Low-intensity pulsed ultrasound in obstetrics and gynecology: advances in clinical application and research progress.

Over recent decades, ultrasound has evolved from a diagnostic imaging modality to therapeutic applications, encompassing both high-intensity and low-intensity ultrasound ( 1 ). High-intensity focused ultrasound (HIFU) has gained widespread use in obstetrics and gynecology for treating various benign and malignant tumors, particularly uterine fibroids and adenomyosis. HIFU induces coagulation necrosis of target tissues without damaging the surrounding normal tissues in producing instantaneous high thermal effects and mechanical effects ( 2 ). In contrast, low-intensity pulsed ultrasound (LIPUS) affects cellular material metabolism processes, accelerates tissue metabolism, improves ischemia and hypoxia states, enhances tissue nutrition, and promotes tissue repair through minimal thermal effects and significant non-thermal effects in the target tissues ( 3 ). The non-thermal effects of LIPUS predominantly involve cavitation-induced micro-bubbles and microjets, acoustic flow, and mechanical stimulation that convert into biochemical signals within cells to produce biological effects ( 4 ). Tissue absorption of ultrasonic energy is essential for exerting biological effects, with different tissues exhibiting diverse absorption capacities for ultrasonic waves. Highly protein-rich and low-water content tissues absorb ultrasonic energy to a greater extent, with bone and cartilage exhibiting the highest energy absorption, followed by tendon, skin, muscle, nerve, fat, and blood ( 5 ). LIPUS is a type of medium-frequency ultrasound (0.7-3 MHz) that is pulsed in wave mode (100 and 1,000 Hz) and delivered at an intensity (<3 W/cm2) much lower than traditional ultrasound energy ( 6 ). Most piezoelectric transducers on the market are made of ceramic materials that can convert input electrical energy into mechanical energy (ultrasound waves). When the ultrasound beam is emitted from the therapeutic ultrasound device’s treatment head, the energy distribution in space within the beam is non-uniform ( 7 ). The ultrasound beam closest to the treatment head is called the near field, where the ultrasound energy is higher and varies significantly locally, making it more commonly used in LIPUS therapy applications. The length of the near field is influenced by the transducer radius, speed of sound in the medium, and frequency, which allows for changes in the size and shape of ultrasound transducers to meet the treatment needs of different parts ( 8 ). LIPUS is a safe, economical and convenient treatment modality that has been demonstrated to effectively promote healing of surgical incisions, fractures, tendon injuries, and nerve damage ( 4 ). The above applications reflect the LIPUS repair of nerves, blood vessels, muscles and other soft tissues and the control of inflammation, which is closely related to many gynecological diseases such as ovarian function decline, pelvic floor dysfunction, and incomplete uterine involution after delivery. In recent years, with the deepening of research on the effects of ultrasound in biology, LIPUS has gradually received widespread attention in the field of obstetrics and gynecology, indicating a broad application prospect ( Figure 1 ). Currently, there is no systematic review summarizing the research progress of LIPUS in the field of obstetrics and gynecology. Thus, this study systematically summarizes the application direction and research advancements of LIPUS in obstetrics and gynecology to promote further LIPUS-related research in these fields. The overview of LIPUS playing a therapeutic role in the field of obstetrics and gynecology.

Ultrasound is a kind of non-ionizing mechanical wave, which has fewer adverse effects than traditional medical or surgical treatment. On the one hand, the cavitation effect of LIPUS within the tumor causes the rapid generation and rupture of micro-bubbles, generating mechanical shock waves, free radicals, and apoptotic initiators that directly inhibit cancer cell growth ( 51 ). The exact reason why LIPUS suppresses cancer cell proliferation may be due to pathways such as promoting cell apoptosis, necrosis, lysis, or disrupting the cell cycle ( 52 , 53 ). On the other hand, current research focuses more on the combined use of LIPUS and other adjuvant therapies, which can play an important role in cancer treatment by enhancing the ability of anti-tumor drugs. Compared with normal cells, malignant cells are more sensitive to ultrasound irradiation due to their unique cell membrane properties. Therefore, ultrasound can selectively modify the membrane of diseased cells. The microjets produced by cavitation make the cancer cell membrane unstable, thereby increasing the uptake of drugs by cells, enhancing the effect of chemotherapy and targeted therapy, and minimizing the toxicity of drugs to nearby healthy cells ( 54 ). LIPUS plays an increasingly clear role in the treatment of cancer, and has also attracted great attention in gynecological cancer. Existing studies mainly focus on ovarian cancer and cervical cancer. Currently, the main adjuvant treatment for ovarian cancer is chemotherapy, using paclitaxel combined with platinum drugs is the first-line regimen. Traditional cancer chemotherapy has limitations such as drug resistance and drug side effects. The effectiveness of LIPUS combined with platinum to overcome chemoresistance has been demonstrated in platinum-resistant ovarian cancer cells by measuring cell viability, colony formation, and cell cycle analysis ( 55 ). The principle may be that LIPUS improves cell membrane permeability and intracellular drug concentration increases the therapeutic effect. Recent studies in a 3D model of cisplatin resistance in ovarian cancer have shown that nanoparticles can further increase the therapeutic effect of ultrasound against resistance ( 56 ). The mechanism of action of paclitaxel is mainly to target microtubules, so as to inhibit cell mitosis and play an anti-cancer role. Amaya et al. ( 57 ) found that ultrasonic shock wave treatment temporarily disrupted the microtubule cytoskeleton and abolished taxol-induced rigid microtubule bundles. Based on the fact that transient exposure to LIPUS can reduce and/or eliminate the cytotoxicity associated with paclitaxel treatment of ovarian cancer cells, a strategy can be developed to combat the side effects of taxol-based chemotherapy in cancer patients. Local use of LIPUS only at the desired site to eliminate cytotoxicity without affecting the effect of paclitaxel on cancer cell activity is expected to be used to prevent chemotreatment-induced alopecism and peripheral neuropathy and improve the quality of life of patients ( 58 ). In addition, the above purpose can also be achieved with the help of molecular materials. Phase-changeable, folate-targeted perfluoropentane nanodroplets loaded with 10- hydroxycamptothecin and superparamagnetic Fe 3 O 4 have been fabricated for multi-modality cancer imaging and targeted therapy. LIPUS-activated nanodroplets can improve the therapeutic effect on cancer cells and relatively reduce the side effects on normal tissues ( 59 ). LIPUS can potentially play a role in radiotherapy and chemotherapy of cervical cancer. Transient mechanical effects mediated by acoustic pores generated by LIPUS enhance membrane permeability and disband the cytoskeleton early after acoustic pores. Cervical cancer HeLa cells were arrested in different cycle stages, and changes in membrane permeability and cytoskeletal arrangement induced by acoustic pore technology were simultaneously analyzed using real-time fluorescence imaging systems. The research showed that S-phase may be considered as the optimal cell cycle for transient acoustic perforation to promote gene/drug delivery therapy ( 60 ). The combination of S-phase blocking drugs with LIPUS may increase the efficacy of chemotherapy in treating cervical cancer. In addition, LIPUS can also be used as a sensitizer for radiotherapy. In HeLa cell experiments, radiation at a dose of 2 Gy combined with ultrasound treatment at any intensity (0.5, 1.0, 1.5 W/cm2) resulted in a significant decrease in cell survival compared to incubation for 72 h after radiation alone ( 61 ). Therefore, it is reasonable to believe that the combination therapy of LIPUS can enhance the effect of radiotherapy for cervical cancer. However, it needs further verification in subsequent animal experiments and clinical trials.

LIPUS is a promising non-invasive method that can promote various tissue repair, inhibit inflammatory response, and change cell membrane permeability through mechanical, thermal and physical and chemical effects. LIPUS has valuable applications in reproductive medicine, perinatal medicine, postpartum recovery, gynecological cancer and other directions. Although there is still insufficient understanding of the biological and biodynamic effects of LIPUS in human tissues and their effects on organs and the whole body, the therapeutic results obtained so far in the preclinical stage are very promising. These results may trigger a new research boom in the clinical field in the next few years. The future goals include studying the biological effects and molecular mechanisms of LIPUS on tissues and cells, screening treatment parameters suitable for different tissues, organs, and diseases, clarifying the treatment standards for various diseases, and effectively translating animal and cellular level studies into clinical applications.

XJ conceived the study and edited the manuscript. HD, SW and YC edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.