{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:02:41Z","timestamp":1788868961495,"version":"build-2803163510"},"reference-count":19,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T00:00:00Z","timestamp":1665360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Horizon 2020 Research and Innovation Programme","award":["814607"],"award-info":[{"award-number":["814607"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The enthesis is an extremely specific region, localized at the tendon\u2013bone interface (TBI) and made of a hybrid connection of fibrocartilage with minerals. The direct type of enthesis tissue is commonly subjected to full laceration, due to the stiffness gradient between the soft tissues and hard bone, and this often reoccurs after surgical reconstruction. For this purpose, the present work aimed to design and develop a tubular scaffold based on pullulan (PU) and chitosan (CH) and intended to enhance enthesis repair. The scaffold was designed with a topographical gradient of nanofibers, from random to aligned, and hydroxyapatite (HAP) nanoparticles along the tubular length. In particular, one part of the tubular scaffold was characterized by a structure similar to bone hard tissue, with a random mineralized fiber arrangement; while the other part was characterized by aligned fibers, without HAP doping. The tubular shape of the scaffold was also designed to be extemporarily loaded with chondroitin sulfate (CS), a glycosaminoglycan effective in wound healing, before the surgery. Micro CT analysis revealed that the scaffold was characterized by a continuous gradient, without interruptions from one end to the other. The gradient of the fiber arrangement was observed using SEM analysis, and it was still possible to observe the gradient when the scaffold had been hydrated for 6 days. In vitro studies demonstrated that human adipose stem cells (hASC) were able to grow and differentiate onto the scaffold, expressing the typical ECM production for tendon in the aligned zone, or bone tissue in the random mineralized part. CS resulted in a synergistic effect, favoring cell adhesion\/proliferation on the scaffold surface. These results suggest that this tubular scaffold loaded with CS could be a powerful tool to support enthesis repair upon surgery.<\/jats:p>","DOI":"10.3390\/pharmaceutics14102153","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:50:01Z","timestamp":1665449401000},"page":"2153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Topographical and Compositional Gradient Tubular Scaffold for Bone to Tendon Interface Regeneration"],"prefix":"10.3390","volume":"14","author":[{"given":"Eleonora","family":"Bianchi","sequence":"first","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8818-817X","authenticated-orcid":false,"given":"Angela","family":"Faccendini","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6584-1869","authenticated-orcid":false,"given":"Elena","family":"Del Favero","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, 20090 Segrate, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0573-4065","authenticated-orcid":false,"given":"Caterina","family":"Ricci","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, 20090 Segrate, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7545-7337","authenticated-orcid":false,"given":"Laura","family":"Caliogna","sequence":"additional","affiliation":[{"name":"Orthopedy, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Vigani","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco Claudio","family":"Pavesi","sequence":"additional","affiliation":[{"name":"Orthopedy, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Perotti","sequence":"additional","affiliation":[{"name":"Immunohaematology and Transfusion Service, Apheresis and Cell Therapy Unit, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui M. A.","family":"Domingues","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, i3Bs\u2014Research Institute on Biomaterials Biodegradables and Biomimetics, University of Minho, 4805-017 Guimar\u00e3es, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-6291","authenticated-orcid":false,"given":"Manuela E.","family":"Gomes","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, i3Bs\u2014Research Institute on Biomaterials Biodegradables and Biomimetics, University of Minho, 4805-017 Guimar\u00e3es, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bianchi, E., Ruggeri, M., Rossi, S., Vigani, B., Miele, D., Bonferoni, M.C., Sandri, G., and Ferrari, F. (2021). Innovative Strategies in Tendon Tissue Engineering. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13010089"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bianchi, E., Vigani, B., Viseras, C., Ferrari, F., Rossi, S., and Sandri, G. (2022). Inorganic Nanomaterials in Tissue Engineering. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061127"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.addr.2015.03.004","article-title":"Strategies to engineer tendon\/ligament-to-bone interface: Biomaterials, cells and growth factors","volume":"94","author":"Balmayor","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1007\/s10439-015-1369-5","article-title":"Current Approaches and Future Trends to Promote Tendon Repair","volume":"43","author":"Morais","year":"2015","journal-title":"Ann. Biomed. Eng."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7533","DOI":"10.1039\/C7RA13510F","article-title":"A functional chitosan-based hydrogel as a wound dressing and drug delivery system in the treatment of wound healing","volume":"8","author":"Liu","year":"2018","journal-title":"RSC Adv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.carbpol.2019.05.069","article-title":"Chitosan\/glycosaminoglycan scaffolds for skin reparation","volume":"15","author":"Sandri","year":"2019","journal-title":"Carbohydr. Polym."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.carbpol.2017.04.089","article-title":"Pullulan: A novel molecule for biomedical applications","volume":"171","author":"Singh","year":"2017","journal-title":"Carbohydr. Polym."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1900200","DOI":"10.1002\/adhm.201900200","article-title":"A textile platform using continuous aligned and textured composite microfibers to engineer tendon-to-bone interface gradient scaffolds","volume":"15","author":"Calejo","year":"2019","journal-title":"Adv. Health Mater."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Costa-Almeida, R., Calejo, I., and Gomes, M.E. (2019). Mesenchymal Stem Cells Empowering Tendon Regenerative Therapies. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123002"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sandri, G., Faccendini, A., Longo, M., Ruggeri, M., Rossi, S., Bonferoni, M.C., Miele, D., Prina-Mello, A., Aguzzi, C., and Viseras, C. (2020). Halloysite- and Montmorillonite-Loaded Scaffolds as Enhancers of Chronic Wound Healing. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020179"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Faccendini, A., Ruggeri, M., Miele, D., Rossi, S., Bonferoni, M.C., Aguzzi, C., Grisoli, P., Viseras, C., Vigani, B., and Sandri, G. (2020). Norfloxacin-Loaded Electrospun Scaffolds: Montmorillonite Nanocomposite vs. Free Drug. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12040325"},{"key":"ref_12","first-page":"223","article-title":"Dry-heat sterilization of parenteral oil vehicles","volume":"4","author":"Kupiec","year":"2000","journal-title":"Int. J. Pharm. Compd."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Faccendini, A., Bianchi, E., Ruggeri, M., Vigani, B., Perotti, C., Pavesi, F.C., Caliogna, L., Natali, F., Del Favero, E., and Cantu\u2019, L. (2021). Smart Device for Biologically Enhanced Functional Regeneration of Osteo\u2013Tendon Interface. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13121996"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1021\/acs.biomac.8b00570","article-title":"Chitin Nanoforms Provide Mechanical and Topological Cues to Support Growth of Human Adipose Stem Cells in Chitosan Matrices","volume":"7","author":"Zubillaga","year":"2018","journal-title":"Biomacromolecules"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1089\/ten.tea.2015.0277","article-title":"Adipose-Derived Stem Cell-Seeded Hydrogels Increase Endogenous Progenitor Cell Recruitment and Neovascularization in Wounds","volume":"22","author":"Kosaraju","year":"2016","journal-title":"Tissue Eng. Part A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.msec.2017.02.175","article-title":"In-vitro cell adhesion and proliferation of adipose derived stem cell on hydroxyapatite composite surfaces","volume":"75","author":"Pulyala","year":"2017","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3855","DOI":"10.1242\/dev.128.19.3855","article-title":"Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments","volume":"19","author":"Schweitzer","year":"2001","journal-title":"Development"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1096\/fj.14-258236","article-title":"Scleraxis is required for the development of a functional tendon enthesis","volume":"1","author":"Killian","year":"2016","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14017","DOI":"10.1038\/boneres.2014.17","article-title":"Bone tissue engineering via nanostructured calcium phosphate biomaterials and stem cells","volume":"30","author":"Wang","year":"2014","journal-title":"Bone Res."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/10\/2153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:49:11Z","timestamp":1760143751000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/10\/2153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,10]]},"references-count":19,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["pharmaceutics14102153"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14102153","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,10]]}}}