{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T02:36:26Z","timestamp":1775097386678,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T00:00:00Z","timestamp":1631318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Interstitial cystitis (IC) or painful bladder syndrome is a chronic dysfunction due to an inflammatory condition, characterized by bladder pain and urinary frequency. Currently, no gold standard therapy is available since IC does not respond to conventional ones. Given these premises, the aim of this work was the in vitro characterization of biological properties (mucoadhesion and anti-inflammatory activity) of a commercial product (HydealCyst\u2013HydC) based on hyaluronic acid (HA) and the benzyl ester of HA (Hydeal-D\u00ae) intended for bladder instillation to restore and\/or protect the urothelial layer of glycosamino glycans (GAGs). The in vitro characterization demonstrated that an interaction product is formed between HA and Hydeal-D\u00ae that has a role in the rheological behavior and mucoadhesive properties. HA was identified as a key component to form the mucoadhesive joint, while the interaction of HA with Hydeal-D\u00ae improved polysaccharide stability and prolonged the activity ex vivo. Moreover, HydC is cytocompatible with urothelial cells (HTB-4) and possesses an anti-inflammatory effect towards these cells by decreasing the secretion of IL-6 and IL-8, which were both increased in patients with IC, and by increasing the secretion of sulfated GAGs. These two findings, along with the resilience properties of the formulation due to mucoadhesion, suggest the active role of HydC in protecting and restoring urothelium homeostasis.<\/jats:p>","DOI":"10.3390\/pharmaceutics13091450","type":"journal-article","created":{"date-parts":[[2021,9,12]],"date-time":"2021-09-12T21:48:01Z","timestamp":1631483281000},"page":"1450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synergy of Hydeal-D\u00ae and Hyaluronic Acid for Protecting and Restoring Urothelium: In Vitro Characterization"],"prefix":"10.3390","volume":"13","author":[{"given":"Marco","family":"Ruggeri","sequence":"first","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4820-5422","authenticated-orcid":false,"given":"Mauro","family":"Pavan","sequence":"additional","affiliation":[{"name":"Fidia Farmaceutici S.p.A., Via Ponte Della Fabbrica 3\/A, 35031 Abano Terme, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9438-5316","authenticated-orcid":false,"given":"Matteo","family":"Soato","sequence":"additional","affiliation":[{"name":"Fidia Farmaceutici S.p.A., Via Ponte Della Fabbrica 3\/A, 35031 Abano Terme, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susi","family":"Panfilo","sequence":"additional","affiliation":[{"name":"Fidia Farmaceutici S.p.A., Via Ponte Della Fabbrica 3\/A, 35031 Abano Terme, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Barbera","sequence":"additional","affiliation":[{"name":"Fidia Farmaceutici S.p.A., Via Ponte Della Fabbrica 3\/A, 35031 Abano Terme, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1193-8067","authenticated-orcid":false,"given":"Devis","family":"Galesso","sequence":"additional","affiliation":[{"name":"Fidia Farmaceutici S.p.A., Via Ponte Della Fabbrica 3\/A, 35031 Abano Terme, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dalila","family":"Miele","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9511-3857","authenticated-orcid":false,"given":"Silvia","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alba","family":"Di Lucia","sequence":"additional","affiliation":[{"name":"Fidia Farmaceutici S.p.A., Via Ponte Della Fabbrica 3\/A, 35031 Abano Terme, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2548-5249","authenticated-orcid":false,"given":"Franca","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6766-9321","authenticated-orcid":false,"given":"Giuseppina","family":"Sandri","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.2165\/00019053-200624010-00005","article-title":"Interstitial Cystitis: Cost, treatment and co-morbidities in an employed population","volume":"24","author":"Wu","year":"2006","journal-title":"Pharmacoeconomics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.juro.2009.08.133","article-title":"Psychosocial phenotyping in women with interstitial cystitis\/painful bladder syndrome: A case control study","volume":"183","author":"Nickel","year":"2010","journal-title":"J. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s11255-014-0908-6","article-title":"Increased risks of healthcare-seeking behaviors of anxiety, depression and insomnia among patients with bladder pain syndrome\/interstitial cystitis: A nationwide population-based study","volume":"47","author":"Chuang","year":"2015","journal-title":"Int. Urol. Nephrol."},{"key":"ref_4","first-page":"9","article-title":"Bladder surface glycosaminoglycan: Efficient mechanism of environmental adaptation","volume":"27","author":"Parsons","year":"1986","journal-title":"Urology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.juro.2012.09.022","article-title":"The distribution and function of chondroitin sulfate and other sulfated glycosaminoglycans in the human bladder and their contribution to the protective bladder barrier","volume":"189","author":"Janssen","year":"2013","journal-title":"J. Urol."},{"key":"ref_6","first-page":"83","article-title":"Glycosaminoglycans: How much do we know about their role in the bladder?","volume":"25","author":"Klingler","year":"2016","journal-title":"Urologia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1007\/s00404-017-4364-2","article-title":"Etiology, pathophysiology and biomarkers of interstitial cystitis\/painful bladder syndrome","volume":"295","author":"Patnaik","year":"2017","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s00192-008-0572-4","article-title":"A combined intravesical therapy with hyaluronic acid and chondroitin for refractory painful bladder syndrome\/interstitial cystitis","volume":"19","author":"Cervigni","year":"2008","journal-title":"Int. Urogynecol. J. Pelvic Floor Dysfunct."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/S0022-5347(17)43180-6","article-title":"Functional and Structural Characteristics of the Glycosaminoglycans of the Bladder Luminal Surface","volume":"138","author":"Hurst","year":"1987","journal-title":"J. Urol."},{"key":"ref_10","unstructured":"Teo, K.S.H., and Biers, S. (2021, September 10). Intravesical Glycosaminoglycan Analogue Instillations for Recurrent Cystitis. Available online: https:\/\/www.urologynews.uk.com\/features\/features\/post\/intravesical-glycosaminoglycan-analogue-instillations-for-recurrent-cystitis."},{"key":"ref_11","first-page":"638","article-title":"Interstitial cystitis\/bladder pain syndrome and glycosaminoglycans replacement therapy","volume":"4","author":"Cervigni","year":"2015","journal-title":"Transl. Androl. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1177\/1756287215621234","article-title":"Managing chronic bladder diseases with the administration of exogenous glycosaminoglycans: An update on the evidence","volume":"8","author":"Lazzeri","year":"2016","journal-title":"Ther. Adv. Urol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/nau.22256","article-title":"GAG layer replenishment therapy for chronic forms of cystitis with intravesical glycosaminoglycans--a review","volume":"32","author":"Madersbacher","year":"2013","journal-title":"NeuroUrol. Urodyn."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1016\/j.eururo.2007.03.020","article-title":"Hyaluronic acid: An effective alternative treatment of interstitial cystitis, recurrent urinary tract infections, and hemorrhagic cystitis?","volume":"51","author":"Iavazzo","year":"2007","journal-title":"Eur. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/art.1780310110","article-title":"Antioxidant activity of synovial fluid, hyaluronic acid, and two subcomponents of hyaluronic acid. Synovial fluid scavenging effect is enhanced in rheumatoid arthritis patients","volume":"31","author":"Sato","year":"1988","journal-title":"Arthritis Rheum."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1002\/art.1780300707","article-title":"Hyaluronate inhibition of cell proliferation","volume":"30","author":"Goldberg","year":"1987","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"48","DOI":"10.12968\/jowc.2004.13.2.26573","article-title":"2004. The role of hyaluronic acid in wound healing\u2019s proliferative phase","volume":"13","author":"Brown","year":"2004","journal-title":"J. Wound Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.actbio.2015.02.030","article-title":"Hyaluronic acid decreases IL-6 and IL-8 secretion and permeability in an inflammatory model of interstitial cystitis","volume":"19","author":"Rooney","year":"2015","journal-title":"Acta Biomater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/S0022-5347(05)65472-9","article-title":"Intravesical sodium hyaluronate inhibits the rat urinary mast cell mediator increase triggered by acute immobilization stress","volume":"167","author":"Boucher","year":"2002","journal-title":"J. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"208","DOI":"10.3109\/09513590.2014.975689","article-title":"The effects of hyaluronic acid vaginal gel on the vaginal epithelium of ovariectomized rats","volume":"31","author":"Liu","year":"2015","journal-title":"Gynecol. Endocrinol."},{"key":"ref_21","unstructured":"Della Valle, F., and Romeo, A. (1989). Esters of Hyaluronic Acid. (4,851,521), U.S. Patent."},{"key":"ref_22","unstructured":"Pizzocaro, C., Zanellato, A.M., and Pavan, M. (2021). Pharmaceutical Composition for Use in the Treatment of Cystitis of Various Etiologies. (WO2021079303)."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jpba.2018.04.041","article-title":"Rheological analysis and mucoadhesion: A 30 year-old and still active combination","volume":"156","author":"Rossi","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4385","DOI":"10.1039\/C9TB00443B","article-title":"Water-based synthesis of keratin micro- and nanoparticles with tunable mucoadhesive properties for drug delivery","volume":"7","author":"Perotto","year":"2019","journal-title":"J. Mater. Chem. B"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/S1773-2247(14)50094-9","article-title":"Associations of natural polymers to modulate mucoadhesion of vaginal rinse-off and leave-on formulations","volume":"24","author":"Rossi","year":"2014","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108314","DOI":"10.1016\/j.carres.2021.108314","article-title":"A versatile and robust analytical method for hyaluronan quantification in crosslinked products and complex matrices","volume":"503","author":"Soato","year":"2021","journal-title":"Carbohydr. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/0022-2836(80)90293-4","article-title":"Competitive Inhibition Evidence for Specific Intermolecular Interactions in Hyaluronate Solutions","volume":"138","author":"Welsh","year":"1980","journal-title":"J. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1021\/acs.molpharmaceut.7b00236","article-title":"A Hyaluronic Acid Molecular Weight-Dependent Modulation of Mucin Nanostructure for Potential Mucosal Therapeutic Applications","volume":"14","author":"Hansen","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1086\/650696","article-title":"Group B Streptococcus (GBS) Urinary Tract Infection Involves Binding of GBS to Bladder Uroepithelium and Potent but GBS-Specific Induction of Interleukin 1\u03b1","volume":"201","author":"Ulett","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.fitote.2016.12.010","article-title":"Traditionally used medicinal plants against uncomplicated urinary tract infections: Hexadecyl coumaric acid ester from the rhizomes of Agropyron repens (L.) P. Beauv. with antiadhesive activity against uropathogenic E. coli","volume":"117","author":"Beydokthi","year":"2017","journal-title":"Fitoterapia"},{"key":"ref_31","unstructured":"Varki, A., Cummings, R.D., Esko, J.D., Stanley, P., Hart, G.W., Aebi, M., Darvill, A.G., Kinoshita, T., Packer, N.H., and Prestegard, J.H. (2021, September 10). Essentials of Glycobiology, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK310274\/."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.urology.2006.04.033","article-title":"Interleukine-6, Histamine, and Methyllhistamine as diagnostic markers for interstitial cystitis","volume":"68","author":"Lamale","year":"2006","journal-title":"Urology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1016\/j.juro.2012.01.034","article-title":"Urinary Chemokines as Noninvasive Predictors of Ulcerative Interstitial Cystitis","volume":"187","author":"Tyagi","year":"2012","journal-title":"J. Urol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/iju.12311","article-title":"Potential urine and serum biomarkers for patients with bladder pain syndrome\/interstitial cystitis","volume":"21","year":"2014","journal-title":"Int. J. Urol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1055\/s-0028-1098784","article-title":"Anti-Inflammatory Action of a Hyaluronic Acid-Chondroitin Sulfate Preparation in an in vitro Bladder Model","volume":"40","author":"Schulz","year":"2009","journal-title":"Aktuel. Urol."},{"key":"ref_36","first-page":"629","article-title":"Review of intravesical therapies for bladder pain syndrome \/ interstitial cystitis","volume":"4","author":"Cvach","year":"2015","journal-title":"Transl. Androl. Urol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s00192-010-1294-y","article-title":"Long-term results of intravesical hyaluronan therapy in bladder pain syndrome\/interstitial cystitis","volume":"22","author":"Engelhardt","year":"2011","journal-title":"Int. Urogynecol. J."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/9\/1450\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:00:51Z","timestamp":1760166051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/9\/1450"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,11]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["pharmaceutics13091450"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13091450","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,11]]}}}