Biotechnology and Biomaterial-Based Therapeutic Strategies for Age-Related Macular Degeneration. Part II: Cell and Tissue Engineering Therapies.

Age-related Macular Degeneration (AMD) is an up-to-date untreatable chronic neurodegenerative eye disease of multifactorial origin, and the main causes of blindness in over 65 y.o. people. It is characterized by a slow progression and the presence of a multitude of factors, highlighting those related to diet, genetic heritage and environmental conditions, present throughout each of the stages of the illness. Current therapeutic approaches, mainly consisting on intraocular drug delivery, are only used for symptoms relief and/or to decelerate the progression of the disease. Furthermore, they are overly simplistic and ignore the complexity of the disease and the enormous differences in the symptomatology between patients. Due to the wide impact of the AMD and the up-to-date absence of clinical solutions, Due to the wide impact of the AMD and the up-to-date absence of clinical solutions, different treatment options have to be considered. Cell therapy is a very promising alternative to drug-based approaches for AMD treatment. Cells delivered to the affected tissue as a suspension have shown poor retention and low survival rate. A solution to these inconveniences has been the encapsulation of these cells on biomaterials, which contrive to their protection, gives them support, and favor their retention of the desired area. We offer a two-papers critical review of the available and under development AMD therapeutic approaches, from a biomaterials and biotechnological point of view. We highlight benefits and limitations and we forecast forthcoming alternatives based on novel biomaterials and biotechnology methods. In this second part we review the preclinical and clinical cell-replacement approaches aiming at the development of efficient AMD-therapies, the employed cell types, as well as the cell-encapsulation and cell-implant systems. We discuss their advantages and disadvantages and how they could improve the survival and integration of the implanted cells.

Biotechnology and Biomaterial-Based Therapeutic Strategies for Age-Related Macular Degeneration. Part I: Biomaterials-Based Drug Delivery Devices.

Age-related Macular Degeneration (AMD) is an up-to-date untreatable chronic neurodegenerative eye disease of multifactorial origin, and the main causes of blindness in over 65 years old people. It is characterized by a slow progression and the presence of a multitude of factors, highlighting those related to diet, genetic heritage and environmental conditions, present throughout each of the stages of the illness. Current therapeutic approaches, mainly consisting of intraocular drug delivery, are only used for symptoms relief and/or to decelerate the progression of the disease. Furthermore, they are overly simplistic and ignore the complexity of the disease and the enormous differences in the symptomatology between patients. Due to the wide impact of the AMD and the up-to-date absence of clinical solutions, the development of biomaterials-based approaches for a personalized and controlled delivery of therapeutic drugs and biomolecules represents the main challenge for the defeat of this neurodegenerative disease. Here we present a critical review of the available and under development AMD therapeutic approaches, from a biomaterials and biotechnological point of view. We highlight benefits and limitations and we forecast forthcoming alternatives based on novel biomaterials and biotechnology methods. In the first part we expose the physiological and clinical aspects of the disease, focusing on the multiple factors that give origin to the disorder and highlighting the contribution of these factors to the triggering of each step of the disease. Then we analyze available and under development biomaterials-based drug-delivery devices (DDD), taking into account the anatomical and functional characteristics of the healthy and ill retinal tissue.

First steps for the development of silk fibroin-based 3D biohybrid retina for age-related macular degeneration (AMD).

Age-related macular degeneration is an incurable chronic neurodegenerative disease, causing progressive loss of the central vision and even blindness. Up-to-date therapeutic approaches can only slow down he progression of the disease. OBJECTIVE: Feasibility study for a multilayered, silk fibroin-based, 3D biohybrid retina. APPROACH: Fabrication of silk fibroin-based biofilms; culture of different types of cells: retinal pigment epithelium, retinal neurons, Müller and mesenchymal stem cells ; creation of a layered structure glued with silk fibroin hydrogel. MAIN RESULTS: In vitro evidence for the feasibility of layered 3D biohybrid retinas; primary culture neurons grow and develop neurites on silk fibroin biofilms, either alone or in presence of other cells cultivated on the same biomaterial; cell organization and cellular phenotypes are maintained in vitro for the seven days of the experiment. SIGNIFICANCE: 3D biohybrid retina can be built using silk silkworm fibroin films and hydrogels to be used in cell replacement therapy for AMD and similar retinal neurodegenerative diseases.

Can the dexamethasone intravitreal implant Ozurdex be safely administered in an out-of-operating room setting?

Purpose: To describe a standardized protocol of the dexamethasone intravitreal (DEX) implant Ozurdex (Allergan, Dublin, Ireland) performed in a controlled environment surgical cabin (CESC). Methods: Retrospective and observational study conducted on patients who underwent a DEX implant between May 2011 and June 2019, in a third level University Hospital. The controlled environment surgical cabin (ArcSterile, Imex, Valencia, Spain) used in this study was the MB 20 (2 m width, 1.60 m depth, and 2 m height) with an uninterrupted power system (ARSSAI1) to keep the cabin working for 20 min. The cabin was used in the open mode. A standardized protocol of intravitreal injections in controlled environment surgical cabin was designed. Results: From May 2011 to February 2015, a total of 454 DEX implants were performed in the operating room, whereas from March 2015 to June 2019, 1054 DEX devices were implanted using the CESC. The mean number of DEX implants/per week was significantly lower in the operating room than in the CESC [2.3 (2.1 to 2.5) versus 3.8 (3.6 to 4.1), mean difference 1.5 (1.2 to 1.8), p < 0.0001]. The incidence of endophthalmitis was similar in the two populations, 0/454 (0.0%; 95% CI 0.0 to 0.81%) and 0/1054 (0.0%; 95% CI 0.0 to 0.35%) in the operating room and in the CESC, respectively. Conclusions: The CESC may be a good alternative to the conventional operating room for the administration of the intravitreal DEX implant.

External subretinal drainage, bevacizumab, and scleral buckling for complete exudative retinal detachment after photocoagulation in retinopathy of prematurity.

BACKGROUND: Total serous retinal detachment after laser photocoagulation for retinopathy of prematurity is an infrequent type of retinal detachment in preterm babies. PURPOSE: To describe the successful outcome for treatment by scleral drainage, bevacizumab, and scleral buckling for complete serous exudative retinal detachment in a patient with retinopathy of prematurity. METHODS: A preterm baby with primary pulmonary hypertension under treatment with sildenafil developed a total (retrolental) serous retinal detachment after photocoagulation for threshold retinopathy. The dense subretinal fluid was externally drained using a bent needle with an infusion placed in the anterior chamber. Additional bevacizumab and scleral buckling helped to control the plus disease and subretinal leakage. RESULTS: Retinal apposition was obtained with the described approach. CONCLUSION: Total serous retinal detachment is a rare but severe visual complication in retinopathy of prematurity. The described technique may restore the retinae immediately in a visually critical period.

Accidental injections of dexamethasone intravitreal implant (Ozurdex) into the crystalline lens.

PURPOSE: To describe the side effects and management after inadvertent injection of a dexamethasone implant (Ozurdex) into the crystalline lens. METHODS: Two case reports. RESULTS: Two patients with macular edema due to unilateral retinal vein occlusion were scheduled for an intravitreal injection of Ozurdex. During the procedure, the implant was accidentally injected into the crystalline lens. Both patients developed cataracts during the course of several weeks and in both there was an intraocular pressure (IOP) increase, which required treatment with topical hypotensives. Macular edema improved only slightly. Cataract surgery with uneventful removal of the implant was performed 3 (case 1) and 6 months (case 2) after the injection. CONCLUSIONS: After inadvertent injection of Ozurdex into the crystalline lens, cataract surgery with removal of the implant should be performed as soon as possible in order to avoid IOP increase and so that the underlying condition may be treated adequately.