Matteo Cadossi

Cartilage repair with osteochondral autografts in sheep: Effect of biophysical stimulation with pulsed electromagnetic fields

The effect of pulsed electromagnetic fields (PEMFs) on the integration of osteochondral autografts was evaluated in sheep. After osteochondral grafts were performed, the animals were treated with PEMFs for 6 h/day or sham‐treated. Six animals were sacrificed at 1 month. Fourteen animals were treated for 2 months and sacrificed at 6 months. At 1 month, the osteogenic activity at the transplant–host subchondral bone interface was increased in PEMF‐treated animals compared to controls. Articular cartilage was healthy in controls and stimulated animals. At 6 months, complete resorption was observed in four control grafts only. Cyst‐like resorption areas were more frequent within the graft of sham‐treated animals versus PEMF‐treated. The average volume of the cysts was not significantly different between the two groups; nevertheless, analysis of the variance of the volumes demonstrated a significant difference. The histological score showed no significant differences between controls and stimulated animals, but the percentage of surface covered by fibrous tissue was higher in the control group than in the stimulated one. Interleukin‐1 and tumor necrosis factor‐α concentration in the synovial fluid was significantly lower, and transforming growth factor‐β1 was significantly higher, in PEMF‐treated animals compared to controls. One month after osteochondral graft implantation, we observed larger bone formation in PEMF‐treated grafts which favors early graft stabilization. In the long term, PEMF exposure limited the bone resorption in subchondral bone; furthermore, the cytokine profile in the synovial fluid was indicative of a more favorable articular environment for the graft.

Locally enhanced chemotherapy by electroporation: clinical experiences and perspective of use of electrochemotherapy

Electroporation is used to enhance drug diffusion and gene delivery into the cytosol. The combination of electroporation and cytotoxic drugs, electrochemotherapy (ECT), is used to treat metastatic tumor nodules located at the skin and subcutaneous tissue. The objective response rate following a single session of treatment exceeds 80%, with minimal toxicity for the patients. The efficacy of ECT in the bone and visceral metastasis is currently investigated, and Phase II studies have been completed. ECT has been used to treat skin primary tumors, except melanoma, and is under investigation for locally advanced pancreatic cancer. Early evidence suggests that treatment of tumor nodules with ECT recruits components of the immune system and eliciting a systemic immune response against cancer is a challenging clinical perspective. Considering the proven safety in several different clinical applications electroporation should be viewed as a clinical platform technology with wide perspectives for use in ECT, gene therapy and DNA vaccination.

Atypical femoral fractures.

Bisphosphonates (BPs) represent the most widely used therapy for osteoporosis. Recently, a relationship between long-term treatment with BPs and a subset of atypical femoral fractures (AFFs) from below the lesser trochanter to the sovracondilar line has been described. Many etiopathogenetic theories have been invoked to explain AFFs: reduced bone turnover and increased osteoblast bone apposition with accumulation of microdamage and decreased bone toughness with subsequent increased risk of micro-cracks and duration fractures, collagen fiber cross-linking and vascularization impairment. Based on published studies, a task force of the American Society for Bone and Mineral Research has redacted the diagnostic criteria of AFFs by classifying them according to their major and minor criteria. The treatment for displaced AFFs is osteosynthesis, but there is a lack of evidence for undisplaced AFFs and the duration of fracture treatment. BPs have a proven efficacy in osteoporotic fracture reduction as well as in the treatment of other bone diseases caused by the downregulation of osteoclast activity. BPs have an excellent benefit-to-risk ratio; however, minor adverse events, such as AFFs, occur in a variable percentage of patients treated over a long period of time.

Electrochemotherapy is effective in the treatment of rat bone metastases

Bone metastases impair general health status, quality of life and survival of patients. Electrochemotherapy (ECT), which combines electroporation (EP) and the administration of anticancer drugs, has been recently introduced into clinical practice for the local treatment of solid tumours. In the present study, the ability of EP with bleomycin (Bleo) to induce MRMT-1 rat breast cancer cell death was investigated in vitro. Then, an in vivo model for bone metastases was set up by the inoculation of MRMT-1 cells in rat proximal tibia. 7xa0days after tumour induction the animals were treated with Bleo, EP, Bleo followed by EP (ECT), or left untreated. ECT eliminated the tumour in 6 out of 8 (75xa0%) treated metastases. Radiological evaluation showed that the Honore score in ECT-treated animals was significantly lower when compared with the other groups (pxa0<xa00.0005) and not significantly different from healthy controls. Bone morphology in ECT-treated animals, evaluated by histological and microtomographical analyses, showed intact cortical and trabecular bone structure with new bone apposition. Histomorphometric evaluation showed that ECT-treated metastases had significantly higher bone volume, trabecular number, trabecular thickness and bone mineral density compared with those of untreated metastases (respectively pxa0<xa00.0005 for BV/TV, Tb.N and BMD; pxa0<xa00.05 for Tb.Th) or metastases treated with Bleo (pxa0<xa00.05 for BV/TV, Tb.N, pxa0<xa00.005 for BMD) or EP (pxa0<xa00.005 for BV/TV, Tb.N; pxa0<xa00.0005 for BMD). These findings suggest that early ECT treatment of bone metastases is minimally invasive, safe and effective, thus providing pre-clinical evidence for its use in the treatment of human bone metastases.

In vivo effect of two different pulsed electromagnetic field frequencies on osteoarthritis

Osteoarthritis (OA) is a joint pathology characterized by fibrillation, reduced cartilage thickness and subchondral bone sclerosis. There is evidence that pulsed electromagnetic fields (PEMFs) counteract OA progression, but the effect of two different PEMF frequencies has not yet been shown. The aim of this study was to test the effectiveness of PEMFs at two different frequencies (37 and 75u2009Hz) in a late OA stage in 21‐month‐old Guinea pigs. After 3 months of 6u2009h/day PEMF stimulation, histological and histomorphometric analyses of the knees were performed. At both frequencies, PEMFs significantly reduced histological cartilage score, fibrillation index (FI), subchondral bone thickness (SBT) and trabecular number (Tb.N) and increased trabecular thickness (Tb.Th) and separation (Tb.Sp) in comparison to the not treated SHAM group. However, PEMFs at 75u2009Hz produced significantly more beneficial effects on the histological score and FI than 37u2009Hz PEMFs. At 75u2009Hz, PEMFs counteracted cartilage thinning as demonstrated by a significantly higher cartilage thickness values than either those of the SHAM or 37u2009Hz PEMF‐treated groups. Although in severe OA both PEMF frequencies were able to limit its progression, 75u2009Hz PEMF stimulation achieved the better results.

Viscosupplementation for grade II osteoarthritis of the ankle: a prospective study at 18 months’ follow-up

BackgroundViscosupplementation, with hyaluronan derivates injected into the intra-space of osteoarthritic joints, is now widely used for the treatment of knee osteoarthritis. This study evaluates the results in terms of pain and disability of intra-articular injections of hyaluronan derivates into the ankle joint in patients suffering from grade II primary or secondary osteoarthritis of the ankle.MethodsTwenty-one patients with a painful ankle and radiographic evidence of grade II osteoarthritis had three weekly intra-articular injections of 2 ml of hylan G-F 20 (10 mg/ml) into the ankle joint. The primary clinical outcome measurement was the ankle osteoarthritis score (AOS) at the baseline, and at 6, 12 and 18 months.ResultsSignificant improvement of the AOS from baseline was seen after 6 months (p=0.0001). This improvement was maintained over time with no further changes at 12- and 18-month follow-ups. Regarding pain, the AOS improved over time from the baseline to the 18-month follow up and became statistically significant at the 12- and 18-month follow-ups (p<0.05).

Do Ion Levels in Metal-on-metal Hip Resurfacing Differ From Those in Metal-on-metal THA at Long-term Followup?

BackgroundMetal-on-metal hip resurfacing arthroplasty (MOM HR) has become an established alternative to traditional metal-on-metal total hip arthroplasty (MOM THA) for younger, more active patients. Nevertheless, concerns remain regarding wear and corrosion of the bearing surfaces and the resulting systemic metal ion distribution.Questions/purposesWe therefore asked whether (1) serum ion concentrations in patients with MOM HR at the time of long-term followup were higher than concentrations in a control population with no hip implants; (2) the ion concentrations in patients with MOM HR were different from those in patients with MOM THA; and (3) sex would influence ion levels with regard to implant type.MethodsThe MOM HR and MOM THA groups consisted of 25 patients (evaluated at a minimum of 96 months) and 16 patients (evaluated at a minimum of 106 months), respectively. Forty-eight healthy donors were recruited for reference values. Cobalt, chromium, nickel, and molybdenum were measured by furnace graphite atomic absorption spectrophotometry.ResultsIon concentrations of cobalt, chromium, and molybdenum in MOM HR were higher than in controls. Chromium and cobalt release were higher in MOM HR than in MOM THA. The sex-based analysis showed the difference was because women had higher concentrations in the MOM HR group than in the MOM THA group, whereas there was no difference between the men in the two groups.ConclusionsIn MOM HR, high metal ion release persists for the long term. Consequently, it is important to implement strict biomonitoring for patients who have received these implants. The sustained high levels of chromium in females within the MOM HR group are concerning and merits strong consideration when choosing implants in this patient group.Level of EvidenceLevel III, therapeutic study. See the Instructions for Authors online for a complete description of level of evidence.

Treatment of keloids and hypertrophic scars with bleomycin and electroporation.

Background: Keloids and hypertrophic scars are the result of abnormal healing responses and dermal tissue proliferation; current surgical procedures can give rise to exuberant scarring and permanent functional loss or disfigurement. Considering the promising results reported when treating keloids and hypertrophic scars with intralesional bleomycin injection and the enhanced effect of bleomycin when combined with electroporation, the authors hypothesized that electrochemotherapy should be used to treat keloids and hypertrophic scars when other treatments have failed. Methods: Twenty patients with keloids or hypertrophic scars were treated with one or more sessions of electrochemotherapy and followed prospectively. Bleomycin was administered intravenously followed by application of electrical pulses to the lesion site. Treatment efficacy was determined either by clinical evaluation (e.g., volume, flattening, pliability, erythema) or by the patient’s self-reported symptomatology (e.g., pruritus, pain). Results: Treatment was well tolerated by patients, and no serious adverse events were observed. A median reduction of 87 percent (range, 41 to 100 percent) was observed in volume size, and 33 lesions (94 percent) showed a volume reduction of more than 50 percent. Scar pliability and erythema scores were also significantly reduced (p < 0.0001). A reduction in hitching was observed in 89 percent of patients (p < 0.0001), and a reduction in pain was observed in 94 percent (p < 0.0001). Only one recurrence was observed after 18 months. Conclusion: Electroporation in combination with bleomycin is an effective treatment for patients affected by large keloids or hypertrophic scars or patients who are nonresponders to other treatments. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Adenosine Receptors as a Biological Pathway for the Anti-Inflammatory and Beneficial Effects of Low Frequency Low Energy Pulsed Electromagnetic Fields

Several studies explored the biological effects of low frequency low energy pulsed electromagnetic fields (PEMFs) on human body reporting different functional changes. Much research activity has focused on the mechanisms of interaction between PEMFs and membrane receptors such as the involvement of adenosine receptors (ARs). In particular, PEMF exposure mediates a significant upregulation of A2A and A3ARs expressed in various cells or tissues involving a reduction in most of the proinflammatory cytokines. Of particular interest is the observation that PEMFs, acting as modulators of adenosine, are able to increase the functionality of the endogenous agonist. By reviewing the scientific literature on joint cells, a double role for PEMFs could be hypothesized in vitro by stimulating cell proliferation, colonization of the scaffold, and production of tissue matrix. Another effect could be obtained in vivo after surgical implantation of the construct by favoring the anabolic activities of the implanted cells and surrounding tissues and protecting the construct from the catabolic effects of the inflammatory status. Moreover, a protective involvement of PEMFs on hypoxia damage in neuron-like cells and an anti-inflammatory effect in microglial cells have suggested the hypothesis of a positive impact of this noninvasive biophysical stimulus.

Hip Resurfacing Implants

EDUCATIONAL OBJECTIVES As a result of reading this article, physicians should be able to: 1. Describe the advantages of hip resurfacing. 2. Describe the disadvantages of hip resurfacing. 3. Identify the population in which hip resurfacing is most often indicated. 4. Demonstrate how to properly postoperatively manage patients with metal-on-metal prostheses. Hip resurfacing offers a suitable solution for young patients affected by hip disease who have high function demands and good bone quality. Bone stock preservation, restoration of the normal proximal femur anatomy, the lack of stress shielding, and the possibility of resuming sporting activity are proven advantages of hip resurfacing. However, there are some disadvantages, such as fracture of the femoral neck, onset of neck narrowing, and possible complications due to the metal-on-metal bearings, including pseudotumors, peri-implant osteolysis, and chronic elevation of metal ions in serum levels. Recent data suggest that the ideal candidate for hip resurfacing is an active male, younger than 65 years, with primary or posttraumatic osteoarthritis, and with a femoral head diameter larger than 50 to 54 mm. Based on these selection criteria, the literature reports implant survival to be similar to that of total hip arthroplasty. The current authors experience confirms a low failure rate and excellent functional outcomes, with metal ion serum levels becoming stable over time in well-functioning implants. Proper surgical technique, correct patient selection, and the right choice of a well-established prosthetic model are essential elements for the long-term success of these implants.