Minimally Invasive Sub-Retinal Transplantation of RPE-J Cells on a Biodegradable Composite PCL/Collagen Nanosheet.

Retinal cells are irreparably damaged by diseases such as age-related macular degeneration (AMD). A promising method to restore partial or whole vision is through cell-based transplantation to the damaged location. However, cell transplantation using conventional vitreous surgery is an invasive procedure that may induce infections and has a high failure rate of cell engraftment. In this study, we describe the fabrication of a biodegradable composite nanosheet used as a substrate to support retinal pigment epithelial (RPE-J) cells, which can be grafted to the sub-retinal space using a minimally invasive approach. The nanosheet was fabricated using polycaprolactone (PCL) and collagen in 80:20 weight ratio, and had size of 200 µm in diameter and 300 nm in thickness. These PCL/collagen nanosheets showed excellent biocompatibility and mechanical strength in vitro. Using a custom designed 27-gauge glass needle, we successfully transplanted an RPE-J cell loaded nanosheet into the sub-retinal space of a rat model with damaged photoreceptors. The cell loaded nanosheet did not trigger immunological reaction within 2 weeks of implantation and restored the retinal environment. Thus, this composite PCL/collagen nanosheet holds great promise for organized cell transplantation, and the treatment of retinal diseases.

Dynamics of AMPA receptors regulate epileptogenesis in patients with epilepsy.

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

A comparative study between a transscleral sustained-release device and eyedrops on intraocular distribution of carteolol hydrochloride.

The objectives of this study were to develop a sustained-release device for carteolol hydrochloride (CH) and investigate any potential difference in the intraocular distribution of this agent between the transscleral administration of the device and treatment with eyedrops. The device was formulated with photocurable resin, poly (ethyleneglycol) dimethacrylate, to fit within the curve of the rabbit eyeball. In vitro study showed that CH was released in a sustained-release manner for 2 weeks. The concentration of CH in the retina, choroid/retinal pigment epithelium, sclera, iris, and aqueous humor was determined by high-performance liquid chromatography. Transscleral administration was able to deliver CH to the posterior segment (i.e., retina and choroid/retinal pigment epithelium) rather than the anterior segment (i.e., aqueous humor), while eyedrops delivered CH only to the anterior segment. Transscleral administration could deliver CH to aqueous humor at half the concentration versus treatment with eyedrops and reduced intraocular pressure (IOP) at 1 day after implantation; however, the IOP-lowering effect was not sustained thereafter. In conclusion, transscleral drug delivery may be a useful method for the reduction of IOP. Notably, the aqueous concentration must be equal to that delivered by the eyedrops, and this approach might be preferable for drug delivery to the posterior segment of the eye.

Release of ranibizumab using a porous poly(dimethylsiloxane) capsule suppressed laser-induced choroidal neovascularization via the transscleral route.

The administration of anti-vascular endothelial growth factor drugs in the posterior eye segment with sustained release through less invasive methods is a challenge in the treatment of age-related macular disease. We developed a flexible capsule device using porous poly(dimethylsiloxane) (PDMS) that was able to release ranibizumab. The porous PDMS sheet was fabricated by salt-leaching of a micro-sectioned PDMS sheet containing salt microparticles. Observation with scanning electron microscopy revealed that the pore densities could be adjusted by the concentration of salt. The in vitro release study showed that the release rate of fluorescein isothiocyanate-tagged albumin could be adjusted based on the pore density of the porous PDMS sheet. Ranibizumab could be released in a sustained-release manner for 16 weeks. The device was implanted on the sclera; its efficacy in terms of the suppression of laser-induced choroidal neovascularization (CNV) in rats was compared with that of monthly intravitreal injections of ranibizumab. At 8 and 18 weeks after implantation, the CNV area was significantly reduced in rats that received the ranibizumab-releasing device compared with those that received the placebo device. However, although monthly intravitreal injections of ranibizumab reduced CNV for 8 weeks, this reduction was not sustained for 18 weeks. In conclusion, we demonstrated a novel controlled-release device using a porous PDMS sheet that could suppress CNV via a less invasive transscleral route versus intravitreal injections. This device may also reduce the occurrence of side effects associated with frequent intravitreal injections.

Anti-SARS-CoV-2 Spike Antibody Titers and Neutralizing Antibodies in Vaccinated Rheumatoid Arthritis Patients.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A serological test is used to assess the efficacy of vaccination. It has been reported that anti-SARS-CoV-2 spike (S) and neutralizing antibody (Ab) levels are lower following vaccination in patients with rheumatic disease. Here, we investigated anti-SARS-CoV-2 S and neutralizing Abs in vaccinated rheumatoid arthritis (RA) patients in Japan. Anti-SARS-CoV-2 S and neutralizing Abs were quantified in 101 RA patients and 117 controls. Anti-SARS-CoV-2 S Ab levels were lower in RA patients than both earlier after vaccination in controls (mean RA 324.1 ± 591.8 SDM vs. control 1216.6 ± 854.4 [U/mL], p < 0.0001) and later after vaccination (324.1 ± 591.8 vs. 582.0 ± 415.6 [U/mL], p = 0.0002). The interval between vaccination of the RA patients and serum collection was longer than for controls early after vaccination (142.1 ± 31.6 vs. 98.3 ± 11.2 [days], p < 0.0001), but shorter than the later sample from the controls (142.1 ± 31.6 vs. 257.3 ± 11.2 [days], p < 0.0001). Importantly, anti-SARS-CoV-2 neutralizing Ab titers in RA patients were higher than in either early or later control samples (10.7 ± 4.9 vs. 8.6 ± 6.6 [%], p = 0.0072, and 10.7 ± 4.9 vs. 3.1 ± 3.7 [%], p < 0.0001, respectively). Anti-SARS-CoV-2 S Ab titers in vaccinated RA patients were lower than in controls, but they were influenced by other clinical manifestations. Anti-SARS-CoV-2 neutralizing Ab levels were independently increased in RA.

Educational Approaches That Enhance Online Clinical Clerkship during the COVID-19 Pandemic.

Objective This cross-sectional national study determined which educational approaches are associated with the effectiveness of online clerkship for medical students. Method A survey was conducted for medical students at 78 medical schools in Japan from May 29 to June 14, 2020. It comprised the following aspects: (a) participants' profiles, (b) number of opportunities to learn from each educational approach (lecture, medical quiz, assignment, oral presentation, observation of a physician's practice, clinical skill practice, participation in interprofessional meetings, and interactive discussions with physicians) in online clerkship, (c) frequency of technical problems, and (d) educational outcome measurement (satisfaction, motivation, knowledge acquisition, skill acquisition, change in self-study time, and understanding of the importance of medical care team). Results Of the 2,640 respondents, 2,594 (98.3%) agreed to cooperate. Ultimately, 1,711 matched our inclusion criteria. All educational approaches but assignments were positively associated with satisfaction and motivation. All educational approaches excluding assignment submission and interprofessional meeting were positively associated with knowledge acquisition. Observation, practice, and interprofessional meeting were positively associated with skill acquisition. Only assignment submission was positively associated with the change in self-study time. Educational approaches excluding medical quizzes were positively associated with understanding the importance of the medical care team. Technical problems were negatively associated with motivation, knowledge acquisition, and skill acquisition. Conclusions Educators should implement various educational approaches, especially observation and practice, even in online clinical clerkship. They also need to minimize the technical problems associated with the Internet, as they reduce the effectiveness of online clerkship.

Detection of SARS-CoV-2 Nucleocapsid, Spike, and Neutralizing Antibodies in Vaccinated Japanese.

Serological detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N), spike (S), and neutralizing antibodies (Abs) is commonly undertaken to evaluate the efficacy of vaccination. However, the relative efficiency of different SARS-CoV-2 Ab detection systems has not been extensively investigated. Here, we evaluated serological test systems in vaccinated Japanese. SARS-CoV-2 N, S, and neutralizing Abs in sera of 375 healthy subjects a mean 253 days after vaccination were assessed. The sensitivity of Elecsys Anti-SARS-CoV-2 S (Roche S) and Anti-SARS-CoV-2 S IgG (Fujirebio S) was 100% and 98.9%, respectively, with a specificity of 100% for both. The sensitivity of Anti-SARS-CoV-2 neutralizing Ab (MBL Neu) was 2.7%, and the specificity was 100%. Fujirebio S correlated with Roche S (rho = 0.9182, p = 3.97 × 10-152). Fujirebio S (rho = 0.1295, p = 0.0121) and Roche S (rho = 0.1232, p = 0.0170) correlated weakly with MBL Neu. However, Roche S did correlate with MBL Neu in patients with COVID-19 (rho = 0.8299, p = 1.01 × 10-12) and in healthy subjects more recently after vaccination (mean of 90 days, rho = 0.5306, p = 0.0003). Thus, the Fujirebio S and Roche S results were very similar, but neither correlated with neutralizing antibody titers by MBL Neu at a later time after vaccination.

Background factors associated with academic motivation for attending medical school immediately after admission in Japan: A single-center study.

Background: To become a doctor with a high level of professionalism and ethical standards, it is important to have and maintain a high level of motivation right from medical school. However, studies in Japan have not quantitatively investigated the factors related to motivation immediately after enrollment. This study aimed to identify the demographic factors that influence the motivation of medical students immediately after admission. Methods: A cross-sectional single-center study was conducted. First-year medical students answered our questionnaire three weeks after the admission. The questionnaire comprised 16 demographic items and the 28-item Academic Motivation Scale, which was used to quantify motivation. Results: Our analysis showed that amotivation, representing low levels of self-determinant motivation, was significantly higher in students whose parents were medical professionals and in students who did not talk about their problems than in those whose parents were not medical professionals and those who did talk about their problems. Intrinsic motivation, which indicates the level of self-determinant motivation, was significantly lower in students who belonged to a sports club. Conclusions: We suggest that having parents who are medical professionals may be associated with an individual's decreased motivation when entering medical school in Japan. Though this is a novel finding, further research is needed to analyze this relationship.

AMPA receptors in schizophrenia: A systematic review of postmortem studies on receptor subunit expression and binding.

BACKGROUND: While altered expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptor has been reported in postmortem studies of schizophrenia, these findings are inconsistent. Therefore, we aimed to systematically review postmortem studies that investigated AMPA receptor expressions in schizophrenia. METHODS: A systematic literature search was conducted for postmortem studies that measured AMPA receptor subunit expressions or receptor bindings in schizophrenia compared to healthy individuals on February 3, 2021, using Medline and Embase. RESULTS: A total of 39 relevant articles were identified from 1360 initial reports. The dorsolateral prefrontal cortex (DLPFC) was the most investigated region (15 studies), followed by the medial temporal lobe (8 studies). For the DLPFC, 4/15 studies (26.7%) showed increased AMPA receptor binding or subunit expression in patients with schizophrenia compared to that in controls, especially in GRIA1 and GRIA4, 2/15 studies (13.3%) reported a decrease, particularly in GRIA2, and 8/15 studies (56.7%) found no significant differences. A decreased expression or receptor binding was observed in 6/8 studies (75.0%) in the subregions of the hippocampus in patients with schizophrenia compared to that in controls, whereas the other two studies found no significant differences. CONCLUSION: Published data have reported decreased subunit expression or receptor binding in the hippocampus in schizophrenia. These findings were inconsistent in other brain regions, which might be due to the heterogeneity of this population, various study design, physiological changes after death, and limited number of studies. Future in vivo studies are warranted to examine AMPA receptor expressions in human brains, together with their comprehensive clinical characterization.

Predicting the effectiveness of the online clinical clerkship curriculum: Development of a multivariate prediction model and validation study.

Given scientific and technological advancements, expectations of online medical education are increasing. However, there is no way to predict the effectiveness of online clinical clerkship curricula. To develop a prediction model, we conducted cross-sectional national surveys in Japan. Social media surveys were conducted among medical students in Japan during the periods May-June 2020 and February-March 2021. We used the former for the derivation dataset and the latter for the validation dataset. We asked students questions in three areas: 1) opportunities to learn from each educational approach (lectures, medical quizzes, assignments, oral presentations, observation of physicians' practice, clinical skills practice, participation in interprofessional meetings, and interactive discussions with physicians) in online clinical clerkships compared to face-to-face, 2) frequency of technical problems on online platforms, and 3) satisfaction and motivation as outcome measurements. We developed a scoring system based on a multivariate prediction model for satisfaction and motivation in a cross-sectional study of 1,671 medical students during the period May-June 2020. We externally validated this scoring with a cross-sectional study of 106 medical students during February-March 2021 and assessed its predictive performance. The final prediction models in the derivation dataset included eight variables (frequency of lectures, medical quizzes, oral presentations, observation of physicians' practice, clinical skills practice, participation in interprofessional meetings, interactive discussions with physicians, and technical problems). We applied the prediction models created using the derivation dataset to a validation dataset. The prediction performance values, based on the area under the receiver operating characteristic curve, were 0.69 for satisfaction (sensitivity, 0.50; specificity, 0.89) and 0.75 for motivation (sensitivity, 0.71; specificity, 0.85). We developed a prediction model for the effectiveness of the online clinical clerkship curriculum, based on students' satisfaction and motivation. Our model will accurately predict and improve the online clinical clerkship curriculum effectiveness.

A review of food poisoning caused by local food in Japan.

Increasingly popular worldwide, Japanese cuisine includes several raw preparations such as sashimi and sushi; however, limited information on food poisoning from Japanese local food is available in English literature. Without appropriate knowledge, physicians may underdiagnose traveler's diarrhea among people returning from Japan. To provide accurate information to primary care physicians worldwide, we conducted a narrative review on food poisoning research published in Japanese and English over the past four years, considering the frequency and clinical importance of various presentations.

Factors and impact of physicians' diagnostic errors in malpractice claims in Japan.

BACKGROUND: Diagnostic errors are prevalent and associated with increased economic burden; however, little is known about their characteristics at the national level in Japan. This study aimed to investigate clinical outcomes and indemnity payment in cases of diagnostic errors using Japan's largest database of national claims. METHODS: We analyzed characteristics of diagnostic error cases closed between 1961 and 2017, accessed through the national Japanese malpractice claims database. We compared diagnostic error-related claims (DERC) with non-diagnostic error-related claims (non-DERC) in terms of indemnity, clinical outcomes, and factors underlying physicians' diagnostic errors. RESULTS: All 1,802 malpractice claims were included in the analysis. The median patient age was 33 years (interquartile range = 10-54), and 54.2% were men. Deaths were the most common outcome of claims (939/1747; 53.8%). In total, 709 (39.3%, 95% CI: 37.0%-41.6%) DERC cases were observed. The adjusted total billing amount, acceptance rate, adjusted median claims payments, and proportion of deaths were significantly higher in DERC than non-DERC cases. Departments of internal medicine and surgery were 1.42 and 1.55 times more likely, respectively, to have DERC cases than others. Claims involving the emergency room (adjusted odds ratio [OR] = 5.88) and outpatient office (adjusted OR = 2.87) were more likely to be DERC than other cases. The initial diagnoses most likely to lead to diagnostic error were upper respiratory tract infection, non-bleeding digestive tract disease, and "no abnormality." CONCLUSIONS: Cases of diagnostic errors produced severe patient outcomes and were associated with high indemnity. These cases were frequently noted in general exam and emergency rooms as well as internal medicine and surgery departments and were initially considered to be common, mild diseases.

Effect of sustained insulin-releasing device made of poly(ethylene glycol) dimethacrylates on retinal function in streptozotocin-induced diabetic rats.

In this study, we developed a subcutaneous insulin-releasing device consisting of a disk-shaped capsule and drug formulation comprised of poly(ethylene glycol) dimethacrylates, then evaluated its efficacy on retinal function in streptozotocin (STZ)-induced diabetic rats. In vitro release studies showed that recombinant human insulin was released with a constant rate for more than 30 days. The device was able to maintain a basal level of blood glucose in diabetic rats for a prolonged period of more than 30 days, simultaneously preventing a decrease in body weight. For assessing the pharmacological effect of the device on retinal function in diabetic rats, electroretinograms were conducted for 12 weeks. The reduction in amplitude and delay in implicit time were attenuated by the device during the initial 4 weeks of application. The increase in gene expression of protein kinase C (PKC)-γ and caspase-3 in the diabetic retina was also attenuated by the device. Immunohistochemistry showed that the increase in glial fibrillary acidic protein expression in the diabetic retina was attenuated by the device. Histological evaluation of subcutaneous tissue around the device showed the biocompatibility of the device. In conclusion, the insulin-releasing device attenuated the reduction of retinal function in STZ-induced diabetic conditions for 4 weeks and the efficacy of the device might be partially related to PKC signaling in the retina. The long-term ability to control the blood glucose level might help to reduce the daily frequency of insulin injections.

A 3D Printed Self-Sustainable Cell-Encapsulation Drug Delivery Device for Periocular Transplant-Based Treatment of Retinal Degenerative Diseases.

Self-sustainable release of brain-derived neurotrophic factor (BDNF) to the retina using minimally invasive cell-encapsulation devices is a promising approach to treat retinal degenerative diseases (RDD). Herein, we describe such a self-sustainable drug delivery device with human retinal pigment epithelial (ARPE-19) cells (cultured on collagen coated polystyrene (PS) sheets) enclosed inside a 3D printed semi-porous capsule. The capsule was 3D printed with two photo curable polymers: triethylene glycol dimethacrylate (TEGDM) and polyethylene glycol dimethylacrylate (PEGDM). The capsule's semi-porous membrane (PEGDM) could serve three functions: protecting the cells from body's immune system by limiting diffusion (5.97 ± 0.11%) of large molecules like immunoglobin G (IgG)(150 kDa); helping the cells to survive inside the capsule by allowing diffusion (43.20 ± 2.16%) of small molecules (40 kDa) like oxygen and necessary nutrients; and helping in the treatment of RDD by allowing diffusion of cell-secreted BDNF to the outside environment. In vitro results showed a continuous BDNF secretion from the device for at least 16 days, demonstrating future potential of the cell-encapsulation device for the treatment of RDD in a minimally invasive and self-sustainable way through a periocular transplant.

Drug Attitude, Insight, and Patient's Knowledge About Prescribed Antipsychotics in Schizophrenia: A Cross-Sectional Survey.

INTRODUCTION: While patients' perspectives toward pharmacotherapy are expected to be directly influenced by their motivation and understanding of the treatment that they are currently receiving, no study has comprehensively investigated the impact of insight into illness and knowledge for the ongoing pharmacotherapy on the attitude towards drug treatment among patients with schizophrenia. MATERIALS AND METHODS: One hundred forty-eight Japanese outpatients diagnosed with schizophrenia, according to the International Classification of Diseases 10th edition, were included (mean±SD age, 47.3±12.4 years; 90 men (60.8%)). Attitudes toward antipsychotic treatment and insight into illness were assessed with the Drug Attitude Inventory-10 (DAI-10) and the VAGUS, respectively. In addition, a multiple-choice questionnaire that was designed to examine patients' knowledge about therapeutic effects, types, and implicated neurotransmitters of antipsychotic drugs they were receiving was utilized. RESULTS: The mean±SD of DAI-10 score was 4.7±4.2. The multiple regression analysis found that lower Positive and Negative Syndrome Scale (PANSS) scores, higher VAGUS scores, and longer illness duration were significantly associated with higher DAI-10 scores (ß=-0.226, P=0.009; ß=0.250, P=0.008; ß=0.203, P=0.034, respectively). There was a significant difference in the DAI-10 scores between the subjects who gave more accurate answers regarding the effects of their primary antipsychotic and those who did not (mean±SD, 5.57±4.38 vs 4.13±4.04, P=0.043); however, this finding failed to survive the multiple regression analysis. CONCLUSION: Better insight into illness and treatment, lower illness severity, longer illness duration, and possibly greater knowledge about the therapeutic effects of medications may lead to better attitudes towards pharmacotherapy among patients with schizophrenia, which has an important implication for this typically chronic mental condition requiring long-term antipsychotic treatment to sustain stability.

Prototyping a Versatile Two-Layer Multi-Channel Microfluidic Device for Direct-Contact Cell-Vessel Co-Culture.

Microfluidic devices are gaining increasing popularity due to their wide applications in various research areas. Herein, we propose a two-layer multi-channel microfluidic device allowing for direct-contact cell-vessel co-culture. Using the device, we built a co-culture model of the outer blood-retina barrier (oBRB), mimicking the in vivo retinal pigment epithelial cells-Bruch membrane-fenestrated choroids. To demonstrate the versatility of the design, we further modified the device by inserting platinum electrodes for trans-epithelial electrical resistance (TEER) measurement, demonstrating the feasibility of on-chip assessment of the epithelial barrier integrity. Our proposed design allows for direct-contact co-culture of cell-cell or cell-vessel, modifiable for real-time evaluation of the state of the epithelial monolayers.

Visualization of AMPA receptors in living human brain with positron emission tomography.

Although aberrations in the number and function of glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are thought to underlie neuropsychiatric disorders, no methods are currently available for visualizing AMPA receptors in the living human brain. Here we developed a positron emission tomography (PET) tracer for AMPA receptors. A derivative of 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide radiolabeled with 11C ([11C]K-2) showed specific binding to AMPA receptors. Our clinical trial with healthy human participants confirmed reversible binding of [11C]K-2 in the brain according to Logan graphical analysis (UMIN000020975; study design: non-randomized, single arm; primary outcome: dynamics and distribution volumes of [11C]K-2 in the brain; secondary outcome: adverse events of [11C]K-2 during the 4-10 d following dosing; this trial met prespecified endpoints). In an exploratory clinical study including patients with epilepsy, we detected increased [11C]K-2 uptake in the epileptogenic focus of patients with mesial temporal lobe epilepsy, which was closely correlated with the local AMPA receptor protein distribution in surgical specimens from the same individuals (UMIN000025090; study design: non-randomized, single arm; primary outcome: correlation between [11C]K-2 uptake measured with PET before surgery and AMPA receptor protein density examined by biochemical study after surgery; secondary outcome: adverse events during the 7 d following PET scan; this trial met prespecified endpoints). Thus, [11C]K-2 is a potent PET tracer for AMPA receptors, potentially providing a tool to examine the involvement of AMPA receptors in neuropsychiatric disorders.

A multilayered sheet-type device capable of sustained drug release and deployment control.

Minimally invasive delivery of a sustained drug release device to the body is a promising approach for treating chronic conditions such as retinal diseases. Herein, we describe a sheet-type device capable of sustained drug release and deployment control after being applied to the body through a small opened hole via a syringe-type injector. Such device consists of a four-layered structure of thin photopolymerized sheets, which are in turn made of different ratios of a mixture of polyethylene glycol dimethacrylate (PEGDM) and triethylene glycol dimethacrylate (TEGDM). A layer containing a model drug, i.e., fluorescein, was sandwiched between a controlled release and guard layer to achieve sustained unidirectional drug release. A deployment layer was then attached onto the guard layer to control the curvature of the device following deployment. The sheet-type device was sufficiently flexible to be rolled up and could be inserted into a syringe-type injector. When the device was injected into the subconjunctival space of a rabbit eye through a small opened hole, it unfolded to fit the eyeball curvature. Moreover, homogenates of the choroid/retinal pigment epithelium (RPE) as well as the retina exhibited fluorescence during 4 weeks after implantation, confirming that the drug could be delivered to the retina by using the device. This developed sheet-type device offers the possibility of achieving minimally invasive transplantation into diseased tissues and organs, and could provide improved therapeutic modalities as well as reduce possible side effects.

Transscleral sustained ranibizumab delivery using an episcleral implantable device: Suppression of laser-induced choroidal neovascularization in rats.

Successful treatment of age-related macular diseases requires an effective controlled drug release system with less invasive route of administration in the eye to reduce the burden of frequent intravitreal injections for patients. In this study, we developed an episcleral implantable device for sustained release of ranibizumab, and evaluated its efficacy on suppression of laser-induced choroidal neovascularization (CNV) in rats. We tested both biodegradable and non-biodegradable sheet-type devices consisting of crosslinked gelatin/chitosan (Gel/CS) and photopolymerized poly(ethyleneglycol) dimethacrylate that incorporated collagen microparticles (PEGDM/COL). In vitro release studies of FITC-labeled albumin showed a constant release from PEGDM/COL sheets compared to Gel/CS sheets. The Gel/CS sheets gradually biodegraded in the sclera during the 24-week implantation; however, the PEGDM/COL sheets did not degrade. FITC-albumin was detected in the retina during 18 weeks implantation in the PEGDM/COL sheet-treated group, and was detected in the Gel/CS sheet-treated group during 6 weeks implantation. CNV was suppressed 18 weeks after application of ranibizumab-loaded PEGDM/COL sheets compared to a placebo PEGDM/COL sheet-treated group, and to the intravitreal ranibizumab-injected group. In conclusion, the PEGDM/COL sheet device suppressed CNV via a transscleral administration route for 18 weeks, indicating that prolonged sustained ranibizumab release could reduce the burden of repeated intravitreal injections.

A drug refillable device for transscleral sustained drug delivery to the retina.

Continuous drug administration with better adherence to treatment and less invasive procedures is important in treating retinal diseases such as age-related macular disease. In this study, we report a drug-refillable device consisting of a silicone reservoir and an injectable gelatin/chitosan gel (iGel). The silicone reservoir was fabricated with polydimethylsiloxane (PDMS) using a computer-aided design and manufacturing to have micropores at a releasing side for uniaxial release to the sclera. A stainless steel wire and sheet were combined in the side and bottom of the reservoir to ensure flexibility and to fit on the curvature of the eyeball and prevent irritation to the sclera through the bottom of the reservoir. The drug was injected and formulated in the reservoir by in situ crosslinking of gelatin/chitosan gel with the crosslinker; 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. The in vitro release study using fluorescein molecules showed that the release rate from encapsulated iGel in the reservoir was slower than that from the original iGel. After reinjecting the iGel into the reservoir, the same release profile as the first injection was observed. The reservoir containing iGel was placed on the sclera of a rabbit and the distribution of 150 kDa fluorescein isothiocyanate-dextran (FD150) in the retina and choroid/retinal pigment epithelium (choroid/RPE) was studied. The cryosections showed that FD150 was observed in the choroid/RPE. Homogenates of the retina and choroid/RPE showed fluorescence during 12 weeks implantation, indicating the drug could be delivered to the retina by using the device. The drug filling was successful into the reservoir implanted on the sclera through the conjunctiva by using a needle. In conclusion, the refillable drug delivery device is a promising tool to administer drugs long-term by reinjection with less invasiveness to intraocular tissues.