{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:52:30Z","timestamp":1792428750704,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T00:00:00Z","timestamp":1579737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Cystoscopic onabotulinumtoxinA (onaBoNTA) intradetrusor injection is an efficient and durable modality for treating sensory bladder disorders. However, the inconvenience of using the cystoscopic technique and anesthesia, and the adverse effects of direct needle injection (e.g., haematuria, pain, and infections) have motivated researchers and clinicians to develop diverse injection-free procedures to improve accessibility and prevent adverse effects. However, determining suitable approaches to transfer onaBoNTA, a large molecular and hydrophilic protein, through the impermeable urothelium to reach therapeutic efficacy remains an unmet medical need. Researchers have provided potential solutions in three categories: To disrupt the barrier of the urothelium (e.g., protamine sulfate), to increase the permeability of the urothelium (e.g., electromotive drug delivery and low-energy shock wave), and to create a carrier for transportation (e.g., liposomes, thermosensitive hydrogel, and hyaluronan-phosphatidylethanolamine). Thus far, most of these novel administration techniques have not been well established in their long-term efficacy; therefore, additional clinical trials are warranted to validate the therapeutic efficacy and durability of these techniques. Finally, researchers may make progress with new combinations or biomaterials to change clinical practices in the future.<\/jats:p>","DOI":"10.3390\/toxins12020075","type":"journal-article","created":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T07:41:11Z","timestamp":1580110871000},"page":"75","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Therapeutic Efficacy of onabotulinumtoxinA Delivered Using Various Approaches in Sensory Bladder Disorder"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7250-2478","authenticated-orcid":false,"given":"Po-Yen","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0701-2285","authenticated-orcid":false,"given":"Wei-Chia","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Jen","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"},{"name":"Center for Shock Wave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1468-3792","authenticated-orcid":false,"given":"Yao-Chi","family":"Chuang","sequence":"additional","affiliation":[{"name":"Division of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"},{"name":"Center for Shock Wave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S0022-5347(17)42717-0","article-title":"Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients","volume":"139","author":"Dykstra","year":"1988","journal-title":"J. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Jhang, J.F., and Kuo, H.C. (2016). Botulinum Toxin A and Lower Urinary Tract Dysfunction: Pathophysiology and Mechanisms of Action. Toxins, 8.","DOI":"10.3390\/toxins8040120"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nrurol.2015.193","article-title":"Current and potential urological applications of botulinum toxin A","volume":"12","author":"Jiang","year":"2015","journal-title":"Nat. Rev. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"931","DOI":"10.3389\/fnins.2018.00931","article-title":"Mechanisms Underlying Overactive Bladder and Interstitial Cystitis\/Painful Bladder Syndrome","volume":"12","author":"Grundy","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_5","first-page":"S7","article-title":"Pathophysiology of overactive bladder and urge urinary incontinence","volume":"4","author":"Steers","year":"2002","journal-title":"Rev. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/luts.12193","article-title":"Prevalence of overactive bladder in China, Taiwan and South Korea: Results from a cross-sectional, population-based study","volume":"11","author":"Chuang","year":"2019","journal-title":"Low. Urin. Tract Symptoms"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s11884-016-0344-9","article-title":"The Burden of Overactive Bladder on US Public Health","volume":"11","author":"Reynolds","year":"2016","journal-title":"Curr. Bladder Dysfunct. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.juro.2011.03.132","article-title":"Prevalence of symptoms of bladder pain syndrome\/interstitial cystitis among adult females in the United States","volume":"186","author":"Berry","year":"2011","journal-title":"J. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1097\/JU.0000000000000309","article-title":"Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: AUA\/SUFU Guideline Amendment 2019","volume":"202","author":"Lightner","year":"2019","journal-title":"J. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1016\/j.juro.2015.01.086","article-title":"Diagnosis and treatment of interstitial cystitis\/bladder pain syndrome: AUA guideline amendment","volume":"193","author":"Hanno","year":"2015","journal-title":"J. Urol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.juro.2011.10.130","article-title":"Effect of onabotulinumtoxinA on intramural parasympathetic ganglia: An experimental study in the guinea pig bladder","volume":"187","author":"Coelho","year":"2012","journal-title":"J. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1152\/physrev.00030.2012","article-title":"Urothelial signaling","volume":"93","author":"Birder","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.urology.2005.01.055","article-title":"In vivo effects of botulinum toxin A on visceral sensory function in chronic spinal cord-injured rats","volume":"66","author":"Khera","year":"2005","journal-title":"Urology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/j.eururo.2012.01.046","article-title":"Spread of onabotulinumtoxinA after bladder injection. Experimental study using the distribution of cleaved SNAP-25 as the marker of the toxin action","volume":"61","author":"Coelho","year":"2012","journal-title":"Eur. Urol."},{"key":"ref_15","first-page":"3","article-title":"Tight junctions and bladder cancer (review)","volume":"16","author":"Haynes","year":"2005","journal-title":"Int. J. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/BF00232022","article-title":"Effect of protamine sulfate on the permeability properties of the mammalian urinary bladder","volume":"133","author":"Tzan","year":"1993","journal-title":"J. Membr. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/S0022-5347(01)66406-1","article-title":"Bladder injury model induced in rats by exposure to protamine sulfate followed by bacterial endotoxin","volume":"155","author":"Stein","year":"1996","journal-title":"J. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.juro.2012.08.189","article-title":"Protamine sulfate induced bladder injury protects from distention induced bladder pain","volume":"189","author":"Stemler","year":"2013","journal-title":"J. Urol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0022-5347(17)61032-2","article-title":"The treatment of patients with interstitial cystitis, with special reference to intravesical DMSO","volume":"107","author":"Stewart","year":"1972","journal-title":"J. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1177\/1756287211398255","article-title":"Role of inflammation in bladder function and interstitial cystitis","volume":"3","author":"Grover","year":"2011","journal-title":"Adv. Urol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1038\/sj.bjp.0707317","article-title":"Dimethyl sulphoxide relaxes rabbit detrusor muscle by decreasing the Ca2+ sensitivity of the contractile apparatus","volume":"151","author":"Shiga","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"702","DOI":"10.4065\/84.8.702","article-title":"Botulinum a toxin\/dimethyl sulfoxide bladder instillations for women with refractory idiopathic detrusor overactivity: A phase 1\/2 study","volume":"84","author":"Petrou","year":"2009","journal-title":"Mayo Clin. Proc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1016\/S0022-5347(01)65638-6","article-title":"Electromotive drug administration to the urinary bladder: An animal model and preliminary results","volume":"156","author":"Gurpinar","year":"1996","journal-title":"J. Urol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1308\/003588414X13946184901001","article-title":"The effects and effectiveness of electromotive drug administration and chemohyperthermia for treating non-muscle invasive bladder cancer","volume":"96","author":"Slater","year":"2014","journal-title":"Ann. R. Coll. Surg. Engl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1097\/01.ju.0000080568.91703.18","article-title":"Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: A prospective randomized study","volume":"170","author":"Giannantoni","year":"2003","journal-title":"J. Urol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/S1470-2045(11)70190-5","article-title":"Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: A randomised controlled trial","volume":"12","author":"Valenti","year":"2011","journal-title":"Lancet. Oncol."},{"key":"ref_27","first-page":"4912","article-title":"Electromotive versus passive diffusion of mitomycin C into human bladder wall: Concentration-depth profiles studies","volume":"59","author":"Giannantoni","year":"1999","journal-title":"Cancer Res."},{"key":"ref_28","unstructured":"CADTH Rapid Response Reports (2014). The Use of the Electromotive Drug Administration System in Patients with Overactive Bladder: A Review of the Clinical Effectiveness, Safety, and Cost-Effectiveness, Canadian Agency for Drugs and Technologies in Health."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.urology.2010.06.003","article-title":"Intravesical electromotive botulinum toxin type A administration--part II: Clinical application","volume":"77","author":"Kajbafzadeh","year":"2011","journal-title":"Urology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.urology.2017.11.039","article-title":"Intravesical Electromotive Botulinum Toxin Type \u201cA\u201d Administration for Management of Urinary Incontinence Secondary to Neuropathic Detrusor Overactivity in Children: Long-term Follow-up","volume":"114","author":"Kajbafzadeh","year":"2018","journal-title":"Urology"},{"key":"ref_31","first-page":"573","article-title":"Potential applications of low-energy shock waves in functional urology","volume":"24","author":"Wang","year":"2017","journal-title":"Int. J. Urol. Off. J. Jpn. Urol. Assoc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.juro.2015.12.078","article-title":"Urodynamic and Immunohistochemical Evaluation of Intravesical Botulinum Toxin A Delivery Using Low Energy Shock Waves","volume":"196","author":"Chuang","year":"2016","journal-title":"J. Urol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1080\/2090598X.2019.1605676","article-title":"Delivery of intravesical botulinum toxin A using low-energy shockwaves in the treatment of overactive bladder: A preliminary clinical study","volume":"17","author":"Nageib","year":"2019","journal-title":"Arab J. Urol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.urols.2014.12.008","article-title":"Role of liposome in treatment of overactive bladder and interstitial cystitis","volume":"26","author":"Hung","year":"2015","journal-title":"Urol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1016\/j.juro.2009.06.024","article-title":"Intravesical liposome versus oral pentosan polysulfate for interstitial cystitis\/painful bladder syndrome","volume":"182","author":"Chuang","year":"2009","journal-title":"J. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.juro.2009.03.083","article-title":"Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes","volume":"182","author":"Chuang","year":"2009","journal-title":"J. Urol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.eururo.2014.01.036","article-title":"Pilot study of liposome-encapsulated onabotulinumtoxina for patients with overactive bladder: A single-center study","volume":"65","author":"Kuo","year":"2014","journal-title":"Eur. Urol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1016\/j.juro.2014.07.008","article-title":"Bladder instillation of liposome encapsulated onabotulinumtoxina improves overactive bladder symptoms: A prospective, multicenter, double-blind, randomized trial","volume":"192","author":"Chuang","year":"2014","journal-title":"J. Urol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.juro.2017.02.021","article-title":"A Prospective, Multicenter, Double-Blind, Randomized Trial of Bladder Instillation of Liposome Formulation OnabotulinumtoxinA for Interstitial Cystitis\/Bladder Pain Syndrome","volume":"198","author":"Chuang","year":"2017","journal-title":"J. Urol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lee, W.C., Su, C.H., Tain, Y.L., Tsai, C.N., Yu, C.C., and Chuang, Y.C. (2018). Potential Orphan Drug Therapy of Intravesical Liposomal Onabotulinumtoxin-A for Ketamine-Induced Cystitis by Mucosal Protection and Anti-inflammation in a Rat Model. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-24239-9"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0168-3659(99)00194-7","article-title":"Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers","volume":"63","author":"Jeong","year":"2000","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1023\/B:PHAM.0000026436.62869.9c","article-title":"Sustained intravesical drug delivery using thermosensitive hydrogel","volume":"21","author":"Tyagi","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"200","DOI":"10.3109\/21681805.2015.1121406","article-title":"Intravesical instillation of onabotulinum toxin A embedded in inert hydrogel in the treatment of idiopathic overactive bladder: A double-blind randomized pilot study","volume":"50","author":"Krhut","year":"2016","journal-title":"Scand. J. Urol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.urology.2017.12.028","article-title":"Safety and Feasibility of Intravesical Instillation of Botulinum Toxin-A in Hydrogel-based Slow-release Delivery System in Patients With Interstitial Cystitis-Bladder Pain Syndrome: A Pilot Study","volume":"114","author":"Rappaport","year":"2018","journal-title":"Urology"},{"key":"ref_45","first-page":"172.e171","article-title":"Early experimental results of using a novel delivery carrier, hyaluronan-phosphatidylethanolamine (HA-PE), which may allow simple bladder instillation of botulinum toxin A as effectively as direct detrusor muscle injection","volume":"14","author":"DeYoung","year":"2018","journal-title":"J. Pediatric Urol."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/2\/75\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:20:32Z","timestamp":1760361632000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/2\/75"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,23]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["toxins12020075"],"URL":"https:\/\/doi.org\/10.3390\/toxins12020075","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,23]]}}}