The Cross-linked Biopolymer Hyaluronic Acid as an Artificial Vitreous Substitute

Schramm, Christian; Spitzer, Martin S.; Henke-Fahle, Sigrid; Steinmetz, Gabriele; Januschowski, Kai; Heiduschka, Peter; Geis-Gerstorfer, J; Biedermann, Tilo; Bartz‐Schmidt, Karl Ulrich; Szurman, Peter

doi:10.1167/iovs.11-7322

Cited by 87 publications

(65 citation statements)

References 35 publications

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“…This is consistent with the excellent biocompatibility of hyaluronic acid seen in other studies [18,19]. Hyaluronic acid is one of the main constituents of natural vitreous and is consistently well-tolerated in different biomedical applications.…”

Section: Our Previous Results and Our Hypothesissupporting

confidence: 88%

“…Such trials are, however, costly, time consuming and might be considered ethically problematic. In some cases in vivo experiments have been precluded by preclinical toxicological assays, mainly targeting apoptosis in cultures of cells from tissues outside the eye [16,17], isolated retinal pigment epithelium (RPE) cells [18,19] or dissociated cells from embryonal retinas [20]. The validity of these findings in relation to a clinical setting is, however, unclear since they represent a large transitional step regarding the impact on the adult neuroretinal sheet [21].…”

Section: Introductionmentioning

confidence: 99%

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A new model for in vitro testing of vitreous substitute candidates

Barth

Crafoord

O’Shea

et al. 2014

Graefes Arch Clin Exp Ophthalmol

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Purpose To describe a new model for in vitro assessment of novel vitreous substitute candidates. Methods The biological impact of three vitreous substitute candidates was explored in a retinal explant culture model; a polyalkylimide hydrogel (Bio-Alcamid®), a two component hydrogel of 20 wt.% poly (ethylene glycol) in phosphate buffered saline (PEG) and a cross-linked sodium hyaluronic acid hydrogel (Healaflow®). The gels where applied to explanted adult rat retinas and then kept in culture for 2, 5 and 10 days. Gel-exposed explants were compared with explants incubated under standard tissue culture conditions. Cryosections of the specimens were stained with hematoxylin and eosin, immunohistochemical markers (GFAP, Vimentin, Neurofilament 160, PKC, Rhodopsin) and TUNEL. Results Explants kept under standard conditions as well as PEG-exposed explants displayed disruption of retinal layers with moderate pyknosis of all neurons. They also displayed moderate labeling of apoptotic cells. Bio-Alcamid®-exposed explants displayed severe thinning and disruption of retinal layers with massive cell death. Healaflow®-treated explants displayed normal retinal lamination with significantly better preservation of retinal neurons compared with control specimens, and almost no signs of apoptosis. Retinas exposed to Healaflow® and retinas kept under standard conditions showed variable labeling of GFAP with generally low expression and some areas of upregulation. PEG-exposed retinas showed increased GFAP labeling and Bio-Alcamid®-exposed retinas showed sparse labeling of GFAP. Conclusions Research into novel vitreous substitutes has important implications for both medical and surgical vitreoretinal disease. The in vitro model presented here provides a method of biocompatibility testing prior to more costly and cumbersome in vivo experiments. The explant culture system imposes reactions within the retina including disruption of layers, cell death and gliosis, and the progression of these reactions can be used for comparison of vitreous substitute candidates. Bio-Alcamid® had strong adverse effects on the retina which is consistent with results of prior in vivo trials. PEG gel elicits reactions similar to the control retinas whereas Healaflow® shows protection from culture-induced trauma indicating favorable biocompatibility.

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Section: Our Previous Results and Our Hypothesissupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

A new model for in vitro testing of vitreous substitute candidates

Barth

Crafoord

O’Shea

et al. 2014

Graefes Arch Clin Exp Ophthalmol

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“…The fluctuation of ERG measurement was similar to other reports. 28,29 The difference between the control group and gel injection groups at the same time points was not statistically significant either (P . 0.05).…”

Section: Discussionmentioning

confidence: 84%

Injectable Chemically Crosslinked Hydrogel for the Controlled Release of Bevacizumab in Vitreous: A 6-Month In Vivo Study

Lau

et al. 2015

Trans. Vis. Sci. Tech.

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Purpose: To evaluate the biocompatibility and 6-month in vivo release of bevacizumab from a hyaluronic acid/dextran-based in situ hydrogel after intravitreal injection in rabbit eye. Methods:The in situ hydrogel was formed by the catalyst-free chemical crosslinking between vinylsulfone functionalized hyaluronic acid (HA-VS) and thiolated dextran (Dex-SH) at physiological condition. The pH 7.4 buffered mixture containing HA-VS, Dex-SH, and bevacizumab were injected into the vitreous of rabbit eyes by a 30-G needle. The biocompatibility was evaluated by intraocular pressure measurement, binocular indirect ophthalmoscope (BIO), full-field electroretinogram (ERG), and histology. The concentrations of both total and active bevacizumab in rabbit vitreous were determined by enzyme-linked immunosorbent assay. The concentration of bevacizumab in rabbit vitreous after bolus injection was simulated by onecompartment first order elimination model. Results:A transparent gel was seen in the vitreous after injection. BIO images, ERG, and histology showed that the gel does not induce hemorrhage, retinal detachment, inflammation, or other gross pathological changes in rabbit eyes after injection. While the bolus intravitreal injected bevacizumab follows the first order elimination kinetics in rabbit eye, the in situ gel formation was able to prolong the retention of bevacizumab in rabbit eye at therapeutic relevant concentration for at least 6 months. The concentration of bevacizumab 6 months after injection was about 10 7 times higher than bolus injection. Conclusions:The new in situ hydrogel formulation of bevacizumab was biocompatible and able to prolong the retention of drug in rabbit eyes in vivo at therapeutic relevant concentration for at least 6 months.Translational Relevance: Although proven to be effective, monthly intravitreal injection of bevacizumab or other protein drugs may cause various complications. Extending the residence time of protein therapeutics in the eye can reduce the injection frequency, its associated complications, and treatment cost, which will be beneficial to both the patients and doctors. In this study, we showed that the in situ hydrogel-based controlled release system is a feasible option to tackle this problem.

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“…The HA is used extensively in ophthalmic surgery, and cataract surgery in particular as an injectable vitreous substitute. 24,25 The injection force data indicated that ESHU formulations are suitable for intravitreal injection through small gauge needles without requiring significant effort to administer. Upon injection into a solution of HA heated to 378C, ESHU formulations undergo a rapid sol-gel phase transition and form spherical-to-ovoidshaped hydrogels.…”

Section: Discussionmentioning

confidence: 99%

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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The Cross-linked Biopolymer Hyaluronic Acid as an Artificial Vitreous Substitute

Abstract: Biopolymers based on UV cross-linked hyaluronic acid may be promising vitreous substitutes.

Cited by 87 publications

References 35 publications

A new model for in vitro testing of vitreous substitute candidates

A new model for in vitro testing of vitreous substitute candidates

Injectable Chemically Crosslinked Hydrogel for the Controlled Release of Bevacizumab in Vitreous: A 6-Month In Vivo Study

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

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