Safety and Efficacy of a New Smartphone-controlled Vibrating Capsule on Defecation in Beagles

Safety and Efficacy of a New Smartphone-controlled Vibrating Capsule on Defecation in Beagles www.nature.com/scientificreports OPEN Safety and Efficacy of a New Smartphone-controlled Vibrating Capsule on Defecation in Beagles Received: 3 February 2017 1 1 2 1 1 1 Jin Yu , Yang-Yang Qian , Chao-Hui He , Shu-Guang Zhu , An-Jing Zhao , Qian-Qian Zhu , 3 3 4 4 1 1 Accepted: 18 April 2017 Cheng-Wei Shao , Tie-Gong Wang , Yang Wang , Gui-Ling Ding , Zhuan Liao & Zhao-Shen Li Published: xx xx xxxx Constipation, mainly manifesting as abdominal discomfort and painful defecation, is considered as a chronic disorder. Due to a lack of effective therapy, it imposes a significant economic burden and greatly impacts patients’ quality of life which prompt searches for new, original approaches. Based on the research of vibrating capsule (VC) carried out by Ron et al., we investigated the safety and efficacy of an innovative, multi-mode VC in terms of its effect on defecation in animal studies. The parameters associated with different operation modes of VCs can be detected and adjusted by smartphone controlled external configuration device (ECD). The results of blood tests, physiological parameters, CT scan and pathological examination showed no significant abnormality, which undoubtedly confirmed the safety of VCs. For efficacy studies, defecation frequency of beagles increased after administration of these capsules without influence on stool characters. Meanwhile, the mean time of capsule evacuation tended to be reduced while showing no significant difference between different modes. In summary, this study elucidates the safety and effectiveness of VC in prompting the passage of gastrointestinal walls thus greatly increasing the defecation frequency. This study innovatively displays the promising application of VC in the treatment of constipation. Constipation, a common cause of abdominal discomfort and painful defecation, is defined as the less-frequent passage of stool or the passage of hard stool . Since most of the patients with constipation have symptoms for many years, it is considered a chronic disorder . Even though a minority of those with constipation seek medical treatment, it still accounts for 8 million annual visits to physicians in the United States . In a systematic review on the global prevalence of idiopathic constipation, Suares and Ford reported a pooled prevalence of 14% . It is revealed that the prevalence over 60 can be up to 22%, and is estimated to be as high as 30% in selected popula- tions especially in women, non-whites, those aged >65 years and those with lower socioeconomic status . With high prevalence, it imposes a significant economic burden in direct healthcare costs as well as having a significant 6, 7 impact on patients’ quality of life and working productivity . Based on current schemata, chronic constipation is usually classified into 2 categories: idiopathic (slow-transit and normal-transit) and secondary constipation . There are many evidence-based therapeutic approaches to the treatment of chronic constipation. World Gastroenterology Organization(WGO) advocates a graded approach to treatment from changes in lifestyle and diet, which includes osmotic laxatives to stimulant laxatives, enemas, and prokinetic drugs. Similarly, the American Society of Colon and Rectal Surgeons regards fiber, fluid supple- mentation and osmotic laxatives as initial management, and stimulant laxatives as second-line treatment. Surgical 1, 5, 9, 10 management is considered for refractory colonic slow-transit constipation . While there are many therapeu- tic options available, the combination of high prevalence, side effects of treatment, high recurrence rate and low patient satisfaction level has prompted searches for new, original approaches. In 2015, Ron et al. carried out research to validate the safety and potential efficacy of a vibrating capsule in the treatment of constipation. The capsule was activated using an electromagnetic signal and the fixed vibrating Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China. Department of Gastroenterology, the Fifth Affiliated Hospital of Zunyi Medical College, Changhai Hospital, Second Military Medical University, Shanghai, China. Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China. Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China. Jin Yu, Yang-Yang Qian and Chao-Hui He contributed equally to this work. Correspondence and requests for materials should be addressed to Z.L. (email: liaozhuan@smmu.edu.cn) or Z.-S.L. (email: zhaoshenli@ hotmail.com) Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 1 www.nature.com/scientificreports/ Figure 1. Radiographic examinations aer admini ft stration of ultra-high frequency capsules. (A) Abdominal plain film aer 2 ft hours’ vibration at ultra-high frequency. (B) CT image of stomach (arrow showing VC in the stomach). (C) CT image of intestine. (D) CT image of rectum. sequence (A or B, as recommended by the physician) began after a predetermined delay of 6–8 h to allow the capsule to arrive at the colon. It reported no serious adverse events and minor adverse effects were transient. A significant increase in the mean number of bowel movements was seen in 23 of the 26 patients. A new kind of vibrating capsule with four vibration modes has been developed. This new vibrating capsule may be modulated by a smart-phone controlled external configurator. Compared with that in previous studies, our capsule is directed and activity-controlled externally. This study investigated the safety and efficacy of an innovative, multi-mode vibrating capsule in terms of its effect on defecation in animals. The main focus was to determine whether the administration of smart phone-controlled VC was feasible in the treatment of constipation with its parameters being detected and adjusted by smartphone externally. Results Safety study. Results of physiological and blood parameters. In the first animal study, eight dogs each swal- lowed three vibrating capsules. In all cases, the dogs’ behaviour and mental status were normal with no signs of nausea, vomiting or oral expulsion of capsules during the follow-up period. Aer t ft he vibrating sequence began, vibration of the abdomen can be perceived and varied with modes. It was feasible to detect and define the cap- sule’s activity parameters by the external smartphone-controlled configurator. Of the 24 administrated capsules, all were evacuated two days after ingestion. There was no problem with expulsion of the capsules and capsules were expelled with no morphological abnormality. Aer admini ft stration of different capsules, there were no clinically significant abnormalities in any of the psy- chological and blood parameters(P > 0.05). Pathological examination results. After two hours’ vibration at ultra-high frequency, no signs of intestinal obstruction and perforation were seen on CT scan (Fig. 1A–D). There was no evidence of perforation, ulceration or bleeding macroscopically in the pathological specimens. Parasites were noticed in the small intestine of one dog. There was no microscopic evidence of interstitial edema, glandular distortion, obvious inflammatory cell infiltration and dysplastic epithelium in any of the pathological specimen (Fig.  2A–F). Efficacy study. No erythrocytes, leukocytes, macrophages, residual chyme or blood was observed in routine stool examination. Meanwhile, fecal transferrin and occult blood test were both negative. Defecation frequency. In the main efficacy endpoint, there was a significant increase in the frequency of defeca- tion (/day) aer c ft apsule ingestion. The median frequency at baseline, low, moderate and high mode were 1 (IQR 0), 2 (IQR 1), 2 (IQR 1) and 2 (IQR 1), respectively (Fig. 3A). The median frequency of defecation was higher than that at the baseline aer admini ft stration of low (P = 0.001), moderate (P = 0.003) and high mode vibrating capsules(P = 0.001), while there was no statistical difference among these three modes (all P > 0.05). Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 2 www.nature.com/scientificreports/ Figure 2. Pathological sections of integrated gastrointestinal wall aer c ft apsule administration. None reported lesion or abnormality. (A) Stomach. (B) Duodenum. (C) Jejunum. (D) Ileum. (E,F) Colon. Stool quantity. Vibrating capsules of different frequency all can increase stool quantity. The median stool quan- tity at baseline, low, moderate and high mode were 280.55 g (IQR 62.63), 308.6 g (IQR 70.88), 309.3 g (IQR 140.8) and 294.8 g (IQR 81.62), respectively (Fig. 3B). Significant difference was shown between dogs in each VC fre- quency group (P < 0.001). Stool quantity increased greatly from baseline aer admini ft stration of vibrating cap- sules (P = 0.001, <0.001 and 0.01 for low, moderate and high frequencies). Again, no statistical difference existed between each pair of the three modes (all P > 0.05). Faecal character. e B Th ristol Stool Chart (BSC) allows patients to identify their stool form using different images with accompanying written descriptors . According to Bristol Stool Chart, stool form can be classified into 7 types. The median scores of BSC for baseline, low, moderate and high frequency VCs were 5(IQR 1), 5(IQR 0), 5(IQR 0) and 5(IQR 0) (Fig. 3C). No significant difference was shown in stool character between dogs. Similarly, compared with that at baseline, stool character at low, moderate and high frequency existed no prominent abnor- malities (all P > 0.05). Meanwhile, no significant changes of stool character were observed between each pair of the three modes. Time of expulsion. The mean time of expulsion were 37.32 h, 30.07 h and 26.77 h for low, moderate and high frequency VCs, presenting a descending trend (Fig. 3D). In the safety study for ultra-high frequency mode, VCs were found in rectums of six dogs while the other two remained in stomach, with parasites showing up in the small intestine of one dog and the other one stopping working due to mechanical troubles. The mean time for eight dogs to expel the capsules showed no statistically difference (P = 0.346), and neither did the expulsion of capsules at different modes (P = 0.137). Discussion Chronic constipation is a disabled disorder affecting approximately 20% of the world’s population. Although considered benign in most cases, chronic constipation can result in chronic illness which can greatly influence the quality of life including fecal impaction, incontinence, hemorrhoids, anal fissures, bleeding, and in the most extreme cases, colon perforation . Yet the pathogenesis of constipation is still unclear. Given the present situation and advances in treatment, a new innovative vibrating capsule has been developed. With the advantage of easy operation, individualization, low cost and no obvious side effects, they can impinge on the gastrointestinal walls physically, inducing increased peristaltic activity that propel the bowel content through bowels, thus relieving constipation. In the safety studies, through analyses with the mental status, physiological, blood, stool parameters, CT scan as well as pathological anatomy of dogs, vibrating capsules proved to be highly safe, which is consistent with the study carried by Ron et al. With the assistance of smartphone and wireless configurator, the remaining power can be measured and the frequency of vibrating capsules can also be precisely adjusted as needed externally. In terms of efficacy studies, the results of the experiment showed a statistically significant increase in the defecation frequency and stool quantity aer ft dogs swallowed VCs, while no significant dier ff ence existed in stool character, which confirmed the safety and effectiveness. But there was no significantly difference of defecation Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 3 www.nature.com/scientificreports/ Figure 3. Efficacy study results. (A) The median defecation frequency increasing greatly aer admini ft stration of VCs at different modes compared with that at the baseline. (B) VC administration proved to improve stool quantity. Median values were denoted by the central horizontal line within the boxplots containing IQR for the results. (C) VC administration did not change the faecal character which showed its safety. (D) Mean expulsion time of capsules at different modes depicted by the horizental line showing no significant difference. (dots, square, triangle indicating beagles swallowing low, moderate and high mode VCs, respectively). frequency and stool quantity between multiple modes, which might have something to do with heterogeneity of dogs. er Th e was a trend towards a reduction in VC expulsion time with increasing vibration frequency. In the safety study of ultra-high frequency mode, VCs were found in rectums of six dogs ae ft r vibrating for three to four hours, which greatly shortened the expulsion time compared with high frequency mode. Given the small sample size, no statistically die ff rence was observed. Thus further studies and constipation models are needed to confirm these issues. In conclusion, VCs proved to be safe and ee ff ctive in animal studies and it is feasible for smartphone to control VCs externally. By mechanical stimulation of the gastrointestinal walls, capsules can greatly promote defecation frequency without any abnormality in stool character. Meanwhile, the mean time of expulsion had a descending trend with frequency of VCs increased. Ron et al. has depicted that vibrating capsules can greatly improve the mean number of bowel movements . Given the defecation promotion effect of VC illustrated by our study, we assumed that VCs may greatly relieve constipation. Thus we will further our research to validate the clinical appli- cation of VCs in constipation management with these encouraging results. Methods Study object. Experimental subjects are all quarantine qualified beagles, purchased from Shanghai Jiagan Biological Technology Co. Ltd (female: male = 1: 1), with 30–40 cm in height and 9.3 ± 1.7 Kg in weight (labora- tory animal production certificate No.SCXK 2010-0028). Dogs were acclimatized for 10–15 days to exclude stress involvement. During the acclimatization period, eight dogs were raised in stainless cages respectively at 19–26 ± 4 °C with humidity 40–70%, gas change 8–10/h and day and night ratio 12 h/12 h. Each dog had free access to 450 g food and 1500 ml water daily. Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 4 www.nature.com/scientificreports/ Figure 4. Activity of capsules can be detected and adjusted by configurator and configurator-matched App externally. Study site. e Th study was conducted in the animal laboratory center of Second Military Medical University (animal laboratory licence No. SYXK 2012-0003).The experimental protocol was approved by Laboratory Animal Ethics Committee of Second Military Medical University (animal ethical review No.13071002121). All experiments were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. Study intervention. e in Th tervention apparatus is composed of the capsule itself and an external configu- ration device (ECD). The capsule is developed by ANKON Medical Technology Co. Ltd., with 26.7 mm in length, 11.8 mm in diameter and 4.5 ± 0.5 g in weight. The vibration of the capsule can be set at four different modes by pushing the corresponding buttons on the ECD, that is dormancy, low, moderate and high. The capsule stops vibrating at the dormancy mode, and the vibration frequency ratio among the mode of high, moderate and low is 1:0.8:0.5°. er Th e is a two-way RF communication between VC and ECD, thus allowing VC to generate abrupt vibration by an eccentric motor. Once the ECD is put near the abdomen, the vibration mode can be activated and changed by the ECD. Moreover, a smartphone can communicate the ECD through an APP called VCP, which makes it feasible to select the mode and define the activity parameters of VCs externally. Semiconductor chip inside each VC with unique serial number is for recognition and manipulation (Figs 4 and 5). Study measurements. Physiological parameters. Continuously recorded physiological parameters includ- ing temperature (°C), heart rate (bpm), respiration (times/m), weight (Kg), conscious status and behaviour (nor- mality, somnolence, stupor, coma, nervousness, restlessness, laziness, barking, groaning, aggression, etc.), daily intake (g) and daily drink (ml) of beagles for 5 days. Blood parameters. Fasting venous blood was examined for white blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), platelet count (PLT),alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (ALB), urea nitrogen (BUN), serum creatinine (SCR), potassium (K) and sodium (Na). Stool parameters. Stool parameters recorded were consisted of daily defecation quantity(g), defecation fre- quency and stool characters. Morning fecal specimen were taken for routine and occult blood test. Study Design. Study at normal mode. In the first animal study, eight dogs began to fast at 20:00 pm the day before the program, and all the psychological and stool parameters were recorded 12 hours later. At 9:00 am, each of the eight dogs initially swallowed one capsule. Then dogs had free access to food and water. The vibrating sequence began at low frequency aer a p ft redetermined delay of 2 h to allow the capsule to pass through the pylorus. Researchers observed and reported all the parameters needed at 11:00, 14:00, 17:00 that day and at 08:00, 14:00, 17:00 every day thereaer un ft til the expulsion of the capsule was confirmed in the stool collection kit. Appearance of capsules, stool characters, quantity and color all needed close observation and record. The day aer admini ft stration of capsules, blood routine, biochemical panel, stool routine and occult blood test were reviewed. Aer t ft he expulsion of first capsule was confirmed, another one would be given at least 3 days later for the investigation of other modes. Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 5 www.nature.com/scientificreports/ Figure 5. Diagram of vibrating capsule and external configuration device. Safety study at ultra-high frequency mode. e v Th ibrating sequence was set at ultra-high frequency and the pre- vious steps were repeated for capsule administration. Abdominal CT scan was performed aer t ft wo hours’ vibra- tion. Thereaer ft , with dogs euthanized and dissected, gastrointestinal explorations were carried out immediately. Biopsies with specimen of 3 cm x3 cm in size were obtained wherever any possible macroscopic lesions were identified. Statistical analyses. Data were presented as median with interquartile range (IQR) for continuous varia- bles. Statistical analyses were conducted using SAS” version 21.0. The covariance analysis was applied for testing the statistical significance of changes between the baseline assessment and the multiple parameters in treatment period with a final two-sided P value of less than 0.05 indicating statistical difference. References 1. Greenwald, B. J. Clinical practice guidelines for pediatric constipation. J Am Acad Nurse Pract. 22(7), 332–338, doi:10.1111/ jaan.2010.22.issue-7 (2010). 2. Dik, V. K. et al. Constipation-related direct medical costs in 16887 patients newly diagnosed with chronic constipation. Eur J Gastroenterol Hepatol. 26(11), 1260–1266, doi:10.1097/MEG.0000000000000167 (2014). 3. Wald, A. Constipation: Advances in Diagnosis and Treatment. Jama 315(2), 185–191, doi:10.1001/jama.2015.16994 (2016). 4. Ford, A. C. et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. e A Th merican journal of gastroenterology. 109 (Suppl 1), S2–26, quiz S27 (2014). 5. Paquette, I. M. et al. The American Society of Colon and Rectal Surgeons’ Clinical Practice Guideline for the Evaluation and Management of Constipation. Dis Colon Rectum. 59(6), 479–492, doi:10.1097/DCR.0000000000000599 (2016). 6. Cai, Q. et al. Healthcare costs among patients with chronic constipation: a retrospective claims analysis in a commercially insured population. J Med Econ. 17(2), 148–158, doi:10.3111/13696998.2013.860375 (2014). 7. Nyrop, K. A. et al. Costs of health care for irritable bowel syndrome, chronic constipation, functional diarrhoea and functional abdominal pain. Aliment Pharmacol Ther. 26(2), 237–248, doi:10.1111/j.1365-2036.2007.03370.x (2007). 8. Brenner, D. M. & Shah, M. Chronic Constipation. Curr Gastroenterol Rep. 17(12), 205–216, doi:10.1016/j.gtc.2016.02.013 (2016). 9. Basilisco, G. & Coletta, M. Chronic constipation: a critical review. Dig Liver Dis. 45(11), 886–893, doi:10.1016/j.dld.2013.03.016 (2013). 10. Lindberg, G. et al. World Gastroenterology Organisation Global Guideline Constipation—A Global Perspective. J Clin Gastroenterol. 45(6), 483–487, doi:10.1097/MCG.0b013e31820fb914 (2011). 11. Ron, Y. et al. Safety and efficacy of the vibrating capsule, an innovative non-pharmacological treatment modality for chronic constipation. Neurogastroenterol Motil. 27(1), 99–104, doi:10.1111/nmo.12485 (2015). 12. Amarenco, G. Bristol Stool Chart: Prospective and monocentric study of “stools introspection” in healthy subjects. Prog Urol. 24(11), 708–713, doi:10.1016/j.purol.2014.06.008 (2014). 13. Brenner, D. M. & Shah, M. Chronic Constipation. Gastroenterol Clin North Am. 45(2), 205–216, doi:10.1016/j.gtc.2016.02.013 (2016). Acknowledgements We would like to thank Prof. Xiao-Dong Duan, Prof. Guo-Hua Xiao, and Prof. Xin-Hong Wang, from Ankon Technologies Co. Ltd., for their technical assistance. We also want to extend our gratitude to Mark Edward McAlindon, from Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, UK, for his constructive comments and reviewing the English text. This study is supported by grants from the National Natural Science Foundation of China (81422010 to ZL), Foundation for the Author of National Excellent Doctoral Dissertation of China (201271 to ZL), the Shuguang Program of Shanghai Education Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 6 www.nature.com/scientificreports/ Development Foundation and Shanghai Municipal Education Commission (15SG33 to ZL); the Chang Jiang Scholars Program of Ministry of Education (Q2015190 to ZL), China; the Shanghai Health and Family Planning Commission Plans to Young Talents (to Z. Liao, No. XYQ2013070), the Shanghai Talent Development Fund (to Z. Liao, No. 201364), and the Outstanding Young Scholars Fund of Second Military Medical University (to Z. Liao). Author Contributions Study concept and design (Z.L.); conduct of the study (J.Y., T.G.W., C.W.S.); acquisition of data (Y.W., S.G.Z., A.J.Z.); analysis and interpretation of data (Z.Q.Q., C.H.H., G.L.D.); drafting of the manuscript (Z.L., Y.J., Q.Y.Y.); critical revision of the manuscript for important intellectual content (Z.S.L.); statistical analysis (Z.Q.Q., T.G.W.); obtained funding (Z.L., Z.S.L.). Additional Information Competing Interests: The authors declare that they have no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre- ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per- mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 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Safety and Efficacy of a New Smartphone-controlled Vibrating Capsule on Defecation in Beagles

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Abstract

www.nature.com/scientificreports OPEN Safety and Efficacy of a New Smartphone-controlled Vibrating Capsule on Defecation in Beagles Received: 3 February 2017 1 1 2 1 1 1 Jin Yu , Yang-Yang Qian , Chao-Hui He , Shu-Guang Zhu , An-Jing Zhao , Qian-Qian Zhu , 3 3 4 4 1 1 Accepted: 18 April 2017 Cheng-Wei Shao , Tie-Gong Wang , Yang Wang , Gui-Ling Ding , Zhuan Liao & Zhao-Shen Li Published: xx xx xxxx Constipation, mainly manifesting as abdominal discomfort and painful defecation, is considered as a chronic disorder. Due to a lack of effective therapy, it imposes a significant economic burden and greatly impacts patients’ quality of life which prompt searches for new, original approaches. Based on the research of vibrating capsule (VC) carried out by Ron et al., we investigated the safety and efficacy of an innovative, multi-mode VC in terms of its effect on defecation in animal studies. The parameters associated with different operation modes of VCs can be detected and adjusted by smartphone controlled external configuration device (ECD). The results of blood tests, physiological parameters, CT scan and pathological examination showed no significant abnormality, which undoubtedly confirmed the safety of VCs. For efficacy studies, defecation frequency of beagles increased after administration of these capsules without influence on stool characters. Meanwhile, the mean time of capsule evacuation tended to be reduced while showing no significant difference between different modes. In summary, this study elucidates the safety and effectiveness of VC in prompting the passage of gastrointestinal walls thus greatly increasing the defecation frequency. This study innovatively displays the promising application of VC in the treatment of constipation. Constipation, a common cause of abdominal discomfort and painful defecation, is defined as the less-frequent passage of stool or the passage of hard stool . Since most of the patients with constipation have symptoms for many years, it is considered a chronic disorder . Even though a minority of those with constipation seek medical treatment, it still accounts for 8 million annual visits to physicians in the United States . In a systematic review on the global prevalence of idiopathic constipation, Suares and Ford reported a pooled prevalence of 14% . It is revealed that the prevalence over 60 can be up to 22%, and is estimated to be as high as 30% in selected popula- tions especially in women, non-whites, those aged >65 years and those with lower socioeconomic status . With high prevalence, it imposes a significant economic burden in direct healthcare costs as well as having a significant 6, 7 impact on patients’ quality of life and working productivity . Based on current schemata, chronic constipation is usually classified into 2 categories: idiopathic (slow-transit and normal-transit) and secondary constipation . There are many evidence-based therapeutic approaches to the treatment of chronic constipation. World Gastroenterology Organization(WGO) advocates a graded approach to treatment from changes in lifestyle and diet, which includes osmotic laxatives to stimulant laxatives, enemas, and prokinetic drugs. Similarly, the American Society of Colon and Rectal Surgeons regards fiber, fluid supple- mentation and osmotic laxatives as initial management, and stimulant laxatives as second-line treatment. Surgical 1, 5, 9, 10 management is considered for refractory colonic slow-transit constipation . While there are many therapeu- tic options available, the combination of high prevalence, side effects of treatment, high recurrence rate and low patient satisfaction level has prompted searches for new, original approaches. In 2015, Ron et al. carried out research to validate the safety and potential efficacy of a vibrating capsule in the treatment of constipation. The capsule was activated using an electromagnetic signal and the fixed vibrating Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China. Department of Gastroenterology, the Fifth Affiliated Hospital of Zunyi Medical College, Changhai Hospital, Second Military Medical University, Shanghai, China. Department of Radiology, Changhai Hospital, Second Military Medical University, Shanghai, China. Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai, China. Jin Yu, Yang-Yang Qian and Chao-Hui He contributed equally to this work. Correspondence and requests for materials should be addressed to Z.L. (email: liaozhuan@smmu.edu.cn) or Z.-S.L. (email: zhaoshenli@ hotmail.com) Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 1 www.nature.com/scientificreports/ Figure 1. Radiographic examinations aer admini ft stration of ultra-high frequency capsules. (A) Abdominal plain film aer 2 ft hours’ vibration at ultra-high frequency. (B) CT image of stomach (arrow showing VC in the stomach). (C) CT image of intestine. (D) CT image of rectum. sequence (A or B, as recommended by the physician) began after a predetermined delay of 6–8 h to allow the capsule to arrive at the colon. It reported no serious adverse events and minor adverse effects were transient. A significant increase in the mean number of bowel movements was seen in 23 of the 26 patients. A new kind of vibrating capsule with four vibration modes has been developed. This new vibrating capsule may be modulated by a smart-phone controlled external configurator. Compared with that in previous studies, our capsule is directed and activity-controlled externally. This study investigated the safety and efficacy of an innovative, multi-mode vibrating capsule in terms of its effect on defecation in animals. The main focus was to determine whether the administration of smart phone-controlled VC was feasible in the treatment of constipation with its parameters being detected and adjusted by smartphone externally. Results Safety study. Results of physiological and blood parameters. In the first animal study, eight dogs each swal- lowed three vibrating capsules. In all cases, the dogs’ behaviour and mental status were normal with no signs of nausea, vomiting or oral expulsion of capsules during the follow-up period. Aer t ft he vibrating sequence began, vibration of the abdomen can be perceived and varied with modes. It was feasible to detect and define the cap- sule’s activity parameters by the external smartphone-controlled configurator. Of the 24 administrated capsules, all were evacuated two days after ingestion. There was no problem with expulsion of the capsules and capsules were expelled with no morphological abnormality. Aer admini ft stration of different capsules, there were no clinically significant abnormalities in any of the psy- chological and blood parameters(P > 0.05). Pathological examination results. After two hours’ vibration at ultra-high frequency, no signs of intestinal obstruction and perforation were seen on CT scan (Fig. 1A–D). There was no evidence of perforation, ulceration or bleeding macroscopically in the pathological specimens. Parasites were noticed in the small intestine of one dog. There was no microscopic evidence of interstitial edema, glandular distortion, obvious inflammatory cell infiltration and dysplastic epithelium in any of the pathological specimen (Fig.  2A–F). Efficacy study. No erythrocytes, leukocytes, macrophages, residual chyme or blood was observed in routine stool examination. Meanwhile, fecal transferrin and occult blood test were both negative. Defecation frequency. In the main efficacy endpoint, there was a significant increase in the frequency of defeca- tion (/day) aer c ft apsule ingestion. The median frequency at baseline, low, moderate and high mode were 1 (IQR 0), 2 (IQR 1), 2 (IQR 1) and 2 (IQR 1), respectively (Fig. 3A). The median frequency of defecation was higher than that at the baseline aer admini ft stration of low (P = 0.001), moderate (P = 0.003) and high mode vibrating capsules(P = 0.001), while there was no statistical difference among these three modes (all P > 0.05). Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 2 www.nature.com/scientificreports/ Figure 2. Pathological sections of integrated gastrointestinal wall aer c ft apsule administration. None reported lesion or abnormality. (A) Stomach. (B) Duodenum. (C) Jejunum. (D) Ileum. (E,F) Colon. Stool quantity. Vibrating capsules of different frequency all can increase stool quantity. The median stool quan- tity at baseline, low, moderate and high mode were 280.55 g (IQR 62.63), 308.6 g (IQR 70.88), 309.3 g (IQR 140.8) and 294.8 g (IQR 81.62), respectively (Fig. 3B). Significant difference was shown between dogs in each VC fre- quency group (P < 0.001). Stool quantity increased greatly from baseline aer admini ft stration of vibrating cap- sules (P = 0.001, <0.001 and 0.01 for low, moderate and high frequencies). Again, no statistical difference existed between each pair of the three modes (all P > 0.05). Faecal character. e B Th ristol Stool Chart (BSC) allows patients to identify their stool form using different images with accompanying written descriptors . According to Bristol Stool Chart, stool form can be classified into 7 types. The median scores of BSC for baseline, low, moderate and high frequency VCs were 5(IQR 1), 5(IQR 0), 5(IQR 0) and 5(IQR 0) (Fig. 3C). No significant difference was shown in stool character between dogs. Similarly, compared with that at baseline, stool character at low, moderate and high frequency existed no prominent abnor- malities (all P > 0.05). Meanwhile, no significant changes of stool character were observed between each pair of the three modes. Time of expulsion. The mean time of expulsion were 37.32 h, 30.07 h and 26.77 h for low, moderate and high frequency VCs, presenting a descending trend (Fig. 3D). In the safety study for ultra-high frequency mode, VCs were found in rectums of six dogs while the other two remained in stomach, with parasites showing up in the small intestine of one dog and the other one stopping working due to mechanical troubles. The mean time for eight dogs to expel the capsules showed no statistically difference (P = 0.346), and neither did the expulsion of capsules at different modes (P = 0.137). Discussion Chronic constipation is a disabled disorder affecting approximately 20% of the world’s population. Although considered benign in most cases, chronic constipation can result in chronic illness which can greatly influence the quality of life including fecal impaction, incontinence, hemorrhoids, anal fissures, bleeding, and in the most extreme cases, colon perforation . Yet the pathogenesis of constipation is still unclear. Given the present situation and advances in treatment, a new innovative vibrating capsule has been developed. With the advantage of easy operation, individualization, low cost and no obvious side effects, they can impinge on the gastrointestinal walls physically, inducing increased peristaltic activity that propel the bowel content through bowels, thus relieving constipation. In the safety studies, through analyses with the mental status, physiological, blood, stool parameters, CT scan as well as pathological anatomy of dogs, vibrating capsules proved to be highly safe, which is consistent with the study carried by Ron et al. With the assistance of smartphone and wireless configurator, the remaining power can be measured and the frequency of vibrating capsules can also be precisely adjusted as needed externally. In terms of efficacy studies, the results of the experiment showed a statistically significant increase in the defecation frequency and stool quantity aer ft dogs swallowed VCs, while no significant dier ff ence existed in stool character, which confirmed the safety and effectiveness. But there was no significantly difference of defecation Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 3 www.nature.com/scientificreports/ Figure 3. Efficacy study results. (A) The median defecation frequency increasing greatly aer admini ft stration of VCs at different modes compared with that at the baseline. (B) VC administration proved to improve stool quantity. Median values were denoted by the central horizontal line within the boxplots containing IQR for the results. (C) VC administration did not change the faecal character which showed its safety. (D) Mean expulsion time of capsules at different modes depicted by the horizental line showing no significant difference. (dots, square, triangle indicating beagles swallowing low, moderate and high mode VCs, respectively). frequency and stool quantity between multiple modes, which might have something to do with heterogeneity of dogs. er Th e was a trend towards a reduction in VC expulsion time with increasing vibration frequency. In the safety study of ultra-high frequency mode, VCs were found in rectums of six dogs ae ft r vibrating for three to four hours, which greatly shortened the expulsion time compared with high frequency mode. Given the small sample size, no statistically die ff rence was observed. Thus further studies and constipation models are needed to confirm these issues. In conclusion, VCs proved to be safe and ee ff ctive in animal studies and it is feasible for smartphone to control VCs externally. By mechanical stimulation of the gastrointestinal walls, capsules can greatly promote defecation frequency without any abnormality in stool character. Meanwhile, the mean time of expulsion had a descending trend with frequency of VCs increased. Ron et al. has depicted that vibrating capsules can greatly improve the mean number of bowel movements . Given the defecation promotion effect of VC illustrated by our study, we assumed that VCs may greatly relieve constipation. Thus we will further our research to validate the clinical appli- cation of VCs in constipation management with these encouraging results. Methods Study object. Experimental subjects are all quarantine qualified beagles, purchased from Shanghai Jiagan Biological Technology Co. Ltd (female: male = 1: 1), with 30–40 cm in height and 9.3 ± 1.7 Kg in weight (labora- tory animal production certificate No.SCXK 2010-0028). Dogs were acclimatized for 10–15 days to exclude stress involvement. During the acclimatization period, eight dogs were raised in stainless cages respectively at 19–26 ± 4 °C with humidity 40–70%, gas change 8–10/h and day and night ratio 12 h/12 h. Each dog had free access to 450 g food and 1500 ml water daily. Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 4 www.nature.com/scientificreports/ Figure 4. Activity of capsules can be detected and adjusted by configurator and configurator-matched App externally. Study site. e Th study was conducted in the animal laboratory center of Second Military Medical University (animal laboratory licence No. SYXK 2012-0003).The experimental protocol was approved by Laboratory Animal Ethics Committee of Second Military Medical University (animal ethical review No.13071002121). All experiments were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. Study intervention. e in Th tervention apparatus is composed of the capsule itself and an external configu- ration device (ECD). The capsule is developed by ANKON Medical Technology Co. Ltd., with 26.7 mm in length, 11.8 mm in diameter and 4.5 ± 0.5 g in weight. The vibration of the capsule can be set at four different modes by pushing the corresponding buttons on the ECD, that is dormancy, low, moderate and high. The capsule stops vibrating at the dormancy mode, and the vibration frequency ratio among the mode of high, moderate and low is 1:0.8:0.5°. er Th e is a two-way RF communication between VC and ECD, thus allowing VC to generate abrupt vibration by an eccentric motor. Once the ECD is put near the abdomen, the vibration mode can be activated and changed by the ECD. Moreover, a smartphone can communicate the ECD through an APP called VCP, which makes it feasible to select the mode and define the activity parameters of VCs externally. Semiconductor chip inside each VC with unique serial number is for recognition and manipulation (Figs 4 and 5). Study measurements. Physiological parameters. Continuously recorded physiological parameters includ- ing temperature (°C), heart rate (bpm), respiration (times/m), weight (Kg), conscious status and behaviour (nor- mality, somnolence, stupor, coma, nervousness, restlessness, laziness, barking, groaning, aggression, etc.), daily intake (g) and daily drink (ml) of beagles for 5 days. Blood parameters. Fasting venous blood was examined for white blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), platelet count (PLT),alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), total protein (TP), albumin (ALB), urea nitrogen (BUN), serum creatinine (SCR), potassium (K) and sodium (Na). Stool parameters. Stool parameters recorded were consisted of daily defecation quantity(g), defecation fre- quency and stool characters. Morning fecal specimen were taken for routine and occult blood test. Study Design. Study at normal mode. In the first animal study, eight dogs began to fast at 20:00 pm the day before the program, and all the psychological and stool parameters were recorded 12 hours later. At 9:00 am, each of the eight dogs initially swallowed one capsule. Then dogs had free access to food and water. The vibrating sequence began at low frequency aer a p ft redetermined delay of 2 h to allow the capsule to pass through the pylorus. Researchers observed and reported all the parameters needed at 11:00, 14:00, 17:00 that day and at 08:00, 14:00, 17:00 every day thereaer un ft til the expulsion of the capsule was confirmed in the stool collection kit. Appearance of capsules, stool characters, quantity and color all needed close observation and record. The day aer admini ft stration of capsules, blood routine, biochemical panel, stool routine and occult blood test were reviewed. Aer t ft he expulsion of first capsule was confirmed, another one would be given at least 3 days later for the investigation of other modes. Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 5 www.nature.com/scientificreports/ Figure 5. Diagram of vibrating capsule and external configuration device. Safety study at ultra-high frequency mode. e v Th ibrating sequence was set at ultra-high frequency and the pre- vious steps were repeated for capsule administration. Abdominal CT scan was performed aer t ft wo hours’ vibra- tion. Thereaer ft , with dogs euthanized and dissected, gastrointestinal explorations were carried out immediately. Biopsies with specimen of 3 cm x3 cm in size were obtained wherever any possible macroscopic lesions were identified. Statistical analyses. Data were presented as median with interquartile range (IQR) for continuous varia- bles. Statistical analyses were conducted using SAS” version 21.0. The covariance analysis was applied for testing the statistical significance of changes between the baseline assessment and the multiple parameters in treatment period with a final two-sided P value of less than 0.05 indicating statistical difference. References 1. Greenwald, B. J. Clinical practice guidelines for pediatric constipation. J Am Acad Nurse Pract. 22(7), 332–338, doi:10.1111/ jaan.2010.22.issue-7 (2010). 2. Dik, V. K. et al. Constipation-related direct medical costs in 16887 patients newly diagnosed with chronic constipation. Eur J Gastroenterol Hepatol. 26(11), 1260–1266, doi:10.1097/MEG.0000000000000167 (2014). 3. Wald, A. Constipation: Advances in Diagnosis and Treatment. Jama 315(2), 185–191, doi:10.1001/jama.2015.16994 (2016). 4. Ford, A. C. et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. e A Th merican journal of gastroenterology. 109 (Suppl 1), S2–26, quiz S27 (2014). 5. Paquette, I. M. et al. The American Society of Colon and Rectal Surgeons’ Clinical Practice Guideline for the Evaluation and Management of Constipation. Dis Colon Rectum. 59(6), 479–492, doi:10.1097/DCR.0000000000000599 (2016). 6. Cai, Q. et al. Healthcare costs among patients with chronic constipation: a retrospective claims analysis in a commercially insured population. J Med Econ. 17(2), 148–158, doi:10.3111/13696998.2013.860375 (2014). 7. Nyrop, K. A. et al. Costs of health care for irritable bowel syndrome, chronic constipation, functional diarrhoea and functional abdominal pain. Aliment Pharmacol Ther. 26(2), 237–248, doi:10.1111/j.1365-2036.2007.03370.x (2007). 8. Brenner, D. M. & Shah, M. Chronic Constipation. Curr Gastroenterol Rep. 17(12), 205–216, doi:10.1016/j.gtc.2016.02.013 (2016). 9. Basilisco, G. & Coletta, M. Chronic constipation: a critical review. Dig Liver Dis. 45(11), 886–893, doi:10.1016/j.dld.2013.03.016 (2013). 10. Lindberg, G. et al. World Gastroenterology Organisation Global Guideline Constipation—A Global Perspective. J Clin Gastroenterol. 45(6), 483–487, doi:10.1097/MCG.0b013e31820fb914 (2011). 11. Ron, Y. et al. Safety and efficacy of the vibrating capsule, an innovative non-pharmacological treatment modality for chronic constipation. Neurogastroenterol Motil. 27(1), 99–104, doi:10.1111/nmo.12485 (2015). 12. Amarenco, G. Bristol Stool Chart: Prospective and monocentric study of “stools introspection” in healthy subjects. Prog Urol. 24(11), 708–713, doi:10.1016/j.purol.2014.06.008 (2014). 13. Brenner, D. M. & Shah, M. Chronic Constipation. Gastroenterol Clin North Am. 45(2), 205–216, doi:10.1016/j.gtc.2016.02.013 (2016). Acknowledgements We would like to thank Prof. Xiao-Dong Duan, Prof. Guo-Hua Xiao, and Prof. Xin-Hong Wang, from Ankon Technologies Co. Ltd., for their technical assistance. We also want to extend our gratitude to Mark Edward McAlindon, from Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, UK, for his constructive comments and reviewing the English text. This study is supported by grants from the National Natural Science Foundation of China (81422010 to ZL), Foundation for the Author of National Excellent Doctoral Dissertation of China (201271 to ZL), the Shuguang Program of Shanghai Education Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 6 www.nature.com/scientificreports/ Development Foundation and Shanghai Municipal Education Commission (15SG33 to ZL); the Chang Jiang Scholars Program of Ministry of Education (Q2015190 to ZL), China; the Shanghai Health and Family Planning Commission Plans to Young Talents (to Z. Liao, No. XYQ2013070), the Shanghai Talent Development Fund (to Z. Liao, No. 201364), and the Outstanding Young Scholars Fund of Second Military Medical University (to Z. Liao). Author Contributions Study concept and design (Z.L.); conduct of the study (J.Y., T.G.W., C.W.S.); acquisition of data (Y.W., S.G.Z., A.J.Z.); analysis and interpretation of data (Z.Q.Q., C.H.H., G.L.D.); drafting of the manuscript (Z.L., Y.J., Q.Y.Y.); critical revision of the manuscript for important intellectual content (Z.S.L.); statistical analysis (Z.Q.Q., T.G.W.); obtained funding (Z.L., Z.S.L.). Additional Information Competing Interests: The authors declare that they have no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre- ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per- mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2017 Scientific Repo R ts | 7: 2841 | DOI:10.1038/s41598-017-02844-4 7

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