Low-intensity Pulsed Ultrasound Therapy Research Articles

Effect of the low-intensity pulsed ultrasound therapy on healing of Achilles tendinopathy in a rat model

Effect of the low-intensity pulsed ultrasound therapy on healing of Achilles tendinopathy in a rat model

Optimal treatment conditions for low-intensity pulsed ultrasound therapy for Alzheimer's disease: applications from mice to humans.

We previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase (eNOS) in mouse models of Alzheimer's disease (AD). In a randomized, double-blind, placebo-controlled pilot trial, we demonstrated that whole-brain LIPUS therapy is safe and tends to suppress the cognitive decline in early AD patients. We herein report the findings of our basic experiments that we performed for the pilot trial in order to apply whole-brain LIPUS therapy to humans, as well. First, we examined the relationship between bone density/thickness and ultrasound transmittance using human temporal bone. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of VEGF, FGF2, and eNOS in response to variable ultrasound frequencies, duty cycles, and sound pressures. There was a significant correlation between bone thickness and transmittance (1.0MHz, P < 0.001), while there was no significant correlation between bone density and transmittance (1.0MHz, P = 0.421). At a frequency of 0.5MHz, the optimum duty cycle was considered to be up to 20%. When the tissue amplitude was in the range of 0.05-0.5MPa, VEGF, FGF2, and eNOS were significantly upregulated by LIPUS. Thus, the conditions necessary for LIPUS therapy for the human brain were identified as sound pressure just below the probe 1.3MPa (tissue amplitude 0.15MPa), duty cycle 5%, and frequency 0.5MHz. We successfully identified the optimal treatment conditions for LIPUS therapy for patients with AD.

Stress fractures of the foot - current evidence on management

Stress fractures are a consequence of repeated submaximal loads with inadequate time for recovery and biologic repair or remodelling. The foot and ankle complex (FAC) represents a common site for development of stress fractures. Whilst the overall incidence of stress fractures is low, they are prevalent in athletes and military personnel causing significant time away from sports or work. Within these populations, certain stress fractures directly correlate to specific activities.Factors that commonly influence these fractures include an acute increase in new repetitive physical activity combined with muscle fatigue, training errors or improper athletic techniques, which challenge the regenerative and remodelling capacity of bone. Depending on the site that is subject to repetitive loading, various biomechanical factors can result in abnormal concentration of forces to specific areas of the FAC resulting in stress fracture. Decreased bone marrow density (BMD) is a major biologic cause for developing stress fractures. The female athlete triad comprising eating disorder, amenorrhea and osteoporosis in competitive athletes also predisposes to stress fractures. Vitamin D deficiency is also postulated to be the cause of these fractures and may contribute to poor healing.Clinical presentation is usually with vague pain of insidious onset which worsens with activity and improves with rest. Diffuse tenderness over the affected bone is common with only a minority having any visible swelling. Plain radiographs are the first line of investigation but rarely reveal an obvious fracture. MRI scans aid in diagnosis and CT scans help in treatment and characterisation of the fracture and monitor healing.Management relates to the site of injury, which stratifies them into high or low-risk. Stress fractures of the calcaneus, cuboid and cuneiforms are classed as low-risk fractures as they usually heal with simple activity modification or short duration of non-weight bearing. Stress fractures of the navicular, talus and hallucal sesamoids are classed as high-risk fractures due to higher rates of non-union and prolonged recovery time. Metatarsal fractures can be considered high or low-risk depending on location. These warrant aggressive management, often requiring surgical intervention. Adjuncts such as vitamin D supplements, external shockwave therapy, low-intensity pulsed ultrasound therapy have been used with varying success but there remains little supportive evidence of superiority in the available literature.

Evaluate the effects of low-intensity pulsed ultrasound on dental implant osseointegration under type II diabetes.

Objective: The objective of this study is to assess the impact of low-intensity pulsed ultrasound (LIPUS) therapy on the peri-implant osteogenesis in a Type II diabetes mellitus (T2DM) rat model. Methods: A total of twenty male Sprague-Dawley (SD) rats were randomly allocated into four groups: Control group, T2DM group, Control-LIPUS group, and T2DM-LIPUS group. Implants were placed at the rats' bilateral maxillary first molar sites. The LIPUS treatment was carried out on the rats in Control-LIPUS group and T2DM-LIPUS group, immediately after the placement of the implants, over three consecutive weeks. Three weeks after implantation, the rats' maxillae were extracted for micro-CT, removal torque value (RTV), and histologic analysis. Results: Micro-CT analysis showed that T2DM rats experienced more bone loss around implant cervical margins compared with the non-T2DM rats, while the LIPUS treated T2DM rats showed similar bone heights to the non-T2DM rats. Bone-implant contact ratio (BIC) were lower in T2DM rats but significantly improved in the LIPUS treated T2DM rats. Bone formation parameters including bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone mineral density (BMD) and RTV were all positively influenced by LIPUS treatment. Histological staining further confirmed LIPUS's positive effects on peri-implant new bone formation in T2DM rats. Conclusion: As an effective and safe treatment in promoting osteogenesis, LIPUS has a great potential for T2DM patients to attain improved peri-implant osteogenesis. To confirm its clinical efficacy and to explore the underlying mechanism, further prospective cohort studies or randomized controlled trials are needed in the future.

Attenuation of orthodontically induced inflammatory root resorption by using low-intensity pulsed ultrasound as a therapeutic modality- a systematic review

Ultrasound is an effective tool for both diagnostic and therapeutic applications. As an imaging tool, ultrasound has mostly been used for real-time noninvasive diagnostic imaging. As ultrasound propagates through a material, a reflected radio-frequency (RF) signal is generated when encountering a mismatch in acoustic impedance. While traditionally recognized for its diagnostic imaging capabilities, the application of ultrasound has broadened to encompass therapeutic interventions, most notably in the form of Low-Intensity Pulsed Ultrasound (LIPUS). Low-Intensity Pulsed Ultrasound (LIPUS) is a form of mechanical energy transmitted transcutaneously by high-frequency acoustic pressure waves. The intensity of LIPUS (30 mW/cm2) is within the range of ultrasound intensities used for diagnostic purposes (1–50 mW/cm2) and is regarded as non-thermal, non-destructive, permeating living tissues and triggering a cascade of biochemical responses at the cellular level. The LIPUS device produces a 200 µs burst of 1.5 MHz acoustic sine waves, that repeats at a modulation frequency of 1 kHz and provides a peak pressure of 30 mW/cm2. Low-intensity pulsed ultrasound (LIPUS) forms one of the currently available non-invasive healing-enhancing devices besides electro-stimulation (pulsed electro-magnetic field, PEMF). This modality has been leveraged to enhance drug delivery, expedite injury recovery, improve muscle mobility, alleviate joint stiffness and muscle pain, and enhance bone fracture healing. Although LIPUS has been embraced within various medical disciplines, its integration into standard dental practices is still in its nascent stages, signifying an unexplored frontier with potentially transformative implications. Low-intensity pulsed ultrasound (LIPUS) has emerged as an attractive adjuvant therapy in various dental procedures, such as orthodontic treatment and maxillary sinus augmentation. Its appeal lies in its simplicity and non-invasive nature, positioning LIPUS as a promising avenue for clinical innovation. One particular area of interest is orthodontically induced inflammatory root resorption (OIIRR), an oftenunavoidable outcome of the orthodontic intervention, resulting in the permanent loss of root structure. Notably, OIIRR is the second most common form of root resorption (RR), surpassed only by root resorption related to pulpal infection. Given the high prevalence and potential long-term consequences of OIIRR, this literature review seeks to evaluate the efficacy of LIPUS as a therapeutic approach, with an emphasis on assessing its capacity to reduce the severity of OIIRR to a level of clinical significance. To conduct this systematic review, a comprehensive automated literature search was executed across multiple databases, including MEDLINE, Embase, PsycINFO, Web of Knowledge, Scopus, CINAHL, LILACS, SciELO, Cochrane, PubMed, trials registries, 3ie, and Google Scholar. Both forward and backward citation tracking was employed, encompassing studies published from database inception through January 2009 to April 2023. The review focused on randomized controlled trials (RCTs) that specifically evaluated the effects of low-intensity pulsed ultrasound therapy on orthodontically induced inflammatory root resorption (OIIRR), without restrictions of publication date. A stringent selection criterion was applied, and only studies demonstrating high levels of statistical significance were included. Ultimately, fourteen studies met the inclusion criteria and were subjected to further analysis. The overall quality of the included randomized controlled trials (RCTs) was rigorously assessed utilizing the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. This analysis revealed certain methodological limitations that posed challenges in drawing definitive conclusions from the available evidence. Despite these constraints, the review offers invaluable insights that can inform and guide future research. Specifically, it delineates recommendations for targeted populations, necessary interventions, appropriate outcome measures, suitable study designs, and essential infrastructure to facilitate further investigations. The synthesis of these insights aims to enhance the development and application of low-intensity pulsed ultrasound therapy within the field of dentistry, thereby contributing to improved patient outcomes.

Neuropsychiatric Behavioral Assessments in Mice After Acute and Long-Term Treatments of Low-Intensity Pulsed Ultrasound.

Introduction: To evaluate whether both acute and chronic low-intensity pulsed ultrasound (LIPUS) affect brain functions of healthy male and female mice. Methods: Ultrasound (frequency: 1.5MHz; pulse: 1.0kHz; spatial average temporal average (SATA) intensity: 25mW/cm2; and pulse duty cycle: 20%) was applied at mouse head in acute test for 20minutes, and in chronic experiment for consecutive 10days, respectively. Behaviors were then evaluated. Results: Both acute and chronic LIPUS at 25mW/cm2 exposure did not affect the abilities of movements, mating, social interaction, and anxiety-like behaviors in the male and female mice. However, physical restraint caused struggle-like behaviors and short-time memory deficits in chronic LIPUS groups in the male mice. Conclusion: LIPUS at 25mW/cm2 itself does not affect brain functions, while physical restraint for LIPUS therapy elicits struggle-like behaviors in the male mice. An unbound helmet targeted with ultrasound intensity at 25-50mW/cm2 is proposed for clinical brain disease therapy.

Optimizing irradiation conditions for low-intensity pulsed ultrasound to upregulate endothelial nitric oxide synthase.

Here we aimed to develop a minimally invasive treatment for ischemic heart disease and demonstrate that low-intensity pulsed ultrasound (LIPUS) therapy improves myocardial ischemia by promoting myocardial angiogenesis in a porcine model of chronic myocardial ischemia. Studies to date determined the optimal treatment conditions within the range of settings available with existing ultrasound equipment and did not investigate a wider range of conditions. We investigated a broad range of five parameters associated with ultrasound irradiation conditions that promote expression of endothelial nitric oxide synthase (eNOS), a key molecule that promotes angiogenesis in human coronary artery endothelial cells (HCAEC). Suboptimal irradiation conditions included 1-MHz ultrasound frequency, 500-kPa sound pressure, 20-min total irradiation time, 32-48-[Formula: see text] pulse duration, and 320-[Formula: see text] pulse repetition time. Furthermore, a proposed index, [Formula: see text], calculated as the product of power and the total number of irradiation cycles applied to cells using LIPUS, uniformly revealed the experimental eNOS expression associated with the various values of five parameters under different irradiation conditions. We determined the suboptimal ultrasound irradiation conditions for promoting eNOS expression in HCAEC.

Multicenter consensus statements on the use of low-intensity pulsed ultrasound (LIPUS) in Hand Surgery.

The purpose of this agreement was to establish consensus statements on the use of low-intensity pulsed ultrasound (LIPUS) in hand surgery. Based on Delphi consensus methodology, a preliminary list of questions on the use of LIPUS in hand surgery was developed by an interdisciplinary team of hand and plastic surgeons as well as psychologists and experts from communications science. Based on these, questionnaires were invented and a total of three Delphi rounds have been conducted. Delphi panelists consisted of 11 German hand surgeons with a mean experience in hand surgery of 15years (7-23years). Questions and statements were revised during this process, resulting in a consensus at the end of round three. After three Delphi rounds, the following recommendations could be derived. LIPUS can be applied for impaired fracture healing of the digits, metacarpals, carpal bones as well as a prophylactic procedure in order to avoid further revision surgery. LIPUS therapy can be useful in addition to revision surgery for delayed union and non-unions. In the case of certain risk factors (replantation, revascularization, osteoporosis, smoking), it can be applied directly postoperatively in order to prevent impaired fracture healing. It should be applied for 90-120days. There is a consensus among German hand surgeons, when and how LIPUS can be applied for improving fracture healing of the hand. Randomized controlled trials with direct comparison of fracture treatment with and without LIPUS are needed to support these statements with objective data.

Low-intensity pulsed ultrasound alleviates doxorubicin-induced cardiotoxicity via inhibition of S100a8/a9-mediated cardiac recruitment of neutrophils.

Doxorubicin (DOX)-induced cardiotoxicity limits its broad use as a chemotherapy agent. The development of effective and non-invasive strategies to prevent DOX-associated adverse cardiac events is urgently needed. We aimed to examine whether and how low-intensity pulsed ultrasound (LIPUS) plays a protective role in DOX-induced cardiotoxicity. Male C57BL/6J mice were used to establish models of both acute and chronic DOX-induced cardiomyopathy. Non-invasive LIPUS therapy was conducted for four consecutive days after DOX administration. Cardiac contractile function was evaluated by echocardiography. Myocardial apoptosis, oxidative stress, and fibrosis were analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining, dihydroethidium (DHE) staining, and picrosirius red staining assays. RNA-seq analysis was performed to unbiasedly explore the possible downstream regulatory mechanisms. Neutrophil recruitment and infiltration in the heart were analyzed by flow cytometry. The S100a8/a9 inhibitor ABR-238901 was utilized to identify the effect of S100a8/a9 signaling. We found that LIPUS therapy elicited a great benefit on DOX-induced heart contractile dysfunction in both acute and chronic DOX models. Chronic DOX administration increased serum creatine kinase and lactate dehydrogenase levels, as well as myocardial apoptosis, all of which were significantly mitigated by LIPUS. In addition, LIPUS treatment prevented chronic DOX-induced cardiac oxidative stress and fibrosis. RNA-seq analysis revealed that LIPUS treatment partially reversed alterations of gene expression induced by DOX. Gene ontology (GO) analysis of the downregulated genes between DOX-LIPUS and DOX-Sham groups indicated that inhibition of neutrophil chemotaxis might be involved in the protective effects of LIPUS therapy. Flow cytometry analysis illustrated the inhibitory effects of LIPUS on DOX-induced neutrophil recruitment and infiltration in the heart. Moreover, S100 calcium binding protein A8/A9 (S100a8/a9) was identified as a potential key target of LIPUS therapy. S100a8/a9 inhibition by ABR-238901 showed a similar heart protective effect against DOX-induced cardiomyopathy to LIPUS treatment. LIPUS therapy prevents DOX-induced cardiotoxicity through inhibition of S100a8/a9-mediated neutrophil recruitment to the heart, suggesting its potential application in cancer patients undergoing chemotherapy with DOX.

Low-intensity pulsed ultrasound and parathyroid hormone improve muscle atrophy in estrogen deficiency mice

Due to aging and long-term estrogen deficiency, postmenopausal women suffer muscle atrophy (MA), which is characterized by decreased muscle mass and muscle quality. Low-intensity pulsed ultrasound (LIPUS) is an acoustic wave inducing biological effects mainly by the mechanical stimulation and used as a non-invasive physical therapy for muscle repair. Parathyroid hormone (PTH) is an 84-amino-acid polypeptide, and its bioactive fragment [PTH (1–34)] has potential application in the treatment of MA. We speculate that the combination of physical therapy (i.e., the LIPUS) and regulatory hormone (i.e., the PTH) would be more effective in the treatment of MA. The objective of this study was to evaluate the individual and combined effects of LIPUS and PTH therapy on MA in estrogen deficiency mice. Seventy 8-week-old female C57BL/6J mice were used in this study and the MA model was induced by an intraperitoneal injection of 4-vinylcyclohexene diepoxide (VCD) for 20 consecutive days. The VCD-induced MA mice were randomly divided into MA, LIPUS, PTH and LIPUS + PTH (Combined) groups (n = 10/group). In the LIPUS group, the mice were treated by LIPUS in bilateral quadriceps muscles for 20 min, five times a week for 6 weeks. In the PTH group, the mice received subcutaneous injection of PTH (1–34) (80 ug/kg/d) five times a week, for 6 weeks. In the Combined group, the PTH was administrated 30 min before each LIPUS session. Hematoxylin-eosin (H&E) staining, serum biochemical analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to evaluate the therapeutic effects of related treatments. The results showed that the MA mice had a disordered estrus cycle, significantly decreased muscle mass and myofibers cross-sectional area (CSA). After treatments, LIPUS, PTH and Combined groups had a significantly increased CSA, compared with the MA mice without treatment. In addition, Combined group had a significantly increased mRNA expression of Pax7, MyoD and MyoG, compared with LIPUS and PTH monotherapy groups. Our findings indicated that the combination of LIPUS and PTH treatment improves muscle regeneration ability, which might have potential for treating MA in postmenopausal women.

LIPUS as a potential strategy for periodontitis treatment: A review of the mechanisms.

Periodontitis is a chronic inflammatory condition triggered by oral bacteria. A sustained inflammatory state in periodontitis could eventually destroy the alveolar bone. The key objective of periodontal therapy is to terminate the inflammatory process and reconstruct the periodontal tissues. The traditional Guided tissue regeneration (GTR) procedure has unstable results due to multiple factors such as the inflammatory environment, the immune response caused by the implant, and the operator's technique. Low-intensity pulsed ultrasound (LIPUS), as acoustic energy, transmits the mechanical signals to the target tissue to provide non-invasive physical stimulation. LIPUS has positive effects in promoting bone regeneration, soft-tissue regeneration, inflammation inhibition, and neuromodulation. LIPUS can maintain and regenerate alveolar bone during an inflammatory state by suppressing the expression of inflammatory factors. LIPUS also affects the cellular behavior of periodontal ligament cells (PDLCs), thereby protecting the regenerative potential of bone tissue in an inflammatory state. However, the underlying mechanisms of the LIPUS therapy are still yet to be summarized. The goal of this review is to outline the potential cellular and molecular mechanisms of periodontitis-related LIPUS therapy, as well as to explain how LIPUS manages to transmit mechanical stimulation into the signaling pathway to achieve inflammatory control and periodontal bone regeneration.

Targeted microRNA delivery by lipid nanoparticles and gas vesicle-assisted ultrasound cavitation to treat heart transplant rejection.

Despite exquisite immune response modulation, the extensive application of microRNA therapy in treating heart transplant rejection is still impeded by poor stability and low target efficiency. Here we have developed a low-intensity pulsed ultrasound (LIPUS) cavitation-assisted genetic therapy after executing the heart transplantation (LIGHT) strategy, facilitating microRNA delivery to target tissues through the LIPUS cavitation of gas vesicles (GVs), a class of air-filled protein nanostructures. We prepared antagomir-155 encapsulated liposome nanoparticles to enhance the stability. Then the murine heterotopic transplantation model was established, and antagomir-155 was delivered to murine allografted hearts via the cavitation of GVs agitated by LIPUS, which reinforced the target efficiency while guaranteeing safety owing to the specific acoustic property of GVs. This LIGHT strategy significantly depleted miR-155, upregulating the suppressors of cytokine signaling 1 (SOCS1), leading to reparative polarization of macrophages, decrease of T lymphocytes and reduction of inflammatory factors. Thereby, rejection was attenuated and the allografted heart survival was markedly prolonged. The LIGHT strategy achieves targeted delivery of microRNA with minimal invasiveness and great efficiency, paving the way towards novel ultrasound cavitation-assisted strategies of targeted genetic therapy for heart transplantation rejection.

Evaluation of Efficacy of Low-Intensity Pulsed Ultrasound on Comorbidities Following Mandibular Impacted Third Molar Surgery: A Prospective Study.

Despite several in vitro and in vivo applications of low-intensity pulsed ultrasound (LIPUS), it remains an under-studied feature of the oral and maxillofacial region. The goal of this in vivo study was to objectively investigate the efficacy of low-intensity pulsed ultrasound on wound healing and related morbidities following surgical removal of an impacted third molar. The following in vivo prospective, comparative, randomised controlled clinical study was carried out amongst 56 patients who reported to the Department of Oral and Maxillofacial Surgery fulfilling the inclusion criteria. Group A received sham ultrasound, whereas Group B received LIPUS therapy. Based on the group allocated LIPUS 1 MHz, pulsed 20% and dose 1.0 watts/square centimetre (W/cm2)/sham, ultrasound therapy was given on 1st, 2nd and 3rd post-operative days. The assessment of post-operative pain, oedema, trismus and wound healing on preoperative, first, third and seventh postoperative days. The quantitative variables of the study were assessed using independent sample t-test, and qualitative variables were assessed using the Chi-square test. The P < 0.05 on third and seventh post-op days for pain, trismus and wound healing in the LIPUS group compared to control group making it statistically significant. There was no statistically significant difference in the reduction of oedema amongst the two groups. Post-LIPUS application in the patients, postoperative pain was significantly reduced, trismus was noticeably improved and wound healing was satisfactory and can be employed as a complementary technique.

Low-Intensity Pulsed Ultrasound Therapy in Patients With Post-traumatic Delayed Union and Non-union.

Background Fracture non-union can lead to significant patient morbidity with poor quality of life. Due to the cost, complexity, and potential risks of revision surgery, there has been an increased popularity in the use of low-intensity pulsed ultrasound therapy (LIPUS), which accelerates and promotes bone consolidation. There is an ongoing debate regarding the use and efficacy of LIPUS in delayed union and non-union. This study aims to assess the success rate of LIPUS therapy in patients treated for delayed and non-union fractures, explicitly focusing on the impact of patient co-morbidities and fracture characteristics. Method A retrospective observational study was performed of all consecutive patients who received LIPUS therapy in a single institution from January 2016 to September 2022. Of 127 identified patients, only 99 patients met our inclusion criteria. Data collection entailed reviewing the clinical notes to assess patients' sex, age, co-morbidities, initial treatment method, time to initiate LIPUS, whether a CT was performed to diagnose non-union, time to union and whether revision surgery was needed. Two independent senior orthopedic doctors reviewed the patients' radiographs, measured the interfragmentary bone gap of all fractures, and assessed whether the radiographic union was achieved. Results The mean age of the included patients was 52.5 (SD±16.9) years with a male-to-female ratio of 1:1.6. At initial presentation, 65 (out of 99) patients were treated surgically, whereas the rest were managed conservatively. 80.8% of patients developed atrophic non-union. All 99 included patients were fitted with LIPUS once delayed/ non-union was diagnosed; the average time to fitting was 5.1 (SD±3.9) months. Of these, 61.6% of patients were successfully treated with LIPUS with a clinical and radiological union at an average of 4.3 (SD±1.9) months. The rest of the patients needed further surgical intervention due to ongoing non-union. The interfragmentary bone gap was the only statistically significant factor influencing the success of LIPUS therapy (p=0.003). In contrast, no statistically significant association was identified between the outcome of LIPUS therapy and the patient's age, sex, diabetes, and smoking status. Conclusion This study demonstrated a 61.6% progression to union rate of patients treated with LIPUS therapy for delayed union and non-union. The interfragmentary bone gap was identified as the only statistically significant factor influencing the success of LIPUS therapy. In the current climate post-lockdown and with ongoing Covid 19 outbreaks impacting elective waiting lists negatively, there is increased value and demand for non-surgical treatment options. LIPUS therapy represents an important complementary non-surgical and low-risk treatment pathway for delayed union and non-union.

Beneficial Effects of Low-Intensity Pulsed Ultrasound Therapy on Right Ventricular Dysfunction in Animal Models

Right ventricular failure (RVF) is a leading cause of death in patients with pulmonary hypertension; however, effective treatment remains to be developed. We have developed low-intensity pulsed ultrasound therapy for cardiovascular diseases. In this study, we demonstrated that the expression of endothelial nitric oxide synthase (eNOS) in RVF patients was downregulated and that eNOS expression and its downstream pathway were ameliorated through eNOS activation in 2 animal models of RVF. These results indicate that eNOS is an important therapeutic target of RVF, for which low-intensity pulsed ultrasound therapy is a promising therapy for patients with RVF.

Electrical, Electromagnetic, Ultrasound Wave Therapies, and Electronic Implants for Neuronal Rejuvenation, Neuroprotection, Axonal Regeneration, and IOP Reduction.

The peripheral nervous system (PNS) of mammals and nervous systems of lower organisms possess significant regenerative potential. In contrast, although neural plasticity can provide some compensation, the central nervous system (CNS) neurons and nerves of adult mammals generally fail to regenerate after an injury or damage. However, use of diverse electrical, electromagnetic and sonographic energy waves are illuminating novel ways to stimulate neuronal differentiation, proliferation, neurite growth, and axonal elongation/regeneration leading to various levels of functional recovery in animals and humans afflicted with disorders of the CNS, PNS, retina, and optic nerve. Tools such as acupuncture, electroacupuncture, electroshock therapy, electrical stimulation, transcranial magnetic stimulation, red light therapy, and low-intensity pulsed ultrasound therapy are demonstrating efficacy in treating many different maladies. These include wound healing, partial recovery from motor dysfunctions, recovery from ischemic/reperfusion insults and CNS and ocular remyelination, retinal ganglion cell (RGC) rejuvenation, and RGC axonal regeneration. Neural rejuvenation and axonal growth/regeneration processes involve activation or intensifying of the intrinsic bioelectric waves (action potentials) that exist in every neuronal circuit of the body. In addition, reparative factors released at the nerve terminals and via neuronal dendrites (transmitter substances), extracellular vesicles containing microRNAs and neurotrophins, and intercellular communication occurring via nanotubes aid in reestablishing lost or damaged connections between the traumatized tissues and the PNS and CNS. Many other beneficial effects of the aforementioned treatment paradigms are mediated via gene expression alterations such as downregulation of inflammatory and death-signal genes and upregulation of neuroprotective and cytoprotective genes. These varied techniques and technologies will be described and discussed covering cell-based and animal model-based studies. Data from clinical applications and linkage to human ocular diseases will also be discussed where relevant translational research has been reported.

A Retrospective Study: Is Low-Intensity Pulsed Ultrasound (LIPUS) an Effective Alternate Treatment Option for Non-union?

BackgroundThere is ongoing controversy regarding the use of low-intensity pulsed ultrasound (LIPUS) therapy in patients with delayed union or non-union. Exogen (Bioventus, Durham, NC) is a well-known brand of LIPUS, and according to their data, 86% of non-union fractures will heal without the need for surgery. A few independent retrospective studies reported much lower healing rates.MethodA retrospective observational study was performed assessing all the patients who underwent Exogen therapy in a single centre. All patients who were initiated on Exogen after three months with radiographic signs of the delayed union were included in the study. Routine follow-up appointments were organised until clinical and radiological healing could be confirmed. Daily 20-minute Exogen sessions were continued until the fracture was healed or up to a maximum of four months as recommended by the manufacturer.ResultsA total of 37 patients received Exogen therapy from 2012 to 2021, of which only 28 patients met our inclusion criteria and were subsequently analysed. The mean age of the patients was 52.0 (SD ± 20.2) with a male to female ratio of 1.7:1. The average time to healing was 115 (±51.2) days with a success rate of 82.14%. The average interfragmentary gap was 7.5 mm (±5.8) for the fractures that healed whereas the failed treatment was 16.1 mm (±13.8). There was no obvious association between outcomes after Exogen therapy and the patient’s age, sex, time to initiate Exogen, diabetes, and smoking status.ConclusionThis study demonstrated a high success rate of LIPUS therapy for patients with delayed union and non-union. LIPUS represents a safe, non-invasive alternative to revision surgery. An independent risk factor for a potentially poor outcome is an increased interfragmentary gap.

The Efficacy and Safety of Thrice vs Twice per Week Low-Intensity Pulsed Ultrasound Therapy for Erectile Dysfunction: A Randomized Clinical Trial

A recent sham-controlled clinical study has shown that low-intensity pulsed ultrasound twice per week can safely and effectively treat patients with mild-to-moderate erectile dysfunction (ED). However, large-scale clinical trials are needed to verify its efficacy and safety and determine a reasonable treatment interval. To study whether low-intensity pulsed ultrasound therapy thrice per week is non-inferior to twice per week in patients with mild-to-moderate ED. A randomized, open-label, parallel-group, non-inferiority clinical trial was conducted in 7 hospitals in China. A total of 323 patients with mild-to-moderate ED were randomized (1:1) into thrice per week (3/W) and twice per week (2/W) groups. Low-intensity pulsed ultrasound was applied on each side of the penis for 16 sessions. The primary outcome was response rate using the minimal clinically important difference in the International Index of Erectile Function (IIEF-EF) score at week 12. Secondary outcomes included Erection Hardness Score (EHS), Sexual Encounter Profile, Global Assessment Question, and Self Esteem and Relationship Questionnaire. Response rates in 3/W and 2/W groups were 62.0% and 62.5%, respectively. Treatment effect in the 3/W group was noninferior to that of the 2/W group, with rate difference lower bound of -0.01% [95% confidence interval -0.11 to 0.10%] within the acceptable margin (-14.0%). No significant difference was found among secondary outcomes. IIEF-EF score showed a significant increase from baseline in the 3/W group (16.8 to 20.7) and 2/W group (17.8 to 21.7), and the percentage of patients with EHS ≥3 increased in the 3/W (54.9% to 84.0%) and 2/W (59.5% to 83.5%) groups. There was no significant difference in response rate between the 2 groups after controlling for strata factors and homogeneous tests. No treatment-related adverse events were reported. Low-intensity pulsed ultrasound therapy displays similar efficacy and safety for mild-to-moderate ED when administered thrice or twice per week for 16 sessions. This study provides two options to suit patients' needs. This is a large-sample, randomized, controlled, noninferiority trial study. Short-term follow-up and mostly younger patients are the main limitations. Low-intensity pulsed ultrasound therapy thrice and twice per week showed equivalent therapeutic effects and safety for mild-to-moderate ED in a young and generally healthy population. This therapy warrants further investigation of its potential value in rehabilitation of ED.

Effect of low-intensity pulsed ultrasound on mast cell degranulation and fibroblast expression on type 2 diabetes mellitus rats wound healing process

Impaired wound healing is one of the Diabetes mellitus complications. Low-intensity Pulsed Ultrasound (LIPUS) therapy may accelerate the impaired wound healing. The use of LIPUS therapy in the early inflammatory phase can induce mast cell degranulation, and in the proliferative phase it can increase collagen synthesis by fibroblasts. The purpose of this study was to determine the effects of LIPUS therapy on mast cell degranulation and fibroblastexpression in the healing process of punch biopsy wound in rats with type 2 diabetes mellitus. Twenty-four Sprague dawley (n=24) were designed into type 2 diabetes mellitus by injecting Nicotinamide and Streptozotocin, then divided into six groups: diabetes mellitus without LIPUS (DM3, DM7, DM14) and diabetes mellitus with LIPUS (DML3, DML7, DML14), 4 each, and punch biopsy wounds were made on the dorsal skin. The DML group received LIPUS therapy in the wound area (frequency 3 MHz, intensity 0.5 W/cm2, duty cycle 20%, duration 3 minutes every day for 3 days (DML3), 7 days (DML7), and 14 days (DML14). The wounded tissue area was stained with toluidine blue to observe mast cell degranulation and immunohistochemical type HSP-47 to observe fibroblast expression. Two-Way ANOVA and Post Hoc LSD tests were used to determine the differences in mast cell degranulation and fibroblast expression. The results showed that mast cell degranulation and fibroblast expression in the DML group were higher than in the DM group (table 1). Pearson test showed a correlation between mast cell degranulation and fibroblast expression (p=0.00; r= 0.839). LIPUS therapy increases mast cell degranulation and fibroblast expression in type 2 diabetes mellitus rat model. The higher the mast cell degranulation, the higher fibroblast expressions.

Low-Intensity Pulsed Ultrasound in the Treatment of Nonunions and Fresh Fractures: A Case Series

It is estimated that approximately 5% to 10% of fractures will evolve into nonunions. Nonunions have a significant impact on patient quality of life and on socioeconomic costs. Low-intensity pulsed ultrasound (LIPUS) is a non-invasive therapy widely used within the orthopedic community to accelerate the healing of fresh fractures, to minimize delayed healing, and to promote healing of nonunions. In this case series, 46 nonunions and 19 fresh fractures were treated with LIPUS for at least three months or until fracture healing. Bone healing was assessed both at a radiological and a functional level. Of the nonunions healed, 89% had a mean healing time of 89 ± 53 days. In the group of fresh fractures, the healing percentage was 95% with a mean healing time of 46 ± 28 days. LIPUS treatment is proven to be safe and well tolerated; there were no adverse events related to the use of the device, even in the presence of internal fixations and infections. LIPUS therapy should be considered a low-risk option both as an adjunct to surgery or as a standalone therapy in the management of nonunion and fresh fractures.