{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:33:40Z","timestamp":1760243620260,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2012,3,12]],"date-time":"2012-03-12T00:00:00Z","timestamp":1331510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The goal of this work was to evaluate tissue-device interactions due to implantation of a mechanically operated drug delivery system onto the posterior sclera. Two test devices were designed and fabricated to model elements of the drug delivery device\u2014one containing a free-spinning ball bearing and the other encasing two articulating gears. Openings in the base of test devices modeled ports for drug passage from device to sclera. Porous poly(tetrafluoroethylene) (PTFE) membranes were attached to half of the gear devices to minimize tissue ingrowth through these ports. Test devices were sutured onto rabbit eyes for 10 weeks. Tissue-device interactions were evaluated histologically and mechanically after removal to determine effects on device function and changes in surrounding tissue. Test devices were generally well-tolerated during residence in the animal. All devices encouraged fibrous tissue formation between the sclera and the device, fibrous tissue encapsulation and invasion around the device, and inflammation of the conjunctiva. Gear devices encouraged significantly greater inflammation in all cases and a larger rate of tissue ingrowth. PTFE membranes prevented tissue invasion through the covered drug ports, though tissue migrated in through other smaller openings. The torque required to turn the mechanical elements increased over 1000 times for gear devices, but only on the order of 100 times for membrane-covered gear devices and less than 100 times for ball bearing devices. Maintaining a lower device profile, minimizing microscale motion on the eye surface and covering drug ports with a porous membrane may minimize inflammation, decreasing the risk of damage to surrounding tissues and minimizing disruption of device operation.<\/jats:p>","DOI":"10.3390\/pharmaceutics4010212","type":"journal-article","created":{"date-parts":[[2012,3,12]],"date-time":"2012-03-12T12:07:51Z","timestamp":1331554071000},"page":"212-229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evaluation of Tissue Interactions with Mechanical Elements of a Transscleral Drug Delivery Device"],"prefix":"10.3390","volume":"4","author":[{"given":"Sarah J.","family":"Cohen","sequence":"first","affiliation":[{"name":"Charles Stark Draper Laboratory, 555 Technology Square, Cambridge, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robison V. Paul","family":"Chan","sequence":"additional","affiliation":[{"name":"Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Keegan","sequence":"additional","affiliation":[{"name":"Charles Stark Draper Laboratory, 555 Technology Square, Cambridge, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"Andreoli","sequence":"additional","affiliation":[{"name":"Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey T.","family":"Borenstein","sequence":"additional","affiliation":[{"name":"Charles Stark Draper Laboratory, 555 Technology Square, Cambridge, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan W.","family":"Miller","sequence":"additional","affiliation":[{"name":"Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelos S.","family":"Gragoudas","sequence":"additional","affiliation":[{"name":"Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2012,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1056\/NEJMoa042760","article-title":"Pegabtanib for neovascular age related macular degeneration","volume":"351","author":"Gragoudas","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_2","first-page":"353","article-title":"Age-related macular degeneration (AMD): pathogenesis and therapy","volume":"58","author":"Nowak","year":"2006","journal-title":"Pharmacol. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1016\/j.addr.2005.09.003","article-title":"Wet age-related macular degeneration","volume":"57","author":"Kulkarni","year":"2005","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"4.\tRosenfeld, P.J., Brown, D.M., Heier, J.S., Boyer, D.S., Kaiser, P.K., Chung, C.Y., and Kim, R.Y. (2006). Ranibizumab for neovascular age related macular degeneration. N. Engl. J. Med., 335, (14), 1419\u20131431.","DOI":"10.1056\/NEJMoa054481"},{"key":"ref_5","unstructured":"FDA Approves New Biologic Treatment for Wet Age-Related Macular Degeneration. FDA. Available online:http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/2006\/ ucm108685.htm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0008-4182(05)80119-X","article-title":"Complications of intravitreal injection of triamcinolone acetonide","volume":"40","author":"Ozkiris","year":"2005","journal-title":"Can. J. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/S0161-6420(02)00975-2","article-title":"Intravitreal triamcinolone for refractory diabetic macular edema","volume":"109","author":"Martidis","year":"2002","journal-title":"Ophthalmology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1097\/IAE.0b013e3180307271","article-title":"Reducing the risk of endophthalmitis following intravitreal injections","volume":"27","author":"Scott","year":"2007","journal-title":"Retina"},{"key":"ref_9","first-page":"485","article-title":"Dendrimers. An innovative and enhanced ocular drug delivery system","volume":"130","author":"Mitra","year":"2003","journal-title":"Opthalmic Drug Delivery Systems. Drugs and Pharmaceutical Sciences"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S1350-9462(01)00018-0","article-title":"Transscleral delivery to the retina and choroid","volume":"21","author":"Ambati","year":"2002","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1167\/iovs.02-1258","article-title":"Feasibility of Drug Delivery to the Posterior Pole of the Rabbit Eye with an Episcleral Implant","volume":"45","author":"Kato","year":"2004","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1167\/iovs.02-0375","article-title":"Biodegradable intrascleral implant for sustained intraocular delivery of betamethasone phosphate","volume":"44","author":"Okabe","year":"2003","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1167\/iovs.06-0954","article-title":"Pharmacokinetics of intraocular drug delivery by periocular injections using ocular fluorophotometry","volume":"48","author":"Ghate","year":"2007","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1089\/108076804773710830","article-title":"Scleral permeability of a small, single-stranded oligonucleotide","volume":"20","author":"Shuler","year":"2004","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1167\/iovs.01-1156","article-title":"Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-co-glycolic) acid microspheres","volume":"44","author":"Carrasquillo","year":"2003","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1167\/iovs.07-1660","article-title":"Human transscleral albumin permeability and the effect of topographical location and donor age","volume":"49","author":"Anderson","year":"2008","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3790","DOI":"10.1167\/iovs.04-1414","article-title":"The influence of intraocular pressure on the transsceral diffusion of high-molecular weight compounds","volume":"46","author":"Cruysberg","year":"2005","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1097\/00006982-200512000-00011","article-title":"Effective transscleral delivery of two retinal anti-angiogenic molecules: Carboxyamido-triazole (CAI) and 2-Methoxyestradiol (2ME2)","volume":"25","author":"Cruysberg","year":"2005","journal-title":"Retina"},{"key":"ref_19","first-page":"1181","article-title":"Diffusion of high molecular weight compounds through sclera","volume":"41","author":"Ambati","year":"2000","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_20","first-page":"1186","article-title":"Transscleral delivery of bioactive protein to the choroid and retina","volume":"41","author":"Ambati","year":"2000","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1016\/j.addr.2005.09.006","article-title":"Micro- and nanoparticulates","volume":"57","author":"Moshfeghi","year":"2005","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1159\/000050849","article-title":"Biodegradable polymers for ocular drug delivery","volume":"215","author":"Kimura","year":"2001","journal-title":"Ophthalmologica"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1167\/iovs.02-0791","article-title":"Ayalasomayajula SP. Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF experession","volume":"44","author":"Kompella","year":"2003","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0168-3659(02)00207-9","article-title":"Design of poly-\u03b5-capralactone nanospheres coated with bioadhesive hyaluronic acid for ocular delivery","volume":"83","author":"Gref","year":"2002","journal-title":"J. Control. Release"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5306","DOI":"10.1002\/jps.21383","article-title":"PLGA nanospheres for the ocular delivery of flurbiprofen: drug release and interactions","volume":"97","author":"Vega","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.jconrel.2005.09.049","article-title":"Iontophoresis: A non-invasive ocular drug delivery","volume":"110","author":"Domb","year":"2006","journal-title":"J. Control. Release"},{"key":"ref_27","first-page":"569","article-title":"Delivery of several forms of DNA, DNA-RNA hybrids, and dyes across human sclera by electrical fields","volume":"9","author":"Davies","year":"2003","journal-title":"Mol. Vis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"192","DOI":"10.3109\/02713680903521936","article-title":"Mini drug pump for ophthalmic use","volume":"35","author":"Saati","year":"2010","journal-title":"Curr. Eye Res."},{"key":"ref_29","first-page":"60","article-title":"Mini drug pump for ophthalmic use","volume":"107","author":"Saati","year":"2009","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1007\/s10544-009-9313-9","article-title":"A passive MEMS drug delivery pump for treatment of ocular diseases","volume":"11","author":"Lo","year":"2009","journal-title":"Biomed. Microdevices"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1039\/b804690e","article-title":"A refillable microfabricated drug delivery device for treatment of ocular diseases","volume":"7","author":"Lo","year":"2008","journal-title":"Lab Chip"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.heares.2010.04.014","article-title":"Murine intracochlear drug delivery: reducing concentration gradients within the cochlea","volume":"268","author":"Borkholder","year":"2010","journal-title":"Hear. Res."},{"key":"ref_33","unstructured":"Adamis, A.P., Miller, J.W., Gragoudas, E.S., Mescher, M.J., Dube, C.E., Borenstein, J.T., Weinstein, M.G., Miller, R.A., and Hansberry, M.L. (2009). Implantable drug delivery device and use thereof. (7563255), U.S. Patent."},{"key":"ref_34","unstructured":"Mescher, M.J., Dube, C.E., Fiering, J.O., Fyler, D.L., Hansberry, M., Kim, E.S., Borenstein, J.T., Bernstein, J.J., Gragoudas, E., and Miller, J. (2006). Transactions of the 31st annual meeting of the Society for Biomaterials, Pittsburgh, PA, USA."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Dee, K.C., Puleo, D.A., and Bizios, R. (2002). An Introduction to Tissue-Biomaterial Interactions, John Wiley & Sons, Inc.","DOI":"10.1002\/0471270598"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0168-3659(01)00502-8","article-title":"Reducing capsular thickness and enhancing angiogenesis around implant drug release systems","volume":"78","author":"Ratner","year":"2002","journal-title":"J. Control. Release"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0168-3659(98)00178-3","article-title":"Issues and perspectives on the biocompatibility and immunotoxicity evaluation of implanted controlled release systems","volume":"57","author":"Anderson","year":"1999","journal-title":"J. Control. Release"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/S0142-9612(00)00237-4","article-title":"Ocular biomaterials and implants","volume":"22","author":"Lloyd","year":"2001","journal-title":"Biomaterials"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/S0161-6420(98)96011-0","article-title":"Encapsulation of scleral buckling materials: A study of six specimens","volume":"105","author":"Korobelnik","year":"1998","journal-title":"Ophthalmology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1001\/archopht.117.2.233","article-title":"Comparison of different biomaterials for glaucoma drainage devices","volume":"117","author":"Ayyala","year":"1999","journal-title":"Arch. Ophthal."},{"key":"ref_41","unstructured":"Cohen, S.J. (2007). Biocompatibility of an Implantable Ophthalmic Drug Delivery Device. [MS Thesis, Massachusetts Institute of Technology]."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/(SICI)1097-4636(1999)48:5<591::AID-JBM1>3.0.CO;2-9","article-title":"Evaluation of an aqueous drainage glaucoma device constructed of ePTFE","volume":"48","author":"Boswell","year":"1999","journal-title":"J. Biomed. Mater. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1016\/S0142-9612(02)00565-3","article-title":"Biocompatibility and biofouling of MEMS drug delivery devices","volume":"24","author":"Voskerician","year":"2003","journal-title":"Biomaterials"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5824","DOI":"10.1016\/j.vaccine.2011.06.083","article-title":"Of mice and not humans: How reliable are animal models for evaluation of herpes CD8+-t cell-epitopes-based immunotherapeutic vaccine candidates?","volume":"29","author":"Dasgupta","year":"2011","journal-title":"Vaccine"},{"key":"ref_45","first-page":"1008","article-title":"Live conjunctiva-associated lymphoid tissue analysis in rabbit under inflammatory stimuli using in vivo confocal microscopy","volume":"51","author":"Liang","year":"2010","journal-title":"IOVS"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3214","DOI":"10.1073\/pnas.051625998","article-title":"Tissue engineered cells producing complex recombinant proteins inhibit ovarian cancer in vivo","volume":"98","author":"Stephen","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1089\/107632704322791673","article-title":"In vivo tissue engineering using mesenchymal stem cells on a novel electrospun nanofibrous scaffold","volume":"10","author":"Shin","year":"2004","journal-title":"Tissue Eng."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ratner, B.D., Hoffman, A.S., Schoen, F.J., and Lemons, J.E. (1996). Biomaterials Science, An Introduction to Materials, Academic Press.","DOI":"10.1016\/B978-012582460-6\/50002-5"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1002\/jbm.a.20027","article-title":"Fibrous encapsulation of single polymer microfibers depends on their vertical dimension in subcutaneous tissue","volume":"67","author":"Sanders","year":"2003","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1586\/17434440.3.4.509","article-title":"Glaucoma drainage devices: state of the art","volume":"3","author":"Ayyala","year":"2006","journal-title":"Expert Rev. Med. 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