Maurizio Mete

A polymer optoelectronic interface restores light sensitivity in blind rat retinas

Interfacing organic electronics with biological substrates offers new possibilities for biotechnology due to the beneficial properties exhibited by organic conducting polymers. These polymers have been used for cellular interfaces in several fashions, including cellular scaffolds, neural probes, biosensors and actuators for drug release. Recently, an organic photovoltaic blend has been exploited for neuronal stimulation via a photo-excitation process. Here, we document the use of a single-component organic film of poly(3-hexylthiophene) (P3HT) to trigger neuronal firing upon illumination. Moreover, we demonstrate that this bio-organic interface restored light sensitivity in explants of rat retinas with light-induced photoreceptor degeneration. These findings suggest that all-organic devices may play an important future role in sub-retinal prosthetic implants.

The synapsin domain E accelerates the exoendocytotic cycle of synaptic vesicles in cerebellar Purkinje cells.

Synapsins are synaptic-vesicle-associated phosphoproteins implicated in the regulation of neurotransmitter release and excitability of neuronal networks. Mutation of synapsin genes in mouse and human causes epilepsy. To understand the role of the highly conserved synapsin domain E in the dynamics of release from mammalian inhibitory neurons, we generated mice that selectively overexpress the most conserved part of this domain in cerebellar Purkinje cells. At Purkinje-cell–nuclear-neuron synapses, transgenic mice were more resistant to depression induced by short or prolonged high-frequency stimulations. The increased synaptic performance was accompanied by accelerated release kinetics and shorter synaptic delay. Despite a marked decrease in the total number of synaptic vesicles, vesicles at the active zone were preserved or slightly increased. The data indicate that synapsin domain E increases synaptic efficiency by accelerating both the kinetics of exocytosis and the rate of synaptic vesicle cycling and decreasing depression at the inhibitory Purkinje-cell–nuclear-neuron synapse. These effects may increase the sensitivity of postsynaptic neurons to inhibition and thereby contribute to the inhibitory control of network activity.

Characterization of a Polymer-Based, Fully Organic Prosthesis for Implantation into the Subretinal Space of the Rat

Replacement strategies arise as promising approaches in case of inherited retinal dystrophies leading to blindness. A fully organic retinal prosthesis made of conjugated polymers layered onto a silk fibroin substrate is engineered. First, the biophysical and surface properties are characterized; then, the long-term biocompatibility is assessed after implantation of the organic device in the subretinal space of 3-months-old rats for a period of five months. The results indicate a good stability of the subretinal implants over time, with preservation of the physical properties of the polymeric layer and a tight contact with the outer retina. Immunoinflammatory markers detect only a modest tissue reaction to the surgical insult and the foreign body that peaks shortly after surgery and progressively decreases with time to normal levels at five months after implantation. Importantly, the integrity of the polymeric layer in direct contact with the retinal tissue is preserved after five months of implantation. The recovery of the foreign-body tissue reaction is also associated with a normal b-wave in the electroretinographic response. The results demonstrate that the device implanted in nondystrophic eyes is well tolerated, highly biocompatible, and suitable as retinal prosthesis in case of photoreceptor degeneration.

A new L-shaped design of macular buckle to support a posterior staphyloma in high myopia.

A New L-Shaped Design of Macular Buckle to Support a Posterior Staphyloma in High Myopia Macular foveoschisis, macular detachment (MD) without macular hole, and macular detachment with macular hole could be different stages of a progressive disease well described as myopic traction maculopathy. The pathogenesis and natural history of myopic traction maculopathy are still uncertain, and the best management is debated. Elimination of epiretinal tractions by means of vitrectomy with or without internal limiting membrane peeling seems an acceptable approach and has proven to be effective. Vitrectomy alone, however, causes a transient release of the traction without addressing the major risk factor of the macular foveoschisis, which is the posterior staphyloma. Furthermore, it should be noted that vitrectomy with internal limiting membrane peeling, in highly myopic eyes, may lead to complications, such as macular hole formation, extrafoveal retinal hole formation, or physiologic changes in the macular area. To give a new shape to the posterior scleral wall, the issue of the posterior staphyloma, by the use of a scleral buckle alone, has been previously reported with good anatomical and functional results. The authors of this article think that an L-shaped buckle design (see Video, Supplemental Digital Content; http://links.lww.com/IAE/A158) is the easiest to place and leads to the lowest risk of intraoperative and postoperative complications. However, it has been used always in combination with vitrectomy. Besides, the newest designs of macular buckle (by Ando and by Stirpe) are not widely available on the market. The present study has a dual purpose. First, we aimed to study the role of the macular buckle alone, in releasing the anteroposterior and tangential tractions of macular foveoschisis, in cases of MD not associated to macular hole. Second, we wanted to test the feasibility, tolerability, and safety of a new L-shaped buckle, which can be made in the operating room.

Inverted Internal Limiting Membrane Flap Technique Versus Complete Internal Limiting Membrane Removal In Myopic Macular Hole Surgery: A Comparative Study

Purpose: To compare the results of vitrectomy with complete internal limiting membrane (ILM) removal and inverted ILM flap in the treatment of myopic macular hole (MMH). Methods: Seventy eyes of 68 patients with MMH undergone pars-plana vitrectomy (PPV) with either complete ILM removal (n = 36, Group 1) or inverted ILM flap technique (n = 34, Group 2) were included in the study. Outcomes measured were the rate of MMH closure assessed by optical coherence tomography (OCT) and visual acuity (BCVA) at six months. Results: Closure of MMH was achieved in 22 cases of Group 1 (61%) and in 32 cases of Group 2 (94%). Surgical failure was reported in 14 cases of Group 1 (39%) and in one case of Group 2 (3%). Average best-corrected visual acuity (BCVA) changed from 0.60 to 0.58 in Group 1 (P = 0.329) and from 0.70 to 0.39 in Group 2 (P < 0.01). Logistic regression analysis showed that inverted ILM flap technique was associated with 22 times higher probability of anatomic success, regardless of the MMH diameter. Conclusion: Inverted ILM flap should be preferred to complete ILM removal for the treatment of MMH. The outcomes reported with this technique were better than any other technique described until now.

Features Involved in the Healing Process of Macular Holes

The mechanism of closure of a macular hole (MH) is not yet fully understood. Spontaneous closure in nontraumatic cases is possible, but quite rare.1 Alternatively, vitrectomy and gas tamponade, with or without internal limiting membrane (ILM) peeling, achieve anatomic success in 80% to 95% of cases. During recent years, different techniques have been attempted to improve the closure rate of MH and bring it closer to 100%. The addition of autologous serum does not appear to alter the prognosis of surgery,1 while the addition of platelet-rich plasma seems to work better,2 even in challenging cases, such as myopic MH. More recently, the ILM flap technique was introduced for cases of MH that pose a high risk of persistence, such as myopic, chronic, or large holes. Initially, many surgeons thought that it would be necessary to put the ILM inside the hole to create a kind of plug. Subsequently, the pioneers of this technique stated that it would be sufficient to cover the hole with a single ILM layer, and they proposed performing the peeling only on the temporal side.3 An MH can be considered a small laceration in the weakest point of the retina, the fovea. The formation of a blood clot is the first step in the repair of a skin wound, which creates a closed environment, within which the repair mechanisms can act. Similarly, there is some evidence that anything that covers the MH and can separate the vitreous cavity from the intraretinal and subretinal space could facilitate its closure. This might explain why a single layer of ILM covering a myopic MH makes such a significant difference in the rate of closure of myopic MH.4 Moreover, the ILM flap was found to be displaced or not present in all MHs that failed to close. For the same reason, platelet-rich plasma is likely to work better than autologous serum that does not stick at the edges of the MH. We could even speculate that the main role of a tamponade might be the formation of a cover over the MH that can promote the maintenance of the homeostatic conditions necessary for the healing process. Silicone oil has been found to be an effective tamponade for the treatment of MH. This is surprising, as it is a lasting, but weaker, tamponade compared with gas. A possible explanation for its positive effect in promoting MH closure is that it creates a kind of bursa inside the edge of the MH and, therefore, compartmentalizes chemotactic and nutrient substances that may support its closure. The ILM flap also acts as substrate for a secondary intention wound-healing mechanism. When the hole is large, the edges are stiff, or the retina is not elastic enough, the ILM plug can support the closure without complete reapposition of the edges. In some cases, this step is followed by further anatomical and functional improvements during follow-up: the plug is slowly displaced toward the inner retina while the external limiting membrane (ELM) and the ellipsoid zone start reappearing between the retinal pigment epithelium and the hyperreflective ILM plug.4 This appears to be a regenerative process that was thought to be impossible in the retina. There are different hypotheses for this phenomenon. In large long-lasting MHs, the ELM is not detectable on the edges of the hole. The ELM is formed by the junctional complexes of Müller cells on the inner segment of the photoreceptors. Nevertheless, even if the ELM is not present, the nucleus of both cells involved in ELM formation—the photoreceptors and Müller cells— may still be alive and have the potential to regenerate their distal part when under optimal homeostatic conditions. This offers a potential explanation for the regeneration of the outer retinal layers that tend to migrate into their original position. At this point, the ILM plug seems to behave as the scar tissue of a skin wound: it is displaced on the surface to enable the complete restoration of the underlying layers.4 This mechanism suggests the importance of the preservation of an intact retinal pigment epithelium layer underneath the hole. In addition to this mechanism, a subset of Müller cells in the mature retina was found to possess neural progenitor properties.5 These cells might be activated during the healing process and act as tissue stem cells to promote the restoration of the outer retinal layers. However, the potential of Müller cells as a source of progenitor cells appears to be age related. The activation of these cells in response to retinal injuries becomes progressively confined to the retinal periphery.5 Thus, it is not clear whether this mechanism can play a role in the repair of an MH in human adults. The function of the ILM plug was also considered to be related to the proliferation of fibroblasts. If this was true, we would expect an increase in hyperreflective material on optical coherence tomographic images during the first postoperative period, as seen for epiretinal membranes. However, the contrary was observed: the ILM plug tends to contract over time and can even disappear in some cases. More recently, neurosensory, retinal free flap transplantation was proposed when no ILM was available to cover the hole.6 This can offer an excellent solution in selected cases. The authors in this particular study6 speculated that the retinal free flap may retain some function, as best-corrected visual acuity and retinal sensitivity improved after surgery. It seems highly unlikely that a retinal free flap could conduct a signal to the optic nerve, as the retinal circulation is interrupted. Previous studies have demonstrated that a central artery occlusion lasting longer than 4 hours causes profound and VIEWPOINT

New Insights Into the Development and Progression of Geographic Atrophy After Full Thickness Autologous Choroidal Graft

Purpose To investigate if the contiguity between native and transplanted retinal pigment epithelium (RPE) represents a protective factor against the progression of atrophy after autologous choroidal graft. In addition, the changes in fundus autofluorescence (FAF) in the contiguous and noncontiguous RPE areas were explored. Methods The first postoperative reliable FAF image was selected and divided into sectors based on the characteristics of the RPE at the edge of the graft. The sectors were categorized into three groups: contiguous RPE, noncontiguous RPE, and not classifiable. The area of RPE atrophy, inside and outside the graft, was measured for each sector at baseline, one, three, and five years of follow-up. The FAF pattern outside the graft was evaluated for every sector at baseline and during the follow-up. Results Nineteen patients met the inclusion criteria and were included in this study. Trend analysis showed that the atrophy progression outside the graft was statistically significant in areas where native and transplanted RPE were noncontiguous (P < 0.0001) yet not so in contiguous areas (P < 0.058). Inside the graft, both groups showed an increase in atrophy over time. In addition, the noncontiguous group developed more severe increased FAF patterns compared with the contiguous group. Conclusions RPE contiguity after autologous choroidal graft seems to be a protective factor against atrophy progression, whereas any area of damaged or absent RPE tends to enlarge over time. This may suggest that the transplantation of an RPE sheet is more likely to be effective than an RPE cell suspension.

Letter to the editor relating to Graefe’s Arch Clin Exp Ophthalmol. 2018 May; 256(5): 863–877. “Macular buckle technique in myopic traction maculopathy: a 16-year review of the literature and a comparison with vitreous surgery”

Dear Editor, We read the article by Alkabes and Mateo titled BMacular buckle technique in myopic traction maculopathy: a 16-year review of the literature and a comparison with vitreous surgery^ with great interest [1]. The authors correctly state that the literature reports significantly heterogeneous results of myopic traction maculopathy (MTM) surgical treatment, in terms of both anatomical and functional results. Few studies included in the review report anatomical results based on ophthalmoscopic appearance, and not on optical coherence tomography (OCT). As the ophthalmoscopic assessment of macular details is very difficult in highly myopic eyes, this may have affected the outcome’s evaluation. Furthermore, the articles are characterized by several differences in follow-up duration, myopia degree and surgical procedures. However, the authors conclude that MTM resolution seems to be more frequently achieved with macular buckle (MB) than pars plana vitrectomy (PPV). In our opinion, an updated comparison between the effectiveness of MB and PPV for MTM treatment could not do without taking into consideration the inverted internal limiting membrane (ILM) flap technique, which has been demonstrated as an extremely helpful adjuvant for PPV in the treatment of MTM associated with macular holes (MMH). It was first introduced in 2010 [2] and, from then on, there have been an increasing number of interesting scientific reports on its relevance in MMH. In 2013, Kuriyama et al. reported an 80% closure rate of MMH, either associated or unassociated with retinal detachment (RD) [3]. One year later, Michalewska described a 100% closure rate of MMH unassociated with RD [4]. In 2016, excellent results from the use of the inverted ILM flap technique in highly myopic eyes were published by Mateo’s group [5]. Similarly, Chen et al. found this technique to be an efficient adjuvant in the treatment ofMMH associated with RD [6]. Our group compared the results of inverted ILM flap versus complete ILM removal for the treatment of MMH without RD; we found that the inverted ILM flap could improve the probability of MMH closure compared to complete ILM removal by a factor of 22 [7]. A similar comparison in MMH with RD by Takahashi et al. reported a significantly higher closure rate with inverted ILM flap than with complete ILM removal (75 vs 25%) and a better visual outcome [8]. Therefore, there is evidence that the inverted ILM flap technique can significantly improve the anatomical outcome of MMH surgery. At present, there is no direct comparative study between MB and PPV with the inverted flap technique. Parolini et al. compared combined surgery (PPV and MB) with MB alone and reported a MMH closure rate of about 60% in both groups [9]. This result is inferior to the outcome of the inverted ILM flap technique described in the literature in these cases. In other studies, the rate of MMH closure with MB varies from 57 to 100%, although not always accurately assessed by OCT [10]. In the presence of a MMH, a favorable visual prognosis mainly depends on its complete closure after surgery: inverted ILM flap has been demonstrated to be superior to conventional ILM peeling with respect to the MMH closure rate [4–6]. * Maurizio Mete mau.mete@gmail.com