Objective To evaluate the promoting effect of continuous low-intensity pulsed ultrasound(LIPUS)combined with microbubble(MB)cavitation therapy(hereinafter referred to as ultrasound cavitation therapy)on microcirculatory perfusion in the ischemic hindlimbs of mice,and to explore the non-invasive therapeutic potential of this treatment for limb arterial ischemic injury.Methods A mouse model of left hindlimb ischemia was established,and the mice were randomly assigned to 4 groups(16 mice per group)according to different treatment methods:model group,ultrasound contrast microbubble group(MB group),LIPUS treatment group(LIPUS group),and ultrasound cavitation therapy group(LIPUS+MB group).Mice in the model group were injected with 0.1 mL of normal saline via the tail vein,those in the MB group were injected with 0.1 mL of MB via the tail vein,those in the LIPUS group were treated with LIPUS on the ischemic hindlimb after injection of 0.1 mL of normal saline via the tail vein,and those in the LIPUS+MB group were treated with LIPUS on the ischemic hindlimb after injection of 0.1 mL of MB via the tail vein;each group was injected once a day for a total of 7 d.On the 1st,4th and 7th days after treatment,the microcirculatory perfusion in the ischemic hindlimbs of mice was evaluated using contrast-enhanced ultrasound.The effects of different treatments on promoting microcirculatory perfusion in the ischemic hindlimbs of mice were assessed by combining hematoxylin-eosin(H-E)staining and CD31 immunohistochemical staining of the gastrocnemius muscle tissue in the hindlimbs.Results The left hindlimb ischemia model was successfully constructed,and all model mice showed obvious ischemic microcirculation perfusion disorders with good model stability.After the 7th day of treatment,the LIPUS+MB group showed a increase in microcirculation perfusion in the ischemic hindlimb,with the ratio of microvascular flow on the ischemic to non-ischemic sides higher than that of the LIPUS group([94.33±4.51]%vs[70.33±2.09]%,P＜0.05).H-E staining results showed that the LIPUS+MB group had more newly formed capillaries and myofibroblasts in the gastrocnemius muscle,with better muscle structure repair compared to the LIPUS group,while the model group and MB group showed muscle cell necrosis,disorganized arrangement of muscle bundles,and sparse capillaries.CD31 immunohistochemical analysis further confirmed that ultrasonic cavitation therapy significantly outperformed traditional LIPUS treatment in promoting microcirculation perfusion,microvascular neogenesis,and tissue repair in ischemic skeletal muscles(CD31 relative expression level 5.03±0.33 vs 3.57±0.21,P＜0.01).Conclusion Compared with single LIPUS treatment,continuous ultrasound cavitation therapy has a more significant effect on promoting microcirculation perfusion in the ischemic hindlimb of mice,which provides a new strategy for microcirculatory perfusion disorders in skeletal muscles of limbs caused by peripheral arterial ischemic diseases.