Imaging of small animal peripheral artery disease models: recent advancements and translational potential.

Peripheral artery disease (PAD) is a broad disorder encompassing multiple forms of arterial disease outside of the heart. As such, PAD development is a multifactorial process with a variety of manifestations. For example, aneurysms are pathological expansions of an artery that can lead to rupture, while ischemic atherosclerosis reduces blood flow, increasing the risk of claudication, poor wound healing, limb amputation, and stroke. Current PAD treatment is often ineffective or associated with serious risks, largely because these disorders are commonly undiagnosed or misdiagnosed. Active areas of research are focused on detecting and characterizing deleterious arterial changes at early stages using non-invasive imaging strategies, such as ultrasound, as well as emerging technologies like photoacoustic imaging. Earlier disease detection and characterization could improve interventional strategies, leading to better prognosis in PAD patients. While rodents are being used to investigate PAD pathophysiology, imaging of these animal models has been underutilized. This review focuses on structural and molecular information and disease progression revealed by recent imaging efforts of aortic, cerebral, and peripheral vascular disease models in mice, rats, and rabbits. Effective translation to humans involves better understanding of underlying PAD pathophysiology to develop novel therapeutics and apply non-invasive imaging techniques in the clinic.

Gene Expression Changes in Cultured Reactive Rat Astrocyte Models and Comparison to Device-Associated Effects in the Brain.

Implanted microelectrode arrays hold immense therapeutic potential for many neurodegenerative diseases. However, a foreign body response limits long-term device performance. Recent literature supports the role of astrocytes in the response to damage to the central nervous system (CNS) and suggests that reactive astrocytes exist on a spectrum of phenotypes, from beneficial to neurotoxic. The goal of our study was to gain insight into the subtypes of reactive astrocytes responding to electrodes implanted in the brain. In this study, we tested the transcriptomic profile of two reactive astrocyte culture models (cytokine cocktail or lipopolysaccharide, LPS) utilizing RNA sequencing, which we then compared to differential gene expression surrounding devices inserted into rat motor cortex via spatial transcriptomics. We interpreted changes in the genetic expression of the culture models to that of 24 hour, 1 week and 6 week rat tissue samples at multiple distances radiating from the injury site. We found overlapping expression of up to ∼250 genes between in vitro models and in vivo effects, depending on duration of implantation. Cytokine-induced cells shared more genes in common with chronically implanted tissue (≥1 week) in comparison to LPS-exposed cells. We revealed localized expression of a subset of these intersecting genes (e.g., Serping1, Chi3l1, and Cyp7b1) in regions of device-encapsulating, glial fibrillary acidic protein (GFAP)-expressing astrocytes identified with immunohistochemistry. We applied a factorization approach to assess the strength of the relationship between reactivity markers and the spatial distribution of GFAP-expressing astrocytes in vivo . We also provide lists of hundreds of differentially expressed genes between reactive culture models and untreated controls, and we observed 311 shared genes between the cytokine induced model and the LPS-reaction induced control model. Our results show that comparisons of reactive astrocyte culture models with spatial transcriptomics data can reveal new biomarkers of the foreign body response to implantable neurotechnology. These comparisons also provide a strategy to assess the development of in vitro models of the tissue response to implanted electrodes.

Atomic Force Microscope Characterization of the Bending Stiffness and Surface Topography of Silicon and Polymeric Electrodes.

Implanted electrodes in the brain are increasingly used in research and clinical settings to understand and treat neurological conditions. However, a foreign body response typically occurs after implantation, and glial encapsulation of the device is a commonly observed. Multiple factors affect how gliosis surrounding the implantable electrodes evolves. Characterizing and measuring the surface features and mechanical properties of these devices may allow us to predict where gliosis will occur, and understanding how electrode design features may impact astrogliosis may give researchers a set of design guidelines to follow to maximize chronic performance. In this study, we used atomic force microscopy to measure surface roughness on parylene, polyimide, and silicon devices. Multiple features on microelectrode arrays were measured, including electrode sites, traces, and the bulk substrate. We found differences in surface roughness according to device material, but not device features. We also directly measured the bending stiffness of silicon devices, providing a more exact quantification of this property to corroborate calculated estimates.

Toward guiding principles for the design of biologically-integrated electrodes for the central nervous system.

Innovation in electrode design has produced a myriad of new and creative strategies for interfacing the nervous system with softer, less invasive, more broadly distributed sites with high spatial resolution. However, despite rapid growth in the use of implanted electrode arrays in research and clinical applications, there are no broadly accepted guiding principles for the design of biocompatible chronic recording interfaces in the central nervous system (CNS). Studies suggest that the architecture and flexibility of devices play important roles in determining effective tissue integration: device feature dimensions (varying from 'sub'- to 'supra'-cellular scales, <10 µm to >100 µm), Young's modulus, and bending modulus have all been identified as key features of design. However, critical knowledge gaps remain in the field with respect to the underlying motivation for these designs: (1) a systematic study of the relationship between device design features (materials, architecture, flexibility), biointegration, and signal quality needs to be performed, including controls for interaction effects between design features, (2) benchmarks for success need to be determined (biological integration, recording performance, longevity, stability), and (3) user results, particularly those that champion a specific design or electrode modification, need to be replicated across laboratories. Finally, the ancillary effects of factors such as tethering, site impedance and insertion method need to be considered. Here, we briefly review observations to-date of device design effects on tissue integration and performance, and then highlight the need for comprehensive and systematic testing of these effects moving forward.