Feng-Sheng Wang

Shock wave therapy induces neovascularization at the tendon-bone junction. A study in rabbits.

Despite the success in clinical application, the exact mechanism of shock wave therapy remains unknown. We hypothesized that shock wave therapy induces the ingrowth of neovascularization and improves blood supply to the tissues. The purpose of this study was to investigate the effect of shock wave therapy on neovascularization at the tendon–bone junction. Fifty New Zealand white rabbits with body weight ranging from 2.5 to 3.5 kg were used in this study. The right limb (the study side) received shock wave therapy to the Achilles tendon near the insertion to bone. The left limb (the control side) received no shock wave therapy. Biopsies of the tendon–bone junction were performed in 0, 1, 4, 8 and 12 weeks. The number of neo‐vessels was examined microscopically with hematoxylin–eosin stain. Neovascularization was confirmed by the angiogenic markers including vessel endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expressions and endothelial cell proliferation determined by proliferating cell nuclear antigen (PCNA) expression examined microscopically with immunohistochemical stains. The results showed that shock wave therapy produced a significantly higher number of neo‐vessels and angiogenesis‐related markers including eNOS, VEGF and PCNA than the control without shock wave treatment. The eNOS and VEGF began to rise in as early as one week and remained high for 8 weeks, then declined at 12 weeks; whereas the increases of PCNA and neo‐vessels began at 4 weeks and persisted for 12 weeks. In conclusion, shock wave therapy induces the ingrowth of neovascularization associated with early release of angiogenesis‐related markers at the Achilles tendon–bone junction in rabbits. The neovascularization may play a role to improve blood supply and tissue regeneration at the tendon–bone junction.

Superoxide Mediates Shock Wave Induction of ERK-dependent Osteogenic Transcription Factor (CBFA1) and Mesenchymal Cell Differentiation toward Osteoprogenitors

Extracorporeal shock wave (ESW) is an alternative non-invasive method for the promotion of bone growth and tendon repair. In an animal model, we have reported that ESW promoted bone marrow osteoprogenitor growth through transforming growth factor-β1 induction. We have further explored the mechanism for the ESW promotion of osteogenesis. Results showed that an optimal ESW treatment at 0.16 mJ/mm2 for 500 impulses rapidly induced a higher O 2 − and ONOO− production associated with a decrease of nitric oxide level in 1 h, and induced a higher transforming growth factor-β1 production in 24 h, and a higher colony-forming units-osteoprogenitor formation in 12 days. The colony-forming units-osteoprogenitor colonies revealed positive staining of bone alkaline phosphatase and turned into bone nodules in 21 days. Early scavenging of O 2 − but not Ca2+, H2O2, or prostaglandin E2 suppressed osteoprogenitor cell growth and maturation. Scavenging of O 2 − by superoxide dismutase raised the nitric oxide level back to the basal level and suppressed ESW-promoted osteoprogenitor cell growth, whereas inhibition of ONOO− by urate or NO byN-nitro-l-arginine methyl ester did not affect ESW promotion of osteogenesis, indicating that O 2 − acted as an early signal for ESW-induced cell growth. Further studies demonstrated that ESW induced ERK activation, and blockage of O 2 − production or inhibition of tyrosine kinase, but not protein kinase A and C inhibitors, suppressed ESW-induced ERK activation. In support that O 2 − mediated the ESW-induced ERK activation and osteogenic differentiation, we further demonstrated that scavenging of O 2 − by superoxide dismutase and inhibition of ERK activation by PD98059 decreased specific osteogenic transcription factor, core binding factor A1 activation, and decreased osteocalcin expression. Taken together, we showed that ESW-induced O 2 − production followed by tyrosine kinase-mediated ERK activation and core binding factor A1 activation resulted in osteogenic cell growth and maturation. Thus, an appropriate modulation of redox reaction by ESW may have some positive effect on the bone regeneration.

Pertussis toxin‐sensitive Gαi protein and ERK‐dependent pathways mediate ultrasound promotion of osteogenic transcription in human osteoblasts1

Bone cells respond to mechanical stimulation via mechanoreceptors and convert biophysical stimulation into biochemical signals that alter gene expression and cellular adaptation. Pulsed acoustic energy treatment raises membrane potential and induces osteogenic activity. How membrane‐bound osteoblast mechanoreceptors convert physical ultrasound (US) stimuli into osteogenic responses is not fully understood. We demonstrated that low‐intensity pulsed US treatment (200‐μs pulse, 1 kHz, 30 mW/cm2) elevated Cbfa1/Runx2 mRNA expression and progressively promoted osteocalcin mRNA expression in human osteoblasts. Pretreatment with pertussis toxin (PTX), but not with cholera toxin, suppressed US‐augmented osteogenic transcription. This indicated that Gi proteins, but not Gs proteins, were involved in US promotion of osteogenic transcription. Further studies demonstrated US treatment could rapidly increase PTX‐sensitive Gαi protein levels and subsequently enhanced phosphorylation of extracellular signal‐regulated kinase (ERK). PTX pretreatment significantly reduced US promotion of ERK activation. Moreover, inhibition of ERK activity by PD98059 suppressed US augmentation of Cbfa1/Runx2 and osteocalcin mRNA expression. Membranous Gαi proteins and cytosolic ERK pathways acted as potent mechanosensitive signals in the response of osteoblasts to pulsed US stimulation.

Shock Wave Therapy for Calcific Tendinitis of the Shoulder A Prospective Clinical Study with Two-Year Follow-up

Background Shock wave therapy is a new modality that has shown efficacy in the treatment of various orthopaedic disorders. Purpose To determine the effectiveness, at 2- to 3-year follow-up, of shock wave therapy for calcific tendinitis of the shoulder. Study Design Prospective clinical study. Methods Thirty-seven patients (39 shoulders) with calcific shoulder tendinitis were treated with shock wave therapy (1000 impulses at 14 kV) and observed for 24 to 30 months. The control group, which underwent sham treatment with a dummy electrode, consisted of 6 patients (6 shoulders) with an average follow-up of 6 months. Evaluation included use of the 100-point Constant score system and shoulder radiographs. Results The overall results in the study group were 60.6% excellent (20 of 33 shoulders), 30.3% good (10), 3.0% fair (1), and 6.1% poor (2), and those of the control group were 16.7% fair (1 of 6 shoulders) and 83.3% poor (5). The symptom recurrence rate in the study group was 6.5%. Dissolution of calcium deposits was complete in 57.6% of the study group, partial in 15.1%, and unchanged in 27.3%. Fragmentation was seen in 16.7% of the control group patients; in 83.3% deposits were unchanged. No recurrence of calcium deposits was observed during the 2 years that the study group was followed. Conclusions Shock wave therapy is a safe and effective noninvasive treatment for patients with calcific tendinitis of the shoulder.

Long-term Results of Extracorporeal Shockwave Treatment for Plantar Fasciitis

Background Extracorporeal shockwave treatment has shown mixed short-term results for plantar fasciitis. However, the long-term results are not available. Hypothesis Long-term results of shockwave treatment are comparable with short-term results. Study Design Randomized controlled clinical trial; Level of evidence, 1. Methods This prospective study consisted of 149 patients (168 heels) with an established diagnosis of chronic plantar fasciitis, including 79 patients (85 heels) in the shockwave treatment group and 70 patients (83 heels) in the control group. In the shockwave group, patients received 1500 impulses of shockwaves at 16 kV to the affected heel in a single session. Patients in the control group received conservative treatment consisting of nonsteroidal anti-inflammatory drugs, orthotics, physical therapy, an exercise program, and/or a local cortisone injection. Patients were evaluated at 60 to 72 months (shockwave group) or 34 to 64 months (control group) with a 100-point scoring system including 70 points for pain and 30 points for function. The clinical outcomes were rated as excellent, good, fair, or poor. Results Before treatment, the groups showed no significant differences in the scores for pain and function. After treatment, the shockwave group showed significantly better pain and function scores as compared with the control group. The overall results were 69.1% excellent, 13.6% good, 6.2% fair, and 11.1% poor for the shockwave group; and 0% excellent, 55% good, 36% fair, and 9% poor for the control group (P< .001). The recurrence rate was 11% (9/81 heels) for the shockwave group versus 55% (43/78 heels) for the control group (P< .001). There were no systemic or local complications or device-related problems. Conclusion Extracorporeal shockwave treatment is effective and safe for patients with plantar fasciitis, with good long-term results.

Shock wave application enhances pertussis toxin protein-sensitive bone formation of segmental femoral defect in Rats

Extracorporeal shock waves (ESWs) elicit a dose‐dependent effect on the healing of segmental femoral defects in rats. After ESW treatment, the segmental defect underwent progressive mesenchymal aggregation, endochondral ossification, and hard callus formation. Along with the intensive bone formation, there was a persistent increase in TGF‐β1 and BMP‐2 expression. Pretreatment with pertussis toxin reduced ESW‐promoted callus formation and gap healing, which presumably suggests that Gi proteins mediate osteogenic signaling.

Shock wave treatment induces angiogenesis and mobilizes endogenous CD31/CD34-positive endothelial cells in a hindlimb ischemia model: Implications for angiogenesis and vasculogenesis

OBJECTIVESnShock waves have been shown to induce recruitment of intravenously injected endothelial progenitor cells to ischemic hind limbs in rats. We hypothesized that shock wave treatment as sole therapy would induce angiogenesis in this ischemia model and would lead to mobilization of endogenous endothelial (progenitor) cells.nnnMETHODSnA total of 18 rats, aged 5 weeks old, were subdivided into 3 groups: sham (nxa0=xa06), ischemic muscle with shock wave treatment (shock wave treatment group, nxa0=xa06), and without shock wave treatment (control, nxa0=xa06). Hind limb ischemia was induced by ligation of the femoral artery. Three weeks later, shock wave treatment (300 impulses at 0.1 mJ/mm(2)) was applied to the adductor muscle; the controls were left untreated. Muscle samples were analyzed using real-time polymerase chain reaction for angiogenic factors and chemoattractants for endothelial progenitor cell mobilization. Fluorescence activated cell sorting analysis of the peripheral blood was performed for CD31/CD34-positive cells. Perfusion was measured using laser Doppler imaging. Functional improvement was evaluated by walking analysis.nnnRESULTSnAngiogenic factors/endothelial progenitor cell chemoattractants, stromal cell-derived factor-1 and vascular endothelial growth factor, were increased in the treatment group, as shown by real-time polymerase chain reaction, indicating the mobilization of endothelial progenitor cells. Fluorescence activated cell sorting analysis of the peripheral blood revealed high numbers of CD31/CD34-positive cells in the treatment group. Greater numbers of capillaries were found in the treated muscles. Blood perfusion increased markedly in the treatment group and led to functional restoration, as shown by the results from the walking analysis.nnnCONCLUSIONSnShock wave therapy therefore could develop into a feasible alternative to stem cell therapy in regenerative medicine, in particular for ischemic heart and limb disease.

Pathomechanism of shock wave injuries on femoral artery, vein and nerve: An experimental study in dogs

PURPOSEnTo study the pathomechanism of shock wave injuries to the femoral artery, vein and nerve in dogs.nnnMATERIALS AND METHODSnHigh-energy shock wave (0.47 mJ/mm(2) energy flux density) were applied to the right femoral artery, vein and nerve in nine mongrels, and the left side was used as control. Macroscopic examinations including structure integrity, edema, discolouration and extravasation; and microscopic examinations including detachment of the intima layer, disruption of the medium layer, capillary congestion, neutrophil margination and extravasation of the outer layer and the surrounding tissues were performed in 2 h, and in 4 days, respectively, after shock wave application.nnnRESULTSnThe most serious injuries included disruption of the medium layer with separation from the adventitia layer of the femoral artery. The injuries to the femoral vein and nerve predominantly involved the outer adventitia layer and the surrounding tissues. Mild nerve bundle swelling was noted in most cases. There were capillary congestion, neutrophil margination and extravasation indicative of inflammatory tissue reaction after shock wave application.nnnCONCLUSIONnHigh-energy shock waves caused serious injuries to the femoral artery, vein and nerve, especially the femoral artery and inflammatory reaction to the surrounding tissues.