Animal models and drug candidates for use in glaucoma filtration surgery: A systematic review

Purpose The PreserFlo MicroShunt is an innovative implant for the surgical treatment of glaucoma. Although usually effective, surgeries can still fail due to fibrosis. This study was conducted to gain insight into the histological aspects of the fibrotic response and find potential targets to reduce postoperative fibrosis. Methods Fifteen New Zealand White rabbits were implanted with a microshunt and followed up for 40 days. Animals were euthanized at postoperative days (PODs) 1, 5, and 40 to collect eyes for histological evaluation. Bleb formation and ocular health were assessed by slit-lamp (SL) biomicroscopy and optical coherence tomography (OCT). Intraocular pressure (IOP) was measured using rebound tonometry. Results Blebs failed after approximately 2 weeks based on bleb survival and IOP measurements. No severe complications were observed with OCT and SL. Histology revealed a wide variety of cells, in the bleb and around the microshunt, including polymorphonuclear leucocytes (PMNs), myofibroblasts, and foreign body giant cells, at different PODs. Conclusions Implantation of a poly(styrene- b -isobutylene- b -styrene) microshunt in rabbits resulted in the occurrence of a wide variety of cells during the wound-healing response. Future research should further elucidate the potential of these (earlier often overlooked) cells to target the fibrotic response in vivo—for example, by developing novel antifibrotic drugs, methods for sustained delivery of medications, or augmenting material properties. Translational Relevance Current antifibrotic therapies aim to inhibit myofibroblasts; however, a wide variety of cells are involved in the fibrotic response. Future research focusing on these cells could offer novel methods for reducing the fibrotic response after glaucoma surgery.

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“…IOP deviations are often small within this type of animal model, as normotensive animals without glaucoma are used. 29 , 30 …”

Section: Discussionmentioning

confidence: 99%

“…Current novel antifibrotic therapies, although often safer in vivo, do not outperform MMC. 30 Novel targets (as described earlier in this section) could be studied to find alternatives. Second, augmenting material properties could be beneficial.…”

Section: Discussionmentioning

confidence: 99%

Wound Healing Response After Bleb-Forming Glaucoma Surgery With a SIBS Microshunt in Rabbits

Mechelen

Wolters

Herfs

et al. 2022

Trans. Vis. Sci. Tech.

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“…Even though these novel drugs often showed to be safer compared to the established MMC and 5-FU, a lower anti-fibrotic effect is often seen. [14] Recently, drug delivery systems (DDS(s) have been emerging in the biomedical industry (e.g., for reducing or substituting eye drops, providing anti-glaucoma neuroprotective drugs, or for releasing anti-fibrotic drugs used within glaucoma surgery). [2,[15][16][17][18][19][20] A continuous-release DDS, loaded with MMC, could reduce postoperative cytotoxic effects of MMC while still maintaining efficacy due to lower concentrations of applied MMC toward the tissue.…”

Section: Doi: 101002/mabi202300075mentioning

confidence: 99%

“…Rabbits were used as the animal model in this study as they have large eyes (comparable to human eyes), and were ideal for the development of biomedical devices related to blebforming glaucoma surgery. [14,30] All animal procedures were conducted in accordance with the European Directive for animal experiments (2010/63/EU) (Approved Dutch license number: AVD1070020197464). The Central Authority for Scientific Procedures on Animals (CCD, Den Haag, NL), and the local ethical committee approved all animal procedures.…”

Section: Animalsmentioning

confidence: 99%

A Degradable Sustained‐Release Drug Delivery System for Bleb‐Forming Glaucoma Surgery

Mechelen

Wolters

Fredrich

et al. 2023

Macromolecular Bioscience

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Fibrosis of the filtering bleb is one of the main causes of failure after bleb‐forming glaucoma surgery. Intraoperative application of mitomycin C (MMC) is the current gold standard to reduce the fibrotic response. However, MMC is cytotoxic and one‐time application is often insufficient. A sustained‐release drug delivery system (DDS), loaded with MMC, may be less cytotoxic and equally or more effective. Two degradable (polycaprolactone (PCL) and polylactic‐co‐glycolic acid (PLGA)) MMC‐loaded DDSs are developed. Release kinetics are first assessed in vitro followed by rabbit implants in conjunction with the PRESERFLO MicroShunt. As a control, the MicroShunt is implanted with adjunctive use of a MMC solution. Rabbits are euthanized at postoperative day (POD) 28 and 90. The PLGA and PCL DDSs release (on average) 99% and 75% of MMC, respectively. All groups show functioning blebs until POD 90. Rabbits implanted with a DDS show more inflammation with avascular thin‐walled blebs when compared to the control. However, collagen is more loosely arranged. The PLGA DDS shows less inflammation, less foreign body response (FBR), and more complete degradation at POD 90 when compared to the PCL DDS. Further optimization with regard to dosage is required to reduce side effects to the conjunctiva.

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“…Antifibrotic gene therapy may alleviate the fibrotic response with fewer associated complications compared to current antiproliferatives. A systematic review comparing gene therapy antifibrotic treatments to mitomycin C found that adenoviral vectors containing p21, P27K1P1, and connective tissue growth factor siRNA were comparably effective with less damage to surrounding tissue [17 ▪▪ ]. Additionally, Lee et al recently used an AAV CRISPR-Cas9 system to suppress connective tissue growth factor in rabbits who underwent glaucoma filtration surgery, resulting in reduced subconjunctival fibrosis and collagen deposition compared to untreated eyes [18].…”

Section: Gene Therapymentioning

confidence: 99%

Future directions of glaucoma treatment: emerging gene, neuroprotection, nanomedicine, stem cell, and vascular therapies

Ciociola,

Fernandez,

Kaufmann

et al. 2023

Current Opinion in Ophthalmology

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Purpose of review The aim of this article is to summarize current research on novel gene, stem cell, neuroprotective, nanomedicine, and vascular therapies for glaucoma. Recent findings Gene therapy using viral vectors and siRNA have been shown to reduce intraocular pressure by altering outflow and production of aqueous humor, to reduce postsurgical fibrosis with few adverse effects, and to increase retinal ganglion cell (RGC) survival in animal studies. Stem cells may treat glaucoma by replacing or stimulating proliferation of trabecular meshwork cells, thus restoring outflow facility. Stem cells can also serve a neuroprotective effect by differentiating into RGCs or preventing RGC loss via secretion of growth factors. Other developing neuroprotective glaucoma treatments which can prevent RGC death include nicotinamide, the NT-501 implant which secretes ciliary neurotrophic factor, and a Fas-L inhibitor which are now being tested in clinical trials. Recent studies on vascular therapy for glaucoma have focused on the ability of Rho Kinase inhibitors and dronabinol to increase ocular blood flow. Summary Many novel stem cell, gene, neuroprotective, nanomedicine, and vascular therapies have shown promise in preclinical studies, but further clinical trials are needed to demonstrate safety and efficacy in human glaucomatous eyes. Although likely many years off, future glaucoma therapy may take a multifaceted approach.

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Animal models and drug candidates for use in glaucoma filtration surgery: A systematic review

Cited by 9 publications

References 170 publications

Wound Healing Response After Bleb-Forming Glaucoma Surgery With a SIBS Microshunt in Rabbits

Wound Healing Response After Bleb-Forming Glaucoma Surgery With a SIBS Microshunt in Rabbits

A Degradable Sustained‐Release Drug Delivery System for Bleb‐Forming Glaucoma Surgery

Future directions of glaucoma treatment: emerging gene, neuroprotection, nanomedicine, stem cell, and vascular therapies

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