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Controlling drug release from the bone cavity through physical stimulation remains a challenge because the unique shielding properties of the bone structure make it difficult for many physical stimuli to be effective in skeletal disorders. Herein, we designed a type of high-loading nanocomposites self-assembled from Icariin (ICA), Ca2+, and Zoledronic acid (ZOL), which could respond to extracorporeal shock wave (ESW) to control drug release in the bone cavity and govern osteoblast-adipocyte lineage commitment to prevent osteoporotic fracture. The nanocomposites contain more than 70 % of the payloads and exhibit excellent function in bone marrow targeting. When shocked with ESW, the payloads including ICA, Ca2+, and ZOL, can be released in the bone marrow. ICA can inhibit the formation of adipocyte lineages and promote the formation of osteoblast lineages by inhibiting the transcription of peroxisome proliferators-activated receptor γ (PPARγ) and fatty acid-binding protein 4 (FABP4), ESW, and Ca2+ further increase osteoblast activity meanwhile, and ZOL acts as an inhibitor of osteoclasts, leading to an overall anabolism. In vivo, the treatment contributed to a significant increase in bone anabolism, including bone-related parameters, bone strength, and bone resilience, ultimately greatly reducing the risk of osteoporotic fracture. This study demonstrated the high feasibility of combining the bone-penetrating ESW-responsive drug-controlled release system with the regulation of osteoblast-adipocyte lineage commitment for osteoporotic fracture prevention. [Display omitted] • The Bone marrow-targeted ZCI nanoparticles deliver ICA to the bone cavity. • Extracorporeal shock wave controls the ICA release in the bone cavity. • The bone-penetrating controlled-release system can enhance osteoblast activity by governing the osteoblast-adipocyte lineage commitment of bone marrow mesenchymal stem cells, finally preventing osteoporotic fractures. [ABSTRACT FROM AUTHOR]

Objective: Extracorporeal shockwave therapy (ESWT) has been shown to have chondroprotective effects on arthritic diseases. We investigated the effects of ESWT on temporomandibular joint osteoarthritis (TMJOA) using rat chondrocytes and TMJOA rat models.Design: Cell viability and expression of pro-inflammatory cytokines, cartilage degradation, and apoptosis markers were measured in control, monosodium iodoacetate (MIA)-treated and ESWT plus MIA-treated chondrocytes in vitro, and intra-articular MIA injection (TMJOA) and ESWT on TMJOA rats in vivo. In vivo99mTc-hydroxymethylene diphosphonate (HDP) single-photon emission computerized tomography/computerized tomography (SPECT/CT) and ex-vivo micro-CT and histologic examinations were performed in rat models.Results: ESWT plus MIA-treated chondrocytes showed increased cell viability significantly (P = 0.007), while decreased genetic expression of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6); P < 0.001 for each] and cartilage degradation markers [matrix metalloproteinase-3 (MMP3), matrix metalloproteinase-13 (MMP13), and bone morphogenetic protein 7 (BMP7); P < 0.001 for each], and number of apoptotic cells (P < 0.001) compared to MIA-treated chondrocytes. Changes in cytochrome c and cleaved caspase-3 levels relative to procaspase-3 were decreased over MIA-treated chondrocytes. ESWT on TMJOA rat models was associated with a significant decrease in pro-inflammatory and cartilage degradation markers, as demonstrated by real-time PCR and immunohistochemistry stains (P < 0.001 for each). On 99mTc-HDP SPECT/CT, the ESWT group showed a significantly lower uptake ratio compared to the TMJOA group (P = 0.008). Micro-CT analysis revealed that the ESWT group showed improved structure and bone quality compared to the TMJOA control group.Conclusions: ESWT was associated with a protective effect on cartilage and subchondral bone structures of TMJOA by reducing inflammation, cartilage degradation, and chondrocyte apoptosis. [ABSTRACT FROM AUTHOR]

To observe the short- and long-term clinical efficacy differences of body acupuncture and scalp acupuncture combined with extracorporeal shock wave and simple extracorporeal shock wave. Sixty patients with scapulohumeral periarthritis were randomly divided into two groups: the treatment group and control group, 30 cases in each one. Both groups underwent basic rehabilitation training. Patients in the treatment group were treated with body acupuncture and scalp acupuncture combined with extracorporeal shock wave.Yújì (鱼际 LU10), Hégŭ (合谷LI4), Zhōngzhŭ (中渚TE3), Hòuxī (后溪SI3). There were three needles for the scalp acupuncture with the first between Shéntíng (神庭 GV 24) and Yìntáng (印堂 EX-HN3), and the other two straightly through the inner canthus and parallel to the first needle. Shock wave treatment was intensively applied in some pressure points around shoulder joint. The control group used the same shock wave therapy as the treatment group. Both groups were all treated once a day, 6 times a week. Patients were treated for one course which lasted for 4 weeks. VAS score, the Constant-Murley score and the HAMA (the Hamilton Anxiety Scale) are as therapeutic effect index. 30 days telephone investigation followed-up after the treatment course was evaluated. Totally 28 cases completed the clinical observation in the treatment group, and 29 cases in the control group. The total effective rate of the treatment group was 85.7% (24/28), which was higher than 69.0% (20/29) of the control group (P < 0.05). VAS score: There were significant statistical differences before and after the treatment in the two groups (the treatment group: 6.67 ± 1.43 vs 3.47 ± 1.35, the control group: 7.57 ± 1.31 vs 5.36 ± 1.45, both P < 0.05). There were significant statistical differences before the treatment and at the follow-up in the two groups (the treatment group: 6.67 ± 1.43 vs 2.68 ± 0.81, the control group: 7.57 ± 1.31 vs 4.56 ± 1.35, both P < 0.05). The VAS scores of the treatment group after treatment and at the follow-up were respectively lower than those of the control group (both P < 0.05). Shoulder joints activity score: There were significant statistical differences before and after the treatment in the two groups (the treatment group: 54.65 ± 1.65 vs 65.54 ± 2.19, the control group: 54.32 ± 2.31 vs 61.01 ± 0.95, both P < 0.05). There were significant statistical differences before treatment and at follow-up in the two groups (the treatment group: 54.65 ± 1.65 vs 66.18 ± 1.35, the control group: 54.32 ± 2.31 vs 62.11 ± 1.49, both P < 0.05). The shoulder activity scores of the treatment group after treatment and at follow-up were respectively higher than those of the control group (both P < 0.05). HAMA scores: There were singificant statistical differences before and after treatment in the two groups (the treatment group: 16.83 ± 1.56 vs 13.26 ± 2.36, the control group: 17.04 ± 1.84 vs 15.23 ± 3.17, both P < 0.05). There were significant statistical differences before treatment and at follow-up in the two groups (the treatment group: 16.83 ± 1.56 vs 11.01 ± 3.20, the control group: 17.04 ± 1.84 vs 13.68 ± 2.49, both P < 0.05). The HAMA scores of the treatment group after treatment and at follow-up were lower than those of the control group (both P < 0.05). Body acupuncture and scalp acupuncture combined with extracorporeal shock wave can relieve the clinical symptoms of patients with scapulohumeral periarthritis, ease anxiety and improve daily life activities. [ABSTRACT FROM AUTHOR]

Abstract We tested the hypothesis that extracorporeal-shock-wave (ECSW)-assisted adipose-derived stromal vascular fraction (SVF) therapy was better than either one for restoring the blood flow in critical limb ischemia (CLI). Adult male-SD rats were categorized into group 1 (sham-operated-control), group 2 (CLI), group 3 [CLI + ECSW (280 impulses/0.10 mJ/mm2) applied to left inguinal area at 3 h after CLI], group 4 [CLI + SVF (1.2 × 106) implanted into CLI area at 3 h after CLI], group 5 (CLI + ECSW-SVF). In vitro studies showed that ECSW significantly enhanced angiogenesis in human umbilical-vein endothelial cells and carotid-artery ring, and SVF significantly suppressed inflammation (TNF-α/NF-Κb/IL-1ß/MMP-9) in smooth-muscle cells treated by LPS (all p <.001). By day 14 after CLI, the ratio of ischemic/normal blood flow (INBF) was highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but no difference was shown between the latter two groups (all p <.001). The fibrotic area in CLI region exhibited an opposite pattern of INBF ratio (all p <.0001). Protein (CD31/vWF/eNOS) and cellular (CD31/vWF) expressions and number of small vessels in CLI area exhibited an identical pattern, whilst protein expressions of apoptotic (caspase3/PARP/mitochondrial-Bax) fibrotic/DNA-damaged (Samd3/TFG-ß/γ-H2AX) biomarkers exhibited an opposite pattern to INBF among five groups (all p <.0001). The numbers of angiogenetic cells in CLI region (SDF-1α/VEGF/CXCR4) and endothelial-progenitor cells (C-kit/CD31+//Sca-1/CD31+//CD34/KDR+/VE-cadherin/CD34+) in circulation significantly and progressively increased from groups 2 to 5 (all p <.0001). In conclusion, ECSW-SVF therapy effectively enhanced angiogenesis and restoration of blood flow in CLI area. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Cavitation plays a substantial role in the clinical effects of extracorporeal shock wave therapy (ESWT). It is also generally accepted as a major mechanism in sonophoresis. To identify the enhancing effect of extracorporeal shock wave-mediated transdermal drug delivery, 24 Wistar rats were randomly assigned to four groups: (i) topical application of a eutectic mixture of local anesthetics (EMLA); (ii) 1-MHz ultrasound; (iii) ESWT pre-treatment combined with EMLA application; (iv) ESWT concurrent with EMLA application on rat tails. The degree of anesthesia was assessed using the amplitude and latency of sensory nerve action potentials within 5 min after a 60-min EMLA application. The results indicated that ESWT pre-treatment and concurrent ESWT accelerated the anesthetic effects of the EMLA cream on the tail nerve (p < 0.05). This finding might indicate that shock wave-mediated transdermal drug delivery is possible during the ESWT period. [ABSTRACT FROM AUTHOR]

An implant-associated bacterial infection is one of the most common and costly complications of orthopedic surgery. Once biofilms develop, it is extremely difficult to cure infections with antimicrobial agents. High-energy extracorporeal shock wave (ESW) treatment has been used for orthopedic-related diseases and has been found to be an effective bactericidal agent that is tolerable both in vitro and in vivo. The broad-spectrum antibiotic gentamicin exhibits bactericidal activity against Staphylococcus aureus, and bacterial resistance to gentamicin is lower. We tested the effectiveness of gentamicin in combination with ESW treatment against S. aureus biofilms in vivo and in vitro. The spread plate method, crystal violet staining, confocal laser scanning microscopy, scanning electron microscopy and microbiologic evaluation were used to compare the effects of combined treatment with those of either treatment alone. The results revealed statistically significant differences between the group treated with ESWs combined with gentamicin and all other groups. Our findings indicate that use of the combination of ESWs with gentamicin is more effective against S. aureus biofilms in vitro and in vivo. [ABSTRACT FROM AUTHOR]

To observe the effect of extracorporeal shock waves (ESWs) on bone marrow mesenchymal stem cells (MSCs) in patients with avascular necrosis of the femoral head, we collected bone marrow donated by patients and then cultivated and passaged MSCs in vitro using density gradient centrifugation combined with adherence screening methods. The P3 generation MSCs were divided into the ESW group and the control group. The cell counting kit for MSCs detected some proliferation differences. Cytochemistry, alkaline phosphatase staining and Alizarin red staining were used to determine alkaline phosphatase content. Simultaneously, real-time polymerase factor α1, osteocalcin and peroxisome proliferator-activated receptor γ. Together, the results of our study first indicate that moderate ESW intensity, which is instrumental in enhancing MSC proliferation, inducing conversion of MSCs into osteoblasts, and inhibiting differentiation of MSCs into adipocytes from MSCs, is one of the effective mechanisms for treating avascular necrosis of the femoral head. [ABSTRACT FROM AUTHOR]

Background We hypothesized that combined therapy with shock wave (SW) and autologous bone marrow-derived mesenchymal stem cells (BMDMSCs) is superior to either therapy alone for alleviating left ventricular (LV) dysfunction. Methods and results Male mini-pigs (n = 30) equally divided into group 1 (sham control), group 2 [acute myocardial infarction (AMI) by left coronary artery ligation], group 3 (AMI-SW), group 4 (AMI-BMDMSC), and group 5 (AMI-SW-BMDMSC) were sacrificed by day 60 and the hearts were collected for studies. Baseline LV injection fraction [LVEF (%)] and LV chamber size did not differ among the five groups (p > 0.5). By day 60, LVEF was highest in group 1 and lowest in group 2, significantly higher in group 5 than that in groups 3 and 4, and significantly higher in group 4 than that in group 3 (p < 0.001). Cellular and protein levels of VEGF, CXCR4, and SDF-1a were significantly increased progressively from groups 1 to 5 (all p < 0.05). Small vessel number and protein expressions of CD31 and eNOS were highest in groups 1 and 5, lowest in group 2, and significantly higher in group 4 than those in group 3 (p < 0.001). Protein (MMP-9, TNF-1a and NF-?B) and cellular (CD14 +, CD40 +) levels of inflammatory biomarkers, protein expressions of oxidative stress (oxidized protein, NOX-1, NOX-2), apoptosis (Bax, caspase-3, PARP), infarct size, and LV dimensions showed a pattern opposite to that of LVEF among all groups (all p < 0.001). Conclusions Combined SW-BMDMSC therapy is superior to either therapy alone for improving LVEF, reducing infarct size, and inhibiting LV remodeling. [ABSTRACT FROM AUTHOR]

Abstract: Background: Extracorporeal shock wave has been used in the noninvasive treatment of various diseases including musculoskeletal disorders. In particular, shock wave with low energy level showed anti-inflammatory effect and increased angiogenesis in ischemic tissues. However, the detailed cellular pathway in endothelial signaling is not fully understood. We investigate the role of shock wave with low energy level in angiogenic gene expression and underlying molecular mechanism by comparing the laminar and oscillatory fluid shear stresses in endothelial cells. Methods and results: We show that shock wave with low energy level (0.012–0.045mJ/mm2) stimulated phosphorylation of Akt, eNOS and Erk 1/2 in a time-dependent manner which is similar to the effect of laminar fluid shear stress. The transfection of endothelial cells with siRNA encoding VEGFR2, VE-cadherin and PECAM-1 inhibited shock wave-induced phosphorylation of Akt, eNOS and Erk 1/2 and angiogenic gene expressions, including Akt, eNOS, KLF2/4, and Nur77. Moreover, mechanical stimulation through extracorporeal shock wave induced endothelial cell migration and tube formation. Conclusions: Our results demonstrate that shock wave-induced Akt/eNOS phosphorylation and angiogenic gene expression were mediated through the mechanosensory complex formation involving VEGFR-2, VE-cadherin and PECAM-1 which was similar to the effect of laminar shear stress. [Copyright &y& Elsevier]

Abstract: Background: Low-intensity extracorporeal shockwave therapy (LI-ESWT) is currently under investigation regarding its ability to promote neovascularization in different organs. Objective: To evaluate the effect of LI-ESWT on men with erectile dysfunction (ED) who have previously responded to oral phosphodiesterase type 5 inhibitors (PDE5-I). Design, setting, and participants: We screened 20 men with vasculogenic ED who had International Index of Erectile Function ED (IIEF-ED) domain scores between 5–19 (average: 13.5) and abnormal nocturnal penile tumescence (NPT) parameters. Shockwave therapy comprised two treatment sessions per week for 3 wk, which were repeated after a 3-wk no-treatment interval. Intervention: LI-ESWT was applied to the penile shaft and crura at five different sites. Measurements: Assessment of erectile function was performed at screening and at 1 mo after the end of the two treatment sessions using validated sexual function questionnaires, NPT parameters, and penile and systemic endothelial function testing. The IIEF-ED questionnaire was answered at the 3- and 6-mo follow-up examinations. Results and limitations: We treated 20 middle-aged men (average age: 56.1 yr) with vasculogenic ED (mean duration: 34.7 mo). Eighteen had cardiovascular risk factors. At 1 mo follow-up, significant increases in IIEF-ED domain scores were recorded in all men (20.9±5.8 vs 13.5±4.1, p <0.001); these remained unchanged at 6 mo. Moreover, significant increases in the duration of erection and penile rigidity, and significant improvement in penile endothelial function were demonstrated. Ten men did not require any PDE5-I therapy after 6-mo follow-up. No pain was reported from the treatment and no adverse events were noted during follow-up. Conclusions: This is the first study that assessed the efficacy of LI-ESWT for ED. This approach was tolerable and effective, suggesting a physiologic impact on cavernosal hemodynamics. Its main advantages are the potential to improve erectile function and to contribute to penile rehabilitation without pharmacotherapy. The short-term results are promising, yet demand further evaluation with larger sham-control cohorts and longer follow-up. [Copyright &y& Elsevier]

There have been several reports on the use of extracorporeal shock waves in the treatment of pseudarthrosis, calcifying tendinitis, and tendinopathies of the elbow. However, the pathomechanism of pain relief has not been clarified. To investigate the analgesic properties of shock wave application, we analyzed changes in calcitonin gene-related peptide (CGRP)-immunoreactive (ir) dorsal root ganglion (DRG) neurons. In the nontreated group, fluorogold-labeled dorsal root ganglion neurons innervating the most middle foot pad of hind paw were distributed in the L4 and L5 dorsal root ganglia. Of these neurons, 61% were CGRP-ir. However, in the shock wave-treated group, the percentage of FG-labeled CGRP-ir DRG neurons decreased to 18%. These data show that relief of clinical pain after shock wave application may result from reduced CGRP expression in DRG neurons. [Copyright &y& Elsevier]

We tested the hypothesis that extracorporeal shock wave (ECSW)-assisted 5-FU therapy effectively suppressed human tongue squamous carcinoma cell line SAS (i.e., SAS cells) proliferation and tumor growth. In vitro study showed that as compared with lower ECSW energy (≤0.12 mJ/mm2), higher ECSW energy (≥0.25–035 mJ/mm2) significantly suppressed the SAS cell proliferation and upregulated tumor cell apoptosis/DNA-damage/oxidative-stress, whereas combined higher ECSW energy (0.35 mJ/mm2) and 5-FU (20uM) further significantly altered the expressions of these parameters (all p < 0.001). Adult male nude mice (NM) (n = 36) were equally categorized into group 1 (2.0 × 105 SAS cells were implanted into NM back), group 2 [SAS in NM back + stepwise-increased ECSW energy (from 0.05/0.1/0.3/to 0.5 mJ/mm2)/500 impulses which applied to the tumor at days 9/12/15/21], group 3 (SAS in NM back + 5-FU/i.p./7 mg/kg/every 3-day) and group 4 (SAS in NM back + ECSW + 5-FU) and tumors were removed from each animal by day-28. The result showed that tumor volume and tumor weight were significantly progressively reduced from group 1 to group 4 (all p < 0.0001). The protein expressions of apoptotic (mitochondrial-Bax/cleaved-caspase3/cleaved-PARP/cyclophyllin-D), autophagic (ratio of LC3B-II/LC3B-I) and oxidative-stress (NOX-1/NOX-2) biomarkers displayed an opposite pattern of tumor mass among the groups, whereas the cell-stress signaling (p-PI3K/p-Akt/p-m-TOR, and ASK1/MKK4/MKK7/p38/p-JNK/p-c-JUN), MAP kinase family members (RAS/cRAF/KRAS/BRAF/p-ERK1/2), tumor protein (p53) and cellular levels of angiogenesis/DNA-damage (α-SMA+/VEGF+/γ-H2AX+) exhibited an identical pattern of tumor mass among the groups (all p < 0.0001). Combined high-energy ECSW and 5-FU offers an additional benefit for suppressing the cancer cell proliferation and tumor growth. [ABSTRACT FROM AUTHOR]

Introduction/Background Basing on the area of pressure ulcer analyses and studies the correlation between the impact dose of extracorporeal shockwave and the curative effect of stage IV pressure ulcer and its safety was studied. Material and method Seventeen patients were randomized into two groups according to the random number table method, including 8 cases in traditional group and 9 cases in modified group. The pressure ulcers in both groups were treated by conventional radical debridement and alginate dressing. The two groups were treated every other day, three times a week, continuous for 12 weeks, at same time the two groups were treated with extracorporeal shockwave. The treatment parameters of traditional group were set at 2.0 ∼ 3.0 bar, 4 ∼ 5 Hz, the total number of pulses was (200 ∼ 300) + 100/cm 2 times, once a week,continuous for 12 weeks. The treatment parameters of the modified group were set at 2.0 ∼ 3.0 bar, 4 ∼ 5 Hz, the total number of pulses was 2000 times, once a week, continuous for 12 weeks. The degree of pressure ulcer healing was evaluated before treatment, 6,12 weeks after treatment by PUSH. Results After 6 weeks of treatment, the areas of pressure ulcer, exudation, wound tissue and total score in the modified group were better than the traditional group, and the difference was statistically significant ( P < 0.05). After 12 weeks, the pressure ulcer area, exudation, wound tissue and total score in the modified group were better than the traditional group, the difference was statistically significant ( P < 0.01). After 12 weeks, the healing rate in the modified group was 66.67%, which was significantly better than traditional group which was 25.00%. Conclusion Based on pressure sores area to determine the impact of extracorporeal shockwave dose, can significantly improve the curative efficacy of extracorporeal shockwave in the treatment of stage IV pressure ulcers. [ABSTRACT FROM AUTHOR]