glycosaminoglycans, collagen II and transforming growth factor ß1 synthesis by using histology, histomorphometry and immunohistochemistry. RESULTS: Making a comparison with control cartilage, IL1ß-treated explants showed a decrease in cartilage matrix, structure and cellularity parameters. PEMFs were able to counteract the progression of OA acting on both cartilage cellularity and ECM in cartilage previously treated with IL1ß. Normal distribution (Kolmogroc-Smirnov test) and homoscedasticity (Levene test) of data were verified, then, the non-parametric Kruskal Wallis test followed by Mann-Whiteny U test for pairwise comparisons were performed. The p-value was adjusted according to the Dunn-Sidak correction. CONCLUSIONS: These results, obtained by culturing and treating cartilage explants from two different joints, confirmed that PEMF stimulation can be used as adjuvant therapy to preserve cartilage from detrimental effects of high inflammatory cytokine levels during OA.

Pulsed electromagnetic fields combined with a collagenous scaffold and bone marrow concentrate enhance osteochondral regeneration: an in vivo study.

BACKGROUND: The study aimed to evaluate the combined effect of Pulsed Electromagnetic Field (PEMF) biophysical stimulation and bone marrow concentrate (BMC) in osteochondral defect healing in comparison to the treatment with scaffold alone. METHODS: An osteochondral lesion of both knees was performed in ten rabbits. One was treated with a collagen scaffold alone and the other with scaffold seeded with BMC. Half of the animals were stimulated by PEMFs (75 Hz, 1.5 mT, 4 h/day) and at 40 d, macroscopic, histological and histomorphometric analyses were performed to evaluate osteochondral defect regeneration. RESULTS: Regarding cartilage, the addition of BMC to the scaffold improved cell parameters and the PEMF stimulation improved both cell and matrix parameters compared with scaffold alone. The combination of BMC and PEMFs further improved osteochondral regeneration: there was an improvement in macroscopic, cartilage cellularity and matrix parameters and a reduction in the percentage of cartilage under the tidemark. Epiphyseal bone healing improved in all the osteochondral defects regardless of treatment, although PEMFs alone did not significantly improve the reconstruction of subchondral bone in comparison to treatment with scaffold alone. CONCLUSIONS: Results show that BMC and PEMFs might have a separate effect on osteochondral regeneration, but it seems that they have a greater effect when used together. Biophysical stimulation is a non-invasive therapy, free from side effects and should be started soon after BMC transplantation to increase the quality of the regenerated tissue. However, because this is the first explorative study on the combination of a biological and a biophysical treatment for osteochondral regeneration, future preclinical and clinical research should be focused on this topic to explore mechanisms of action and the correct clinical translation.

Vertebral Bone Marrow Edema (VBME) in Conservatively Treated Acute Vertebral Compression Fractures (VCFs): Evolution and Clinical Correlations.

STUDY DESIGN: Prospective observational study. OBJECTIVE: To assess (1) the evolution of vertebral bone marrow edema (VBME) in patients with A1 vertebral compression fractures (VCFs) conservatively treated and (2) the relationship between VBME and clinical symptoms, evaluated as Visual Analogue Scale (VAS) back pain and Oswestry Disability Index (ODI). SUMMARY OF BACKGROUND DATA: VBME is a marker of acute-subacute vertebral fractures. Little is known about the evolution of VBME in conservatively managed VCFs, as well as its clinical meaning. METHODS: 82 thoracic or lumbar VCFs (21 post-traumatic; 61 osteoporotic VCFs), type A1 according to the AOSpine thoracolumbar spine injury classification system, in 80 patients were treated with C35 hyperextension brace for 3 months, bed rest for the first 25 days. Patients with osteoporotic fractures also received antiresorptive therapy and vitamin D supplementation. At 0 (T0), 30 (T1), 60 (T2), and 90 (T3) days, patients underwent magnetic resonance imaging evaluation and clinical evaluation, using VAS for pain and ODI.The paired t test was used to compare changes within groups at each follow-up versus baseline. The unpaired t test after ANOVA (analysis of variance) was used to compare the 2 groups at each follow-up.The association between VBME area, VAS score, and ODI score was analyzed by the Pearson correlation test. The tests were 2-tailed with a confidence level of 5%. RESULTS: A significant VBME mean area, VAS, and ODI scores reduction was recorded at 60 and 90-days follow-ups versus baseline. A positive correlation between VBME reduction and clinical symptoms improvement (VAS and ODI scores improvement) was found in both traumatic and osteoporotic VCFs. CONCLUSION: In benign A1 VCFs conservatively managed, VBME slowly decreases in the first 3 months of magnetic resonance imaging follow-up. This VBME reduction is related to clinical symptoms improvement. LEVEL OF EVIDENCE: 4.

I-ONE therapy in patients undergoing total knee arthroplasty: a prospective, randomized and controlled study.

BACKGROUND: Total knee arthroplasty (TKA) is often associated with a severe local inflammatory reaction which, unless controlled, leads to persistent pain up to one year after surgery. Standard and accelerated rehabilitation protocols are currently being implemented after TKA, but no consensus exists regarding the long-term effects. Biophysical stimulation with pulsed electromagnetic fields (PEMFs) has been demonstrated to exert an anti-inflammatory effect, to promote early functional recovery and to maintain a positive long-term effect in patients undergoing joint arthroscopy. The aim of this study was to evaluate whether PEMFs can be used to limit the pain and enhance patient recovery after TKA. METHODS: A prospective, randomized, controlled study in 30 patients undergoing TKA was conducted. Patients were randomized into experimental PEMFs or a control group. Patients in the experimental group were instructed to use I-ONE stimulator 4hours/day for 60days. Postoperatively, all patients received the same rehabilitation program. Treatment outcome was assessed using the Knee Society Score, SF-36 Health-Survey and VAS. Patients were evaluated pre-operatively and one, two, six and 12 months after TKA. Joint swelling and Non Steroidal Anti Inflammatory Drug (NSAID) consumption were recorded. Comparisons between the two groups were carried out using a two-tail heteroschedastic Student's t-test. Analysis of variance for each individual subject during the study was performed using ANOVA for multiple comparisons, applied on each group, and a Dunnet post hoc test. A p value < 0.05 was considered statistically significant. RESULTS: Pre-operatively, no differences were observed between groups in terms of age, sex, weight, height, Knee-Score, VAS, SF-36 and joint swelling, with the exception of the Functional Score. The Knee-Score, SF-36 and VAS demonstrated significantly positive outcomes in the I-ONE stimulated group compared with the controls at follow-ups. In the I-ONE group, NSAID use was reduced and joint swelling resolution was more rapid than in controls. The effect of I-ONE therapy was maintained after use of the device was discontinued. CONCLUSIONS: The results of the study show early functional recovery in the I-ONE group. I-ONE therapy should be considered after TKA to prevent the inflammatory reaction elicited by surgery, for pain relief and to speed functional recovery.

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 x 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.

Effect of pulsed electromagnetic field stimulation on knee cartilage, subchondral and epyphiseal trabecular bone of aged Dunkin Hartley guinea pigs.

It has been demonstrated that pulsed electromagnetic field (PEMF) stimulation has a chondroprotective effect on osteoarthritis (OA) progression in the knee joints of the 12-month-old guinea pigs. The aim of the present study was to discover whether the therapeutic efficacy of PEMFs was maintained in older animals also in more severe OA lesions. PEMFs were administered daily (6 h/day for 6 months) to 15-month-old guinea pigs. The knee joints (medial and lateral tibial plateaus, medial and lateral femoral condyles) were evaluated by means of a histological/histochemical Mankin modified by Carlsson grading score and histomorphometric measurements of cartilage thickness (CT), fibrillation index (FI), subchondral bone thickness (SBT) and epiphyseal bone microarchitecture (bone volume: BV/TV; trabecular thickness: Tb.Th; trabecular number: Tb.N; trabecular separation: Tb.SP). Periarticular knee bone was also evaluated with dual X-ray absorptiometry (DXA). PEMF stimulation significantly changed the progression of OA lesions in all examined knee areas. In the most affected area of the knee joint (medial tibial plateau), significant lower histochemical score (p<0.0005), FI (p<0.005), SBT (p<0.05), BV/TV (p<0.0005), Tb.Th (p<0.05) and Tb.N (p<0.05) were observed while CT (p<0.05) and Tb.Sp (p<0.0005) were significantly higher than in SHAM-treated animals. DXA confirmed the significantly higher bone density in SHAM-treated animals. Even in the presence of severe OA lesions PEMFs maintained a significant efficacy in reducing lesion progression.