Transpupillary-Guided Trans-Scleral Transplantation of Subretinal Grafts in a Retinal Degeneration Mouse Model.

Transplantation of photoreceptor cells and retinal pigment epithelial (RPE) cells provide a potential therapy for retinal degeneration diseases. Subretinal transplantation of therapeutic donor cells into mouse recipients is challenging due to the limited surgical space allowed by the small volume of the mouse eye. We developed a trans-scleral surgical transplantation platform with direct transpupillary vision guidance to facilitate the subretinal delivery of exogenous cells in mouse recipients. The platform was tested using retinal cell suspensions and three-dimensional retinal sheets collected from rod-rich Rho::EGFP mice and cone-rich OPN1LW-EGFP;NRL-/- mice, respectively. Live/dead assay showed low cell mortality for both forms of donor cells. Retinal grafts were successfully delivered into the subretinal space of a mouse model of retinal degeneration, Rd1/NS, with minimum surgical complications as detected by multimodal confocal scanning laser ophthalmoscope (cSLO) imaging. Two months post-transplantation, histological staining demonstrated evidence of advanced maturation of the retinal grafts into 'adult' rods and cones (by robust Rho::EGFP, S-opsin, and OPN1LW:EGFP expression, respectively) in the subretinal space. Here, we provide a surgical platform that can enable highly accurate subretinal delivery with a low rate of complications in mouse recipients. This technique offers precision and relative ease of skill acquisition. Furthermore, the technique could be used not only for studies of subretinal cell transplantation but also for other intraocular therapeutic studies including gene therapies.

Antiresorptive Medications Prior to Stereotactic Body Radiotherapy for Spinal Metastasis are Associated with Reduced Incidence of Vertebral Body Compression Fracture.

STUDY DESIGN: Retrospective Cohort. OBJECTIVE: Antiresorptive drugs are often given to minimize fracture risk for bone metastases, but data regarding optimal time or ability to reduce stereotactic body radiotherapy (SBRT)-induced fracture risk is limited. This study examines the association between antiresorptive use surrounding spinal SBRT and vertebral compression fracture (VCF) incidence to provide information regarding effectiveness and optimal timing of use. METHODS: Patients treated with SBRT for spinal metastases at a single institution between 2009-2020 were included. Kaplan-Meier analysis was used to compare cumulative incidence of VCF for those taking antiresorptive drugs pre-SBRT, post-SBRT only, and none at all. Cox proportional hazards and Fine-Gray competing risk models were used to identify additional factors associated with VCF. RESULTS: Of the 234 patients (410 vertebrae) analyzed, 49 (20.9%) were taking bisphosphonates alone, 42 (17.9%) were taking denosumab alone, and 25 (10.7%) were taking both. Kaplan-Meier analysis revealed a statistically significant lower VCF incidence for patients initiating antiresorptive drugs before SBRT compared to those taking none at all (4% vs 12% at 1 year post-SBRT, P = .045; and 4% vs 23% at 2 years, P = .008). On multivariate analysis, denosumab duration (HR: .87, P = .378) or dose (HR: 1.00, P = .644) as well as bisphosphonate duration (HR: .98, P= .739) or dose (HR: .99, P= .741) did not have statistical significance on VCF incidence. CONCLUSION: Initiating antiresorptive agents before SBRT may reduce the risk of treatment-induced VCF. Antiresorptive drugs are underutilized in patients with spine metastases and may represent a useful intervention to minimize toxicity and improve long-term outcomes.

2D Gadolinium Oxide Nanoplates as T1 Magnetic Resonance Imaging Contrast Agents.

Millions of people a year receive magnetic resonance imaging (MRI) contrast agents for the diagnosis of conditions as diverse as fatty liver disease and cancer. Gadolinium chelates, which provide preferred T1 contrast, are the current standard but face an uncertain future due to increasing concerns about their nephrogenic toxicity as well as poor performance in high-field MRI scanners. Gadolinium-containing nanocrystals are interesting alternatives as they bypass the kidneys and can offer the possibility of both intracellular accumulation and active targeting. Nanocrystal contrast performance is notably limited, however, as their organic coatings block water from close interactions with surface Gadoliniums. Here, these steric barriers to water exchange are minimized through shape engineering of plate-like nanocrystals that possess accessible Gadoliniums at their edges. Sulfonated surface polymers promote second-sphere relaxation processes that contribute remarkable contrast even at the highest fields (r1 = 32.6 × 10-3 m Gd-1 s-1 at 9.4 T). These noncytotoxic materials release no detectable free Gadolinium even under mild acidic conditions. They preferentially accumulate in the liver of mice with a circulation half-life 50% longer than commercial agents. These features allow these T1 MRI contrast agents to be applied for the first time to the ex vivo detection of nonalcoholic fatty liver disease in mice.

Electronically integrated, mass-manufactured, microscopic robots.

Fifty years of Moore's law scaling in microelectronics have brought remarkable opportunities for the rapidly evolving field of microscopic robotics1-5. Electronic, magnetic and optical systems now offer an unprecedented combination of complexity, small size and low cost6,7, and could be readily appropriated for robots that are smaller than the resolution limit of human vision (less than a hundred micrometres)8-11. However, a major roadblock exists: there is no micrometre-scale actuator system that seamlessly integrates with semiconductor processing and responds to standard electronic control signals. Here we overcome this barrier by developing a new class of voltage-controllable electrochemical actuators that operate at low voltages (200 microvolts), low power (10 nanowatts) and are completely compatible with silicon processing. To demonstrate their potential, we develop lithographic fabrication-and-release protocols to prototype sub-hundred-micrometre walking robots. Every step in this process is performed in parallel, allowing us to produce over one million robots per four-inch wafer. These results are an important advance towards mass-manufactured, silicon-based, functional robots that are too small to be resolved by the naked eye.