scholarly journals An Indispensable tool for ultrasound based diagnostics and therapies - Microbubbles

2020 ◽  
Vol 1 (3) ◽  
Author(s):  
Alec Nelson Thomas ◽  
Eleanor Stride
Keyword(s):  
Clinical Trial ◽  
Biological Effects ◽  
Region Of Interest ◽  
Ultrasonic Field ◽  
Ultrasound Contrast Agents ◽  
Tissue Response ◽  
Acoustic Energy ◽  
Hydrophilic Drugs ◽  
Drug Molecules ◽  
Therapeutic Platform

Microbubbles (MBs) are micrometre sized gas spheres comprising a biocompatible shell that provide vascular contrast for diagnostic ultrasound (US) imaging. MBs volumetrically oscillate in an ultrasonic field and scatter acoustic energy over a range of frequencies that can be separated from the tissue response. MBs can also provide organ perfusion rates by imaging their “wash-in” to a region of interest which can be correlated to vascular flow. When driven at higher acoustic pressures, localized biological effects can be induced, including increased tissue permeabilization, thermal effects and localised release of drugs that can be encapsulated in the MBs themselves. Both hydrophobic and hydrophilic drugs can be loaded on to MBs e.g. through the use of liposomal carriers or direct attachment of drug molecules to the bubble shell. Since the early 2000s, MB-based technologies have been well researched, though there was significant regulatory push back starting in 2006 based on a controversial clinical trial. From that point, both physicians and researchers have consistently demonstrated the robust safety of MBs as ultrasound contrast agents and their significant clinical utility. Within the last 5 years, more indications have been approved. A recent first-in-man clinical trial of therapeutic US with MBs reversibly opening the blood brain barrier has also been shown to be safe in amyotrophic lateral sclerosis patients. The following article outlines the coupling of US and MBs as a diagnostic and therapeutic platform with a particular focus on their application to the therapy of surgical diseases.

Nonlinear dynamics of a shell encapsulated microbubble near solid boundary in an ultrasonic field

2020 ◽  
Vol 14 (3) ◽  
pp. 7235-7243
Author(s):  
N.M. Ali ◽  
F. Dzaharudin ◽  
E.A. Alias
Keyword(s):  
Oscillation Amplitude ◽  
Ultrasonic Field ◽  
Dynamical Behaviour ◽  
Ultrasound Contrast Agents ◽  
Chaotic Behaviour ◽  
Solid Boundary ◽  
Driving Frequency ◽  
Pressure Amplitude ◽  
Radial Expansion ◽  
Therapeutic Delivery

Microbubbles have the potential to be used for diagnostic imaging and therapeutic delivery. However, the transition from microbubbles currently being used as ultrasound contrast agents to achieve its’ potentials in the biomedical field requires more in depth understanding. Of particular importance is the influence of microbubble encapsulation of a microbubble near a vessel wall on the dynamical behaviour as it stabilizes the bubble. However, many bubble studies do not consider shell encapsulation in their studies. In this work, the dynamics of an encapsulated microbubble near a boundary was studied by numerically solving the governing equations for microbubble oscillation. In order to elucidate the effects of a boundary to the non-linear microbubble oscillation the separation distances between microbubble will be varied along with the acoustic driving. The complex nonlinear vibration response was studied in terms of bifurcation diagrams and the maximum radial expansion. It was found that the increase in distance between the boundary and the encapsulated bubble will increase the oscillation amplitude. When the value of pressure amplitude increased the single bubble is more likely to exhibit the chaotic behaviour and maximum radius also increase as the inter wall-bubble distance is gradually increased. While, with higher driving frequency the maximum radial expansion decreases and suppress the chaotic behaviour.

scholarly journals The Biological Effects of Combining Metals in a Posterior Spinal Implant: In Vivo Model Development Report of the First Two Cases

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Christine L. Farnsworth ◽  
Peter O. Newton ◽  
Eric Breisch ◽  
Michael T. Rohmiller ◽  
Jung Ryul Kim ◽  
...  
Keyword(s):  
Galvanic Corrosion ◽  
Biological Effects ◽  
Model Development ◽  
Spinal Instrumentation ◽  
Pedicle Screws ◽  
Tissue Response ◽  
In Vivo Model ◽  
Particle Count ◽  
Spinal Implant

Study Design. Combinations of metal implants (stainless steel (SS), titanium (Ti), and cobalt chrome (CC)) were placed in porcine spines. After 12 months, tissue response and implant corrosion were compared between mixed and single metal junctions. Objective. Model development and an attempt to determine any detriment of combining different metals in posterior spinal instrumentation. Methods. Yucatan mini-pigs underwent instrumentation over five unfused lumbar levels. A SS rod and a Ti rod were secured with Ti and SS pedicle screws, SS and Ti crosslinks, SS and CC sublaminar wires, and Ti sublaminar cable. The resulting 4 SS/SS, 3 Ti/Ti, and 11 connections between dissimilar metals per animal were studied after 12 months using radiographs, gross observation, and histology (foreign body reaction (FBR), metal particle count, and inflammation analyzed). Results. Two animals had constructs in place for 12 months with no complications. Histology of tissue over SS/SS connections demonstrated 11.1 ± 7.6 FBR cells, 2.1 ± 1.7 metal particles, and moderate to extensive inflammation. Ti/Ti tissue showed 6.3 ± 3.8 FBR cells, 5.2 ± 6.7 particles, and no to extensive inflammation (83% extensive). Tissue over mixed components had 14.1 ± 12.6 FBR cells and 13.4 ± 27.8 particles. Samples surrounding wires/cables versus other combinations demonstrated FBR (12.4 ± 13.5 versus 12.0 ± 9.6 cells, P = 0.96), particles (19.8 ± 32.6 versus 4.3 ± 12.7, P = 0.24), and inflammation (50% versus 75% extensive, P = 0.12). Conclusions. A nonfusion model was developed to study corrosion and analyze biological responses. Although no statistical differences were found in overlying tissue response to single versus mixed metal combinations, galvanic corrosion between differing metals is not ruled out. This pilot study supports further investigation to answer concerns when mixing metals in spinal constructs.

A Patient-specific in vivo Tumor and Normal Tissue Model for Prediction of the Response to Radiotherapy

2007 ◽  
Vol 46 (03) ◽  
pp. 367-375 ◽  
Author(s):  
V. P. Antipas ◽  
N. K. Uzunoglu ◽  
G. S. Stamatakos
Keyword(s):  
Cancer Biology ◽  
Normal Tissue ◽  
Region Of Interest ◽  
Neural Tissue ◽  
Simulation Models ◽  
Specific Model ◽  
Tissue Response ◽  
Patient Specific ◽  
Treatment Optimization

Summary Objectives: Integration of multiscale experimental cancer biology through the development of computer simulation models seems to be a necessary step towards the better understanding of cancer and patient-individualized treatment optimization. The integration of a four-dimensional patient-specific model of in vivo tumor response to radiotherapy developed by our group with a model of slowly responding normal tissue based on W. Duechting’s approach is presented in this paper. The case of glioblastoma multiforme and its surrounding neural tissue is addressed as a modeling paradigm. Methods: A cubic discretizing mesh is superimposed upon the anatomic region of interest as is reconstructed from pertinent imaging (e.g. MRI) data. On each geometrical cell of the mesh the most crucial biological “laws” e.g. metabolism, cell cycling, tumor geometry changes, cell kill following irradiation etc. are applied. Slowly responding normal neural tissue is modeled by a functional compartment containing indivisible cells and a divisible compartment containing glial cells. Results: The model code has been executed for a simulated period normally covering the radiotherapy course duration and extending a few days after its completion. The following schemes have been simulated: standard fractionation, hyperfractionation, accelerated fractionation, accelerated hyperfractionation and hypofractionation. The predictions are in agreement with the outcome of the RTOG 83-02 phase I/II trial, the retrospective study conducted by Sugawara et al. and the theoretical predictions of Duechting et al. Conclusions: The presented model, although oversimplified, may serve as a basis for a refined simulation of the biological mechanisms involved in tumor and normal tissue response to radiotherapy.

First-in-human clinical trial with intratumoral BO-112 in solid malignancies: A novel immunotherapy based in double-stranded RNA (dsRNA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3082-3082 ◽  
Author(s):  
Ivan Marquez Rodas ◽  
Maria E. Rodriguez-Ruiz ◽  
Sara Lopez-Tarruella ◽  
Jose Luis Perez-Gracia ◽  
Enrique de Miguel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mouse Models ◽  
Immune Cells ◽  
Biological Effects ◽  
Safety Data ◽  
Metastatic Lesion ◽  
Post Treatment ◽  
It Use ◽  
Antitumor Effects ◽  
Solid Malignancies

3082 Background: BO-112 is a double stranded synthetic RNA, formulated with the cationic carrier polyethyleneimine that preclinically improves its intracellular delivery and resistance towards nuclease degradation. In melanoma mouse models, systemic administration activates MDA-5 and NOXA, leading to anti-tumoral activity connected to a sustained and extended expression of IFN-response genes. Intratumoral (IT) delivery, seeking a safer and more focused enhancement of local and systemic antitumor effects has been tested in transplanted mouse models. The potential of its IT use as an immune-modulatory treatment, as well as its toxicity profile, is being analyzed in this first in human, proof of concept, clinical trial (NCT02828098). Methods: Four patients with malignant solid tumors and palpable cutaneous/subcutaneous or lymph node metastases >1 cm were treated with a single BO-112 dose of 0.6 mg/ml IT. Pre and post treatment biopsies from the injected metastatic lesion were obtained. Pharmacokinetics, serum cytokines and circulating immune cells were sequentially studied in pre and post treatment samples. Results: Patients did not experience relevant toxicity with the exception of a single episode of completely reversible grade 4 thrombocytopenia in one patient, attributed to the drug. BO-112 was not detectable in bloodstream following IT delivery. No changes in circulating cytokines were detected. Main immunobiological effects are summarized in the table. Conclusions: BO-112 has shown changes in tumoral immune cells in 1/4 patients, while in 3/4 induced both necrosis and changes in circulating immune cells. This ongoing trial will compile more safety data with repeated sequential administrations, escalated to higher doses of BO-112, and will thoroughly characterize its biological effects in humans with solid malignancies amenable to IT injection. Clinical trial information: NCT02828098. [Table: see text]

scholarly journals BIMG-23. SINGLE-VOXEL VERSUS MULTI-SLICE MRSI IN PATIENTS WITH GLIOMA ON A KETOGENIC DIET INTERVENTION

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i6-i6
Author(s):  
Vasu Munjapara ◽  
David Kamson ◽  
Adam Berrington ◽  
Roy Strowd ◽  
Karisa Schreck ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Spin Echo ◽  
Biological Effects ◽  
Region Of Interest ◽  
Residual Tumor ◽  
Normal Brain ◽  
Total N ◽  
Single Voxel ◽  
Spin Echo Sequence ◽  
Lactate Levels

Abstract BACKGROUND Ketogenic diet therapies (KDTs) may be beneficial by exploiting glioma metabolic vulnerabilities. The GLioma modified Atkins-based Diet study (GLAD; NCT02286167) evaluated systemic and cerebral (MR spectroscopy) biomarkers to determine the feasibility and biological effects of a KDT in glioma patients. While we observed metabolic changes in tumor and normal brain after KDT using single-voxel MRS (SV-MRS), optimal voxel placement was not always achieved. AIMS: We performed an exploratory analysis comparing cerebral metabolite changes using multi-slice MRSI (MS-MRSI) versus SV-MRS acquisition. METHODS We evaluated four patients from the GLAD study (mean age 39years; 2 female, 3 AA IDH-mutant, 1 GBM IDH-wildtype) who underwent MRS at baseline and following eight weeks of KDT. SV-MRS (sLASER, TR/TE 2.2s/34ms) was acquired from a 2x2x2cm voxel placed in the residual tumor and the contralateral homologous brain. MS-MRSI was acquired with a multi-slice spin echo sequence (TR/TE 3.6/144ms, 4 slices, nominal resolution 13x7x7mm, SENSE factor 3) and maps of total choline (tCho), total N-acetyl-aspartate (tNAA), and lactate (Lac) were reconstructed and normalized relative to creatine. Metabolite levels were measured on the MS-MRSI maps using a region of interest placed in the same areas studied with the SV-MRS. RESULTS Lesional tCho and tNAA levels showed strong correlation between SV-MRS and MS-MRSI both at baseline (Pearson’s r=0.92 and 0.97, respectively) and after 8 weeks of KDT (r=0.96 and 0.84, respectively). tCho and tNAA correlated less robustly between SV-MRS and MS-MRSI in the contralesional region (r=0.56–0.96). Lesional Lac was significantly lower after KDT (1.01±0.48 versus 0.59±0.24, paired t-test p=0.02). CONCLUSIONS While SV and MS-MRSI provided generally concordant lesional results, MS-MRSI offers added potential to map regional variations not captured by SV-MRS and thus may better define the control regions. MS-MRSI detected a decrease in tumoral lactate levels following study intervention, suggesting KDT-related changes in tumoral energy metabolism.

Modeling Microbubble Microvessel Interaction for Sonoporation Application

2020 ◽  
Author(s):  
Aswin Gnanaskandan ◽  
Xiaolong Deng ◽  
Chao-Tsung Hsiao ◽  
Georges Chahine
Keyword(s):  
Acoustic Waves ◽  
Ultrasound Contrast Agents ◽  
Material Interfaces ◽  
Mapping Procedure ◽  
Flow Solver ◽  
Maximum Deformation ◽  
Drug Molecules ◽  
Lagrangian Solution ◽  
Potential Applications ◽  
Two Phases

Abstract Modeling the dynamics of microbubbles inside confined spaces has many potential applications in biomedicine, sonoporation being one classic example. Sonoporation is the permeabilization of a blood vessel’s endothelial cell membrane by acoustic waves in order to non-invasively deliver large-sized drug molecules into cells for therapeutic applications. By controlled activation of ultrasound contrast agents (UCA) in a microvessel, one can achieve better permeabilization without causing permanent damage associated with high intensity ultrasound. This paper considers numerically, the fluid-structure interactions (FSI) of UCA microbubbles with a microvessel accounting for large deformations. The modeling approach is based on a multi-material compressible flow solver that uses a Lagrangian treatment for numerical discretization of cells containing an interface between two phases and an Eulerian treatment for cells away from material interfaces. A re-mapping procedure is employed to map the Lagrangian solution back to the Eulerian grid. The model is first validated by simulating a microbubble oscillating due to an imposed ultrasound inside a microvessel and good agreement with experiments is obtained for both the bubble and vessel dynamics. The effect of vessel elasticity is then studied and it is shown that increasing the vessel elasticity damps the bubble oscillations. Then the effect of placing the bubble away from the axis of vessel is studied and it is shown that bubbles closer the vessel wall are capable of creating maximum deformation on the wall compared to those away from the wall.

scholarly journals A SYSTEMATIC REVIEW ON SELF-MICRO EMULSIFYING DRUG DELIVERY SYSTEMS: A POTENTIAL STRATEGY FOR DRUGS WITH POOR ORAL BIOAVAILABILITY

2019 ◽  
Vol 11 (1) ◽  
pp. 23
Author(s):  
G V Radha ◽  
K Trideva Sastri ◽  
Sadhana Burada ◽  
Jampala Rajkumar
Keyword(s):  
Biological Effects ◽  
Water Soluble ◽  
Lipophilic Compounds ◽  
Solid Dosage ◽  
Drug Molecules ◽  
Dynamic Strategy ◽  
Lipid System ◽  
Potential Strategy ◽  
Lipid Excipients ◽  
Optimum Formula

Currently a marked interest in developing lipid-based formulations to deliver lipophilic compounds. Self-emulsifying system has emerged as a dynamic strategy for delivering poorly water-soluble compounds. These systems can embrace a wide variety of oils, surfactants, and co-solvents. An immediate fine emulsion is obtained on exposure to water/gastro-intestinal fluids. The principal interest is to develop a robust formula for biopharmaceutical challenging drug molecules. Starting with a brief classification system, this review signifies diverse mechanisms concerning lipid-based excipients besides their role in influencing bioavailability, furthermore pertaining to their structured formulation aspects. Consecutive steps are vital in developing lipid-based systems for biopharmaceutical challenging actives. Such a crucial structured development is critical for achieving an optimum formula. Hence lipid excipients are initially scrutinized for their solubility and phase behavior, along with biological effects. Blends are screened by means of simple dilution test and are consequently studied with more advanced biopharmaceutical tests. After discerning of the principle formula, diverse technologies are offered to incorporate the fill-mass either in soft/hard gelatin capsules. There is also feasibility to formulated lipid-system as a solid dosage form. Although such solid technologies are desirable but such should not undermine the biopharmaceutical potential of lipid-formulations.

Evaluation of the safety and immunogenicity of intratumoral injection of interferon gamma (IFNg) during vaccination in patients with subcutaneous or cutaneous metastases of melanoma (Mel51; NCT00977145).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3118-TPS3118
Author(s):  
Craig L. Slingluff ◽  
Gina R. Petroni ◽  
Lynn Dengel ◽  
David W. Mullins ◽  
William W. Grosh ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Interferon Gamma ◽  
Biological Effects ◽  
Peptide Vaccine ◽  
Combination Regimen ◽  
Cell Trafficking ◽  
Tumor Site ◽  
Cutaneous Metastases

TPS3118^ Background: One mechanism to improve immunologic outcomes of vaccine therapy, and other immune therapies, is to optimize T cell trafficking to sites of tumor. CXCR3 is expressed by Th1 and Tc1 T cells and directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC)) are induced by interferon gamma (IFNg). This protocol tests whether administering peptide vaccine activates circulating tumor antigen-specific CD8+ CXCR3+ T cells, followed by intratumoral IFNg to increase CXCR3 ligands (CXCL9-11) at the tumor site and thus to recruit the CXCR3+T cells. Methods: This pilot clinical trial is enrolling patients (n=14) with subcutaneous or cutaneous metastases of melanoma (stage IIIB-IV), who have adequate accessible tumor in 1-4 lesions to provide 100-300 mm3 tumor on each of the three biopsy days, and with at least one lesion amenable to intratumoral IFNg injection. Patients must also express HLA-A1, A2, A3, or A11. Patients undergo tumor biopsy d1, then are vaccinated days 1, 8, and 15 with a multipeptide vaccine. A biopsy day 22 provides information on the effect of vaccination alone on T cell infiltration into tumor. IFNg (up to 2 million units) is injected into at least 1 metastasis, which is biopsied day 24. Additional vaccines are given days 24, 43, and 64. Primary goals are to determine the safety of intratumoral interferon gamma (IFNg) plus a multipeptide melanoma vaccine, and to evaluate the biological effects of vaccine plus IFN-g at the tumor site, to include expression of CXCR3 ligands (CXCL9, CXCL10 & CXCL11) and the magnitude of infiltration of CD8+ CXCR3+ T cells and vaccine-specific T cells. Secondary goals include evaluating effects of vaccine on CXCR3 expression by circulating antigen-experienced CD4 and CD8 T cells, estimating the effects of vaccine plus IFNg on changes in the percentage of FoxP3+ CD25hi CD4+(putative regulatory T cells, Tregs) among tumor infiltrating T cells and to obtain preliminary data on the clinical response of cutaneous or subcutaneous metastases of melanoma to the proposed combination regimen. Clinical trial information: NCT00977145.

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