30-day and lasting impacts on utilizing a novel orthotic insole for tactile stimulation in diabetic peripheral neuropathy: a double-blind, randomized, sham-controlled trial

30-day and lasting impacts on utilizing a novel orthotic insole for tactile stimulation in diabetic peripheral neuropathy: a double-blind, randomized, sham-controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 30-day and lasting impacts on utilizing a novel orthotic insole for tactile stimulation in diabetic peripheral neuropathy: a double-blind, randomized, sham-controlled trial Wachirayongyot Thimabut, Natapatchakrid Thimabut, Liang Peng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5306397/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Diabetic peripheral neuropathy (DPN) can lead to diabetic foot ulceration (DFU) and disabilities. DPN also increases vibration perception threshold (VPT) and decreases tactile sensitivity. Applying a vibrating insole is an efficient way to decrease VPT and improve tactile sensibility. Objective To investigate the continuing and lasting effects of applying a novel vibrating orthotic insole (VOI) combined with a newly designed stimulus (a random 0–100 Hz square wave pulse signal integrated with pseudorandom white noise via a stochastic resonance approach) for tactile stimulation in DPN. Methods A randomized sham-controlled trial with a parallel design and a double-blind strategy was conducted in this study. Sixty-four mild-to-moderate DPN were randomized by a computer-generated algorithm into two interventions: 1) using the VOI mixed with the newly designed stimulus; 2) using the VOI with only 100 Hz frequency vibration. Each intervention was done at home for sixty minutes a day over thirty days. VPT outcomes were assessed on the 1st, 15th, and 30th days. Following up on the remaining effects of employing the VOI combined with the newly designed stimulus was performed after completing Intervention 1 by evaluating VPT values every seven days. Results Intervention 1 could significantly reduce VPT and effectively enhance tactile sensation ( P <0.001). In contrast, Intervention 2 considerably increased VPT. Follow-up, VPT was steady at the end of Intervention 1 for the first week before progressively rising over a month; after that, it rose until it exceeded baseline, which took approximately two to three months. Conclusions Utilizing the VOI in conjunction with a random 0–100 Hz square wave pulse signal and pseudorandom white noise via a stochastic resonance approach could offer lowering VPT, maintaining decreased VPT, and improving tactile sensitivity. The VOI may benefit neurorehabilitation in DPN, e.g., preventing DFU and its recurrence, restoring/prolonging tactile sensation, slowing DPN deterioration, and avoiding lower extremity amputation. Trial registration Thai Clinical Trials Registry: TCTR20230601001 (ThaiClinicalTrials.org). Diabetes Noise Peripheral neuropathy Stochastic Resonance Tactile Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Diabetic peripheral neuropathy (DPN) can cause sensory anomalies, a rise in vibration perception threshold (VPT), diabetic foot ulceration (DFU), and lower extremity amputation (LEA) [ 1 , 2 ]. In type 2 diabetes mellitus (T2DM), VPT > 25V increases the incidence of DFU recurrence [ 3 ]. DFU can cause morbidity, enormous treatment expenses, and poor quality of life (QOL) in diabetics and their caretakers [ 4 – 6 ]. Tactile is essential for somatosensory and protective sensations in perceiving vibration, pressure, and tension [ 7 ]. Vibration perception (vibrotactile) is vital for cutaneous mechanoreceptors, especially Pacinian corpuscles [ 8 ]. Reduced vibrotactile leads to loss of protective sensation and extends risks of DFU [ 9 ]. Impaired vibrotactile is a precursor sign of DPN, which also increases VPT [ 10 ]. VPT is a critical measure for detecting vibrotactile and DPN [ 11 ]. High VPT indicates considerable DPN severity, vibrotactile loss, and risks of DFU and LEA [ 12 , 13 ]. VPT predicts DFU development [ 12 ], and every rise unit in VPT maximizes the opportunity of developing a first foot ulcer by 5·6% [ 13 ]. High VPT correlates with reduced sural nerve myelinated nerve fiber density, resulting in slower sural nerve conduction velocity and decreased amplitude, affecting tactile sensitivity [ 14 ]. Hence, enhancing VPT may be beneficial in preventing DFU and its recurrence. A vibrating insole is a novel medical gadget that can improve vibrotactile and VPT sensibility [ 15 ]. A noise-based technique and a stochastic resonance (SR) mechanism are applied to enhance tactile sensation [ 16 ]. Benefits of noise and SR in nervous system may increase information processing in a nonlinear system [ 17 ]. Adding noise and SR at subthreshold efficiently escalates threshold capacity [ 18 ]. When information is conveyed across chemical synapses, using noise and SR as a stimulus can help magnify it [ 19 ]. Evidently, electrical noise stimulation in conjunction with a mechanical stimulus at subthreshold could improve tactile and somatosensation [ 20 ]. Vibrotactile sensitivity was increased by ≥ 50 Hz frequency stimuli with noise, which was mediated via mechanoreceptors [ 21 ]. Threshold responses in mechanoreceptors might be heightened by a stimulus in square wave form [ 22 ]. SR in noise-exposed sensory neurons could help improve biological information processing in threshold system [ 23 – 25 ]. Regarding Pacinian corpuscles, repetitive sensory stimulation (RSS) might raise vibrotactile [ 26 – 29 ]. Microangiopathy in diabetic foot impairs peripheral nerve function, resulting in DPN and DFU [ 30 ]. Whole body vibration (WBV) could enhance skin blood flow and oxygenation in diabetes [ 31 ]; therefore, applying the WBV concept to vibrating stimulation on plantar surface may help recover microangiopathy. Therapeutic footwear is recommended to help prevent DFU [ 32 ]. Therapeutic footwear such as orthotic insoles benefits ulcer prevention and ulcer recurrence avoidance [ 33 ]. Total-contact footwear is utilized in DFU prevention and treatment [ 34 ]. Custom-made therapeutic footwear could minimize plantar pressure and callus formation [ 35 ]. Previous studies on adding 0–100 Hz low-level white noise to a stimulus signal for tactile stimulation demonstrated: vibrotactile could be regained using a custom-made vibrating insole [ 36 ]; employing a vibro-medical insole could improve vibrotactile [ 37 ]; a bandage shoe was effective in restoring vibrotactile [ 38 ]. Besides, a low-voltage stimulus delivered through a vibrating insole could stimulate vibrotactile [ 39 ]. Prior studies had mostly focused on a flat-design insole with noise and SR in stimulating tactile sensation; however, a total contact insole and a suitable design for diabetic foot are necessary. Even though previous research showed the acute positive effects of using a vibrating insole for stimulating tactile, the continuing and lasting effects of using a vibrating insole for tactile stimulation are unknown. In this current study, a vibrating orthotic insole (VOI) with a total contact design was newly developed based on orthotics, medical quality, and the purpose of a noninvasive and low-cost device. In contrast to prior research, a newly designed stimulus was generated by combining a random 0–100 Hz square wave pulse signal stimulus with pseudorandom white noise (PRWN) using a SR approach to stimulate tactile sensation via the VOI. The goal of this study was to investigate the continuing thirty-day effectiveness of using the VOI combined with the newly designed stimulus for tactile stimulation in people who have T2DM with mild-to-moderate DPN. After completing this intervention, observation on the remaining effects was also the aim of this study. In addition to the advantages of recovering DPN and DFU management, we anticipated that the findings of this study will be advantageous for medical device development and neurorehabilitation. Methods A. Novel Design of Vibrating Orthotic Insole (VOI) A VOI consists of two main components (Fig. 1 a): 1) a personalized foot orthosis (PFO) and 2) a vibration generator machine (VGM). A prosthetist and orthotist (PO) fabricated the PFO according to each person’s foot structure and pathology. The PFO was made of medical-grade materials, i.e., Plastazote® (a low-hardness material, shore-A 30) [ 40 ]; ethyl vinyl acetate: EVA (a high-hardness material, shore-A 50) [ 41 ]; and a PITEX reinforcement sheet (Fig. 1 b). The PFO was composed of three layers: 1) a bottom layer (0.8 mm PITEX reinforcement sheet); 2) a middle layer (5 mm EVA); and 3) a top layer (5 mm Plastazote®). The PFO’s medial arch support was made of EVA, and its height was determined by the personal foot structure. A total contact design of the PFO was identified by using foot casting with a partial weight-bearing method in the sitting posture [ 42 ]. In the middle layer of the PFO, a housing for attaching a vibratory actuator was situated on the regions of the 1st metatarsophalangeal joint (MTP), 5th MTP, and calcaneus/heel (Fig. 1 c). Every housing had a single vibratory actuator, which was attached to a coaxial wire and an RCA plug to receive a newly designed stimulus (the combination of a random 0–100 Hz square wave pulse stimulus and PRWN via a SR approach) from the VGM. RCA jacks installed on the VGM were used to receive the newly designed stimulus, which were then connected to RCA plugs fastened to vibratory actuators. Coaxial wires were linked between RCA plugs and vibratory actuators to transfer the newly designed stimulus with minimal losses (Fig. 1 d). The PFO component contains simply vibratory actuators; there is no power source or electric circuitry. The VGM was comprised of a random signal generator circuit (Fig. 1 e) and a PRWN generator circuit (Fig. 1 f). The random signal generator circuit generated a random signal (a random 0–100 Hz square wave pulse signal). This circuit was made up of two microcontrollers, AD9833 (Analog Devices Inc., USA) and Arduino Nano 3.0 (Arduino SA, Switzerland), to generate the random signal. The random signal was transformed into a novel stimulus (Fig. 1 g) for subthreshold stimulation by modifying them to 90% of each person’s VPT level. The PRWN generator circuit created PRWN (Fig. 1 h) based on a pseudorandom binary sequence (PRBS) and a linear-feedback shift register. In order to produce a continuous signal over sixty minutes for tactile stimulation, this circuit used an XOR gate-CD4030BM96 (Texas Instruments, USA) and a shift register-CD4015BM96 (Texas Instruments, USA) with a 31-bit pattern. A random sequence with over two billion bits in length was produced by a PRBS-31 algorithm. This random sequence lasted approximately seventy-two minutes with a 500 kHz clock frequency. The stimulus signals and PRWN were combined by using a SR approach (Fig. 1 i) to serve as a newly designed stimulus (Fig. 1 j). The newly designed stimulus was routed to a cut-off frequency of 100 Hz. Following that, a voltage buffer circuit assisted in maintaining the voltage level of the newly designed stimulus. Then, a signal driver circuit assisted to transmit the newly designed stimulus to a vibratory actuator (Fig. 1 k). A vibratory actuator (a DC micro vibratory disk motor with a 3 mm thickness and a 10 mm diameter, Vybronics Inc., USA) vibrated in response to the newly designed stimulus’ intensity. As vibratory actuators were embedded in the PFO, the whole PFO insole vibrated when the vibratory actuators vibrated. Consequently, the VOI performed vibration to stimulate tactile sensation throughout the entire sole of the foot. When utilizing the VOI, the PFO and VGM components were connected together using RCA plugs and jacks (Fig. 1 l). To operate the VOI, a power supply switch (Fig. 1 m), a random signal generator switch (Fig. 1 n), and a PRWN generator switch (Fig. 1 o) were activated. The intensity of the newly designed stimulus was displayed on a digital voltmeter screen (Fig. 1 p). Owing to the requirement of spending more than sixty minutes in the experiments of this study, household electrical current was converted to a power source of DC 24V for a major circuit and DC 5V for minor circuits in order to preserve the newly designed stimulus’ potency. A removable 3-pin plug was employed to connect the VGM and a household power source. The VGM was connected to a household power source using a detachable 3-pin plug (Fig. 1 q). To ensure safety and security, all of the VOI circuits were enclosed in a plastic waterproof box with closed sealing and electrical insulation (Fig. 1 r). Furthermore, the VOI was designed to be safe and secure with features, i.e., a fuse system, a residual-current circuit breaker, a grounding system, and the use of shield wires. The VOI was safe for use with patients and clinical trials. Electrical safety testing and risk management for medical devices were verified according to EN IEC 60601-1, ISO 14971, and the protocol for permission on medical devices by the Medical Device Control Division of the Food and Drug Administration of Thailand. B. Participants From the HRH Princess Maha Chakri Sirindhorn Medical Centre (Srinakharinwirot University), Ongkharak, Nakhon Nayok, Thailand, sixty-four sufferers from T2DM with mild-to-moderate peripheral neuropathy were recruited. The study protocol was approved by the Human Research Ethics Committee of Srinakharinwirot University (SWUEC-661032), and registered with the Thai Clinical Trials Registry (TCTR20230601001). Participants gave written informed consent before participating in this study. Inclusion criteria: 1) aged 18–80 years; 2) T2DM and DPN diagnosis; 3) absence of foot problems such as ulcers, calluses, skin problems, etc.; 4) no muscle weakness; 5) stability in neurological and vital signs; 6) adequate cognitive and language skills to follow instructions; 7) ability to sense vibration; 8) ability to sit for at least 60 minutes. Exclusion criteria: 1) musculoskeletal problem that makes it difficult to use the VOI, such as severe pain or joint contracture in any foot joints; 3) mental disorders; 4) hypersensitivity to material substances in the VOI. C. Study Design A randomized sham-controlled trial was investigated in this study. The experiments in this study were conducted in a parallel design with random allocation and a double-blind study (blinded participants and researchers). Participants were randomized into two interventions by a computer-generated algorithm. Intervention 1 was using the VOI with the newly designed stimulus for tactile stimulation. Intervention 2 was using the VOI without the newly designed stimulus (only vibration with 100 Hz frequency) for tactile stimulation. Each intervention was performed for thirty days. The PO was invited to distribute the interventions to participants by opening a concealed envelope and to assess a pretest/baseline and three posttests. Posttests were given in three consecutive appointments on the 1st, 15th, and 30th days. A physician was invited to care for the participants. At random points during the intervention periods, the PO or physician asked participants about vibration perception. Participants were required to notify the PO or physician as soon as they experienced vibration. Participants discontinued the intervention if they felt any vibrations. The intensity of tactile stimulation would be modified after reassessing the VPT level, and then the PO would resume the intervention with participants. In addition, if VPT changed after the 1st and 2nd posttests, the PO would adjust the intensity of the stimulation to 90% VPT. Notably, no participant reported a sense of vibration during the interventions. VPT values assessed at the 1st MTP and the 5th MTP were indicated as the outcomes. Participants who received Intervention 1 and had their doctors’ permission were voluntarily required to continue the follow-up VPT change after the experiments were completed. The follow-up would end when VPT exceeded baseline. In the follow-up, inspection of VPT would be evaluated every seven days after Intervention 1 terminated. The study diagram is depicted in Fig. 2 . D. Procedures Clinical assessment was assessed as baseline characteristics, i.e., muscle strength by the Medical Research Council manual muscle testing, sensation by the Semmes-Weinstein monofilament test (SWMT): a 5.07 gauge with 10-site testing, peripheral neuropathy by the Michigan neuropathy screening instrument (MNSI: MNSI-A, history; MNSI-B, physical assessment), vibration perception by a 128 Hz tuning fork (a graduated Rydel-Seiffer version), VPT values by the Vibratory Sensory Analyzer: VSA-3000 (Medoc Ltd., USA), body mass index (BMI), vital signs, and diabetic foot abnormalities. Prior to participating in the study, participants were requested to refrain from taking any medications that influence neurological system maintenance, but they continued to take their regular diabetes prescriptions. A researcher trained participants and their caregivers on how to use the VOI before bringing them back home to conduct the interventions. During the interventions, participants sat comfortably with a backrest chair and placed their bare feet on the VOI (Fig. 3 a). Velcro straps or sandal shoes were applied to keep their feet from sliding off during the interventions. If participants wore sandals, the shoe size had to be larger than the PFO (Fig. 3 b). The PO and physician used a video call application to monitor them during conducting the interventions. They received the interventions for 60 minutes a day in leisure time at home, with the exception of visits to the experimental location on the 1st, 15th, and 30th days to administer the interventions and posttest assessments by the PO. The VPT value assessment was performed by the VSA-3000. In the assessment, participants placed their feet on the VSA-3000 pedestal and laid the 1st and 5th MTP on the tip of the VSA-3000 stylus without pressing. The stylus would raise vibration from zero to a level perceived by participants. When participants detected the vibration, they immediately pressed the stop mouse to halt the vibrating stylus. Then a VPT value was obtained, and the assessment was repeated five times to determine an average VPT value (Fig. 3 c). The VPT outcome at the calcaneal area was excluded from the assessment because participants weighted their heels against the VSA-3000, resulting in an inaccurate VPT value. After completing 30-day intervention, the PO followed up the intervention 1 group. The intervention 1 group had to continue to abstain from taking neurological drugs throughout the follow-up period. E. Sample Size Calculation 0.9 power, a 2-sided significance level of 0.05, 20% dropout, and based on the data from the previous study [ 38 ] were used to calculate the sample size. 64 participants were required for this study. F. Statistical Analysis The means of both intervention outcomes were compared using an independent sample t -test. A paired sample t -test was performed to compare the means of the two interventions in the pre- and post-tests. Qualitative data were analyzed by a chi-square. The Shapiro-Wilk test was used to consider data’s normal distribution. Levene’s test was used to observe data’s homogeneity and variances. Comparisons between groups were conducted by a repeated-measures ANCOVA. Comparisons within group were analyzed by the paired samples t -test and a repeated-measures ANOVA. Analysis with the elimination of the covariates’ effect on the relationship between the independent grouping variables and the continuous dependent variables by a MANCOVA. The findings’ effect sizes were determined using Cohen’s d, and Cohen’s d values ( d ) were classified as small (0.0–0.20), medium (0.21–0.50), or large (0.51–0.8) effect sizes [ 43 ]. Statistical analysis was performed utilizing IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY), with a two-tailed significance level of P < 0.05. Results The study was completed by 55 participants, and demographic data are shown in Table 1 . In the group of Intervention 1, 5 participants were excluded from the study due to infection with COVID-19 (3 participants), having a car accident (1 participant), and moving to live in other provinces (1 participant). In the group of Intervention 2, 4 participants were excluded from the study because of infection with COVID-19 (3 participants) and having an appendectomy (1 participant). After completing Intervention 1, 18 participants proceeded to follow up, whereas 9 participants were eliminated because they were uninterested in the follow-up (1 participant) or lacked physician consent (8 participants). No adverse events occurred during or after the study. The chi-square test found that these two intervention groups were not different in age, gender, disease severity condition, weight, height, BMI, MNSI-A, MNSI-B, and SWMT. The Shapiro-Wilk test revealed that both intervention groups had normal data distributions. The Levene’s test demonstrated that both intervention groups had equal variance and homogeneity. The MANCOVA test was conducted using a set of outcome parameters, including the VPT values of the 1st and 5th MTP of both feet in the posttest on the 1st, 15th, and 30th days as dependent variables, the two interventions as fixed factors, and covariates (i.e., age, gender, disease duration, weight, height, BMI, MNSI-A, MNSI-B, and SWMT). The results showed that disease duration and MNSI-A were the two significant covariables. Thus, disease duration and MNSI-A were controlled for a covariance analysis when compared between groups. Table 1 Demographics of study population Intervention 1 ( n = 27) Intervention 2 ( n = 28) Age, years; mean (SD); range 57.70 (9.65); 38–72 56.93 (10.65); 38–72 Gender, n (%) Male Female 13 (48.1) 14 (51.9) 15 (53.6) 13 (46.4) Condition of DPN, n (%) Mild Moderate 14 (51.9) 13 (48.1) 14 (50.0) 14 (50.0) Duration of DPN, months; median (range) 47.59 (22–78) 51.29 (26–8) Weight, kg; mean (SD) 78.56 (8.42) 75.76 (8.24) Height, cm; mean (SD) 163.31 (8.98) 164.69 (7.50) BMI, kg/m 2 ; mean (SD) 29.42 (1.51) 27.88 (1.58) MNSI-A, scores; mean (SD) 8.15 (0.86) 8.07 (0.94) MNSI-B, scores; mean (SD) 7.07 (0.27) 7.07 (0.26) SWMT, sites; mean (SD) 6.0 (1.18) 5.93 (1.18) Intervention 1: using the VOI with the combination of a random 0–100 Hz square wave pulse signal with PRWN via a SR approach for tactile stimulation Intervention 2: using the VOI with only vibration with 100 Hz frequency for tactile stimulation VOI: vibrating orthotic insole, PRWN: pseudorandom white noise, SR: stochastic resonance SD: standard deviation, DPN: diabetic peripheral neuropathy, BMI: body mass index, SWMT: Semmes-Weinstein monofilament test (a 10-site test) MNSI: Michigan neuropathy screening instrument; MNSI-A (history) has a total possible score of 13 points, with a score of 7 deemed abnormal; MNSI-B (physical assessment) has a total possible score of 10 points, with a score of 2.5 considered abnormal. At least one of the MNSI assessments (MNSI-A or MSNI-B) was abnormal for each participant. In within-group comparisons, there was no significant difference in the baseline/pretest of the VPT values between both intervention groups. At each pair time point, both groups’ VPT values decreased significantly when compared to the baseline/pretest. In the group of Intervention 1, the VPT values of the posttest at the left 1st MTP on the 1st, 15th, and 30th days were significantly decreased from the baseline by 19.45% ( P < 0.001, a medium effect size), 20.9% ( P < 0.001, a medium effect size), and 22.72% ( P < 0.001, a medium effect size), respectively; the VPT values of the posttest at the left 5th MTP on the 1st, 15th, and 30th days were significantly reduced from the baseline by 20.02% ( P < 0.001, a medium effect size), 22.5% ( P < 0.001, a medium effect size), and 24.6% ( P < 0.001, a large effect size), respectively; the VPT values of the posttest at the right 1st MTP on the 1st, 15th, and 30th days were significantly declined from the baseline by 19.73% ( P < 0.001, a medium effect size), 21.08% ( P < 0.001, a medium effect size), and 22.98% ( P < 0.001, a medium effect size), respectively; the VPT values of the posttest at the right 5th MTP on the 1st, 15th, and 30th days were significantly diminished from the baseline by 20.96% ( P < 0.001, a medium effect size), 22.64% ( P < 0.001, a medium effect size), and 25.05% ( P < 0.001, a large effect size), respectively. In the group of Intervention 2, the VPT values of the posttest at the left 1st MTP did not change on the 1st day ( P = 0.688, a small effect size) and significantly increased from the baseline by 5.63% ( P < 0.001, a small effect size) and 11.21% ( P < 0.001, a medium effect size), respectively, on the 15th and 30th days; the VPT values of the posttest at the left 5th MTP on the 1st, 15th, and 30th days were significantly raised from the baseline by 0.56% ( P = 0.003, a small effect size), 5.31% ( P < 0.001, a small effect size), and 12.01% ( P < 0.001, a medium effect size), respectively; the VPT values of the posttest at the right 1st MTP did not change on the 1st day ( P = 0.247, a small effect size) and were significantly intensified from the baseline by 3.07% ( P < 0.001, a small effect size), and 7.35% ( P < 0.001, a small effect size), respectively, on the 15th and 30th days; the VPT values of the posttest at the right 5th MTP on the 1st, 15th, and 30th days were significantly rose from the baseline by 0·33% ( P = 0.014, a small effect size), 5.28% ( P < 0.001, a small effect size), and 11.46% ( P < 0.001, a medium effect size), respectively. Comparisons between both intervention groups revealed that the group of Intervention 1 had the decreased VPT values, whereas the group of Intervention 2 seemed to increase the VPT values. On the 1st day: at the left 1st MTP revealed that the group of Intervention 1 had the lessened VPT values, by contrast, the group of Intervention 2 had the heightened VPT values; at the left 5th MTP represented that the group of Intervention 1 had the reduced VPT values, while the group of Intervention 2 had the aggravated VPT values; at the right 1st MTP displayed the group of Intervention 1 had the lowered VPT values, whereas the group of Intervention 2 had the increased VPT values; at right the 5th MTP presented that the group of Intervention 1 had the abated VPT values, meanwhile, the group of Intervention 2 had the rose VPT values. On the 15th day: at the left 1st MTP demonstrated that the group of Intervention 1 had the decreased VPT values, while the group of Intervention 2 had the raised VPT values; at the left 5th MTP showed that the group of Intervention 1 had the declined VPT values, whereas the group of Intervention 2 had the rose VPT values; at the right 1st MTP demonstrated that the group of Intervention 1 had the lessened VPT values, but the group of Intervention 2 had the raised VPT values; at the right 5th MTP revealed that the group of Intervention 1 had the subsided VPT values, by contrast, the group of Intervention 2 had the increased VPT values. On the 30th day: at the left 1st MTP represented that the group of Intervention 1 had the lowered VPT values, while the group of Intervention 2 had the higher VPT values; at the left 5th MTP presented that the group of Intervention 1 had the lessened VPT values, by contrast, the group of Intervention 2 had the heightened VPT values; at the right 1st MTP demonstrated that the group of Intervention 1 had the reduced VPT values, whereas the group of Intervention 2 had the increased VPT values; and at the right 5th MTP showed that the group of Intervention 1 had the decreased VPT values, meanwhile, the group of Intervention 2 had the raised VPT values. Comparisons of VPT outcomes of both interventions are represented in Table 2 . Table 2 Comparisons of VPT outcomes when using Intervention 1 and Intervention 2 Within Group Comparison Between Groups Comparison Intervention 1 ( n = 27) Intervention 2 ( n = 28) VPT (volts) Mean (SD) Mean Difference (SD) P * 95% CI d Mean (SD) Mean Difference (SD) P * 95% CI d Mean difference P † 95% CI d Left 1st MTP Baseline 21.39 (10.88) 24.71 (12.60) -3.32 0.301 -9.70, 3.05 -0.26 1st day 17.23 (11.00) 4.16 (1.28) < 0.001 ‡ 3.65, 4.66 0.38 24.71 (12.60) 0.0 (0.02) 0.688 -0.01, 0.01 0 -7.48 0.023 ‡ -13.88, -1.07 -0.59 15th day 16.92 (10.87) 4.47 (1.30) < 0.001 ‡ 3.96, 4.98 0.41 26.10 (12.65) -1.39 (0.53) < 0.001 ‡ -1.59, -1.18 -0.11 -9.18 0.006 ‡ -15.57, -2.79 -0.73 30th day 16.53 (10.74) 4.86 (1.39) < 0.001 ‡ 4.31, 5.41 0.45 27.48 (12.60) -2.77 (0.74) < 0.001 ‡ -3.05, -2.48 -0.22 -10.95 0.001 ‡ -17.30, -4.61 -0.87 5th MTP Baseline 23.33 (10.91) 26.72 (12.18) -3.39 0.282 -9.65, 2.87 -0.28 1st day 18.66 (11.32) 4.67 (1.39) < 0.001 ‡ 4.12, 5.22 0.43 26.87 (12.18) -0.15 (0.25) 0.003 ‡ -0.25, -0.06 -0.01 -8.21 0.012 ‡ -14.58, -1.85 -0.67 15th day 18.08 (11.06) 5.25 (1.37) < 0.001 ‡ 4.70, 5.79 0.48 28.14 (12.13) -1.42 (0.31) < 0.001 ‡ -1.54, -1.30 -0.12 -10.06 0.002 ‡ -16.34, -3.77 -0.83 30th day 17.59 (10.95) 5.74 (1.47) < 0.001 ‡ 5.15, 6.32 0.53 29.93 (12.39) -3.21 (0.50) < 0.001 ‡ -3.41, -3.02 -0.26 -12.34 < 0.001 ‡ -18.66, -6.02 -1.0 Right 1st MTP Baseline 23.06 (11.33) 25.71 (12.15) -2.65 0.408 -9.00, 3.72 -0.22 1st day 18.51 (11.50) 4.55 (1.31) < 0.001 ‡ 4.03, 5.07 0.40 25.72 (12.15) -0.01 (0.03) 0.247 -0.02, 0.01 -0.001 -7.21 0.028 ‡ -13.61, -0.81 -0.59 15th day 18.20 (11.39) 4.86 (1.33) < 0.001 ‡ 4.33, 5.39 0.43 26.50 (12.20) -0.79 (0.29) < 0.001 ‡ -0.90, -0.68 -0.07 -8.30 0.012 ‡ -14.69, -1.91 -0.68 30th day 17.76 (11.27) 5.30 (1.43) < 0.001 ‡ 4.74, 5.87 0.47 27.60 (12.44) -1.89 (0.57) < 0.001 ‡ -2.11, -1.67 -0.16 -9.84 0.003 ‡ -16.27, -3.41 -0.79 5th MTP Baseline 25.71 (11.64) 26.88 (12.32) -1.17 0.718 -7.66, 5.31 -0.09 1st day 20.32 (12.06) 5.39 (1.48) < 0.001 ‡ 4.80, 5.98 0.46 26.97 (12.29) -0.09 (0.18) 0.014 ‡ -0.16, -0.02 -0.007 -6.65 0.048 ‡ -13.24, -0.06 -0.54 15th day 19.89 (11.97) 5.82 (1.52) < 0.001 ‡ 5.21, 6.42 0.50 28.30 (12.40) -1.42 (0.36) < 0.001 ‡ -1.56, -1.28 -0.12 -8.41 0.013 ‡ -15.00, -1.81 -0.68 30th day 19.27 (11.86) 6.44 (1.59) < 0.001 ‡ 5.81, 7.07 0.55 29.96 (12.72) -3.08 (0.72) < 0.001 ‡ -3.36, -2.80 -0.25 -10.69 0.002 ‡ -17.35, -4.04 -0.84 Intervention 1: using the VOI with the combination of a random 0–100 Hz square wave pulse signal with PRWN via a SR approach for tactile stimulation Intervention 2: using the VOI with only vibration with 100 Hz frequency for tactile stimulation VOI: vibrating orthotic insole, PRWN: pseudorandom white noise, SR: stochastic resonance VPT: vibration perception threshold, SD: standard deviation, CI: confidence interval, MTP: metatarsophalangeal joint * Paired t -test, † Analysis of covariance, ‡ Significant at P < 0.05 The observation on remaining effectiveness after completing Intervention 1 in 14 mild DPN participants and 4 moderate DPN participants found: approximately 12 weeks were the maximum periods; approximately 9 weeks were the minimum periods; and the mean of the remaining effectiveness was 10.5 ± 1.04 weeks. A line chart depicting VPT values of the 18 follow-up participants is demonstrated in Fig. 4 . Discussion The findings demonstrated that utilizing Intervention 1 could effectively improve tactile sensibility in mild-to-moderate DPN and help reduce VPT from baseline by 21.89% on average. Applying the VOI might result in a medium effect size for tactile stimulation. In posttests, VPT was highly reduced from baseline on the 1st day (range 2.07V–8.32V, 7.68–46.14%); on the 15th day VPT was slowly lower from the 1st day posttest, ranging from 0.07V to 0.92V, 0.66–7.49%; and on the 30th day VPT was gradually decreased from the 15th day posttest (range 0.08V–1.34V, 0.84–12.86%). These findings indicated that VPT was reduced most during the initial stages of tactile stimulation and thereafter gradually declined. It seems VPT may be ploddingly decreased to one point and then steady, but investigation over thirty days is required to confirm. Following up revealed that VPT in seven days after completing Intervention 1 remained the same as in the 30th day posttest. Then, VPT slowly rose over around thirty days. Following that, VPT increased more rapidly than the previous periods until the VPT values exceeded the baseline, which took approximately two to three months. DPN conditions may have an impact on the remaining effects of Intervention 1; hence, it is necessary to investigate the effectiveness of Intervention 1 for stimulating tactile in various DPN conditions. The remaining effects of Intervention 1 may be influenced by other factors, e.g., participant self-care, nutrition, rest, exercise, drinking and smoking habits, etc. DPN is also a progressive illness that can raise VPT all the time, which might affect the remaining effects of Intervention 1. Therefore, continuing to use the VOI with the combination of a random 0–100 Hz square wave pulse signal and PRWN via a SR approach for tactile stimulation is recommended in order to maintain the lowered VPT values and prolong tactile sensitivity improvement. The results of using the VOI with only 100 Hz frequency vibration revealed that VPT was significantly increased. A small effect size from using this intervention might relate to increased VPT and DPN progression, and further investigation is required. Orthotic and total contact designs of the VOI may provide tactile simulation across the entire plantar surface. Fabricating the VOI from foam materials might perform more effective stimulation throughout the insoles than viscous materials such as gel insoles. Manufacturing the VOI with medical-grade materials may contribute to appropriate therapeutic footwear for diabetic foot and provide benefits as noted in prior research [ 32 , 33 ]. Based on total contact and individual-tailored insole ideas [ 34 , 35 ], the PFO might help prevent DFU, calluses, and LEA. Stimulating tactile at 90% VPT by the combination of a random 0–100 Hz square wave pulse stimulus and PRWN via a SR approach could significantly improve tactile sensation, similar to mixing a stimulus signal with white noise (0–100 Hz bandwidth) by a SR technique [ 36 – 39 ]. Adding PRWN to a random 0–100 Hz square wave pulse stimulus might magnify its potential for stimulating tactile. This newly designed stimulus using a SR method may aid in the optimization of information transmission and nerve cell responses at chemical synapses, as well as the enhancement of cutaneous mechanoreceptors and thresholds [ 17 , 18 , 21 , 23 ]. PRWN could help amplify the intensity of a stimulus in tactile stimulation at subthreshold while also utilizing noise [ 23 – 25 ]. Based on RSS [ 26 – 29 ], a novel design for tactile stimulation via the VOI may enhance Pacinian corpuscles and mechanoreceptor, corticomuscular, and somatosensory capacities. Lowering VPT using the VOI might increase conduction velocity and amplitude of sural nerve [ 14 ]. According to WBV [ 31 ], employing the VOI may not only increase tactile sensitivity but also lessen the issues of skin blood flow and oxygenation. The effectiveness of using the VOI might benefit the prevention of DFU and LEA. Utilizing the VOI may help reduce the risk of DFU by 2.9% and 19.8% compared to VPT 25V, respectively [ 12 ]. According to a previous study [ 13 ], each lowered 1V VPT by the VOI may decrease the 1st DFU occurrence by 5.6%. Considering VPT > 25V [ 3 ], applying the VOI may help minimize the chance of DFU recurrence. The VOI may help mitigate negative impacts from DFU, i.e., morbidity, treatment costs, and low QOL among DFU sufferers and their caregivers [ 4 – 6 ]. However, these presumptions of the advantages of using the VOI are still required further investigation. Despite lack of the continuing effects of employing a vibrating insole for tactile stimulation, there are certain aspects about the acute impacts from previous studies that can be compared to the findings of this study. A continuous 60-minute stimulation via a vibrating insole in twenty type 1 and 2 diabetics with moderate-to-severe neuropathy could decline VPT at right big toe by 11.91% (31.9 ± 13.0V vs. 28.1 ± 11.0, P = 0.031) [ 36 ]. Utilizing the VOI for tactile stimulation could lower VPT at the right 1st MPT on the 1st day by 19.73% (23.06V vs. 18.51V, P < 0.001) in T2DM patients with mild-to-moderate DPN. The VOI appears to be more effective in reducing VPT, but further investigation is needed to evaluate the results of employing the VOI in severe DPN to a previous study [ 36 ]. Evaluating by a 256 Hz tuning fork ( P < 0.05) found that vibrotactile at both big toes was improved after employing 30-minute walking vibro-medical insoles in twenty mild-to-moderate DPN patients, but there was no vibrotactile improvement when evaluated by a 128 Hz tuning fork ( P > 0.05) [ 37 ]. The current investigation may imply that using the VOI with 60-minute static stimulation could enhance vibrotactile as clinical assessment by a 128 Hz graduated Rydel-Seiffer tuning fork ( P < 0.05), contrary to the previous study [ 37 ]. Nevertheless, vibrotactile assessment by 128 Hz and 256 Hz tuning forks is required to clarify the assumption of the current study. Comparisons of the results of using a bandage shoe between actuator-off and actuator-on showed that the median VPT values were decreased by 10.34% (43.5V vs. 39.3V, P < 0.001, the left 1st MTP), 10.07% (41.7V vs. 37.5V, P < 0.001, the left 5th MTP), 8.45% (42.6V vs. 39.0V, P < 0.001, the right 1st MTP), and 15.44% (40.8V vs. 34.5V, P < 0.001, the right 5th MTP) [ 38 ]. While the difference between utilizing the VOI with and without the newly designed stimulus on the 1st day demonstrated that the mean VPT values were reduced by 19.45% (21.39V vs. 17.23V, P < 0.001, the left 1st MTP), 20.02% (23.33V vs. 18.66V, P < 0.001, the left 5th MTP), 19.73% (23.06V vs. 18.51V, P < 0.001, the right 1st MTP), and 20.96% (25.71V vs. 20.32V, P < 0.001, the right 5th MTP). It appears that employing the VOI could stimulate tactile sensation more effectively than a bandage shoe. VPT at the left big toe could be decreased by 20.83% (24 ± 11V vs. 19 ± 10V, P < 0.0001) when stimulating tactile by 0–1,000 arbitrary vibration with low level mechanical noise and SR in twenty type 1 and 2 diabetics with moderate-to-severe peripheral neuropathy [ 39 ]. The current study found that a 19.45% reduction in VPT at the left 1st MTP on the 1st day (21.39 ± 2.09V vs. 17.23 ± 2.12V, P < 0.0001), similar to the finding of the prior study [ 39 ]. However, the stimulation duration of the previous study was not specified. The VOI can provide a noninvasive intervention, but safety validation is required before contributions. Moreover, ergonomic assessment is also required. The VGM consisted of low-cost components, but the PFO was composed of expensive materials because of their medical quality. If the PFO could be fabricated with inexpensive medical-grade materials, the VOI would be able to realize its goal of providing an affordable device. Generally, vibratory frequency will be indicated by the factory’s motor rotation setting; thus, the final vibratory frequency might vary from the input frequency. Participants might not experience vibration during the thirty-day interventions due to the factory-setting rotation. Hence, the vibratory actuator’s maximum frequency is required to be tested. It is possible that if the vibratory actuator executes the final vibratory frequency at the same level as the input, VPT improvements may be greater than those found in the present study. Although a three-layer design of the PFO may help avoid heat during vibrating actuator operation, heat prevention assessment is still necessary. The next VOI design requires modifications for dynamic activities, i.e., walking, running, and climbing stairs, as well as a wireless design. The future VOI design also requires long-lasting batteries and portables. Significantly, the VOI may contribute to neurorehabilitation, foot ulcers and their recurrence prevention, and disability avoidance; however, further investigations on the effectiveness of utilizing the VOI for preventing DFU and its recurrence are required. Applying the VOI in the early stages of DPN is suggested. Employing the VOI along with regular DPN treatment is recommended for enhancing, restoring, and prolonging tactile sensation. Conclusion Using the combination of a random 0–100 Hz square wave pulse signal and PRWN by a SR approach via the VOI could effectively improve tactile sensitivity in mild-to-moderate DPN. The continuing effects of utilizing the VOI for tactile stimulation revealed VPT values were highly reduced during the initial stage of the intervention and then gradually decreased. In the follow-up, VPT values remained constant at the end of the intervention on the first week and gradually increased over approximately four weeks. After that, VPT values increased at a faster rate until they exceeded baseline, which took around eight to twelve weeks. Based on orthotics, custom-made, total contact, and medical quality, the VOI may offer tactile stimulation over the entire plantar surface and be suitable for diabetic foot. In addition, the VOI could offer a noninvasive intervention for tactile stimulation. Significantly, applying the VOI may benefit neurorehabilitation, DFU management, and disability prevention in DPN. Declarations Ethics approval and consent to participate The Human Research Ethics Committee of Srinakharinwirot University approved the protocol of this study. The approval protocol code is SWUEC-661032. All participants provided written informed consent prior to participation in this study. Consent for publication Not applicable. Availability of data and materials Considerable data are provided within the manuscript. Supplementary data may be available upon reasonable request. Competing interests All authors declare no competing interests. Funding Not applicable. Authors’ contributions W.T. conceived the research project, conceptualized the study, designed the study, developed the device, designed the experiments, designed the data collection, analyzed the results, interpreted the findings, and drafted the manuscript. N.T. helped design the clinical trials and data collection, processed the request for ethics approval and clinical trial registry, recruited participants, conducted clinical trials, supported facilities for data collection, performed the statistical analysis, and was responsible for data management. P.L. performed co-supervision, made substantive revisions, and provided support in every process. Z.G.H. performed supervision, made substantive revisions, and provided support in every process. All authors accessed and verified the underlying data reported in the manuscript. All authors critically reviewed and contributed to the final draft of the manuscript. All authors approved the final version of the manuscript and had final responsibility for the decision to submit for publication. References Iqbal Z, Azmi S, Yadav R, et al. Diabetic peripheral neuropathy: epidemiology, diagnosis, and pharmacotherapy. Clin Ther. 2018;40:828-49. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. Diabetic neuropathic foot ulcers and amputation. Wound Repair Regen. 2005;13:230-36. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376:2367-75. Meijer JW, Trip J, Jaegers SM, et al. Quality of life in patients with diabetic foot ulcers. Disabil Rehabil. 2001;23:336-40. Rinkel WD, Luiten J, van Dongen J, et al. In-hospital costs of diabetic foot disease treated by a multidisciplinary foot team. Diabetes Res Clin Pract. 2017;132:68-78. Nabuurs-Franssen MH, Huijberts MSP, Kruseman ACN, Willems J, Schaper NC. Health-related quality of life of diabetic foot ulcer patients and their caregivers. Diabetologia. 2005;48:1906-10. McGlone F, Reilly D. The cutaneous sensory system. Neurosci Biobehav Rev. 2010;34:148-59. Bell J, Bolanowski S, Holmes MH. The structure and function of Pacinian corpuscles: a review. Prog Neurobiol. 1994;42:79-128. Kars HJJC, Hijmans JM, Geertzen JHB, Zijlstra W. The effect of reduced somatosensation on standing balance: a systematic review. J Diabetes Sci Technol. 2009:3:931-43. van Deursen RW, Sanchez MM, Derr JA, Becker MB, Ulbrecht JS, Cavanagh PR. Vibration perception threshold testing in patients with diabetic neuropathy: ceiling effects and reliability. Diabet Med. 2001;18:469-75. Domínguez-Muñoz FJ, Adsuar JC, Villafaina S, et al. Test-retest reliability of vibration perception threshold test in people with type 2 diabetes mellitus. Int J Environ Res Public Health. 2020;17:1773. Young MJ, Breddy JL, Veves A, Boulton AJ. The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study. Diabetes Care. 1994;17:557-60. Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care. 1998;21:1071-75. Sundkvist G, Dahlin LB, Nilsson H, et al. Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance. Diabet Med. 2000;17:259-68. Hijmans JM, Geertzen JHB, Zijlstra W, Hof AL, Postema K. Effects of vibrating insoles on standing balance in diabetic neuropathy. J Rehabil Res Dev. 2008;45:1441-49. Collins JJ, Imhoff TT, Grigg P. Noise-enhanced tactile sensation. Nature. 2008;383:770. McDonnell MD, Ward LM. The benefits of noise in neural systems: bridging theory and experiment. Nat Rev Neurosci. 2011;12:415-26. Faisal AA, Selen LPJ, Wolpert DM. Noise in the nervous system. Nat Rev Neurosci. 2008;9:292-303. Li X, Wang J, Hu W. Effects of chemical synapses on the enhancement of signal propagation in coupled neurons near the canard regime. Phys Rev E Stat Nonlin Soft Matter Phys. 2007;76:041902. Breen PP, ÓLaighin G, McIntosh C, Dinneen SF, Quinlan LR, Serrador JM. A new paradigm of electrical stimulation to enhance sensory neural function. Med Eng Phys. 2014;36:1088-91. Wells C, Ward LM, Chua R, Inglis JT. Touch noise increases vibrotactile sensitivity in old and young. Psychol Sci. 2005;4:313-20. Cain DM, Khasabov SG, Simone DA. Response properties of mechanoreceptors and nociceptors in mouse glabrous skin: an in vivo study. J Neurophysiol. 2001;85:1561-74. Hänggi P. Stochastic resonance in biology. How noise can enhance detection of weak signals and help improve biological information processing. Chemphyschem. 2002;3:285-90. McDonnell MD, Abbott D. What is stochastic resonance? Definitions, misconceptions, debates, and its relevance to biology. PLoS Comput Biol. 2009;5:e1000348. Moss F, Ward LM, Sannita WG. Stochastic resonance and sensory information processing: a tutorial and review of application. Clin Neurophysiol. 2004;115:267-81. Ennion L, Hijmans J. Improving vibration perception in a patient with type 2 diabetes and sensory peripheral neuropathy. S Afr J Physiother.2019;75:602. Pleger B, Foerster AF, Ragert P, et al. Functional imaging of perceptual learning in human primary and secondary somatosensory cortex. Neuron. 2003;40:643-53. Sathian K, Deshpande G, Stilla R. Neural changes with tactile learning reflect decision-level reweighting of perceptual readout. J Neurosci. 2013;33:5387-98. Trenado C, Mendez-Balbuena I, Manjarrez E, et al. Enhanced corticomuscular coherence by external stochastic noise. Front Hum Neurosci. 2014;8:325. Ergul A. Endothelin-1 and diabetic complications: focus on the vasculature. Pharm Res. 2011;63:477-82. Johnson PK, Feland JB, Johnson AW, Mack GW, Mitchell UH. Effect of whole body vibration on skin blood flow and nitric oxide production. J Diabetes Sci Technol. 2014;8:889-94. Bus SA, Lavery LA, Monteiro-Soares M, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36:e3269. Bus SA, van Deursen RW, Armstrong DG, et al. Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review. Diabetes Metab Res Rev. 2016;32:99-118. Bus SA, Valk GD, van Deursen RW, et al. The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review. Diabetes Metab Res Rev. 2008;24:S162-80. van Netten JJ, Sacco ICN, Lavery LA, et al. Treatment of modifiable risk factors for foot ulceration in persons with diabetes: a systematic review. Diabetes Metab Res Rev . 2020;36:e3271. Cloutier R, Horr S, Niemi JB, et al. Prolonged mechanical noise restores tactile sense in diabetic neuropathic patients. Int J Low Extrem Wounds. 2009;8:6-10. Cham MB, Mohseni-Bandpei MA, Bahramizadeh M, Kalbasi S, Biglarian A. The effects of Vibro-medical insole on vibrotactile sensation in diabetic patients with mild-to-moderate peripheral neuropathy. Neurol Sci. 2018;39:1079-84. Zwaferink JBJ, Hijmans JM, Schrijver CM, Schrijver LK, Postema K, van Netten JJ. Mechanical noise improves the vibration perception threshold of the foot in people with diabetic neuropathy. J Diabetes Sci Technol. 2020;14:16-21. Khaodhiar L, Niemi JB, Earnest R, Lima C, Harry JD, Veves A. Enhancing sensation in diabetic neuropathic foot with mechanical noise. Diabetes Care. 2003;26:3280-83. Birke JA, Foto JG, Pfiefer LA. Effect of orthosis material hardness on walking pressure in high-risk diabetes patients. J Prosthet Orthot. 1999;11:43-6. Guldemond NA, Leffers P, Schaper NC, et al. The effects of insole configurations on forefoot plantar pressure and walking convenience in diabetic patients with neuropathic feet. Clin Biomech (Bristol, Avon). 2007;22:81-7. Hijmans JM, Geertzen JHB, Schokker B, Postema K. Development of vibrating insoles. Int J Rehabil Res. 2007;30:343-45. Cohen J. A power primer. Psychol Bull. 1992;112:155-59. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5306397","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":369676881,"identity":"7759b0bc-9b40-4667-adb8-9c49ebbe9b99","order_by":0,"name":"Wachirayongyot Thimabut","email":"","orcid":"","institution":"Institute of Automation","correspondingAuthor":false,"prefix":"","firstName":"Wachirayongyot","middleName":"","lastName":"Thimabut","suffix":""},{"id":369676882,"identity":"0e8d8196-50d1-46bc-8612-3b10b34056fd","order_by":1,"name":"Natapatchakrid Thimabut","email":"","orcid":"","institution":"Srinakharinwirot 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Hou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYHADHiCukCBZyxmStTC2EaFOvr338MuvbXZ58g68Bx/zzrOQZ2A//IDh5w7cWhh7zqVZy7YlFxse4Es25t0mYdjAk2bA2HsGtxZmiRwzY8k25sSNDTxm0kAtjA0MOQzM+FzIJv8GpKUeqmWOhH0D/xv8WngkeIwffmw7nDifAaSlQSKxQYKALRI8OWbMDOeOJ25g5jE2nHNMIrlN4pnBwV48WuTbzxh//FFWnTi/vcfwwZuaOtt+/uSHD37iD202aVAkGhyGcYH4AF4NwED7+ANkXQMBZaNgFIyCUTByAQDIykayabiBZgAAAABJRU5ErkJggg==","orcid":"","institution":"Institute of Automation","correspondingAuthor":true,"prefix":"","firstName":"Zeng-Guang","middleName":"","lastName":"Hou","suffix":""}],"badges":[],"createdAt":"2024-10-21 17:53:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5306397/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5306397/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67496958,"identity":"f0251bb6-4064-43b4-a966-3f8aa59f4139","added_by":"auto","created_at":"2024-10-25 15:56:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":712214,"visible":true,"origin":"","legend":"\u003cp\u003eA vibrating orthotic insole (VOI).\u003cstrong\u003e (a) \u003c/strong\u003eA VOI consists of two major components: a personalized foot orthosis (PFO) and a vibration generator machine (VGM). \u003cstrong\u003e(b) \u003c/strong\u003eThe PFO was composed of top, middle, and bottom layers, and the medial arch support was defined according to the individual foot structure. \u003cstrong\u003e(c) \u003c/strong\u003eThe locations for embedding a vibratory actuator in the PFO. \u003cstrong\u003e(d) \u003c/strong\u003eRCA jacks, RCA plugs, and coaxial wires were used in receiving and delivering a newly designed stimulus from the VGM to an embedded vibratory actuator in the PFO. \u003cstrong\u003e(e) \u003c/strong\u003eA random signal generator circuit generates a square wave pulse with a random frequency (0–100 Hz) to serve as a random signal. \u003cstrong\u003e(f) \u003c/strong\u003eA pseudorandom white noise (PRWN) generator circuit creates PRWN. \u003cstrong\u003e(g) \u003c/strong\u003eA novel stimulus was produced by adjusting the random signal to 90% VPT. \u003cstrong\u003e(h) \u003c/strong\u003ePRWN was created based on a pseudorandom binary sequence and a linear-feedback shift register. \u003cstrong\u003e(i) \u003c/strong\u003eThe novel stimulus and PRWN were combined by using a SR approach. \u003cstrong\u003e(j) \u003c/strong\u003eA newly designed stimulus was developed by mixing the novel stimulus and PRWN utilizing a SR approach. \u003cstrong\u003e(k) \u003c/strong\u003eA vibratory actuator was employed to receive the newly designed stimulus and perform vibration for stimulating tactile. \u003cstrong\u003e(l) \u003c/strong\u003eThe PFO and VGM components were connected together employing RCA plugs and jacks. \u003cstrong\u003e(m) \u003c/strong\u003eA power supply switch was used to control a power supply. \u003cstrong\u003e(n) \u003c/strong\u003eA random signal generator switch was used to control the random signal generator circuit. \u003cstrong\u003e(o) \u003c/strong\u003eA PRWN generator switch was used to control the PRWN generator circuit. \u003cstrong\u003e(p) \u003c/strong\u003eA digital voltmeter screen was used to display the intensity of the newly designed stimulus. \u003cstrong\u003e(q) \u003c/strong\u003eA detachable 3-pin plug was used to connect the VGM to a household power source. \u003cstrong\u003e(r) \u003c/strong\u003eA plastic waterproof box with closed sealing and electrical insulation was used to contain all circuits of the VOI.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5306397/v1/151b113888ab1055d3d19f8e.png"},{"id":67496953,"identity":"4e5542be-6a72-4f01-aa89-3d6ccc4bc04f","added_by":"auto","created_at":"2024-10-25 15:56:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":304757,"visible":true,"origin":"","legend":"\u003cp\u003eStudy diagram.\u003cstrong\u003e \u003c/strong\u003eThe CONSORT flow diagram of this study.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5306397/v1/aa45767408e9f5d62bee720f.png"},{"id":67496955,"identity":"4a9d43e8-42de-4d04-8636-846eee945f5e","added_by":"auto","created_at":"2024-10-25 15:56:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":662688,"visible":true,"origin":"","legend":"\u003cp\u003eInterventions and outcome assessment.\u003cstrong\u003e (a)\u003c/strong\u003e During the interventions, participants were assigned to sit on a backrest chair and place their bare feet on the VOI. \u003cstrong\u003e(b)\u003c/strong\u003e Velcro straps or sandal shoes were applied to prevent participants’ feet from slipping off the VOI during the interventions. \u003cstrong\u003e(c)\u003c/strong\u003e The VSA-3000 was used for the outcome assessment: participants laid the 1st and 5th MTP on the stylus and pressed the stop mouse when sensing the vibration; then, the VSA-3000 software calculated a VPT value.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5306397/v1/ac6595d5a440878b65b85184.png"},{"id":67496957,"identity":"866be702-1f03-4dc6-b95e-d1f5c874e736","added_by":"auto","created_at":"2024-10-25 15:56:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":524571,"visible":true,"origin":"","legend":"\u003cp\u003eA line chart demonstrated VPT values of the 18 follow-up participants.\u003cstrong\u003e \u003c/strong\u003eAfter completing Intervention 1, the follow-up was undertaken to assess the VPT values every seven days until they exceeded the baseline.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5306397/v1/db05ca5f9f63db3e59ffa1a3.png"},{"id":67622451,"identity":"314d3fd0-96df-4ebe-b593-3da0d8b06901","added_by":"auto","created_at":"2024-10-28 07:17:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3061888,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5306397/v1/4860114c-9725-4d05-aec9-79445be8aa20.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"30-day and lasting impacts on utilizing a novel orthotic insole for tactile stimulation in diabetic peripheral neuropathy: a double-blind, randomized, sham-controlled trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiabetic peripheral neuropathy (DPN) can cause sensory anomalies, a rise in vibration perception threshold (VPT), diabetic foot ulceration (DFU), and lower extremity amputation (LEA) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In type 2 diabetes mellitus (T2DM), VPT \u0026gt; 25V increases the incidence of DFU recurrence [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. DFU can cause morbidity, enormous treatment expenses, and poor quality of life (QOL) in diabetics and their caretakers [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Tactile is essential for somatosensory and protective sensations in perceiving vibration, pressure, and tension [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Vibration perception (vibrotactile) is vital for cutaneous mechanoreceptors, especially Pacinian corpuscles [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Reduced vibrotactile leads to loss of protective sensation and extends risks of DFU [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Impaired vibrotactile is a precursor sign of DPN, which also increases VPT [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. VPT is a critical measure for detecting vibrotactile and DPN [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. High VPT indicates considerable DPN severity, vibrotactile loss, and risks of DFU and LEA [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. VPT predicts DFU development [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and every rise unit in VPT maximizes the opportunity of developing a first foot ulcer by 5·6% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. High VPT correlates with reduced sural nerve myelinated nerve fiber density, resulting in slower sural nerve conduction velocity and decreased amplitude, affecting tactile sensitivity [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Hence, enhancing VPT may be beneficial in preventing DFU and its recurrence.\u003c/p\u003e \u003cp\u003eA vibrating insole is a novel medical gadget that can improve vibrotactile and VPT sensibility [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A noise-based technique and a stochastic resonance (SR) mechanism are applied to enhance tactile sensation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Benefits of noise and SR in nervous system may increase information processing in a nonlinear system [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Adding noise and SR at subthreshold efficiently escalates threshold capacity [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. When information is conveyed across chemical synapses, using noise and SR as a stimulus can help magnify it [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Evidently, electrical noise stimulation in conjunction with a mechanical stimulus at subthreshold could improve tactile and somatosensation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Vibrotactile sensitivity was increased by ≥ 50 Hz frequency stimuli with noise, which was mediated via mechanoreceptors [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Threshold responses in mechanoreceptors might be heightened by a stimulus in square wave form [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. SR in noise-exposed sensory neurons could help improve biological information processing in threshold system [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e–\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Regarding Pacinian corpuscles, repetitive sensory stimulation (RSS) might raise vibrotactile [\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e–\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Microangiopathy in diabetic foot impairs peripheral nerve function, resulting in DPN and DFU [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Whole body vibration (WBV) could enhance skin blood flow and oxygenation in diabetes [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]; therefore, applying the WBV concept to vibrating stimulation on plantar surface may help recover microangiopathy. Therapeutic footwear is recommended to help prevent DFU [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Therapeutic footwear such as orthotic insoles benefits ulcer prevention and ulcer recurrence avoidance [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Total-contact footwear is utilized in DFU prevention and treatment [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Custom-made therapeutic footwear could minimize plantar pressure and callus formation [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Previous studies on adding 0–100 Hz low-level white noise to a stimulus signal for tactile stimulation demonstrated: vibrotactile could be regained using a custom-made vibrating insole [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]; employing a vibro-medical insole could improve vibrotactile [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]; a bandage shoe was effective in restoring vibrotactile [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Besides, a low-voltage stimulus delivered through a vibrating insole could stimulate vibrotactile [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Prior studies had mostly focused on a flat-design insole with noise and SR in stimulating tactile sensation; however, a total contact insole and a suitable design for diabetic foot are necessary. Even though previous research showed the acute positive effects of using a vibrating insole for stimulating tactile, the continuing and lasting effects of using a vibrating insole for tactile stimulation are unknown.\u003c/p\u003e \u003cp\u003eIn this current study, a vibrating orthotic insole (VOI) with a total contact design was newly developed based on orthotics, medical quality, and the purpose of a noninvasive and low-cost device. In contrast to prior research, a newly designed stimulus was generated by combining a random 0–100 Hz square wave pulse signal stimulus with pseudorandom white noise (PRWN) using a SR approach to stimulate tactile sensation via the VOI. The goal of this study was to investigate the continuing thirty-day effectiveness of using the VOI combined with the newly designed stimulus for tactile stimulation in people who have T2DM with mild-to-moderate DPN. After completing this intervention, observation on the remaining effects was also the aim of this study. In addition to the advantages of recovering DPN and DFU management, we anticipated that the findings of this study will be advantageous for medical device development and neurorehabilitation.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch3\u003eA. Novel Design of Vibrating Orthotic Insole (VOI)\u003c/h3\u003e\n\u003cp\u003eA VOI consists of two main components (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea): 1) a personalized foot orthosis (PFO) and 2) a vibration generator machine (VGM). A prosthetist and orthotist (PO) fabricated the PFO according to each person\u0026rsquo;s foot structure and pathology. The PFO was made of medical-grade materials, i.e., Plastazote\u0026reg; (a low-hardness material, shore-A 30) [\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e]; ethyl vinyl acetate: EVA (a high-hardness material, shore-A 50) [\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e]; and a PITEX reinforcement sheet (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb). The PFO was composed of three layers: 1) a bottom layer (0.8 mm PITEX reinforcement sheet); 2) a middle layer (5 mm EVA); and 3) a top layer (5 mm Plastazote\u0026reg;). The PFO\u0026rsquo;s medial arch support was made of EVA, and its height was determined by the personal foot structure. A total contact design of the PFO was identified by using foot casting with a partial weight-bearing method in the sitting posture [\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e]. In the middle layer of the PFO, a housing for attaching a vibratory actuator was situated on the regions of the 1st metatarsophalangeal joint (MTP), 5th MTP, and calcaneus/heel (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec). Every housing had a single vibratory actuator, which was attached to a coaxial wire and an RCA plug to receive a newly designed stimulus (the combination of a random 0\u0026ndash;100 Hz square wave pulse stimulus and PRWN via a SR approach) from the VGM. RCA jacks installed on the VGM were used to receive the newly designed stimulus, which were then connected to RCA plugs fastened to vibratory actuators. Coaxial wires were linked between RCA plugs and vibratory actuators to transfer the newly designed stimulus with minimal losses (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ed). The PFO component contains simply vibratory actuators; there is no power source or electric circuitry. The VGM was comprised of a random signal generator circuit (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ee) and a PRWN generator circuit (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ef). The random signal generator circuit generated a random signal (a random 0\u0026ndash;100 Hz square wave pulse signal). This circuit was made up of two microcontrollers, AD9833 (Analog Devices Inc., USA) and Arduino Nano 3.0 (Arduino SA, Switzerland), to generate the random signal. The random signal was transformed into a novel stimulus (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eg) for subthreshold stimulation by modifying them to 90% of each person\u0026rsquo;s VPT level. The PRWN generator circuit created PRWN (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eh) based on a pseudorandom binary sequence (PRBS) and a linear-feedback shift register. In order to produce a continuous signal over sixty minutes for tactile stimulation, this circuit used an XOR gate-CD4030BM96 (Texas Instruments, USA) and a shift register-CD4015BM96 (Texas Instruments, USA) with a 31-bit pattern. A random sequence with over two billion bits in length was produced by a PRBS-31 algorithm. This random sequence lasted approximately seventy-two minutes with a 500 kHz clock frequency.\u003c/p\u003e\n\u003cp\u003eThe stimulus signals and PRWN were combined by using a SR approach (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ei) to serve as a newly designed stimulus (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ej). The newly designed stimulus was routed to a cut-off frequency of 100 Hz. Following that, a voltage buffer circuit assisted in maintaining the voltage level of the newly designed stimulus. Then, a signal driver circuit assisted to transmit the newly designed stimulus to a vibratory actuator (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ek). A vibratory actuator (a DC micro vibratory disk motor with a 3 mm thickness and a 10 mm diameter, Vybronics Inc., USA) vibrated in response to the newly designed stimulus\u0026rsquo; intensity. As vibratory actuators were embedded in the PFO, the whole PFO insole vibrated when the vibratory actuators vibrated. Consequently, the VOI performed vibration to stimulate tactile sensation throughout the entire sole of the foot. When utilizing the VOI, the PFO and VGM components were connected together using RCA plugs and jacks (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003el). To operate the VOI, a power supply switch (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003em), a random signal generator switch (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003en), and a PRWN generator switch (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eo) were activated. The intensity of the newly designed stimulus was displayed on a digital voltmeter screen (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ep). Owing to the requirement of spending more than sixty minutes in the experiments of this study, household electrical current was converted to a power source of DC 24V for a major circuit and DC 5V for minor circuits in order to preserve the newly designed stimulus\u0026rsquo; potency. A removable 3-pin plug was employed to connect the VGM and a household power source. The VGM was connected to a household power source using a detachable 3-pin plug (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eq). To ensure safety and security, all of the VOI circuits were enclosed in a plastic waterproof box with closed sealing and electrical insulation (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003er).\u003c/p\u003e\n\u003cp\u003eFurthermore, the VOI was designed to be safe and secure with features, i.e., a fuse system, a residual-current circuit breaker, a grounding system, and the use of shield wires. The VOI was safe for use with patients and clinical trials. Electrical safety testing and risk management for medical devices were verified according to EN IEC 60601-1, ISO 14971, and the protocol for permission on medical devices by the Medical Device Control Division of the Food and Drug Administration of Thailand.\u003c/p\u003e\n\u003ch2\u003eB. Participants\u003c/h2\u003e\n\u003cp\u003eFrom the HRH Princess Maha Chakri Sirindhorn Medical Centre (Srinakharinwirot University), Ongkharak, Nakhon Nayok, Thailand, sixty-four sufferers from T2DM with mild-to-moderate peripheral neuropathy were recruited. The study protocol was approved by the Human Research Ethics Committee of Srinakharinwirot University (SWUEC-661032), and registered with the Thai Clinical Trials Registry (TCTR20230601001). Participants gave written informed consent before participating in this study.\u003c/p\u003e\n\u003cp\u003eInclusion criteria: 1) aged 18\u0026ndash;80 years; 2) T2DM and DPN diagnosis; 3) absence of foot problems such as ulcers, calluses, skin problems, etc.; 4) no muscle weakness; 5) stability in neurological and vital signs; 6) adequate cognitive and language skills to follow instructions; 7) ability to sense vibration; 8) ability to sit for at least 60 minutes.\u003c/p\u003e\n\u003cp\u003eExclusion criteria: 1) musculoskeletal problem that makes it difficult to use the VOI, such as severe pain or joint contracture in any foot joints; 3) mental disorders; 4) hypersensitivity to material substances in the VOI.\u003c/p\u003e\n\u003ch3\u003eC. Study Design\u003c/h3\u003e\n\u003cp\u003eA randomized sham-controlled trial was investigated in this study. The experiments in this study were conducted in a parallel design with random allocation and a double-blind study (blinded participants and researchers). Participants were randomized into two interventions by a computer-generated algorithm. Intervention 1 was using the VOI with the newly designed stimulus for tactile stimulation. Intervention 2 was using the VOI without the newly designed stimulus (only vibration with 100 Hz frequency) for tactile stimulation. Each intervention was performed for thirty days. The PO was invited to distribute the interventions to participants by opening a concealed envelope and to assess a pretest/baseline and three posttests. Posttests were given in three consecutive appointments on the 1st, 15th, and 30th days. A physician was invited to care for the participants. At random points during the intervention periods, the PO or physician asked participants about vibration perception. Participants were required to notify the PO or physician as soon as they experienced vibration. Participants discontinued the intervention if they felt any vibrations. The intensity of tactile stimulation would be modified after reassessing the VPT level, and then the PO would resume the intervention with participants. In addition, if VPT changed after the 1st and 2nd posttests, the PO would adjust the intensity of the stimulation to 90% VPT. Notably, no participant reported a sense of vibration during the interventions. VPT values assessed at the 1st MTP and the 5th MTP were indicated as the outcomes. Participants who received Intervention 1 and had their doctors\u0026rsquo; permission were voluntarily required to continue the follow-up VPT change after the experiments were completed. The follow-up would end when VPT exceeded baseline. In the follow-up, inspection of VPT would be evaluated every seven days after Intervention 1 terminated. The study diagram is depicted in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003ch3\u003eD. Procedures\u003c/h3\u003e\n\u003cp\u003eClinical assessment was assessed as baseline characteristics, i.e., muscle strength by the Medical Research Council manual muscle testing, sensation by the Semmes-Weinstein monofilament test (SWMT): a 5.07 gauge with 10-site testing, peripheral neuropathy by the Michigan neuropathy screening instrument (MNSI: MNSI-A, history; MNSI-B, physical assessment), vibration perception by a 128 Hz tuning fork (a graduated Rydel-Seiffer version), VPT values by the Vibratory Sensory Analyzer: VSA-3000 (Medoc Ltd., USA), body mass index (BMI), vital signs, and diabetic foot abnormalities. Prior to participating in the study, participants were requested to refrain from taking any medications that influence neurological system maintenance, but they continued to take their regular diabetes prescriptions. A researcher trained participants and their caregivers on how to use the VOI before bringing them back home to conduct the interventions.\u003c/p\u003e\n\u003cp\u003eDuring the interventions, participants sat comfortably with a backrest chair and placed their bare feet on the VOI (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea). Velcro straps or sandal shoes were applied to keep their feet from sliding off during the interventions. If participants wore sandals, the shoe size had to be larger than the PFO (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb). The PO and physician used a video call application to monitor them during conducting the interventions. They received the interventions for 60 minutes a day in leisure time at home, with the exception of visits to the experimental location on the 1st, 15th, and 30th days to administer the interventions and posttest assessments by the PO. The VPT value assessment was performed by the VSA-3000. In the assessment, participants placed their feet on the VSA-3000 pedestal and laid the 1st and 5th MTP on the tip of the VSA-3000 stylus without pressing. The stylus would raise vibration from zero to a level perceived by participants. When participants detected the vibration, they immediately pressed the stop mouse to halt the vibrating stylus. Then a VPT value was obtained, and the assessment was repeated five times to determine an average VPT value (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec). The VPT outcome at the calcaneal area was excluded from the assessment because participants weighted their heels against the VSA-3000, resulting in an inaccurate VPT value. After completing 30-day intervention, the PO followed up the intervention 1 group. The intervention 1 group had to continue to abstain from taking neurological drugs throughout the follow-up period.\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE. Sample Size Calculation\u003c/strong\u003e\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003e0.9 power, a 2-sided significance level of 0.05, 20% dropout, and based on the data from the previous study [\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e] were used to calculate the sample size. 64 participants were required for this study.\u003c/p\u003e\n\u003c/span\u003e\u003cspan\u003e\n \u003cp\u003e\u003cstrong\u003eF. Statistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003c/span\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eThe means of both intervention outcomes were compared using an independent sample \u003cem\u003et\u003c/em\u003e-test. A paired sample \u003cem\u003et\u003c/em\u003e-test was performed to compare the means of the two interventions in the pre- and post-tests. Qualitative data were analyzed by a chi-square. The Shapiro-Wilk test was used to consider data\u0026rsquo;s normal distribution. Levene\u0026rsquo;s test was used to observe data\u0026rsquo;s homogeneity and variances. Comparisons between groups were conducted by a repeated-measures ANCOVA. Comparisons within group were analyzed by the paired samples \u003cem\u003et\u003c/em\u003e-test and a repeated-measures ANOVA. Analysis with the elimination of the covariates\u0026rsquo; effect on the relationship between the independent grouping variables and the continuous dependent variables by a MANCOVA. The findings\u0026rsquo; effect sizes were determined using Cohen\u0026rsquo;s d, and Cohen\u0026rsquo;s d values (\u003cem\u003ed\u003c/em\u003e) were classified as small (0.0\u0026ndash;0.20), medium (0.21\u0026ndash;0.50), or large (0.51\u0026ndash;0.8) effect sizes [\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]. Statistical analysis was performed utilizing IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY), with a two-tailed significance level of \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe study was completed by 55 participants, and demographic data are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In the group of Intervention 1, 5 participants were excluded from the study due to infection with COVID-19 (3 participants), having a car accident (1 participant), and moving to live in other provinces (1 participant). In the group of Intervention 2, 4 participants were excluded from the study because of infection with COVID-19 (3 participants) and having an appendectomy (1 participant). After completing Intervention 1, 18 participants proceeded to follow up, whereas 9 participants were eliminated because they were uninterested in the follow-up (1 participant) or lacked physician consent (8 participants). No adverse events occurred during or after the study.\u003c/p\u003e \u003cp\u003eThe chi-square test found that these two intervention groups were not different in age, gender, disease severity condition, weight, height, BMI, MNSI-A, MNSI-B, and SWMT. The Shapiro-Wilk test revealed that both intervention groups had normal data distributions. The Levene\u0026rsquo;s test demonstrated that both intervention groups had equal variance and homogeneity. The MANCOVA test was conducted using a set of outcome parameters, including the VPT values of the 1st and 5th MTP of both feet in the posttest on the 1st, 15th, and 30th days as dependent variables, the two interventions as fixed factors, and covariates (i.e., age, gender, disease duration, weight, height, BMI, MNSI-A, MNSI-B, and SWMT). The results showed that disease duration and MNSI-A were the two significant covariables. Thus, disease duration and MNSI-A were controlled for a covariance analysis when compared between groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographics of study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntervention 1\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntervention 2\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years; mean (SD); range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.70 (9.65); 38\u0026ndash;72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56.93 (10.65); 38\u0026ndash;72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (48.1)\u003c/p\u003e \u003cp\u003e14 (51.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (53.6)\u003c/p\u003e \u003cp\u003e13 (46.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCondition of DPN, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003cp\u003eMild\u003c/p\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (51.9)\u003c/p\u003e \u003cp\u003e13 (48.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (50.0)\u003c/p\u003e \u003cp\u003e14 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of DPN, months; median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47.59 (22\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.29 (26\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, kg; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78.56 (8.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.76 (8.24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight, cm; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e163.31 (8.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e164.69 (7.50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.42 (1.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.88 (1.58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMNSI-A, scores; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.15 (0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.07 (0.94)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMNSI-B, scores; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.07 (0.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.07 (0.26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSWMT, sites; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.0 (1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.93 (1.18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eIntervention 1: using the VOI with the combination of a random 0\u0026ndash;100 Hz square wave pulse signal with PRWN via a SR approach for tactile stimulation\u003c/p\u003e \u003cp\u003eIntervention 2: using the VOI with only vibration with 100 Hz frequency for tactile stimulation\u003c/p\u003e \u003cp\u003eVOI: vibrating orthotic insole, PRWN: pseudorandom white noise, SR: stochastic resonance\u003c/p\u003e \u003cp\u003eSD: standard deviation, DPN: diabetic peripheral neuropathy, BMI: body mass index, SWMT: Semmes-Weinstein monofilament test (a 10-site test)\u003c/p\u003e \u003cp\u003eMNSI: Michigan neuropathy screening instrument; MNSI-A (history) has a total possible score of 13 points, with a score of 7 deemed abnormal; MNSI-B (physical assessment) has a total possible score of 10 points, with a score of 2.5 considered abnormal. At least one of the MNSI assessments (MNSI-A or MSNI-B) was abnormal for each participant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn within-group comparisons, there was no significant difference in the baseline/pretest of the VPT values between both intervention groups. At each pair time point, both groups\u0026rsquo; VPT values decreased significantly when compared to the baseline/pretest. In the group of Intervention 1, the VPT values of the posttest at the left 1st MTP on the 1st, 15th, and 30th days were significantly decreased from the baseline by 19.45% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), 20.9% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), and 22.72% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), respectively; the VPT values of the posttest at the left 5th MTP on the 1st, 15th, and 30th days were significantly reduced from the baseline by 20.02% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), 22.5% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), and 24.6% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a large effect size), respectively; the VPT values of the posttest at the right 1st MTP on the 1st, 15th, and 30th days were significantly declined from the baseline by 19.73% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), 21.08% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), and 22.98% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), respectively; the VPT values of the posttest at the right 5th MTP on the 1st, 15th, and 30th days were significantly diminished from the baseline by 20.96% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), 22.64% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), and 25.05% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a large effect size), respectively. In the group of Intervention 2, the VPT values of the posttest at the left 1st MTP did not change on the 1st day (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.688, a small effect size) and significantly increased from the baseline by 5.63% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a small effect size) and 11.21% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), respectively, on the 15th and 30th days; the VPT values of the posttest at the left 5th MTP on the 1st, 15th, and 30th days were significantly raised from the baseline by 0.56% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003, a small effect size), 5.31% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a small effect size), and 12.01% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), respectively; the VPT values of the posttest at the right 1st MTP did not change on the 1st day (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.247, a small effect size) and were significantly intensified from the baseline by 3.07% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a small effect size), and 7.35% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a small effect size), respectively, on the 15th and 30th days; the VPT values of the posttest at the right 5th MTP on the 1st, 15th, and 30th days were significantly rose from the baseline by 0\u0026middot;33% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014, a small effect size), 5.28% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a small effect size), and 11.46% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, a medium effect size), respectively.\u003c/p\u003e \u003cp\u003eComparisons between both intervention groups revealed that the group of Intervention 1 had the decreased VPT values, whereas the group of Intervention 2 seemed to increase the VPT values. On the 1st day: at the left 1st MTP revealed that the group of Intervention 1 had the lessened VPT values, by contrast, the group of Intervention 2 had the heightened VPT values; at the left 5th MTP represented that the group of Intervention 1 had the reduced VPT values, while the group of Intervention 2 had the aggravated VPT values; at the right 1st MTP displayed the group of Intervention 1 had the lowered VPT values, whereas the group of Intervention 2 had the increased VPT values; at right the 5th MTP presented that the group of Intervention 1 had the abated VPT values, meanwhile, the group of Intervention 2 had the rose VPT values. On the 15th day: at the left 1st MTP demonstrated that the group of Intervention 1 had the decreased VPT values, while the group of Intervention 2 had the raised VPT values; at the left 5th MTP showed that the group of Intervention 1 had the declined VPT values, whereas the group of Intervention 2 had the rose VPT values; at the right 1st MTP demonstrated that the group of Intervention 1 had the lessened VPT values, but the group of Intervention 2 had the raised VPT values; at the right 5th MTP revealed that the group of Intervention 1 had the subsided VPT values, by contrast, the group of Intervention 2 had the increased VPT values. On the 30th day: at the left 1st MTP represented that the group of Intervention 1 had the lowered VPT values, while the group of Intervention 2 had the higher VPT values; at the left 5th MTP presented that the group of Intervention 1 had the lessened VPT values, by contrast, the group of Intervention 2 had the heightened VPT values; at the right 1st MTP demonstrated that the group of Intervention 1 had the reduced VPT values, whereas the group of Intervention 2 had the increased VPT values; and at the right 5th MTP showed that the group of Intervention 1 had the decreased VPT values, meanwhile, the group of Intervention 2 had the raised VPT values. Comparisons of VPT outcomes of both interventions are represented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparisons of VPT outcomes when using Intervention 1 and Intervention 2\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"16\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"10\" nameend=\"c12\" namest=\"c3\"\u003e \u003cp\u003eWithin Group Comparison\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" morerows=\"1\" nameend=\"c16\" namest=\"c13\" rowspan=\"2\"\u003e \u003cp\u003eBetween Groups Comparison\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c7\" namest=\"c3\"\u003e \u003cp\u003e\u003cb\u003eIntervention 1\u003c/b\u003e (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c12\" namest=\"c8\"\u003e \u003cp\u003e\u003cb\u003eIntervention 2\u003c/b\u003e (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVPT (volts)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eMean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eMean\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eDifference\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e95% CI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003ed\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003eMean\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003eMean\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eDifference\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cb\u003e95% CI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u003cb\u003ed\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003eMean\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003edifference\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e \u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e\u003cb\u003e95% CI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e\u003cb\u003ed\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e1st MTP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.39\u003c/p\u003e \u003cp\u003e(10.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e24.71\u003c/p\u003e \u003cp\u003e(12.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-3.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-9.70, 3.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1st day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.23\u003c/p\u003e \u003cp\u003e(11.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.16\u003c/p\u003e \u003cp\u003e(1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.65, 4.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e24.71\u003c/p\u003e \u003cp\u003e(12.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003cp\u003e(0.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.688\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-0.01, 0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-7.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.023\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-13.88, -1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15th day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.92\u003c/p\u003e \u003cp\u003e(10.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.47\u003c/p\u003e \u003cp\u003e(1.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.96, 4.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.10\u003c/p\u003e \u003cp\u003e(12.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-1.39\u003c/p\u003e \u003cp\u003e(0.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-1.59, -1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-9.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.006\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-15.57, -2.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30th day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.53\u003c/p\u003e \u003cp\u003e(10.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.86\u003c/p\u003e \u003cp\u003e(1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.31, 5.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e27.48\u003c/p\u003e \u003cp\u003e(12.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-2.77\u003c/p\u003e \u003cp\u003e(0.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-3.05, -2.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-10.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-17.30, -4.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e5th MTP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.33\u003c/p\u003e \u003cp\u003e(10.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.72\u003c/p\u003e \u003cp\u003e(12.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-3.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-9.65, 2.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1st day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.66\u003c/p\u003e \u003cp\u003e(11.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.67\u003c/p\u003e \u003cp\u003e(1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.12, 5.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.87\u003c/p\u003e \u003cp\u003e(12.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.15\u003c/p\u003e \u003cp\u003e(0.25)\u003c/p\u003e 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\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.74, 5.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e27.60\u003c/p\u003e \u003cp\u003e(12.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-1.89\u003c/p\u003e \u003cp\u003e(0.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-2.11, -1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-9.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.003\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-16.27, -3.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e5th MTP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.71\u003c/p\u003e \u003cp\u003e(11.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.88\u003c/p\u003e \u003cp\u003e(12.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.718\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-7.66, 5.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1st day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.32\u003c/p\u003e \u003cp\u003e(12.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.39\u003c/p\u003e \u003cp\u003e(1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.80, 5.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26.97\u003c/p\u003e \u003cp\u003e(12.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-0.09\u003c/p\u003e \u003cp\u003e(0.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.014\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-0.16, -0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-6.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.048\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-13.24, -0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15th day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.89\u003c/p\u003e \u003cp\u003e(11.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.82\u003c/p\u003e \u003cp\u003e(1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.21, 6.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e28.30\u003c/p\u003e \u003cp\u003e(12.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-1.42\u003c/p\u003e \u003cp\u003e(0.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-1.56, -1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-8.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.013\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-15.00, -1.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30th day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.27\u003c/p\u003e \u003cp\u003e(11.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.44\u003c/p\u003e \u003cp\u003e(1.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.81, 7.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29.96\u003c/p\u003e \u003cp\u003e(12.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-3.08\u003c/p\u003e \u003cp\u003e(0.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-3.36, -2.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-10.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.002\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e-17.35, -4.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e-0.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIntervention 1: using the VOI with the combination of a random 0\u0026ndash;100 Hz square wave pulse signal with PRWN via a SR approach for tactile stimulation\u003c/p\u003e \u003cp\u003eIntervention 2: using the VOI with only vibration with 100 Hz frequency for tactile stimulation\u003c/p\u003e \u003cp\u003eVOI: vibrating orthotic insole, PRWN: pseudorandom white noise, SR: stochastic resonance\u003c/p\u003e \u003cp\u003eVPT: vibration perception threshold, SD: standard deviation, CI: confidence interval, MTP: metatarsophalangeal joint\u003c/p\u003e \u003cp\u003e \u003csup\u003e*\u003c/sup\u003e Paired \u003cem\u003et\u003c/em\u003e-test, \u003csup\u003e\u0026dagger;\u003c/sup\u003e Analysis of covariance, \u003csup\u003e\u0026Dagger;\u003c/sup\u003e Significant at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eThe observation on remaining effectiveness after completing Intervention 1 in 14 mild DPN participants and 4 moderate DPN participants found: approximately 12 weeks were the maximum periods; approximately 9 weeks were the minimum periods; and the mean of the remaining effectiveness was 10.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04 weeks. A line chart depicting VPT values of the 18 follow-up participants is demonstrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings demonstrated that utilizing Intervention 1 could effectively improve tactile sensibility in mild-to-moderate DPN and help reduce VPT from baseline by 21.89% on average. Applying the VOI might result in a medium effect size for tactile stimulation. In posttests, VPT was highly reduced from baseline on the 1st day (range 2.07V\u0026ndash;8.32V, 7.68\u0026ndash;46.14%); on the 15th day VPT was slowly lower from the 1st day posttest, ranging from 0.07V to 0.92V, 0.66\u0026ndash;7.49%; and on the 30th day VPT was gradually decreased from the 15th day posttest (range 0.08V\u0026ndash;1.34V, 0.84\u0026ndash;12.86%). These findings indicated that VPT was reduced most during the initial stages of tactile stimulation and thereafter gradually declined. It seems VPT may be ploddingly decreased to one point and then steady, but investigation over thirty days is required to confirm. Following up revealed that VPT in seven days after completing Intervention 1 remained the same as in the 30th day posttest. Then, VPT slowly rose over around thirty days. Following that, VPT increased more rapidly than the previous periods until the VPT values exceeded the baseline, which took approximately two to three months. DPN conditions may have an impact on the remaining effects of Intervention 1; hence, it is necessary to investigate the effectiveness of Intervention 1 for stimulating tactile in various DPN conditions. The remaining effects of Intervention 1 may be influenced by other factors, e.g., participant self-care, nutrition, rest, exercise, drinking and smoking habits, etc. DPN is also a progressive illness that can raise VPT all the time, which might affect the remaining effects of Intervention 1. Therefore, continuing to use the VOI with the combination of a random 0\u0026ndash;100 Hz square wave pulse signal and PRWN via a SR approach for tactile stimulation is recommended in order to maintain the lowered VPT values and prolong tactile sensitivity improvement. The results of using the VOI with only 100 Hz frequency vibration revealed that VPT was significantly increased. A small effect size from using this intervention might relate to increased VPT and DPN progression, and further investigation is required.\u003c/p\u003e \u003cp\u003eOrthotic and total contact designs of the VOI may provide tactile simulation across the entire plantar surface. Fabricating the VOI from foam materials might perform more effective stimulation throughout the insoles than viscous materials such as gel insoles. Manufacturing the VOI with medical-grade materials may contribute to appropriate therapeutic footwear for diabetic foot and provide benefits as noted in prior research [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Based on total contact and individual-tailored insole ideas [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], the PFO might help prevent DFU, calluses, and LEA.\u003c/p\u003e \u003cp\u003eStimulating tactile at 90% VPT by the combination of a random 0\u0026ndash;100 Hz square wave pulse stimulus and PRWN via a SR approach could significantly improve tactile sensation, similar to mixing a stimulus signal with white noise (0\u0026ndash;100 Hz bandwidth) by a SR technique [\u003cspan additionalcitationids=\"CR37 CR38\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Adding PRWN to a random 0\u0026ndash;100 Hz square wave pulse stimulus might magnify its potential for stimulating tactile. This newly designed stimulus using a SR method may aid in the optimization of information transmission and nerve cell responses at chemical synapses, as well as the enhancement of cutaneous mechanoreceptors and thresholds [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. PRWN could help amplify the intensity of a stimulus in tactile stimulation at subthreshold while also utilizing noise [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Based on RSS [\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], a novel design for tactile stimulation via the VOI may enhance Pacinian corpuscles and mechanoreceptor, corticomuscular, and somatosensory capacities. Lowering VPT using the VOI might increase conduction velocity and amplitude of sural nerve [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. According to WBV [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], employing the VOI may not only increase tactile sensitivity but also lessen the issues of skin blood flow and oxygenation. The effectiveness of using the VOI might benefit the prevention of DFU and LEA. Utilizing the VOI may help reduce the risk of DFU by 2.9% and 19.8% compared to VPT\u0026thinsp;\u0026lt;\u0026thinsp;15V and \u0026gt;\u0026thinsp;25V, respectively [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. According to a previous study [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], each lowered 1V VPT by the VOI may decrease the 1st DFU occurrence by 5.6%. Considering VPT\u0026thinsp;\u0026gt;\u0026thinsp;25V [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], applying the VOI may help minimize the chance of DFU recurrence. The VOI may help mitigate negative impacts from DFU, i.e., morbidity, treatment costs, and low QOL among DFU sufferers and their caregivers [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, these presumptions of the advantages of using the VOI are still required further investigation.\u003c/p\u003e \u003cp\u003eDespite lack of the continuing effects of employing a vibrating insole for tactile stimulation, there are certain aspects about the acute impacts from previous studies that can be compared to the findings of this study. A continuous 60-minute stimulation via a vibrating insole in twenty type 1 and 2 diabetics with moderate-to-severe neuropathy could decline VPT at right big toe by 11.91% (31.9\u0026thinsp;\u0026plusmn;\u0026thinsp;13.0V vs. 28.1\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Utilizing the VOI for tactile stimulation could lower VPT at the right 1st MPT on the 1st day by 19.73% (23.06V vs. 18.51V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in T2DM patients with mild-to-moderate DPN. The VOI appears to be more effective in reducing VPT, but further investigation is needed to evaluate the results of employing the VOI in severe DPN to a previous study [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Evaluating by a 256 Hz tuning fork (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) found that vibrotactile at both big toes was improved after employing 30-minute walking vibro-medical insoles in twenty mild-to-moderate DPN patients, but there was no vibrotactile improvement when evaluated by a 128 Hz tuning fork (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The current investigation may imply that using the VOI with 60-minute static stimulation could enhance vibrotactile as clinical assessment by a 128 Hz graduated Rydel-Seiffer tuning fork (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), contrary to the previous study [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Nevertheless, vibrotactile assessment by 128 Hz and 256 Hz tuning forks is required to clarify the assumption of the current study. Comparisons of the results of using a bandage shoe between actuator-off and actuator-on showed that the median VPT values were decreased by 10.34% (43.5V vs. 39.3V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, the left 1st MTP), 10.07% (41.7V vs. 37.5V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, the left 5th MTP), 8.45% (42.6V vs. 39.0V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, the right 1st MTP), and 15.44% (40.8V vs. 34.5V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, the right 5th MTP) [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. While the difference between utilizing the VOI with and without the newly designed stimulus on the 1st day demonstrated that the mean VPT values were reduced by 19.45% (21.39V vs. 17.23V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, the left 1st MTP), 20.02% (23.33V vs. 18.66V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, the left 5th MTP), 19.73% (23.06V vs. 18.51V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, the right 1st MTP), and 20.96% (25.71V vs. 20.32V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, the right 5th MTP). It appears that employing the VOI could stimulate tactile sensation more effectively than a bandage shoe. VPT at the left big toe could be decreased by 20.83% (24\u0026thinsp;\u0026plusmn;\u0026thinsp;11V vs. 19\u0026thinsp;\u0026plusmn;\u0026thinsp;10V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) when stimulating tactile by 0\u0026ndash;1,000 arbitrary vibration with low level mechanical noise and SR in twenty type 1 and 2 diabetics with moderate-to-severe peripheral neuropathy [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The current study found that a 19.45% reduction in VPT at the left 1st MTP on the 1st day (21.39\u0026thinsp;\u0026plusmn;\u0026thinsp;2.09V vs. 17.23\u0026thinsp;\u0026plusmn;\u0026thinsp;2.12V, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), similar to the finding of the prior study [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, the stimulation duration of the previous study was not specified.\u003c/p\u003e \u003cp\u003eThe VOI can provide a noninvasive intervention, but safety validation is required before contributions. Moreover, ergonomic assessment is also required. The VGM consisted of low-cost components, but the PFO was composed of expensive materials because of their medical quality. If the PFO could be fabricated with inexpensive medical-grade materials, the VOI would be able to realize its goal of providing an affordable device. Generally, vibratory frequency will be indicated by the factory\u0026rsquo;s motor rotation setting; thus, the final vibratory frequency might vary from the input frequency. Participants might not experience vibration during the thirty-day interventions due to the factory-setting rotation. Hence, the vibratory actuator\u0026rsquo;s maximum frequency is required to be tested. It is possible that if the vibratory actuator executes the final vibratory frequency at the same level as the input, VPT improvements may be greater than those found in the present study. Although a three-layer design of the PFO may help avoid heat during vibrating actuator operation, heat prevention assessment is still necessary. The next VOI design requires modifications for dynamic activities, i.e., walking, running, and climbing stairs, as well as a wireless design. The future VOI design also requires long-lasting batteries and portables.\u003c/p\u003e \u003cp\u003eSignificantly, the VOI may contribute to neurorehabilitation, foot ulcers and their recurrence prevention, and disability avoidance; however, further investigations on the effectiveness of utilizing the VOI for preventing DFU and its recurrence are required. Applying the VOI in the early stages of DPN is suggested. Employing the VOI along with regular DPN treatment is recommended for enhancing, restoring, and prolonging tactile sensation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eUsing the combination of a random 0\u0026ndash;100 Hz square wave pulse signal and PRWN by a SR approach via the VOI could effectively improve tactile sensitivity in mild-to-moderate DPN. The continuing effects of utilizing the VOI for tactile stimulation revealed VPT values were highly reduced during the initial stage of the intervention and then gradually decreased. In the follow-up, VPT values remained constant at the end of the intervention on the first week and gradually increased over approximately four weeks. After that, VPT values increased at a faster rate until they exceeded baseline, which took around eight to twelve weeks. Based on orthotics, custom-made, total contact, and medical quality, the VOI may offer tactile stimulation over the entire plantar surface and be suitable for diabetic foot. In addition, the VOI could offer a noninvasive intervention for tactile stimulation. Significantly, applying the VOI may benefit neurorehabilitation, DFU management, and disability prevention in DPN.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Human Research Ethics Committee of Srinakharinwirot University approved the protocol of this study. The approval protocol code is SWUEC-661032.\u0026nbsp;All participants provided written informed consent prior to participation in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsiderable data are provided within the manuscript. Supplementary\u0026nbsp;data may be available upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eW.T. conceived the research project, conceptualized the study, designed the study, developed the device, designed the experiments, designed the data collection, analyzed the results, interpreted the findings, and drafted the manuscript. N.T. helped design the clinical trials and data collection, processed the request for ethics approval and clinical trial registry, recruited participants, conducted clinical trials, supported facilities for data collection, performed the statistical analysis, and was responsible for data management. P.L. performed co-supervision, made substantive revisions, and provided support in every process. Z.G.H. performed supervision, made substantive revisions, and provided support in every process. All authors accessed and verified the underlying data reported in the manuscript. All authors critically reviewed and contributed to the final draft of the manuscript. All authors approved the final version of the manuscript and had final responsibility for the decision to submit for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIqbal Z, Azmi S, Yadav R, et al. Diabetic peripheral neuropathy: epidemiology, diagnosis, and pharmacotherapy. Clin Ther. 2018;40:828-49.\u003c/li\u003e\n\u003cli\u003eMargolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. Diabetic neuropathic foot ulcers and amputation. Wound Repair Regen.\u003cem\u003e \u003c/em\u003e2005;13:230-36.\u003c/li\u003e\n\u003cli\u003eArmstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376:2367-75.\u003c/li\u003e\n\u003cli\u003eMeijer JW, Trip J, Jaegers SM, et al. Quality of life in patients with diabetic foot ulcers. Disabil Rehabil. 2001;23:336-40.\u003c/li\u003e\n\u003cli\u003eRinkel WD, Luiten J, van Dongen J, et al. In-hospital costs of diabetic foot disease treated by a multidisciplinary foot team. Diabetes Res Clin Pract. 2017;132:68-78.\u003c/li\u003e\n\u003cli\u003eNabuurs-Franssen MH, Huijberts MSP, Kruseman ACN, Willems J, Schaper NC. Health-related quality of life of diabetic foot ulcer patients and their caregivers. Diabetologia. 2005;48:1906-10.\u003c/li\u003e\n\u003cli\u003eMcGlone F, Reilly D. The cutaneous sensory system. Neurosci Biobehav Rev. 2010;34:148-59.\u003c/li\u003e\n\u003cli\u003eBell J, Bolanowski S, Holmes MH. The structure and function of Pacinian corpuscles: a review. Prog Neurobiol. 1994;42:79-128.\u003c/li\u003e\n\u003cli\u003eKars HJJC, Hijmans JM, Geertzen JHB, Zijlstra W. The effect of reduced somatosensation on standing balance: a systematic review. J Diabetes Sci Technol. 2009:3:931-43.\u003c/li\u003e\n\u003cli\u003evan Deursen RW, Sanchez MM, Derr JA, Becker MB, Ulbrecht JS, Cavanagh PR. Vibration perception threshold testing in patients with diabetic neuropathy: ceiling effects and reliability. Diabet Med. 2001;18:469-75.\u003c/li\u003e\n\u003cli\u003eDom\u0026iacute;nguez-Mu\u0026ntilde;oz FJ, Adsuar JC, Villafaina S, et al. Test-retest reliability of vibration perception threshold test in people with type 2 diabetes mellitus. Int J Environ Res Public Health. 2020;17:1773.\u003c/li\u003e\n\u003cli\u003eYoung MJ, Breddy JL, Veves A, Boulton AJ. The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study. Diabetes Care. 1994;17:557-60.\u003c/li\u003e\n\u003cli\u003eAbbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care. 1998;21:1071-75.\u003c/li\u003e\n\u003cli\u003eSundkvist G, Dahlin LB, Nilsson H, et al. Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance. Diabet Med. 2000;17:259-68.\u003c/li\u003e\n\u003cli\u003eHijmans JM, Geertzen JHB, Zijlstra W, Hof AL, Postema K. Effects of vibrating insoles on standing balance in diabetic neuropathy. J Rehabil Res Dev. 2008;45:1441-49.\u003c/li\u003e\n\u003cli\u003eCollins JJ, Imhoff TT, Grigg P. Noise-enhanced tactile sensation. Nature. 2008;383:770.\u003c/li\u003e\n\u003cli\u003eMcDonnell MD, Ward LM. The benefits of noise in neural systems: bridging theory and experiment. Nat Rev Neurosci. 2011;12:415-26.\u003c/li\u003e\n\u003cli\u003eFaisal AA, Selen LPJ, Wolpert DM. Noise in the nervous system. Nat Rev Neurosci. 2008;9:292-303.\u003c/li\u003e\n\u003cli\u003eLi X, Wang J, Hu W. Effects of chemical synapses on the enhancement of signal propagation in coupled neurons near the canard regime. Phys Rev E Stat Nonlin Soft Matter Phys. 2007;76:041902.\u003c/li\u003e\n\u003cli\u003eBreen PP, \u0026Oacute;Laighin G, McIntosh C, Dinneen SF, Quinlan LR, Serrador JM. A new paradigm of electrical stimulation to enhance sensory neural function. Med Eng Phys. 2014;36:1088-91.\u003c/li\u003e\n\u003cli\u003eWells C, Ward LM, Chua R, Inglis JT. Touch noise increases vibrotactile sensitivity in old and young. Psychol Sci. 2005;4:313-20.\u003c/li\u003e\n\u003cli\u003eCain DM, Khasabov SG, Simone DA. Response properties of mechanoreceptors and nociceptors in mouse glabrous skin: an in vivo study. J Neurophysiol. 2001;85:1561-74.\u003c/li\u003e\n\u003cli\u003eH\u0026auml;nggi P. Stochastic resonance in biology. How noise can enhance detection of weak signals and help improve biological information processing. Chemphyschem. 2002;3:285-90.\u003c/li\u003e\n\u003cli\u003eMcDonnell MD, Abbott D. What is stochastic resonance? Definitions, misconceptions, debates, and its relevance to biology. PLoS Comput Biol. 2009;5:e1000348.\u003c/li\u003e\n\u003cli\u003eMoss F, Ward LM, Sannita WG. Stochastic resonance and sensory information processing: a tutorial and review of application. Clin Neurophysiol. 2004;115:267-81.\u003c/li\u003e\n\u003cli\u003eEnnion L, Hijmans J. Improving vibration perception in a patient with type 2 diabetes and sensory peripheral neuropathy. S Afr J Physiother.2019;75:602.\u003c/li\u003e\n\u003cli\u003ePleger B, Foerster AF, Ragert P, et al. Functional imaging of perceptual learning in human primary and secondary somatosensory cortex. Neuron. 2003;40:643-53.\u003c/li\u003e\n\u003cli\u003eSathian K, Deshpande G, Stilla R. Neural changes with tactile learning reflect decision-level reweighting of perceptual readout. J Neurosci. 2013;33:5387-98.\u003c/li\u003e\n\u003cli\u003eTrenado C, Mendez-Balbuena I, Manjarrez E, et al. Enhanced corticomuscular coherence by external stochastic noise. Front Hum Neurosci. 2014;8:325.\u003c/li\u003e\n\u003cli\u003eErgul A. Endothelin-1 and diabetic complications: focus on the vasculature. Pharm Res. 2011;63:477-82.\u003c/li\u003e\n\u003cli\u003eJohnson PK, Feland JB, Johnson AW, Mack GW, Mitchell UH. Effect of whole body vibration on skin blood flow and nitric oxide production. J Diabetes Sci Technol. 2014;8:889-94.\u003c/li\u003e\n\u003cli\u003eBus SA, Lavery LA, Monteiro-Soares M, et al. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36:e3269.\u003c/li\u003e\n\u003cli\u003eBus SA, van Deursen RW, Armstrong DG, et al. Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review. Diabetes Metab Res Rev. 2016;32:99-118.\u003c/li\u003e\n\u003cli\u003eBus SA, Valk GD, van Deursen RW, et al. The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review. Diabetes Metab Res Rev. 2008;24:S162-80.\u003c/li\u003e\n\u003cli\u003evan Netten JJ, Sacco ICN, Lavery LA, et al. Treatment of modifiable risk factors for foot ulceration in persons with diabetes: a systematic review. Diabetes Metab Res Rev\u003cstrong\u003e. \u003c/strong\u003e2020;36:e3271.\u003c/li\u003e\n\u003cli\u003eCloutier R, Horr S, Niemi JB, et al. Prolonged mechanical noise restores tactile sense in diabetic neuropathic patients. Int J Low Extrem Wounds. 2009;8:6-10.\u003c/li\u003e\n\u003cli\u003eCham MB, Mohseni-Bandpei MA, Bahramizadeh M, Kalbasi S, Biglarian A. The effects of Vibro-medical insole on vibrotactile sensation in diabetic patients with mild-to-moderate peripheral neuropathy. Neurol Sci. 2018;39:1079-84.\u003c/li\u003e\n\u003cli\u003eZwaferink JBJ, Hijmans JM, Schrijver CM, Schrijver LK, Postema K, van Netten JJ. Mechanical noise improves the vibration perception threshold of the foot in people with diabetic neuropathy. J Diabetes Sci Technol. 2020;14:16-21.\u003c/li\u003e\n\u003cli\u003eKhaodhiar L, Niemi JB, Earnest R, Lima C, Harry JD, Veves A. Enhancing sensation in diabetic neuropathic foot with mechanical noise. Diabetes Care. 2003;26:3280-83.\u003c/li\u003e\n\u003cli\u003eBirke JA, Foto JG, Pfiefer LA. Effect of orthosis material hardness on walking pressure in high-risk diabetes patients. J Prosthet Orthot. 1999;11:43-6.\u003c/li\u003e\n\u003cli\u003eGuldemond NA, Leffers P, Schaper NC, et al. The effects of insole configurations on forefoot plantar pressure and walking convenience in diabetic patients with neuropathic feet. Clin Biomech (Bristol, Avon). 2007;22:81-7.\u003c/li\u003e\n\u003cli\u003eHijmans JM, Geertzen JHB, Schokker B, Postema K. Development of vibrating insoles. Int J Rehabil Res. 2007;30:343-45.\u003c/li\u003e\n\u003cli\u003eCohen J. A power primer. Psychol Bull. 1992;112:155-59.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diabetes, Noise, Peripheral neuropathy, Stochastic Resonance, Tactile","lastPublishedDoi":"10.21203/rs.3.rs-5306397/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5306397/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiabetic peripheral neuropathy (DPN) can lead to diabetic foot ulceration (DFU) and disabilities. DPN also increases vibration perception threshold (VPT) and decreases tactile sensitivity. Applying a vibrating insole is an efficient way to decrease VPT and improve tactile sensibility.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate the continuing and lasting effects of applying a novel vibrating orthotic insole (VOI) combined with a newly designed stimulus (a random 0–100 Hz square wave pulse signal integrated with pseudorandom white noise via a stochastic resonance approach) for tactile stimulation in DPN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA randomized sham-controlled trial with a parallel design and a double-blind strategy was conducted in this study. Sixty-four mild-to-moderate DPN were randomized by a computer-generated algorithm into two interventions: 1) using the VOI mixed with the newly designed stimulus; 2) using the VOI with only 100 Hz frequency vibration. Each intervention was done at home for sixty minutes a day over thirty days. VPT outcomes were assessed on the 1st, 15th, and 30th days. Following up on the remaining effects of employing the VOI combined with the newly designed stimulus was performed after completing Intervention 1 by evaluating VPT values every seven days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntervention 1 could significantly reduce VPT and effectively enhance tactile sensation (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). In contrast, Intervention 2 considerably increased VPT. Follow-up, VPT was steady at the end of Intervention 1 for the first week before progressively rising over a month; after that, it rose until it exceeded baseline, which took approximately two to three months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUtilizing the VOI in conjunction with a random 0–100 Hz square wave pulse signal and pseudorandom white noise via a stochastic resonance approach could offer lowering VPT, maintaining decreased VPT, and improving tactile sensitivity. The VOI may benefit neurorehabilitation in DPN, e.g., preventing DFU and its recurrence, restoring/prolonging tactile sensation, slowing DPN deterioration, and avoiding lower extremity amputation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThai Clinical Trials Registry: TCTR20230601001 (ThaiClinicalTrials.org).\u003c/p\u003e","manuscriptTitle":"30-day and lasting impacts on utilizing a novel orthotic insole for tactile stimulation in diabetic peripheral neuropathy: a double-blind, randomized, sham-controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-25 15:56:38","doi":"10.21203/rs.3.rs-5306397/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8750647e-e150-4261-97b3-b4cf62773a33","owner":[],"postedDate":"October 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-28T07:09:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-25 15:56:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5306397","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5306397","identity":"rs-5306397","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}