Vitreous substitutes remain a fundamental unmet need in regenerative medicine: current tamponade agents, gases and silicone oil, address immediate surgical challenges but neglect the long-term functional role of the tissue they replace. A paradigm shift towards durable, biomimetic hydrogel substitutes is not a distant ambition, but a clinical necessity.

BACKGROUND:The human vitreous body plays an important role in intraocular homeostasis and fulfils structural, metabolic and immunological functions. In the context of vitreoretinal surgery artificial endotamponades are introduced to stabilize the retina. OBJECTIVE:Clinically established endotamponades, their applications, advantages and disadvantages, the distinction from total vitreous body replacement and the development of hydrophilic vitreous body substitutes are presented. The current state of development and the potential of synthetic hydrogels as vitreous body substitutes are analyzed. MATERIAL AND METHODS:Discussion of the basic literature and review articles on surgical endotamponades and hydrogel-based vitreous body substitutes. RESULTS:All established endotamponades exert a local stabilizing function through the principle of buoyancy or counterbuoyancy combined with surface tension and show disadvantages for the patient. Vitreous body substitutes, which can fully replace the physiological functions of the natural vitreous body, must be distinguished from endotamponades. The development of hydrogels has progressed through four generations, each offering promising approaches. CONCLUSION:There are promising solutions involving synthetic hydrogels that could undertake and even expand the physiological role of the vitreous body as vitreous body substitutes, thereby improving therapeutic outcomes and patient satisfaction.

To present an overview of emerging pharmacological strategies for the prevention and treatment of proliferative vitreoretinopathy (PVR). This review critically examines recent experimental and clinical evidence on pharmacological agents targeting key pathogenic mechanisms of PVR, including epithelial–mesenchymal transition, profibrotic cytokine signaling (TGF-β, PDGF, VEGF), and inflammation-driven tissue remodeling. Investigated compounds include clinically tested substances such as daunorubicin, 5-fluorouracil, corticosteroids, anti-VEGF agents, methotrexate, isotretinoin, decorin and infliximab, as well as newer experimental approaches including Topotecan, Melphalan, ROCK-Inhibitors and gene-regulated therapies. Mechanistic insights into receptor crosstalk, intracellular signaling cascades, and cell survival pathways are integrated with findings from preclinical models and clinical studies. Several agents have shown anti-proliferative and anti-inflammatory effects in vitro and in vivo, with methotrexate and infliximab emerging as particularly promising candidates. However, clinical data remain heterogeneous, and no pharmacological agent has yet received regulatory approval for PVR treatment. Risk stratification based on preoperative PVR, vitreous hemorrhage, or ocular trauma may help optimize patient selection in future trials. Pharmacological modulation of PVR is conceptually well supported by preclinical data, but clinical translation remains limited. Well-designed randomized trials in clearly defined high-risk populations are needed to validate efficacy, determine optimal treatment windows, and develop standardized protocols for both prophylaxis and therapy.

OBJECTIVES:Charles Bonnet Syndrome (CBS) involves visually impaired yet mentally healthy individuals experiencing visual hallucinations (VH) while being aware of the hallucinations' unreality. Its prevalence varies across different conditions, with low vision, bilateral vision loss and advanced age being established as risk factors. This meta-analysis aims to comprehensively assess CBS literature with regard to CBS prevalence in ophthalmic patients. METHODS:A comprehensive literature search was conducted on June 11th and June 13th 2023, using the databases PubMed/MEDLINE and Web of Science. Data evaluation and extraction was accomplished by two separate authors. Study analysis was performed qualitatively, thereafter quantitatively by a subsequent meta-analysis, including subgroup assessments for variations among demographic and ophthalmic variables. RESULTS:49 eligible studies were identified, encompassing data from 20 303 patients. The collective prevalence of CBS in literature was determined to be 10.2 % (95 % confidence interval: 7.23 % - 14.1 %). Vision rehabilitation patients suffer most frequently from CBS (24.6 %). Patients with retinal diseases, low vision, and glaucoma suffer from CBS at similar rates. The prevalence of CBS among these cohorts spans from 11.8 % to 17.7 %. Age (p = 0.0013) and sex (p = 0.003) correlated statistically significantly with the prevalence of CBS. CONCLUSIONS:CBS is prevalent among ophthalmic patients with various eye diseases, especially in the presence of low vision. Ophthalmologists should consider that about one in six patients with retinal diseases, glaucoma, or low vision they assessed might experience CBS. Awareness among medical professionals should be increased, as education provides patients with relief.

During vitreoretinal surgery, the vitreous body is removed and requires a suitable replacement to ensure ocular homeostasis, as the native vitreous does not regenerate. An ideal vitreous substitute should mimic the optical, mechanical, and biochemical properties of the natural vitreous while maintaining long-term biocompatibility. Currently, clinically used substitutes such as gases and silicone oils facilitate retinal reattachment but deviate significantly from the native vitreous, leading to complications such as cataract formation, increased intraocular pressure, and emulsification. Given these limitations, there is a growing interest in hydrogels as potential vitreous substitutes due to their similarity to the native vitreous. This review therefore aspires to provide a comprehensive and detailed overview of current knowledge on the structural and biochemical composition of the vitreous, the challenges associated with existing substitutes, and recent advancements in vitreous replacement technologies. Particular attention is given to preformed and in-situ forming hydrogels, based on biopolymers and synthetic polymers, discussing their chemical composition, diverse characteristics with regard to the multiple requirements for vitreous substitutes, and clinical applicability. Finally, future challenges and opportunities in developing an ideal vitreous substitute are highlighted, including vitreous substitutes as drug delivery systems as well as cellularized vitreous substitutes by combining advanced hydrogel systems with hyalocytes as vitreous cells to further replicate the versatile characteristics and functions of the native vitreous.

PURPOSE OF REVIEW:In contrast to current clinically used tamponades including oils and gases, hydrogels offer a vitreous replacement that has the potential to present a niche for vitreous cells and elevate vitreous substitutes to the level of tissue engineering. This article, therefore, highlights and discusses recent hydrogel-based vitreous replacement strategies as well as the latest progress on vitreous cells, towards the development of a cellularized vitreous substitute. RECENT FINDINGS:A variety of different crosslinked hydrogel systems have been recently investigated as preformed and in situ forming vitreous substitutes, based on biopolymers and/or synthetic polymers. In addition, a comprehensive understanding of the precise function and immunological significance of hyalocytes as vitreous macrophages has recently emerged using advanced imaging techniques and high-throughput transcriptional and protein analyses. SUMMARY:Tissue engineering offers transformative potential for vitreous replacement by combining advanced hydrogel systems with hyalocytes as vitreous cells to further replicate the versatile characteristics and functions of the native vitreous.

Charles Bonnet Syndrome (CBS) is a complex and underrecognized condition characterized by visual hallucinations in individuals with visual impairment but preserved cognitive function. This review examines the evolving definitions, epidemiology, risk factors, and pathophysiological models of CBS. Drawing from a broad range of studies, the review identifies key diagnostic inconsistencies and highlights the syndrome’s multifactorial origins, including sensory deprivation and cortical processing imbalances. Epidemiological data suggest CBS affects up to 10% of visually impaired individuals, though prevalence estimates vary widely due to definitional discrepancies. Risk factors include low visual acuity, female sex, social isolation, and possibly certain medications, though evidence remains inconclusive. Pathophysiological theories such as deafferentation, predictive coding, and the perception-attention deficit model underscore the interplay between bottom-up and top-down mechanisms in hallucination formation. The review also explores differential diagnoses and discusses therapeutic approaches, including vision restoration, pharmacological agents, and psychoeducation. While no standardized treatment exists, early recognition and patient reassurance can significantly improve outcomes. The review calls for clearer diagnostic criteria, further research into neurobiological mechanisms, and longitudinal studies to better understand the prognosis and potential links between CBS and cognitive decline.

Recombinant tissue-type plasminogen activator (rtPA) has become central to the treatment of subretinal hemorrhages. However, individual results show highly variable and unpredictable efficacy of thrombolytic function. The aim of this study is to investigate the thrombolytic activity of rtPA in an in-vitro model for submacular hemorrhages. Using UV/Vis spectroscopy, the thrombolytic activity of rtPA was analyzed in an in-vitro model for subretinal hemorrhages with citrated human venous blood from 24 volunteers. The effects of blood clot volume (20 µL and 100 µL) and age (1d and 4d), rtPA concentration (0, 10, 50, 100, 150, and 200 µg/mL), and incubation time (30 min, 1d, and 2d) on thrombolysis was analyzed on blood clots prepared through different synthesis routes (tube vs. hanging droplet). For each period of incubation with rtPA, thrombolysis was significantly reduced for large blood clots with a volume of 100 μL compared with 20 μL blood clots. We found significantly more thrombolysis in 4-day-old clots than in 1-day-old clots after 30 min incubation with rtPA for each blood clot size studied. For each blood clot size and age as well as rtPA incubation time, thrombolysis did not increase linearly across the tested concentrations. Thrombolysis was significantly lower after 30 min than after 1d and 2d rtPA incubations. The effectiveness of thrombolysis with rtPA increases with smaller clot size (20 µL), increasing clot age (4d), and increasing incubation time (1–2d). Within the range of biocompatible rtPA concentrations, there was no concentration effect of rtPA on thrombolysis.

PURPOSE:To develop and evaluate a photovoltaic, wireless wide-field epiretinal prosthesis for the treatment of retinitis pigmentosa. METHODS:A mosaic array of thinned silicon-based photodiodes with integrated thin-film stimulation electrodes was fabricated with a flexible polyimide substrate film to form a film-based miniaturized electronic system with wireless optical power and signal transmission and integrated electrostimulation. Manufactured implants were characterized with respect to their optoelectronic performance and biocompatibility following DIN EN ISO 10993. RESULTS:A 14 mm diameter prosthesis containing 1276 pixels with a maximum sensitivity at a near infrared wavelength of 905 nm and maximized stimulation current density 30-50 μm below the electrodes was developed for direct activation of retinal ganglion cells during epiretinal stimulation. Fabricated prostheses demonstrated mucosal tolerance and the preservation of both metabolic activity, proliferation and membrane integrity of human fibroblasts as well as the retinal functions of bovine retinas. Illumination of the prosthesis, which was placed epiretinally on an isolated perfused bovine retina, with infrared light resulted in electrophysiological recordings reminiscent of an a-wave (hyperpolarization) and b-wave (depolarization). CONCLUSIONS:A photovoltaic, wireless wide-field epiretinal prosthesis for the treatment of retinitis pigmentosa using near infrared light for signal transmission was designed, manufactured and its biocompatibility and functionality demonstrated in vitro and ex vivo.

After removal of the native vitreous during vitreoretinal surgery, an adequate replacement is required to ensure ocular homeostasis. To mimic the functions of the native vitreous body, the design of an ideal replacement material is based on the optical, physicochemical and physiological properties of the healthy, juvenile vitreous body. Current clinically used tamponades including oils, gases and semifluorinated alkanes cannot meet the requirements of a suitable vitreous substitute due to fundamentally different characteristics, leading to a variety of postoperative complications. Given these challenges, there has been a call for a critical re-evaluation of materials used as vitreous substitutes. Here, hydrogels represent an authentic replacement option due to their similarity to the native vitreous. Beyond mere replacement, vitreous substitutes can also be tailored as drug delivery systems for the rapid or sustained release of therapeutic agents to address various ocular pathologies.

The occurrence of visual hallucinations in visually impaired people without mental impairment is known as Charles Bonnet Syndrome (CBS). To date, the prevalence of CBS has been reported with high variance. The present study aims at evaluating the prevalence of CBS among low-vision patients. From March 2018 to February 2022, 194 patients with a visual acuity ≥ 0.5 logMAR approached the low vision section of the Eye Clinic Sulzbach. Of these, 50 patients were found eligible, agreed to participate in the study and were screened for CBS. The course of the disease, its phenomenology and characteristics, the circumstance of onset, the ability to manipulate and resolve the hallucinations, and the psychosocial aspects of CBS were investigated. 26

Purpose We aimed to establish a rabbit model with retinal atrophy induced by an iatrogenic retinal pigment epithelium (RPE) removal, for future testing of the efficacy and safety of cell therapy strategies. Methods A localized detachment of the retina from the RPE/choroid layer was created in 18 pigmented rabbits. The RPE was removed by scraping with a custom-made extendable loop instrument. The resulting RPE wound was observed over a time course of 12 weeks with optical coherence tomography and angiography. After 4 days (group 1) and 12 weeks (group 2), histology was done and staining with hematoxylin and eosin, as well as immunofluorescence performed to further investigate the effects of debridement on the RPE and the overlying retina. Results Already after 4 days, we observed a closure of the RPE wound by proliferating RPE and microglia/macrophage cells forming a multilayered clump. This pattern continued over the observation time course of 12 weeks, whereby the inner and outer nuclear layer of the retina became atrophic. No neovascularization was observed in the angiograms or histology. The observed changes were limited to the site of the former RPE wound. Conclusions Localized surgical RPE removal induced an adjacent progressive retinal atrophy. Altering the natural course of this model may serve as a basis to test RPE cell therapeutics.

PURPOSE:To assess the safety and performance of hyaluronic acid-based vitreous substitutes in phthitic eyes.METHODS:In this retrospective interventional study a total of 21 eyes from 21 patients with phthisis bulbi were treated at the Eye Clinic Sulzbach between August 2011 and June 2021. Patients who underwent a 23G pars plana vitrectomy received a vitreous substitute composed of (I) a non-crosslinked hyaluronic acid (Healon GV), (II) a crosslinked hyaluronic acid-based hydrogel (UVHA), or (III) silicone oil (SO-5000). Main outcome measures were the intraocular pressure (IOP), the visual acuity and the structural integrity of the retina and choroid assessed by optical coherence tomography.RESULTS:An increase in IOP ≥ 5 mmHg was achieved with SO-5000 in 5/8 eyes (6/10 interventions, 60.0%) for 36.4 ± 39.5 days, with Healon GV in 4/8 eyes (7/11 interventions, 63.6%) for 82.6 ± 92.5 days and with UVHA in 4/5 eyes (5/6 interventions, 83.3%) for 93.6 ± 92.5 days. Visual acuity increased in 5/21 eyes (23.8%), remained constant in 12/21 eyes (57.1%) and decreased in 4/21 eyes (19.0%). No enucleations were required during the mean follow-up time of 192 ± 182 days. The OCT images indicated the preservation of retinal structures, while choroidal folds were only diminished in UVHA eyes.CONCLUSIONS:Hyaluronic acid-based hydrogels are biocompatible vitreous substitutes in humans and can increase and stabilize IOP in patients with phthisis bulbi for about 3 months.

In the treatment of various retinal pigment epithelium (RPE) related retinal diseases, selective retina therapy (SRT) is highly demanded, as SRT intends to selectively damage the RPE while sparing the neurosensory retina (NSR) and the choroid. A gentle method for removing diseased host RPE cells is still missing regarding RPE stem cell therapy. Cell therapeutics for age -related macular degeneration are often implanted regardless of host RPE status in the target zone, which may result in RPE multilayering. Here, we study a novel laser for selective large -area RPE removal without damaging the surrounding tissue prior to RPE implantation to promote subretinal integration. Therefore, pigmented rabbit eyes were exposed to laser pulses of 8 las in duration (wavelength, 532 nm; top -hat beam profile, 223 x 223 mu m(2)). Postirradiation retinal changes were assessed with color fundus photography, fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT). Here we present the histological outcome of four animals after laser treatment. Following euthanization, the eyes of the animals were processed for histology, sectioned in 5 mu m paraffin sections and stained with hematoxylin and eosin. Particular emphasis was given to an OCT vs light microscopy comparison. Our results reveal that RPE can be removed selectively using laser pulses of 8 mu s duration in the green spectral range without damaging the NSR. Therefore, this regime proves to be applicable in the sense of SRT.

PURPOSE:Hydrogel-based vitreous substitutes have the potential to overcome the limitations of current clinically used endotamponades. With the goal of entering clinical trials, the present study aimed to (I) transfer the material synthesis of hyaluronic acid-based hydrogels into a routine, pharmaceutical-appropriate production and (II) evaluate the properties of the vitreous substitutes in terms of the current regulations for medical devices (MDR/ISO standards).METHODS:The multistep manufacturing process of the vitreous substitutes, including the modification of hyaluronic acid with glycidyl methacrylate, photocopolymerization with N-vinylpyrrolidone, and successive hydrogel purification, was developed under laboratory conditions, characterized using 1 H-NMR, FT-IR and UV/Vis spectroscopies and HPLC, and transferred towards a pharmaceutical production environment considering GMP standards. The optical and viscoelastic characteristics of the hyaluronic acid-based hydrogels were compared with those of extracted human vitreous and silicone oil. The effect of the hydrogels on the metabolic activity, proliferation and apoptosis of fibroblast (MRC-5, BJ, L929), retinal pigment epithelial (ARPE-19, hiPSC-derived RPE) and photoreceptor cells (661W) was studied as well as their mucosal tolerance via a HET-CAM assay.RESULTS:Hyaluronic acid-based hydrogels having a suitable purity, sterility, high transparency (>90%), appropriate refractive index (1.3365) and viscoelasticity (G' > G″) were prepared in a standardized manner under controlled process conditions. The metabolic activity, proliferation and apoptosis of various cell types as well as egg choroid were unaffected by the hyaluronic acid-based vitreous substitutes, demonstrating their biocompatibility.CONCLUSIONS:The present study demonstrates the successful transferability of the crucial synthesis steps of hyaluronic acid-based hydrogels into a routine, GMP-compliant production process while achieving the optical and viscoelastic properties, biocompatibility and purity required for their clinical use as vitreous substitutes.

Vitreous substitutes are traditionally used to stabilize the retina after vitrectomy. In recent years, various approaches have been developed for using the vitreous substitute not only as a tamponade but also as a drug release system to tackle ocular diseases. This review provides an overview of the requirements for vitreous substitutes and discusses the current clinically applied as well as novel polymer-based vitreous substitutes as drug delivery systems, including their release mechanisms, efficiencies, challenges, and future perspectives.