A transparent cornea is paramount for vision. Corneal opacity is one of the leading causes of blindness. Although conventional corneal transplantation has been successful in recovering patients’ vision, the outcomes are challenged by a global lack of donor tissue availability. Bioengineered corneal tissues are gaining momentum as a new source for corneal wound healing and scar management. Extracellular matrix (ECM)-scaffold-based engineering offers a new perspective on corneal regenerative medicine. Ultrathin stromal laminar tissues obtained from lenticule-based refractive correction procedures, such as SMall Incision Lenticule Extraction (SMILE), are an accessible and novel source of collagen-rich ECM scaffolds with high mechanical strength, biocompatibility, and transparency. After customization (including decellularization), these lenticules can serve as an acellular scaffold niche to repopulate cells, including stromal keratocytes and stem cells, with functional phenotypes. The intrastromal transplantation of these cell/tissue composites can regenerate native-like corneal stromal tissue and restore corneal transparency. This review highlights the current status of ECM-scaffold-based engineering with cells, along with the development of drug and growth factor delivery systems, and elucidates the potential uses of stromal lenticule scaffolds in regenerative therapeutics.
Corneal blindness due to scarring is conventionally treated by corneal transplantation, but the shortage of donor materials has been a major issue affecting the global success of treatment. Pre-clinical and clinical studies have shown that cell-based therapies using either corneal stromal stem cells (CSSC) or corneal stromal keratocytes (CSK) suppress corneal scarring at lower levels. Further treatments or strategies are required to improve the treatment efficacy. This study examined a combined cell-based treatment using CSSC and CSK in a mouse model of anterior stromal injury. We hypothesize that the immuno-regulatory nature of CSSC is effective to control tissue inflammation and delay the onset of fibrosis, and a subsequent intrastromal CSK treatment deposited collagens and stromal specific proteoglycans to recover a native stromal matrix. Using optimized cell doses, our results showed that the effect of CSSC treatment for suppressing corneal opacities was augmented by an additional intrastromal CSK injection, resulting in better corneal clarity. These in vivo effects were substantiated by a further downregulated expression of stromal fibrosis genes and the restoration of stromal fibrillar organization and regularity. Hence, a combined treatment of CSSC and CSK could achieve a higher clinical efficacy and restore corneal transparency, when compared to a single CSSC treatment.
induction of posterior vitreous detachment (pVD) by pharmacologic vitreolysis has been largely attempted through the use of enzymatic reagents. ocriplasmin has been the only fDA-approved clinical reagent so far. Several adverse effects of ocriplasmin have emerged, however, and the search for alternative pVD-inducing reagents continues. Since i) collagen forms an important structural component of the vitreous, and ii) strong vitreo-retinal adhesions exist between the cortical vitreous and the internal limiting membrane (ILM) of the retina, an effective PVD-inducing reagent would require both, vitreous liquefaction, and concurrent dehiscence of vitreoretinal adhesion, without being toxic to retinal cells. We designed a combination of two reagents to achieve these two objectives; a triple helix-destabilizing collagen binding domain (cBD), and a fusion of RGD (integrin-binding) tripeptide with cBD (RcBD) to facilitate separation of posterior cortical vitreous from retinal surface. Based on in vitro, ex-vivo, and in vivo experiments, we show that a combination of cBD and RcBD displays potential for safe pharmacologic vitreolysis. Our findings assume significance in light of the fact that synthetic RGD-containing peptides have already been used for inhibition of tumor cell invasion. proteins such as variants of collagen binding domains could have extended therapeutic uses in the future. The vitreous humor is a hydrogel present in the eye; an intact vitreous gel is important for ocular health. However, with aging, the gel undergoes a gradual, spontaneous process of liquefaction, and separates from the retina, resulting in posterior vitreous detachment or PVD 1-3. Therefore, it is not surprising that there is a high incidence of vitreo-retinal disorders in later decades of life, with the peak of incidence of retinal conditions matching the peak age of incidence of posterior vitreous separation 4-6. When the gel liquefaction exceeds the extent of vitreo-retinal dehiscence, anomalous PVD occurs, which is characterized by partial or incomplete detachment of vitreous from the retina. Anomalous PVD can involve exertion of excessive tractional forces acting upon the retina, which can lead to many ophthalmic complications such as hemorrhage, retinal tears, or detachment, macular hole formation, and vitreomacular traction syndrome 3,7,8. The mainstream treatment of incomplete PVD is surgical intervention or vitrectomy, to create a clean retinal surface devoid of any vitreous remnants and thus avoid further complications such as proliferative vitreoretinopathy (PVR). However, owing to its invasive nature and associated risks, surgical vitrectomy is not an ideal choice, except in cases complicated by retinal detachments. In paediatric patients, induction of posterior vitreous detachment (PVD) is an important and challenging step in the successful management of retinal detachment or traumatic macular hole, owing to the firm vitreoretinal adhesions. Pharmacological vitrectomy has been explored as a non-surgical, safer and cleaner al...
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