The effects of cross-linked thermo-responsive PNIPAAm-based hydrogel injection on retinal function

Turturro, Sanja; Guthrie, Micah J.; Appel, Alyssa A.; Drapala, Pawel W.; Brey, Eric M.; Pérez-Luna, Víctor H.; Mieler, William F.; Kang-Mieler, Jennifer J.

doi:10.1016/j.biomaterials.2011.01.058

Cited by 89 publications

(76 citation statements)

References 35 publications

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“…The suitability of thermoresponsive hydrogels for intravitreal applications has been explored previously using nondegradable poly(N-isopropylacrylamide) (PNIPAAM)-based hydrogels, as well as biodegradable poly(2-ethyl-2-oxazoline)-bpoly(e-caprolactone)-b-poly(2-ethyl-2-oxazoline) (PEOz-PCLPEOz), or ECE gels. 16,17,28,29 These studies demonstrated that intravitreal injection of synthetic hydrogels caused no longterm (up to 2 months) changes to retinal function, IOP, or histomorphology in rabbits, corroborating our observations. However, PNIPAAM gels are nondegradable and, therefore, would require surgical removal.…”

Section: Discussionsupporting

confidence: 79%

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Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Rauck

Friberg

Mendez

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We assessed the in vivo release profile of bevacizumab from and biocompatibility of poly(ethylene glycol)-poly-(serinol hexamethylene urethane), or ESHU, a thermoresponsive hydrogel administered intravitreally for drug delivery.METHODS. The technical feasibility of injection was assessed quantitatively via mechanical testing. For in vivo studies, New Zealand White rabbit eyes were injected intravitreally with 0.05 mL of either: ESHU dissolved in 25 mg/mL bevacizumab, ESHU dissolved in PBS, or 25 mg/mL bevacizumab. Clinical examination included IOP measurements and examination with indirect ophthalmoscopy for signs of inflammation. Additionally, eyes were examined histologically following euthanasia. To quantify bevacizumab release, aqueous humor samples were obtained via anterior chamber paracentesis and ELISA was used to determine the concentration of drug weekly. In vitro cytotoxicity testing also was performed using bovine corneal endothelial cells. RESULTS.The ESHU was injected easily through a 31-gauge needle, was well tolerated in vivo, and caused minimal cell death in vitro when compared to other common materials, such as silicone oil. The long-term presence of the gel did not affect IOP, and there was no evidence of inflammation histologically or through indirect observation. The ESHU sustained the release of bevacizumab for over 9 weeks and maintained a drug concentration that averaged 4.7 times higher than eyes receiving bolus bevacizumab injections.CONCLUSIONS. To our knowledge, this is the first report demonstrating sustained bevacizumab release in vivo from an intravitreally injected hydrogel formulation, suggesting that this delivery system may be a promising candidate for ocular drug delivery.Keywords: thermally responsive hydrogel, ocular drug delivery, sustained release, biocompatibility, injectable gel C horoidal neovascularization (CNV) is the hallmark of many blinding disorders, most notably wet age-related macular degeneration (AMD) and diabetic retinopathy. It is characterized by pathologic blood vessel growth, which originates in the choroid and progresses through the Bruch's membrane into the subretinal space.1 These vessels are fragile and permeable, causing hemorrhage, retinal detachment, scarring, and ultimately, loss of central vision. Elevated levels of VEGF is a central cause of CNV.2-4 Thus, intravitreal injection of anti-VEGF medications, such as bevacizumab (Avastin) or ranibizumab (Lucentis), has emerged as a leading treatment strategy. [5][6][7] The efficacy of these drugs, however, is limited severely by rapid clearance from the eye; their half-lives are on the order of 7 days. 8,9 This necessitates frequent injections, imposing a significant burden on patients and increasing healthcare costs as well as procedure-related complications, such as endophthalmitis, retinal detachment, cataract, and uveitis.10-13 Therefore, a delivery system that extends the presence of intravitreal drugs in the eye is highly desirable for reducing injection frequency and adverse effects, w...

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Section: Discussionsupporting

confidence: 79%

“…Studies with nondegradable, thermally-responsive hydrogels have demonstrated excellent protein encapsulation, minimal toxicity, and easy injectability with no long-term effects on retinal function in vivo. 16,17 These studies established that …”

mentioning

confidence: 93%

Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Rauck

Friberg

Mendez

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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“…113 In most of these applications, hydrogels are used because of 114 their favorable physicochemical properties (e.g., transparency, high 115 water content, and mechanical flexibility) or in combination with 116 active pharmaceutical ingredients. In this review article, we pre-117 sent a general overview on ophthalmic applications of hydrogels 118 with special emphasis on drug delivery systems for the posterior 119 segment of the eye. We particularly focus on the different 120 gel-forming polymers, the physicochemical properties of the 121 resulting hydrogels, and the challenges associated with the prepa-122 ration of hydrogel-based drug delivery systems.…”

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confidence: 99%

Hydrogels in ophthalmic applications

Kirchhof

Goepferich

Brandl

2015

European Journal of Pharmaceutics and Biopharmaceutics

188

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“…This novel property of "intelligent" for external stimuli can be used to design sensing systems [8,18,19]. Among them, poly(N-isopropylacrylamide) (PNIPAM) is the most studied thermoresponsive polymer for biomedical applications because its volume phase transition temperature (VPTT) at 32°C is close to the temperature of the human body [20]. However, it is hard to guide the microgels in particular parts.…”

Section: Introductionmentioning

confidence: 99%

Fabrication of 1D Fe3O4/P(NIPAM-MBA) thermosensitive nanochains by magnetic-field-induced precipitation polymerization

Zhang

Dou

et al. 2012

Colloid Polym Sci

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The effects of cross-linked thermo-responsive PNIPAAm-based hydrogel injection on retinal function

Cited by 89 publications

References 35 publications

Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Hydrogels in ophthalmic applications

Fabrication of 1D Fe3O4/P(NIPAM-MBA) thermosensitive nanochains by magnetic-field-induced precipitation polymerization

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