An endoluminal cylindrical sectored-ring ultrasound phased-array applicator for minimally-invasive therapeutic ultrasound.

Background: The size of catheter-based ultrasound devices for delivering ultrasound energy to deep-seated tumors is constrained by the access pathway which limits their therapeutic capabilities.

Purpose: To devise and investigate a deployable applicator suitable for minimally-invasive delivery of therapeutic ultrasound, consisting of a 2D cylindrical sectored-ring ultrasound phased array, integrated within an expandable paraboloid-shaped balloon-based reflector. The balloon can be collapsed for compact delivery and expanded close to the target position to mimic a larger-diameter concentric-ring sector-vortex array for enhanced dynamic control of focal depth and volume.

Deployable ultrasound applicators for endoluminal delivery of volumetric hyperthermia.

Purpose: To investigate the design of an endoluminal deployable ultrasound applicator for delivering volumetric hyperthermia to deep tissue sites as a possible adjunct to radiation and chemotherapy.

Method: This study considers an ultrasound applicator consisting of two tubular transducers situated at the end of a catheter assembly, encased within a distensible conical shaped balloon-based reflector that redirects acoustic energy distally into the tissue. The applicator assembly can be inserted endoluminally or laparoscopically in a compact form and expanded after delivery to the target site.

Generation of recombinant hyperimmune globulins from diverse B-cell repertoires.

Plasma-derived polyclonal antibody therapeutics, such as intravenous immunoglobulin, have multiple drawbacks, including low potency, impurities, insufficient supply and batch-to-batch variation. Here we describe a microfluidics and molecular genomics strategy for capturing diverse mammalian antibody repertoires to create recombinant multivalent hyperimmune globulins. Our method generates of diverse mixtures of thousands of recombinant antibodies, enriched for specificity and activity against therapeutic targets.

High Contrast Ultrasonic Method With Multi-Spatiotemporal Compounding for Monitoring Catheter-Based Ultrasound Thermal Therapy: Development and Ex Vivo Evaluations.

Objective: Changes in ultrasound backscatter energy (CBE) imaging can monitor thermal therapy. Catheter-based ultrasound (CBUS) can treat deep tumors with precise spatial control of energy deposition and ablation zones, of which CBE estimation can be limited by low contrast and robustness due to small or inconsistent changes in ultrasound data. This study develops a multi-spatiotemporal compounding CBE (MST-CBE) imaging approach for monitoring specific to CBUS thermal therapy.

LIPUS far-field exposimetry system for uniform stimulation of tissues in-vitro: development and validation with bovine intervertebral disc cells.

Therapeutic Low-intensity Pulsed Ultrasound (LIPUS) has been applied clinically for bone fracture healing and has been shown to stimulate extracellular matrix (ECM) metabolism in numerous soft tissues including intervertebral disc (IVD). In-vitro LIPUS testing systems have been developed and typically include polystyrene cell culture plates (CCP) placed directly on top of the ultrasound transducer in the acoustic near-field (NF). This configuration introduces several undesirable acoustic artifacts, making the establishment of dose-response relationships difficult, and is not relevant for targeting deep tissues such as the IVD, which may require far-field (FF) exposure from low frequency sources.

In silico feasibility assessment of extracorporeal delivery of low-intensity pulsed ultrasound to intervertebral discs within the lumbar spine.

Low intensity pulsed ultrasound (LIPUS) may have utility for non-invasive treatment of discogenic lower back pain through stimulating, remodeling and accelerating healing of injured or degenerated intervertebral disc (IVD) tissues. This study investigates the feasibility of delivering LIPUS to lumbar IVDs between L2 and S1 spine vertebra using a planar extracorporeal phased array (8 × 8 cm, 1024 elements, 500 kHz). Three 3D anatomical models with heterogenous tissues were generated from patient CT image sets and used in the simulation-based analysis.

Endobronchial high-intensity ultrasound for thermal therapy of pulmonary malignancies: simulations with patient-specific lung models.

This study investigates the feasibility of endobronchial ultrasound applicators for thermal ablation of lung tumors using acoustic and biothermal simulations. Endobronchial ultrasound applicators with planar (10 mm width) or tubular transducers (6 mm outer diameter (OD)) encapsulated by expandable coupling balloons (10 mm OD) are considered for treating tumors from within major airways; smaller catheter-based applicators with tubular transducers (1.7-4 mm OD) and coupling balloons (2.

Deployable cylindrical phased-array applicator mimicking a concentric-ring configuration for minimally-invasive delivery of therapeutic ultrasound.

A novel design for a deployable catheter-based ultrasound applicator for endoluminal and laparoscopic intervention is introduced. By combining a 1D cylindrical ring phased array with an expandable paraboloid or conical-shaped balloon-based reflector, the applicator can be controllably collapsed for compact delivery and deployed to mimic a forward-firing larger diameter concentric ring array with tight focusing and electronic steering capabilities in depth. Comprehensive acoustic and biothermal parametric studies were employed to characterize the capabilities of the applicator design as a function of transducer dimensions, phased array configuration, and balloon reflector geometry.

Antibody repertoire analysis of mouse immunization protocols using microfluidics and molecular genomics.

Immunization of mice followed by hybridoma or B-cell screening is one of the most common antibody discovery methods used to generate therapeutic monoclonal antibody (mAb) candidates. There are a multitude of different immunization protocols that can generate an immune response in animals. However, an extensive analysis of the antibody repertoires that these alternative immunization protocols can generate has not been performed.

Noninvasive, Targeted Creation of Neuromyelitis Optica Pathology in AQP4-IgG Seropositive Rats by Pulsed Focused Ultrasound.

Neuromyelitis optica spectrum disorders (herein called NMO) is an autoimmune disease of the CNS characterized by astrocyte injury, inflammation, and demyelination. In seropositive NMO, immunoglobulin G autoantibodies against aquaporin-4 (AQP4-IgG) cause primary astrocyte injury. A passive transfer model of NMO was developed in which spatially targeted access of AQP4-IgG into the CNS of seropositive rats was accomplished by pulsed focused ultrasound through intact skin.

Assessing high-intensity focused ultrasound treatment of prostate cancer with hyperpolarized C dual-agent imaging of metabolism and perfusion.

The goal of the study was to establish early hyperpolarized (HP) C MRI metabolic and perfusion changes that predict effective high-intensity focused ultrasound (HIFU) ablation and lead to improved adjuvant treatment of partially treated regions. To accomplish this a combined HP dual-agent ( C pyruvate and C urea) C MRI/multiparametric H MRI approach was used to measure prostate cancer metabolism and perfusion 3-4 h, 1 d, and 5 d after exposure to ablative and sub-lethal doses of HIFU within adenocarcinoma of mouse prostate tumors using a focused ultrasound applicator designed for murine studies. Pathologic and immunohistochemical analysis of the ablated tumor demonstrated fragmented, non-viable cells and vasculature consistent with coagulative necrosis, and a mixture of destroyed tissue and highly proliferative, poorly differentiated tumor cells in tumor tissues exposed to sub-lethal heat doses in the ablative margin.

Transurethral high-intensity ultrasound for treatment of stress urinary incontinence (SUI): simulation studies with patient-specific models.

Background: Stress urinary incontinence (SUI) is prevalent in adult women, attributed to weakened endopelvic supporting tissues, and typically treated using drugs and invasive surgical procedures. The objective of this in silico study is to explore transurethral high-intensity ultrasound for delivery of precise thermal therapy to the endopelvic tissues adjacent to the mid-urethra, to induce thermal remodeling as a potential minimally invasive treatment alternative.

Methods: 3D acoustic (Rayleigh-Sommerfeld) and biothermal (Pennes bioheat) models of the ultrasound applicator and surrounding tissues were devised.

A natively paired antibody library yields drug leads with higher sensitivity and specificity than a randomly paired antibody library.

Deep sequencing and single-chain variable fragment (scFv) yeast display methods are becoming more popular for discovery of therapeutic antibody candidates in mouse B cell repertoires. In this study, we compare a deep sequencing and scFv display method that retains native heavy and light chain pairing with a related method that randomly pairs heavy and light chain. We performed the studies in a humanized mouse, using interleukin 21 receptor (IL-21R) as a test immunogen.

Rare, high-affinity mouse anti-PD-1 antibodies that function in checkpoint blockade, discovered using microfluidics and molecular genomics.

Conventionally, mouse hybridomas or well-plate screening are used to identify therapeutic monoclonal antibody candidates. In this study, we present an alternative to hybridoma-based discovery that combines microfluidics, yeast single-chain variable fragment (scFv) display, and deep sequencing to rapidly interrogate and screen mouse antibody repertoires. We used our approach on six wild-type mice to identify 269 molecules that bind to programmed cell death protein 1 (PD-1), which were present at an average of 1 in 2,000 in the pre-sort scFv libraries.

Rare, high-affinity anti-pathogen antibodies from human repertoires, discovered using microfluidics and molecular genomics.

Affinity-matured, functional anti-pathogen antibodies are present at low frequencies in natural human repertoires. These antibodies are often excellent candidates for therapeutic monoclonal antibodies. However, mining natural human antibody repertoires is a challenge.

Integration of deployable fluid lenses and reflectors with endoluminal therapeutic ultrasound applicators: Preliminary investigations of enhanced penetration depth and focal gain.

Purpose: Catheter-based ultrasound applicators can generate thermal ablation of tissues adjacent to body lumens, but have limited focusing and penetration capabilities due to the small profile of integrated transducers required for the applicator to traverse anatomical passages. This study investigates a design for an endoluminal or laparoscopic ultrasound applicator with deployable acoustic reflector and fluid lens components, which can be expanded after device delivery to increase the effective acoustic aperture and allow for deeper and dynamically adjustable target depths. Acoustic and biothermal theoretical studies, along with benchtop proof-of-concept measurements, were performed to investigate the proposed design.

Theoretical investigation of transgastric and intraductal approaches for ultrasound-based thermal therapy of the pancreas.

Background: The goal of this study was to theoretically investigate the feasibility of intraductal and transgastric approaches to ultrasound-based thermal therapy of pancreatic tumors, and to evaluate possible treatment strategies.

Methods: This study considered ultrasound applicators with 1.2 mm outer diameter tubular transducers, which are inserted into the tissue to be treated by an endoscopic approach, either via insertion through the gastric wall (transgastric) or within the pancreatic duct lumen (intraductal).

Formulating an Anarchist Sociology: Peter Kropotkin's Reading of Herbert Spencer.

The work of Herbert Spencer was a crucial influence on the development of Peter Kropotkin's historical sociology. However, scholars have underestimated this relationship; either overlooking it entirely, or minimizing Kropotkin's attachment to Spencer with the aim of maintaining the utility of his political thought in the present. This article contests these interpretations by analyzing Kropotkin's reading of Spencer's epistemological, biological, and political ideas.

Endoluminal ultrasound applicators for MR-guided thermal ablation of pancreatic tumors: Preliminary design and evaluation in a porcine pancreas model.

Purpose: Endoluminal ultrasound may serve as a minimally invasive option for delivering thermal ablation to pancreatic tumors adjacent to the stomach or duodenum. The objective of this study was to explore the basic feasibility of this treatment strategy through the design, characterization, and evaluation of proof-of-concept endoluminal ultrasound applicators capable of placement in the gastrointestinal (GI) lumen for volumetric pancreas ablation under MR guidance.

Methods: Two variants of the endoluminal applicator, each containing a distinct array of two independently powered transducers (10 × 10 mm 3.

Thermal therapy of pancreatic tumours using endoluminal ultrasound: Parametric and patient-specific modelling.

Purpose: The aim of this study is to investigate endoluminal ultrasound applicator configurations for volumetric thermal ablation and hyperthermia of pancreatic tumours using 3D acoustic and biothermal finite element models.

Materials And Methods: Parametric studies compared endoluminal heating performance for varying applicator transducer configurations (planar, curvilinear-focused, or radial-diverging), frequencies (1-5 MHz), and anatomical conditions. Patient-specific pancreatic head and body tumour models were used to evaluate feasibility of generating hyperthermia and thermal ablation using an applicator positioned in the duodenal or stomach lumen.

Development of an endoluminal high-intensity ultrasound applicator for image-guided thermal therapy of pancreatic tumors.

An ultrasound applicator for endoluminal thermal therapy of pancreatic tumors has been introduced and evaluated through acoustic/biothermal simulations and experimental investigations. Endoluminal therapeutic ultrasound constitutes a minimally invinvasive conformal therapy and is compatible with ultrasound or MR-based image guidance. The applicator would be placed in the stomach or duodenal lumen, and sonication would be performed through the luminal wall into the tumor, with concurrent water cooling of the wall tissue to prevent its thermal injury.

Synovial Fluid Lubricant Properties are Transiently Deficient after Arthroscopic Articular Cartilage Defect Repair with Platelet-Enriched Fibrin Alone and with Mesenchymal Stem Cells.

Background: Following various types of naturally-occurring traumatic injury to an articular joint, the lubricating ability of synovial fluid is impaired, with a correlated alteration in the concentration and/or structure of lubricant molecules, hyaluronan and proteoglycan-4. However, the effect of arthroscopic cartilage repair surgery on synovial fluid lubricant function and composition is unknown.

Hypothesis: Arthroscopic treatment of full-thickness chondral defects in horses with (1) platelet-enriched fibrin or (2) platelet-enriched fibrin+mesenchymal stem cells leads to equine synovial fluid with impaired lubricant function and hyaluronan and proteoglycan-4 composition.

Coherence between cellular responses and in vitro splicing inhibition for the anti-tumor drug pladienolide B and its analogs.

Pladienolide B (PB) is a potent cancer cell growth inhibitor that targets the SF3B1 subunit of the spliceosome. There is considerable interest in the compound as a potential chemotherapeutic, as well as a tool to study SF3B1 function in splicing and cancer development. The molecular structure of PB, a bacterial natural product, contains a 12-member macrolide ring with an extended epoxide-containing side chain.