Collagen Corneal Shields Research Articles

Novel Drug Delivery Systems Fighting Glaucoma: Formulation Obstacles and Solutions.

Glaucoma is considered to be one of the biggest health problems in the world. It is the main cause of preventable blindness due to its asymptomatic nature in the early stages on the one hand and patients’ non-adherence on the other. There are several approaches in glaucoma treatment, whereby this has to be individually designed for each patient. The first-line treatment is medication therapy. However, taking into account numerous disadvantages of conventional ophthalmic dosage forms, intensive work has been carried out on the development of novel drug delivery systems for glaucoma. This review aims to provide an overview of formulation solutions and strategies in the development of in situ gel systems, nanosystems, ocular inserts, contact lenses, collagen corneal shields, ocular implants, microneedles, and iontophoretic devices. The results of studies confirming the effectiveness of the aforementioned drug delivery systems were also briefly presented.

Release of Moxifloxacin From Corneal Collagen Shields.

To investigate the diffusion of moxifloxacin through bandage contact lenses (BCLs) versus corneal collagen shields (CSs), the relative ability of BCLs and CSs to release moxifloxacin, and the potential of release of moxifloxacin from CSs in the clinical setting. Using an in vitro model, the diffusion of 5% moxifloxacin across BCLs and CSs was compared. Next, the amount of drug release from BCLs and CSs soaked in 0.5% moxifloxacin was measured. Finally, based on a clinical model, CSs were soaked in Vigamox (commercial moxifloxacin) and the total concentration released was detected. Collagen shields remained intact after 24 hr; therefore, enzymatic digestion and mechanical grinding of the CS were performed to determine whether further drug could be released. The concentration of moxifloxacin was measured using a spectrophotometer at set time points up to 24 hr. In the diffusion assay, 35.7±10.5% diffused through the BCLs and 36.2±11.8% diffused through the CSs (P=0.77). The absorption assay demonstrated at 120 min, a total of 33.3±6.77 μg/mL was released from BCLs compared with 45.8±5.2 μg/mL from the CSs (P=0.0008). In vitro experiments to simulate clinical application of Vigamox-soaked CS found the concentration of moxifloxacin released of 127.7±7.25 μg/mL in 2 mL of phosphate-buffered saline over 24 hr. Moxifloxacin diffuses through BCLs and CSs at similar rates; however, CSs have greater capacity to absorb and release moxifloxacin compared with BCLs. Vigamox-soaked CSs released 250 μg of moxifloxacin and may be a useful method to prevent endophthalmitis.

Use of collagen shields for treatment of chronic bilateral corneal ulcers in a pet rabbit

A four-year-old, 1·3-kg entire male Holland Lop pet rabbit (Oryctolagus cuniculus) was presented with a two-day history of bilateral epiphora and blepharospasm. Fluorescein staining revealed bilateral medio-ventral corneal ulceration. Initial topical treatment included ophthalmic broad-spectrum antibiotics and artificial tear solutions. Over a six-month period, antibiotics were changed based on corneal culture and sensitivity test results, and periodic corneal debridement was performed. With little to no improvement, and recurrence of the previous clinical signs, surgical intervention was considered but withheld because of individual pet consideration and owner's reluctance. Hydrophilic contact lenses were placed for corneal support but failed and caused a severe ocular response. Corneal collagen shields were placed bilaterally in order to promote corneal healing. Recheck examination performed seven days after placement revealed complete resolution of the ulcer in one eye and major reduction of the corneal ulcer in the contra-lateral eye.

Randomized comparison of postoperative use of hydrogel ocular bandage and collagen corneal shield for wound protection and patient tolerability after cataract surgery

To compare the safety and efficacy of a hydrogel bandage and a collagen corneal shield in providing wound protection and relief of pain/discomfort in the acute period after uneventful unilateral clear corneal phacoemulsification cataract surgery with foldable intraocular lens (IOL) implantation. Seventeen investigational sites in the United States. Prospective randomized single-masked parallel study. The study comprised patients scheduled to have unilateral clear corneal cataract surgery with posterior chamber intraocular lens implantation. The patients were examined preoperatively and frequently for 30 days postoperatively. The design was a noninferiority study of the 2 primary endpoints, device performance and maximum reported postoperative pain. The device performance success was 78.6% (228/290) for the hydrogel bandage and 26.5% (26/98) for the corneal shield (P<.0001 for noninferiority). Analyses indicated that the hydrogel bandage was superior to the corneal shield in device performance (P<.001; difference = 52.1%; 95% confidence interval, 41.6%-61.4%). The maximum postoperative pain/discomfort score of the hydrogel bandage (mean 1.3 ± 1.8 [SD]; scale 0 to 10) was noninferior to that of the corneal shield (1.1 ± 1.6) in the first 4 hours after surgery (P<.001). Adverse events in the cataract surgeries were reported in 22.2% (70/316) and 36.5% (38/104) of hydrogel bandage patients and corneal shield patients, respectively (P = .0045). The hydrogel bandage was safe and effective for ocular surface protection and relief of pain/discomfort when applied topically to clear corneal incisions used in cataract or IOL implantation surgery. No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are found in the footnotes.

Ocular Surface Restoration Using Non-Surgical Transplantation of Tissue-Cultured Human Amniotic Epithelial Cells

To assess the effect of tissue-cultured human amniotic epithelial cells (AECs) in restoring the ocular surface, transplanted using a collagen shield seeded with AECs supported by a soft contact lens. Prospective interventional single-institutional case series with crossover controls. Three eyes in three patients were identified with persistent corneal epithelial defects (PEDs) refractory to medical therapy. Two cases were secondary to neurotrophic keratopathy, while one case was attributable to longstanding alkali injury. AECs were isolated from serologically screened donor human placenta, seeded onto collagen corneal shields, and incubated in tissue culture medium for 7 days. These collagen shields were placed over the PED and supported by an overlying soft contact lens. The collagen shields dissolved by 72 hours, and the contact lenses were removed after this time. This cycle was repeated every week until healing was achieved. As a crossover control, collagen shields without AECs were placed in the same eye 1 week before placing collagen shields containing AECs. The PED was assessed by vital staining and slit-lamp color photography. The PEDs had a mean duration of 4 months and involved 20% to 37% of the corneal surface area, one case secondary to longstanding alkali injury and two cases attributable to neurotrophic keratopathy. No change in PED size was observed in those control eyes receiving collagen shields without AECs. Complete resolution of the PED was seen after two cycles of AEC-seeded collagen shield in one case, and four cycles in two cases, from 7 to 12 weeks following treatment in all patients. No loss of visual acuity was seen and clinical improvement was maintained in all cases, with a mean follow-up of 6.3 months. Nonsurgical transplantation of tissue-cultured AECs on a collagen shield provides a promising approach to restoring the ocular surface in cases of PED.

Experimental Transplantation of Cultured Human Limbal and Amniotic Epithelial Cells onto the Corneal Surface

Tissue-cultured corneal epithelial transplantation is a novel procedure that uses tissue-cultured epithelial cells to restore severely damaged ocular surfaces. In this study, we used tissue-cultured human limbal and amniotic epithelial cells as donor cells to investigate the feasibility of this procedure for reestablishment of a damaged ocular surface in experimental conditions.Primary human limbal epithelial cultures were established from banked limbal tissue. Amniotic epithelial cells were isolated from serologically screened human placenta and maintained in a specialized nutrient medium. Suspended cells (5 x 10(5)/ml) were seeded onto the concave surface of collagen corneal shields and incubated at 37 degrees C for 2-3 days. These cell-covered shields were then placed on a denuded stromal surface in organ culture and on New Zealand albino rabbit ocular surfaces that had the native epithelium previously removed. Specimens were collected 24, 48, 72, and 96 h later from organ-cultured corneal buttons and recipient animals, processed, and evaluated histologically.The cells grown on the collagen shield were spread uniformly and unpolarized after 48 h in culture. They were repolarized and tightly adhered to the recipient corneal stroma 24 h after transplantation, as demonstrated by formation of cell-substrate hemidesmosomes (HDs) and donor-specific antigen immunostaining. The donor cells were retained in six of 15 rabbits receiving limbal cells and four of 12 rabbits receiving amniotic cells for as long as 10 days after surgery.Cultured human limbal and amniotic epithelial cells can be successfully transplanted onto a denuded corneal surface where they adhere tightly to underlying stroma by hemidesmosomes.

Effect of collagen cross-linking in collagen corneal shields on ocular drug delivery.

It is well known that some ocular diseases can be treated more effectively with a collagen shield containing drug. The influence of collagen cross-linking on drug delivery is not known. We determined if collagen cross-linking affects ofloxacin bioavailability at three different collagen shield dissolution times. In this study, the collagen shields were not impregnated in drug but an eye drop was simply instilled after application of collagen shield. A non-cross-linked collagen shield, with a dissolution time of 12 h, disappeared more rapidly from the rabbits' eyes due to proteolysis after application in vivo. On the other hand, the cross-linked collagen shields, with dissolution times of 24 and 72 h, served as an ofloxacin depot and enhanced topical ofloxacin penetration into the cornea and the aqueous humor. As the dissolution times for the cross-linked collagen shield are longer than those of the non-cross-linked type, they serve as drug reservoirs. Therefore, cross-linked collagen shields might be useful ocular drug delivery devices because they can allow drug concentrations to achieve higher levels in the cornea and aqueous humor.

Impregnation of collagen corneal shields with liposomes: Uptake and release of hydrophilic and lipophilic marker substances

Liposomes and collagen corneal shields (CCS) have been used as ophthalmic drug delivery devices. With regard to a possibly combined application, we studied the effects of surface charge and bilayer fluidity of liposomes on their uptake and release by CCS. 12-hours-CCS were soaked in large unilamellar liposomes, which had been labelled with 4,5-carboxyfluorescein (CF) and N-(lissamine rhodamine B sulfonyl)-diacyl-phosphatidylethanolamine (PE-RhB) in the aqueous space and in the liposome bilayer, respectively. Released fluorophores were determined fluorometrically in the elution buffer at intervals from 1 to 240 min after immersion. The CF concentration in the CCS soaked in a CF solution was two to seven times higher than immersion in the liposome suspensions. Among those, the negatively charged, cholesterol-containing preparation led to the highest CF concentration in the CCS. The PE-RhB concentration was highest after soaking the CCS in neutral, cholesterol-free liposomes. All types of liposomes were found inside the CCS by freeze fracture electron microscopy. The release kinetics data indicate a first order release. More than 90% of CF was released by the CCS within the first 30 min. This was equal after soaking the CCS in the CF solution or in liposomes. With DOPC-liposomes, the maximal release was already attained after 10 min. In general, the differences in the release kinetics of both hydrophilic and lipophilic markers, obtained by the various liposome types were small. Our results indicate that surface charge and bilayer fluidity are of minor importance for the interaction with collagen corneal shields. However, since the release kinetics of a liposome-encapsulated hydrophilic or lipophilic substance are similar to the release of a non-encapsulated drug, the combination of liposomes with collagen shields may be useful mainly with respect to the encapsulation of drugs which do not penetrate the ocular surface as well as to prolong corneal contact time of the liposomes.

Aminoglycoside Macular Infarction in Association With Gentamicin-Soaked Collagen Corneal Shield

Presoaked collagen corneal shields are used as a means for the delivery of antibiotics to the corneal epithelium and stroma and the anterior chamber. We report a case of macular infarction that occurred in a patient after the placement of a gentamicin sulfate-impregnated collagen corneal shield following cataract surgery. Report of a Case. An 80-year-old man underwent extracapsular cataract extraction with phacoemulsification of the lens nucleus and implantation of a posterior chamber intraocular lens in the left eye. Preoperative visual acuity was 6/120 OS. Clinical evaluation demonstrated a visually significant cataract and mild atrophic retinal pigment epithelial changes. Visual acuity in the fellow eye was 6/12 with similar retinal pigment epithelial changes noted. A 5-mL peribulbar injection was performed with a 1.6-cm 27-gauge needle using equal amounts of 1% lidocaine hydrochloride (without epinephrine) and 0.5% bupivacaine hydrochloride and 0.5 mL (75 U) of hyaluronidase. Light digital massage of the globe

Tear film, pharmacology of eye drops, and toxicity.

Various new topical ophthalmic drug delivery systems show promise for increasing bioavailability, reducing epithelial toxicity, and improving patient compliance. Microparticulates are drug-containing polymeric particles that are placed in the fornix and release ocular medication by diffusion, chemical reaction, polymer degradation, or ion exchange and can be used to deliver many topical ophthalmic medications, including antibiotics and antimetabolites. Soft drugs are activated enzymatically at the site of application and are rapidly converted to inactive metabolites when exposed to the ocular environment, improving bioavailability at the target site, and reducing the potential for ocular and systemic side effects. Applications include soft beta-blockers, soft corticosteroids, and soft anticholinergics. Collasomes are made up of collagen pieces suspended in a viscous vehicle; this formulation is similar to that of corneal collagen shields, but is more useful for chronic therapy because the collasomes can be instilled by the patient and cause less blurring of vision. Potential uses include delivery of hydrophobic antimetabolites such as cyclosporine to prevent graft rejection and delivery of lipids for the therapy of dry eyes. Ideal replacements for dysfunctional tear layers, especially the lipid layer, have not yet been developed. The toxic effects of preservatives in topical ocular medications, particularly in artificial tears, often outweigh the benefits and preservative-free tear preparations are almost always preferable.

Pharmacokinetic considerations in the treatment of bacterial keratitis.

The eye is relatively impermeable to micro-organisms and other environmental elements. However, if corneal integrity is breached by trauma, a sight-threatening bacterial infection can result. Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae are the most common bacterial pathogens associated with infection of compromised corneas. Bacterial enzymes and toxins, as well as factors associated with the host immune response, can lead to tissue destruction during corneal infection. For successful therapy, an antibacterial agent must be active against the pathogen and must be able to overcome the permeability barrier of the cornea. Topical application of antibacterial agents adequately delivers drugs to the cornea and aqueous humour. However, drug concentrations at the site of infection are not always sufficient to rapidly kill infective organisms. Infections with antibiotic-resistant strains present an even greater therapeutic challenge. In addition, sterilisation of the cornea by antibacterial agents does not eliminate inflammation and corneal scarring that accompany infection. Steroidal and non-steroidal antiinflammatory agents limit corneal scarring during experimentally induced bacterial keratitis. However, although promising, concomitant use of these drugs with antibacterial agents remains controversial. Two ocular drug delivery systems that provide high and sustained concentrations of drug to ocular tissues are corneal collagen shields and transcorneal iontophoresis. The collagen shield, originally designed as a bandage lens, prolongs drug contact with the cornea. Chemotherapeutic studies of experimental bacterial keratitis demonstrate that shields hydrated with antibacterial agents reduce bacteria in the cornea as well as or better than frequent applications of fortified antibacterial drops. Transcorneal iontophoresis uses an electric current to drive charged drugs into the cornea. In experimentally induced bacterial keratitis, transcorneal iontophoresis of antibacterial agents is superior to topically administered ocular drops for reducing the numbers of bacteria in the cornea. Although both drug delivery systems appear to be well tolerated and nontoxic in animal models, clinical trials in patients are required to determine the usefulness of these drug delivery systems in clinical trials. Based on present experimental results, future therapy of bacterial keratitis will involve efficient drug delivery devices, the use of new antibacterial agents or combinations of presently available antibacterial agents, and careful use of adjuvant anti-inflammatory agents.

Contact lenses and corneal shields.

Contact lens wear has been associated with a wide spectrum of corneal complications. Disposable contact lenses have not eliminated the problem of corneal ulcers associated with extended-wear contact lenses. Rigid, gas-permeable extended-wear lenses may be considered as an acceptable alternative to extended wear of soft contact lenses. Collagen corneal shields are a clinical indicator of collagenase activity on the ocular surface and serve as a collagenase inhibitor.

Comparative study of a collagen corneal shield and a subconjunctival injection at the end of cataract surgery

To compare the effectiveness of subconjunctival injections and collagen shields in delivering anti-inflammatory agents and antibiotics after cataract surgery, we conducted a prospective study of 61 patients. They were randomly assigned to three groups: subconjunctival injection of gentamicin and dexamethasone; the same route plus a collagen shield without drug; collagen shield soaked in gentamicin and dexamethasone. All subjects had a manual extracapsular cataract extraction with posterior chamber intraocular lens implantation. Eyes were evaluated at the end of surgery and 24 hours later. The collagen shield achieved a progressive effect on pain and a decrease in conjunctival redness after 24 hours. The occurrence of folds in Descemet's membrane was less frequent and aqueous flare less severe than when subconjunctival injections were used. No adverse effect was reported. We conclude that the collagen shield could be a safe, better, noninvasive technique because of its double action of bandage and enhancement of drug penetration. Key Words: bandage, cataract extraction, collagen corneal shields, postoperative inflammation, subconjunctival injection

Evaluation of Corneal Collagen Shields as a Drug Delivery Device for the Treatment of Experimental Pseudomonas Keratitis

To clarify the role of corneal collagen shields as a drug delivery device for the treatment of bacterial keratitis, the authors studied the effectiveness of topical gentamicin treatment, with and without the use of corneal collagen shields, in a rabbit model of Pseudomonas keratitis. Forty-eight New Zealand white rabbits were infected by injecting 500 colony-forming units (CFU) of Pseudomonas aeruginosa into the corneal stroma, and treatment was begun 24 hours later. A 13.6 mg/ml solution of gentamicin was topically administered during a 24-hour period. Collagen shields were soaked in gentamicin 13.6 mg/ml for 5 minutes before placing them on the cornea. Corneas were quantitatively cultured 1 hour after the treatment period ended. Six different groups of rabbits were tested, with the results analyzed as the mean log10 of bacterial CFU. An untreated control group had significantly more bacteria (7.96 +/- 0.74) than any of 5 treatment groups. No difference was found between groups given a loading dose of antibiotic drops at the beginning of treatment, either with (4.90 +/- 2.41) or without (6.25 +/- 0.54) an antibiotic-impregnated collagen shield. A group treated with a collagen shield augmented with gentamicin drops every 3 hours had fewer bacteria (1.52 +/- 1.82) than a group receiving drops alone (4.15 +/- 1.83) (P less than 0.05). However, treatment with a collagen shield supplemented with drops every 3 hours was not as effective as gentamicin drops administered every 30 minutes (no bacterial growth) (P less than 0.05). These results show that antibiotic-impregnated collagen shields should not replace traditional antibiotic drop therapy as the mainstay of treatment but may be a useful adjunct to treatment with topical antibiotics.

Growing human corneal epithelium on collagen shield and subsequent transfer to denuded corneain vitro

Three fundamental in vitro experiments have been done in the present report: 1) comparison of three different nutrient media on their abilities to culture and passage the human corneal epithelial cells; 2) evaluation of the ability of extracellular matrix material to promote the growth of cultured human corneal epithelium on collagen corneal shields; and 3) determination of the feasibility of the shield to serve as a carrier for the transfer of cultured cells to allogeneic, denuded corneal surface in vitro. Primary cultures of human corneal epithelium were established from explants which were obtained from limbal and peripheral corneal tissue by three different nutrient media respectively: KGM (Keratinocyte Growth Medium), SHEM (Supplemental Hormonal Epithelial Medium), and one combination of the two media (KGM/SHEM). We found the KGM/SHEM combination to be more favorable because morphology was better preserved, the proliferation rate increased five-fold over the 14 days observed time course, and we were able to subculture the tissue for at least three passages. With this combined medium, a suspension of cultured corneal epithelial cells (5 x 10(5)/ml) was seeded onto either the concave surface of collagen corneal shields or onto shields which had been coated with extracellular matrix materials (Matrigel or type IV collagen). The cells attached readily to all the coated shields (20/20) but to only a few of the uncoated shields (3/10), and formed a stratified tissue (2 to 3 layers) within seven days once the cells attached. However, the cells on the shields coated with Matrigel failed to become confluent under these conditions. The stratified tissue on type IV collagen coated shields could then be subsequently transferred to denuded human corneal stroma in organ culture by placing them together and incubating for 2-7 days. After that, histologic examinations showed that the epithelial cells had attached tightly to the recipient stromal surface, even after the removal of the collagen shield.

Ocular acyclovir delivery by collagen discs: a mouse model to screen anti-viral agents.

Discs 1.6 mm in diameter trephined from corneal collagen shields were used to deliver acyclovir (ACV) to the cornea of mice inoculated with herpes simplex virus type 1 (HSV-1). In the first minute after application to the cornea, there was a 23% decrease of ACV in the discs. After the first minute, ACV clearance from the discs appeared to be exponential with a half-life of 21 minutes. Treatment given 3 times a day reduced HSV-1 titer in tear film, corneal tissue, and trigeminal ganglia. This animal model should be useful to conserve novel potential anti-viral drugs undergoing initial screening.

Delivery of Fluorescein to the Anterior Chamber Using the Corneal Collagen Shield

Collagen corneal shields show promise as an alternative method of drug delivery to the eye. The authors quantified collagen shield delivery of sodium fluorescein to the aqueous humor in human volunteers using fluorophotometry. Collagen shields that had been immersed in 0.01 % sodium fluorescein were applied to eyes of human volunteers. The shields delivered significantly more fluorescein to the aqueous humor at 2 and 4 hours compared with drops of the same concentration instilled every 30 minutes for 4 hours (P < 0.0001 and P = 0.0003, respectively) or daily wear soft contact lenses presoaked in 0.01 fluorescein (P < 0.0001 and P < 0.0025, respectively). Collagen shields did not induce damage to the corneal epithelium over a 2-hour wearing period. These results suggest that the collagen shield may be superior to topical drops in delivering water-soluble compounds to the cornea and aqueous humor.

Collagen corneal shields enhance penetration of topical prednisolone acetate

We used an animal model to compare the corneal and aqueous penetration of topical prednisolone acetate 1% with and without the presence of a commercially available collagen corneal shield. A significant (P <.02) increase in penetration into cornea and aqueous humor at 30 minutes and 120 minutes was found in eyes with a collagen corneal shield in place. Increased concentrations were achieved by soaking the shield in prednisolone acetate for 15 minutes prior to application.

Collagen shield enhancement of topical dexamethasone penetration.

Collagen corneal shields were investigated as a vehicle for enhancing the ocular penetration of topical 0.1% dexamethasone alcohol in rabbit eyes. Four protocols were compared: a single dexamethasone drop, hourly drops, a 24-hour collagen shield presoaked in 0.1% dexamethasone, and a presoaked collagen shield followed by hourly drops. Dexamethasone concentrations in the cornea, aqueous, iris, and vitreous were measured by radioassay at six time intervals, and cumulative drug delivery over 6 hours was calculated for each tissue. Treatment with a presoaked collagen shield plus hourly drops resulted in peak and cumulative drug delivery to the cornea, aqueous, iris, and vitreous that was twofold to fourfold higher than delivery achieved with hourly drops alone. A presoaked shield by itself yielded equivalent or superior peak and cumulative drug delivery compared with a regimen of hourly drops. Collagen shields significantly enhance topical dexamethasone penetration and may be useful for maximizing the intraocular delivery of dexamethasone and for decreasing the required frequency of topical dexamethasone administration.

Use of collagen corneal shields in the treatment of bacterial keratitis.

We used an animal model of Pseudomonas keratitis to compare treatment by topical tobramycin with and without the presence of a commercially available collagen corneal shield. Pilot studies showed a significant, 30-fold increase in penetration of tobramycin into the anterior chamber in eyes with a collagen shield in place. Twenty albino rabbit eyes were inoculated with P. aeruginosa to produce stromal keratitis. After 12 hours of topical tobramycin dosing, eyes with a collagen corneal shield in place had a statistically significant (P less than .01) decrease in colony forming unit counts in comparison to treated eyes without a shield and control eyes.