Aniridia classically presents with a bilateral congenital absence or malformation of the irides, foveal hypoplasia, and nystagmus, and patients tend to develop visually significant pre-senile cataracts and keratopathy. Additionally, they are at high risk for developing glaucoma. Classic aniridia can be genetically defined as the presence of a PAX6 gene deletion or loss-of-function mutation that results in haploinsufficiency. Variants of aniridia, which include a condition previously referred to as autosomal dominant keratitis, are likely due to PAX6 mutations that lead to partial loss of PAX6 function. Aniridia-associated keratopathy (AAK) is a progressive and potentially debilitating problem affecting aniridic patients. The current treatments for AAK are to replace the limbal stem cells through keratolimbal allograft (KLAL) with or without subsequent keratoplasty for visual rehabilitation, or to implant a Boston type 1 keratoprosthesis. Future therapies for AAK may be aimed at the genetic modification of corneal limbal stem cells.

High frequency of chromosomal deletions elicited as losses of heterozygosity is a hallmark of genomic instability in cancer. Functional losses of tumor suppressor genes caused by loss of heterozygosity at defined regions during clonal selection for growth advantage define the minimally lost regions as their likely locations on chromosomes. Loss of heterozygosity is elicited at the molecular or cytogenetic level as a deletion, a gene conversion, single or double homologous and nonhomologous mitotic recombinations, a translocation, chromosome breakage and loss, chromosomal fusion or telomeric end-to-end fusions, or whole chromosome loss with or without accompanying duplication of the retained chromosome. Because of the high level of specificity, loss of heterozygosity has recently become invaluable as a marker for diagnosis and prognosis of cancer. The molecular defects for the occurrence of loss of heterozygosity are derived from disabled caretaker genes, which protect the integrity of DNA, or chromosome segregator genes, which mediate faithful chromosome disjunction.

Objective: Low-intensity transcranial ultrasound stimulation (TUS) is emerging as noninvasive brain stimulation technique with superior spatial resolution and the ability to reach deep brain areas. Medical image-based computational modeling could be an important tool for individualized TUS dose control and targeting optimization, but requires further validation. This study aims to assess the impact of the transducer model on the accuracy of the simulations.Approach: Using hydrophone measurements, the acoustic beam of a single-element focused transducer (SEFT) with a flat piezoelectric disc and an acoustic lens was characterized. The acoustic beam was assessed in a homogeneous water bath and after transmission through obstacles (3D-printed shapes and skull samples). The acoustic simulations employed the finite-difference time-domain method and were informed by computed tomography (CT) images of the obstacles. Transducer models of varying complexity were tested, representing the SEFT either as a surface boundary condition with variable curvature, or also accounting for its internal geometry. In addition, a back-propagated pressure distribution from the first measurement plane was used as source model. The simulations and measurements were quantitatively compared using key metrics for peak location, focus size, intensity and spatial distribution.Main results: While a surface boundary with an adapted, 'effective' curvature radius based on the specifications given by the manufacturer could reproduce the measured focus location and size in a homogeneous water bath, it regularly failed to accurately predict the beam after obstacle transmission. In contrast, models that were based on a one-time 1 calibration to the homogeneous water bath measurements performed substantially better in all cases with obstacles. For one of the 3D-printed obstacles, the simulated intensities deviated substantially from the measured ones, irrespective of the transducer model. We attribute this finding to a standing wave effect, and further studies should clarify its relevance for accurate simulations of skull transmission.Significance: Validated transducer models are important to ensure accurate simulations of the acoustic beam of SEFTs, in particular in the presence of obstacles such as the skull.

Silk fibroin is an excellent candidate for biomedical implantable devices because of its biocompatibility, controllable biodegradability, solution processability, flexibility, and transparency. Thus, fibroin has been widely explored in biomedical applications as biodegradable films as well as functional microstructures. Although there exists a large number of patterning methods for fibroin thin films, multilayer micropatterning of fibroin films interleaved with metal layers still remains a challenge. Herein, we report a new wafer-scale multilayer microfabrication process named aluminum hard mask on silk fibroin (AMoS), which is capable of micropatterning multiple layers composed of both fibroin and inorganic materials (e.g., metal and dielectrics) with high-precision microscale alignment. To the best of our knowledge, our AMoS process is the first demonstration of wafer-scale multilayer processing of both silk fibroin and metal micropatterns. In the AMoS process, aluminum deposited on fibroin is first micropatterned using conventional ultraviolet (UV) photolithography, and the patterned aluminum layer is then used as a mask to pattern fibroin underneath. We demonstrate the versatility of our fabrication process by fabricating fibroin microstructures with different dimensions, passive electronic components composed of both fibroin and metal layers, and functional fibroin microstructures for drug delivery. Furthermore, because one of the crucial advantages of fibroin is biocompatibility, we assess the biocompatibility of our fabrication process through the culture of highly susceptible primary neurons. Because the AMoS process utilizes conventional UV photolithography, the principal advantages of our process are multilayer fabrication with high-precision alignment, high resolution, wafer-scale large area processing, no requirement for chemical modification of the protein, and high throughput and thus low cost, all of which have not been feasible with silk fibroin. Therefore, the proposed fabrication method is a promising candidate for batch fabrication of functional fibroin microelectronics (e.g., memristors and organic thin film transistors) for next-generation implantable biomedical applications.