Dissertations / Theses on the topic 'Ultrasound trigger'

Thesis (Ph.D.)--Boston University<br>PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.<br>Chemotherapy requires the systemic administration of large doses of highly toxic antineoplastic agents in order to achieve therapeutically relevant concentrations at the tumor. These drugs typically act by impairing cell mitosis, effectively targeting rapidly-dividing cells that are the hallmarks of cancer. Non-cancerous cells that divide rapidly under normal circumstances are often damaged, leading to adverse side effects including myelosuppression, alopecia, and organ-specific toxicities. One potential means of reducing off-site toxicities is to encapsulate highly toxic chemotherapeutics into thermosensitive liposomes (TSL). These nanoscale structures are formed from temperature-sensitive lipids, and are designed to passively target the tumor by being large enough to avoid renal clearance while small enough to slip through leaky blood vessels characteristic of tumor vasculature. At the tumor, externally applied heating triggers a burst release of therapeutically relevant concentrations of drug. Current TSL formulations suffer from (i) approaches for heating that put healthy tissue surrounding the tumor at risk; (ii) lack of stability at physiological conditions (e.g. premature leakage of drug); and (iii) lack of noninvasive approaches for monitoring temperature elevation. This project presents a dual pH/thermosensitive liposome (PTSL) for the deliver of Doxorubicin (DOX), a commonly administered chemotherapeutic. Copolymers of temperature-responsive N-isopropylacrylamide (NIPAAm) and pH-responsive propylacrylic acid (PAA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, yielding copolymers with dual pH/temperaturedependent phase transition properties. When attached to liposomes, copolymers were membrane-disruptive m a pH/temperature-dependent manner, conferring pH/temperature-sensitive drug release properties to the liposome. These dual-sensitive properties can potentially exploit the slightly acidic environment of the tumor when PTSL are administered with externally applied heating. PTSL demonstrated enhanced release profile, significantly lower thermal dose threshold, and lower IC50 when compared to traditional TSL, and were stable in serum with minimal premature drug leakage. The application of MR-guided focused ultrasound (MRgFUS) as a noninvasive, highly controllable thermal source for triggering drug release and monitoring temperature elevations was demonstrated in vivo. PTSL combined with MRgFUS treatment resulted in delayed tumor growth when compared to PTSL alone and control treatments. This PTSL-MRgFUS delivery system thus addresses the limitations of existing TSL therapies and has potential applications in the clinic.<br>2031-01-01

La capacité de certains matériaux à changer d'état fondamental sous excitation laser a ouvert un champ de recherche autour de la manipulation de leurs propriétés par la lumière. Les processus chimiques et physiques mis alors en jeu sont riches et complexes. Dans ce contexte, le rôle prédominant de la coopérativité élastique pour l’amplification et la stabilisation de la transition a été mis en évidence récemment dans un matériau à transitions de spin irradié par laser. Ces observations font apparaître la perspective de commuter de façon permanente certaines propriétés des matériaux par des ultrasons non-linéaires, des ondes de choc excitées par laser.Dans un premier temps, nous introduisons le dispositif expérimental d’imagerie mono-coup résolu en temps, associée à la technique de focalisation des ondes de chocs excitées par laser au niveau de la surface de l’échantillon. La séparation spatiale des régions irradiées par le laser et influencées par les ondes de choc propagatives permet de discerner clairement les changements du matériaux induits uniquement par les ondes de choc. Dans un second temps, nous présentons nos résultats expérimentaux en lien avec cette technique innovante, aux matériaux dont les changements de phases impliquent un changement de volume macroscopique (systèmes spin-crossover, isolants de Mott). Des analyses post-mortem des échantillons ont permis de confirmer, dans certaines conditions expérimentales, une modification permanente de la phase du matériau par action de l'onde de choc. Ces résultats ouvrent des perspectives pour la généralisation à de nombreux matériaux du phénomène de coopérativité élastique donnant lieu à des transition permanent<br>The ability of certain materials to change its ground state due to laser excitation has arisen a lot of opportunities for light-control of material properties. The field of photo-induced phase transitions counts a rich variety of chemical and physical processes triggered by light-matter interactions involved during the phase transition process. Recently it was reported that elastically driven cooperativity leads to the amplification of spin state in molecular crystals and prolonged the lifetime of the transient state with an ultra-short laser pulse. The cooperative response appears during the propagation of non-linear coherent strain waves, in other words shock waves, coupled with the order parameter field. Shock waves can be seen as a new challenging pathway to achieve a permanently switched state with appropriate excitations.First, we introduce time-resolved single-shot imaging combined with the laser shock focusing technique that makes it possible to generate, acoustically focus, and directly visualize under a microscope shock waves propagating and focusing along the sample surface. The spatial separation of the laser-influenced and strain-influenced regions makes it possible to disentangle the material changes produced solely by the shock waves. Second, we present experimental results involving the shock-focusing technique to materials undergoing phase transitions linked with a macroscopic change of their volume (spin-crossover systems, Mott insulators). Post-mortem analyses of the samples confirm permanent phase transition under specific experimental conditions. These innovative results open doors for a generic elastically driven cooperativity

Nous avons optimisé des liposomes thermosensibles, encapsulant un principe actif anticancéreux, le 5-Fluorouracile (5-FU), afin de déclencher sa libération par une hyperthermie locale modérée (39-42°C) induite par des ultrasons focalisés. L'hyperthermie sera appliquée au niveau de la tumeur, afin d'améliorer l’efficacité thérapeutique et de réduire la toxicité systémique. Les liposomes ont été formulés par hydratation du film lipidique en mélangeant la 1,2-dipalmitoyl-sn-glycéro-3-phosphocholine (DPPC) pour sa thermosensibilité à 41,5 ± 0,5°C, le cholestérol (CHOL) pour favoriser la stabilité des liposomes vis-à-vis des composants du sang, et le 1,2-distéaroyl-sn-glycéro-3-phosphoéthanolamine-N-[méthoxy(polyéthylène glycol)-2000] (DSPE-PEG) pour assurer la furtivité de la formulation. Les expériences ont confirmé que les liposomes formulés à base de DPPC/CHOL/DSPE-PEG dans un ratio molaire 90 : 5 : 5 mol% sont thermosensibles. Des liposomes composés du même mélange lipidique dans un rapport 65 : 30 : 5 mol% ont été considérés comme contrôle négatif non thermosensible. L’optimisation de l’encapsulation passive du 5-FU a permis d’obtenir une efficacité d’encapsulation (5-FU encapsulé/5-FU total) de 13%, mais le 5-FU est très faiblement retenu (12%) dans la cavité aqueuse des liposomes du fait du gradient osmotique à la dilution. La rétention du 5-FU a été optimisée (93%) par la technique d’encapsulation active basée sur la complexation intraliposomale du 5-FU avec le complexe cuivre-polyéthylèneimine préalablement encapsulé dans les liposomes. Cette technique a également permis d’améliorer l’efficacité d’encapsulation d’un facteur trois environ (37%), avec un taux de charge (ratio final 5-FU/lipides, mole/mole) de 50% environ. Nous avons alors obtenu des liposomes thermosensibles d'un diamètre hydrodynamique de 65 nm et de charge de surface de -10 mV. Les liposomes non thermosensibles, ont été caractérisés par un diamètre hydrodynamique de 105 nm et une charge de surface de -4,9 mV. La libération du 5-FU déclenchée par une hyperthermie induite par des ultrasons focalisés a été mesurée in vitro. En réponse à une hyperthermie de 42°C, les liposomes thermosensibles libèrent 68% de leur contenu, au bout de 10 min, alors que les liposomes non thermosensibles en libèrent moins de 20%. En outre, la cytotoxicité des liposomes encapsulant le complexe 5-FU-cuivre-polyéthylèneimine a été évaluée vis-à-vis de la lignée cellulaire HT-29 du carcinome colorectal humain. Les résultats ont révélé que les lipides à une concentration de 800 µM ne sont pas cytotoxiques (80% de viabilité). De plus, la complexation du 5-FU n’influence pas sa cytotoxicité ce qui prouve que la toxicité provient du 5-FU et non des excipients. En revanche, l’encapsulation du complexe 5-FU-cuivre-polyéthylèneimine dans les liposomes induit une diminution de la concentration inhibitrice médiane de 115 (solution du complexe) à 49 µM environ, corrélée à leur internalisation cellulaire. La pharmacocinétique chez des souris porteuses d’un modèle de tumeur colorectale HT-29 xénogreffée a montré que les liposomes permettent de prolonger d’un facteur 1,4 la demi-vie plasmatique de distribution du 5-FU. De plus, les aires sous la courbe des concentrations plasmatiques sur 24 h sont 1,9 et 2,9 fois plus élevées lorsque le 5-FU est administré sous forme de liposomes thermosensibles et non thermosensibles, respectivement, par rapport à la solution de 5-FU. Enfin, les liposomes non thermosensibles augmentent significativement d'un facteur 2 l'accumulation du 5-FU dans la tumeur par rapport à la solution de 5-FU. En conclusion, les liposomes thermosensibles développés présentent un fort intérêt pour une application thérapeutique en combinaison avec des ultrasons focalisés<br>We optimized thermosensitive liposomes encapsulating an anticancer drug, 5-Fluorouracil (5-FU), in order to trigger the release upon focused ultrasound-mediated mild hyperthermia at the tumor. This approach would improve drug efficacy and would lower side effects. Liposomes were prepared by the lipid hydration method by mixing 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) for its temperature sensitivity at 41.5 ± 0.5°C, cholesterol (CHOL) to promote liposome stability towards blood components, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) to confer stealthiness to the formulation. The experiments confirmed that the liposomes formulated with DPPC/CHOL/DSPE-PEG in a molar ratio 90:5:5 mol% are thermosensitive, while liposomes composed of the same lipid mixture in a ratio 65:30:5 mol% were considered non thermosensitive negative control. The optimization of passive encapsulation of 5-FU yielded an encapsulation efficacy (encapsulated 5-FU/total 5-FU) of 13%. 5-FU was, however, very weakly retained (12%) in the aqueous core of liposomes following dilution due to the generation of an osmotic gradient. The retention of 5-FU has been optimized (93%) by the active encapsulation technique based on the intraliposomal complexation of 5FU with copper-polyethylenimine complex encapsulated beforehand into liposomes. This technique also improved 5-FU encapsulation efficacy by 3-fold (37%), yielding a loading efficiency (final drug/lipid ratio, mol/mol) of approximately 50%. The resulting thermosensitive liposomes and non thermosensitive liposomes have a hydrodynamic diameter and a surface charge around 65 nm and -10 mV, and 105 nm and -4.9 mV, respectively. Heat-triggered drug delivery was evaluated using focused ultrasound, and showed a release of 68% of the encapsulated 5-FU from thermosensitive liposomes, within 10 min, whereas release remained below 20% for the non thermosensitive formulation. Furthermore, the cytotoxicity of 5-FU-copper-polyethylenimine complex-loaded liposomes towards HT-29 human colorectal carcinoma cell line was evaluated. Results revealed that lipids at a concentration of 800 µM are not cytotoxic (80% viability). Moreover, 5-FU complexation has no impact on its cytotoxic activity, disclosing that liposomes toxicity arose from 5-FU and not from the excipients. Nevertheless, 5-FU-copper-polyethylenimine complex-loaded liposomes exhibited a lower half maximal inhibitory concentration of 49 µM compared to 115 µM for complex solution. This enhancement of cytotoxicity was attributed to the cellular internalization of liposomes. Pharmacokinetics in mice bearing HT-29 xenograft tumor showed that liposomes can extend the plasma distribution half-life of 5-FU by a factor 1.4. Furthermore, areas under the concentration-time curve over 24 h were higher by 1.9- and 2.9-fold when the drug was encapsulated into thermosensitive and non thermosensitive liposomes, respectively, compared to free 5-Fluorouracil. Finally, non thermosensitive liposomes significantly increased 5-FU accumulation in tumor by 2-fold, compared to 5-FU solution. In conclusion, these 5-FU-loaded thermosensitive liposomes represent valuable carriers to investigate the therapeutic efficacy following focused ultrasound-mediated heat application

碩士<br>國立成功大學<br>資訊工程學系碩博士班<br>100<br>Multimodality image fusion has become important in clinical diagnosis and treatment because it can integrate anatomical information acquired from various image modalities to provide complete 3D geometry of human internal structures. However, it is usually challenging due to pose (i.e., orientation and position) and intensity variations among different image modalities. In this thesis, we propose a new image fusion system of magnetic resonance (MR) and ultrasound (US) images for finger joints, and apply it to construct the surgical trainer for ultrasound-guided percutaneous trigger finger release (UGPR). The proposed system consists of three main steps, which are three-dimensional (3D) finger model construction from MR images, registration of MR and US images, and hand phantom image construction. At first, a drivable 3D finger model, containing bone, tendon, skin surfaces, and finger joint mechanism, is constructed from multi-postural hand MR images by using a registration-based segmentation strategy. Then, the 3D finger model is aligned to the 3D US images via articulated registration, and the resulting registration transformations are subsequently utilized to fuse the 3D MR and US images. At last, the fused images are warped to match the spatial configuration of hand phantom based on two-staged radial basis function (RBF). As a result, the hand phantom can be provided with both MR and US image contents to realistically simulate the surgery environment of UGPR. Combining with an optical tracking system to integrate the image, phantom and surgical tools’ coordinate systems, a surgical trainer is built to improve the proficiency of clinicians for UGPR. Experimental results showed that the proposed method can overcome the pose and intensity variations among different image modalities to fuse the images by referring to the structural information of anatomical models (e.g., bone, tendon and skin). It also has great potential to fuse multimodality images of the other joint structures.

碩士<br>國立成功大學<br>生物醫學工程學系<br>102<br>The role of finger tendon excursion during rehabilitation protocol is to avoid the adhesion phenomenon which occurs at tissue or tendon repair. In previous studies, the main focus of these investigations were cadaveric or static study, there were few studies measuring tendon excursion in-vivo that have been made in intraoperative observations, electromyography, or ultrasound. Currently, the maximum tendon excursion and the tendon excursion pattern on active finger motion were varied in different study that did not have a main reference. There is a common disease seen in hand clinics called trigger finger, or stenosing tenosynovitis. Patients who suffer from trigger finger present discomfort during finger movement. The discomfort is caused by the size discrepancy between flexor tendons and annular pulley system, which results in greater resistance. “Triggering”, the sudden release phenomenon during finger extension movement, when the tendon passes through the affected region. The tendon nodule is a swelling of the flexor tendon resulting in constriction of the flexor tendon sheath, triggering occurs when deformation of the tendon is induced. Due to different motions, different tendon gliding patterns maybe improve the triggering. We are interested in understanding this possibility. The purpose of this study is to use ultrasonography, kinematic, and kinetic analysis to obtain the tendon gliding pattern during different active finger motion, and use this technique to evaluate the triggering condition of trigger finger patients. In the study, we recruited 19 healthy subjects who did not have any hand disease or injury, and 7 trigger finger patients. The finger motions we used are active fist motion and a modified tendon gliding exercise. First, participants were asked to flex and extend their finger in the neutral speed; another motion was a specific finger motion similar with tendon gliding exercise. In the initial stage, participants were ask to extend all finger joints, and then sequentially flex MP, PIP, DIP joints to their maximum angles. Next, participants will extend MP, PIP, DIP joints to the initial position. In the case of patients, in addition to the above motion, the passive pulling test was done in order to observe the relationship between tendon gliding and joint angle at triggering moment. In this test we will use a string to pull the affected finger passively from a flexed posture to an extended posture. The motion data and ultrasound image will be collected simultaneously. The force data was collected in the passive pulling test. The tendon excursion, normalized tendon excursion versus differential joint angle, FDS/FDP excursion ratio were used to evaluate the relationship between tendon and joint angle, and between each flexor tendons. As a result, the characteristic are similar at the maximum joint angle between each active finger motion. For active fist motion, FDS/FDP excursion ratio show decrease with larger finger flexion angle, which means FDP tendon play a more important role at larger flexion angles. For the modified tendon gliding exercise, the result shows FDS tendon made larger excursion at phase 1 with respect to FDP tendon. The adjusted excursion ratio shows different patterns at all assigned phases between active fist motion and modified tendon gliding exercise. This characteristic may be reference data for the future work. In the patient study, using ultrasound and external force to find that the relationship between performance of external force and tendon movement on image. This is a potential method to evaluate the tendon performance of trigger finger at triggering moment. In the current study we used ultrasonography to evaluate the relationship between tendon gliding and joint angle on healthy subjects and trigger finger patients, and used passive pulling tests to estimate condition of triggering. Further, the tendon excursion pattern was building to become a reference to help evaluation of rehabilitation and hand research. This model might be a safe and direct method to evaluate the finger movement pattern of trigger finger in the future.

Yes<br>The hydrophobicity of a drug can be a major challenge in its development and prevents the clinical translation of highly potent anti-cancer agents. We have used a lipid-based nanoemulsion termed Lipid-Oil-Nanodroplets (LONDs) for the encapsulation and in vivo delivery of the poorly bioavailable Combretastatin A4 (CA4). Drug delivery with CA4 LONDs was assessed in a xenograft model of colorectal cancer. LC-MS/MS analysis revealed that CA4 LONDs, administered at a drug dose four times lower than drug control, achieved equivalent concentrations of CA4 intratumorally. We then attached CA4 LONDs to microbubbles (MBs) and targeted this construct to VEGFR2. A reduction in tumor perfusion was observed in CA4 LONDs-MBs treated tumors. A combination study with irinotecan demonstrated a greater reduction in tumor growth and perfusion (P = 0.01) compared to irinotecan alone. This study suggests that LONDs, either alone or attached to targeted MBs, have the potential to significantly enhance tumor-specific hydrophobic drug delivery.<br>The work was funded by the Medical Research Council (grant number: MR/L01629X MRC Medical Bioinformatics Centre) and the EPSRC (grant number EP/P023266/1 Health Impact Partnership). EPSRC (EP/I000623/1, EP/K023845/1). Laura E. McVeigh was funded by an EPSRC PhD Studentship (EP/L504993/1).

M.Tech. (Chiropractic)<br>Myofascial pain syndrome has become a significant cause of chronic pain and disability in today‟s society. Conditions causing chronic pain can not only cause disability due to pain, but can also lead to other problems such as psychological and behavioural disturbances. Physical deconditioning can also occur due to lack of exercise because of myofascial pain (Rachlin, 1994). The aim of this study was to compare dry needling therapy and ultrasound therapy in the treatment of myofascial trigger points in order to demonstrate any superiority between the two modalities. Participants for this study were recruited by word of mouth and advertisements that were placed around the University of Johannesburg Doornfontein Campus. Thirty people participated in the trial, all of whom conformed to the specific inclusion and exclusion criteria. The participants were randomly placed into two groups. Group A received dry needling therapy, namely the fanning technique, and Group B received ultrasound therapy. Participants in Group A received one treatment per week for four weeks and subjective and objective measurements were taken at each visit. Participants in Group B received two treatments per week for three weeks and measurements were taken at visits one, three, five and seven. Subjective data was obtained through the use of the Visual Analogue Pain Scale, which measured the perception of pain of the participants. Objective data was obtained from pressure algometer readings, which measured pain pressure thresholds of participants, and through the Cervical Range Of Motion (CROM) device. The results of this study indicated that dry needling therapy and ultrasound therapy both significantly benefited participants in terms of the treatment of active myofascial trigger points. Based on the final results, both dry needling therapy and ultrasound therapy are equally effective modalities in the treatment of active myofascial trigger points, with neither modality showing superiority over the other.

Thesis (M.Tech.: Chiropractic) - Dept. of Chiropractic, Durban Institute of Technology, 2003 1 v. (various pagings)<br>This study was a prospective, randomised, double blinded, placebo controlled, comparative clinical trial to establish the efficacy of therapeutic ultrasound and compare the effectiveness of the two waveforms of ultrasound in the treatment of myofascial pain syndrome.

M.Tech. (Chiropractic)<br>The aim of the study was to compare the efficacy of treating the active levator scapulae trigger point (TP1) with either chiropractic adjustments combined with ischemic compression or chiropractic adjustments combined with ultrasound therapy in physically active people in order to determine which of the two treatment protocols was superior.This study was a comparative study consisting of two groups of fifteen participants each. Participants were between the ages of eighteen and forty-five and there was an equal male to female ratio. Prior to becoming a participant in this study individuals were assessed according to the inclusion and exclusion criteria. The International Physical Activity Questionnaire, a clinical case history, full physical examination, a cervical regional examination and examination of the levator scapulae muscle for an active central trigger point (TP1) were completed. The method of treatment for each participant was determined by random group allocation. Group 1 received cervical spine chiropractic adjustments combined with ischemic compression to the active levator scapulae trigger point. Group 2 received cervical spine chiropractic adjustments combined with ultrasound therapy to the active levator scapulae trigger point. Subjective and objective readings were based on the above treatment protocols.Treatment consisted of seven consultation sessions over a three week period. There were six treatment visits with the seventh visit used only for data collection. There were two treatments each week with at least two days in between visits. The third week consisted of three visits with the last visit used only for data collection. Subjective data was collected from the Vernon-Mior Neck Pain and Disability Index Questionnaire and the Numerical Pain Rating Scale. Objective data was collected from the pressure algometer readings. Subjective and objective data was collected before treatment on the first and fourth visits and on the seventh final data collection visit. Analysis of the data collected was done by a statistician. The chiropractic adjustments used were based on motion palpation findings on the treatment visits and re-assessed on each visit.Clinically significant improvements regarding neck pain and disability and trigger point severity were seen in both Group 1 and Group 2 over the three week period. Group 2 showed greater improvements in all subjective and objective readings over the three weeks compared to Group 1.

Thesis (M.Tech.: Chiropractic) -Dept. of Chiropractic, Durban Institute of Technology, 2002<br>The purpose of this randomized controlled clinical trial was to investigate the relative effectiveness of proprioceptive neuromuscular facilitation (PNF) versus ultrasound therapy for the treatment of Temporomandibular joint (TMJ) dysfunction caused by masticatory myofascial trigger points, in terms of subjective and objective clinical findings.

碩士<br>國立陽明大學<br>醫學工程研究所<br>98<br>In this study, a novel remote-triggered drug carrier with superparamagnetic characteristic demonstrated a prompt response to the ultrasound with diagnosis frequency (1-3 MHz) and power density (0.2-1 watt/cm2) was successfully synthesized. The remote-triggered drug carrier exhibited a core/shell structure which was prepared via coating a thin layer of magnetic-hydroxyapatite onto liposome (MHA-liposome) through the ammonia decomposition route. The MHA-liposome was characterized by XRD, SQUID and TEM observation. The effects of MHA coating on the background leakage, ultrasound response, and MR signal were investigated. It was found that the core/shell structure could be efficiently triggered by ultrasound with high frequency (1 and 3 MHz). In addition, the inorganic coating layer significantly resisted the background leakage compared to unmodified liposome. These results suggested that the molecules encapsulated in the novel MHA-liposome core/shell structure can be released in a highly controllable manner through the use of ultrasound stimulus. On the other hand, it was found that the ultrasonically triggered vehicle could exhibit T2 contrast in MR images by coating magnetic-HA. Most importantly, the r2* - r2 value of MHA-coated liposome decreased after sonication, suggesting that the proposed vehicle could be used not only as a MR-guided drug vehicle capable of ultrasonically triggered release but also as a MR reporter to probe ultrasonic triggering.

Medical ultrasound imaging is ubiquitous in clinics due to its safety, low cost, portability, and imaging depth. The development of technologies to assist ultrasound in the diagnosis of diseases thus have a potentially broad clinical impact. More recently, photoacoustics has emerged as a complementary, high contrast modality for imaging optical absorption. Injectable dyes and nanoparticles locally amplify ultrasound and photoacoustic signal, helping to identify disease markers and track its progression. We have constructed a dual ultrasound and photoacoustic contrast agent that can be activated using an external optical trigger. In response to pulsed laser irradiation, the particle undergoes a liquid to gas phase change, or vaporization, which emits a strong acoustic wave and results in an echogenic microbubble, simultaneously enhancing contrast for both modalities. We designed and developed several iterations of particles, altering parameters to optimize biocompatibility, cost, and image contrast enhancement, and we then characterized key traits of the particles. Next, we imaged the contrast agents in phantom, ex vivo, and in vivo models to validate the image enhancement, developing image process algorithms to maximize image quality. These optically triggered contrast agents are a valuable tool for minimally invasive, highly specific, early identification of cancer.<br>text

碩士<br>國立清華大學<br>生醫工程與環境科學系<br>103<br>The new ultrasound drug carrier, phase-change droplet (PCD), with liquid perfluorocarbon in lipid shell, and steady in the circulation, was proposed by R. E. Apfel in 1998. PCDs were promising for local drug delivery due to their ability to undergo acoustic droplet vaporization (ADV) under ultrasound excitations. However, no study has investigated the transient dynamics of drug release, since ADV occurred on microsecond scale and drugs were hardly identified in conventional bright field microscopy. Here, we established a high-speed fluorescence imaging system to visualize the process of drug release during ADV. The aim of the study was to find out the way of drug release from PCDs, the distribution of the released drug, the effect between acoustic parameters and release number, and finally the mechanism of drug release from PCDs. Drug release from PCDs must be triggered by acoustic parameter higher than specific level (at least 9 MPa). At the pressures higher than ADV threshold, the shedding drug were observed only on contacted wall between droplets and tube. To figure out the mechanism of drug release from PCDs, the process was captured by high-speed fluorescence imaging system. From quantified images, acoustic pressure had effect on lipid dynamic on bubble shell, which was resulted from directionally converging flow. Moreover, the bright-field images were quantified to verify the effects of the evolution of bubble resulting in converging flow. In summary, the mechanism of drug release from PCDs was that ADV triggered the evolution of bubble, which resulting in converging flow. The flow induced the effect of lipid bending and shedding with drugs. Finally, small PCDs or high pressure induced the high efficiency on either release number or release distance. Through high-speed images, it was proved that the release efficiency was related to evolution of bubble.

碩士<br>國立陽明大學<br>醫學工程研究所<br>101<br>In this research work, the drug carrier alginate liposome composite (ALC) beads capable of being ultrasound triggered and sustained release have been studied. ALC beads were made of two different structures, in which hydrogel was to provide sustained releases and liposome ultrasound responses. The ALC beads were characterized by utilizing fluorescent microscopy, confocal microscopy, transmission electron microscopy (TEM) and multimode micro-plate readers. The effects of ultrasound response and sustained release were investigated. It was found that the proposed composite carrier could sustain release growth factor and could be efficiently and remotely triggered by using therapeutic ultrasound. Furthermore, in vitro / vivo experiments confirmed that the growth factor in ALC beads could still work.

Yes<br>Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2 targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues.<br>EPSRC funding (EP/I000623/1, EP/K023845/1 and EP/P023266/1) and the MRC for a Confidence in Concept award and MR/L01629X. L.E. McVeigh was funded by an EPSRC PhD Studentship (EP/L504993/1).

acase@tulane.edu<br>Introduction: High-Intensity Focused Ultrasound (HIFU) is the only noninvasive method available today for thermal ablation of tumors. HIFU-induced rapid heating and mechanical disruption of tissue, not only has a direct destructive effect on tumors, but also provides a noninvasive way for targeted release of chemotherapeutic drugs from drug delivery vehicles such as temperature sensitive liposomes (SfTSLs). The objective of this work was to evaluate the synergistic treatment of Sorafenib-loaded TSLs (SfTSLs) and HIFU via in vitro analysis of cell viability and proliferation using an aggressive human liver cancer cell line and corresponding in vivo analysis of tumor growth and survival using a human xenograft mouse model. Materials and Methods: Liposomes were developed using 70% Dipalmitoylphosphatidylcholine, 20% L-a-Phosphatidylcholinehydrogenated Soy, and 10% Cholesterol using thin film hydration method to encapsulate Sorafenib at 10μM. Pellets of Hep3B human liver cancer cells (100 μl, 2.7 million cells/ml) were placed in a 0.2 ml thin-wall PCR tube to mimic dense tumor aggregation. Cell pellets were then inoculated with HIFU alone, SfTSLs, or exposed to a combination of HIFU and SfTSLs. The focused ultrasound signal was generated by a 1.1 MHz transducer with acoustic power ranging from 4.1 W to 12.0 W. Cell viability and proliferation experiments were conducted to measure cancer cell damage at 24, 48, 72, and 96 h post treatment via Annexin V/PI and WST-8 staining. In our in vivo study, 1.0×106 Hep3B cells in Matrigel were injected into left and right flanks of athymic nude mice. Tumors were allowed to grow to 8-10 mm size and then separated into the following treatment groups: HIFU alone, SfTSLs (50 μl) alone, SfTSLs + HIFU, and sham. Tumor sizes were measured by caliper every day and a diagnostic ultrasound system was used pre-treatment, 5 days, 14 days, and prior to sacrificing. Tumors were grouped and processed at 5 days, 14 days, or placed in a survival study to evaluate whether treatment facilitated longer lifespans. Tumor tissues were collected for H&E staining and evaluated by a blinded pathologist post euthanasia. Results and Discussion: Our in vitro data indicate that Hep3B cells exposed to both SfTSLs and HIFU have a significantly lower viability and proliferation rate than untreated cells or the cells treated with only SfTSLs or HIFU. According to our in vivo study, tumor growth in the SfTSLs + HIFU group was reduced as compared to Sham, SfTSLs only, or HIFU only groups. Conclusions: The results of our in vitro and in vivo experiments clearly indicate that chemotherapeutic drug-loaded SfTSLs and HIFU can be an effective therapy for locally aggressive liver cancer. This combination treatment leads to more cellular damage, reduction in tumor growth, and better survival.<br>1<br>Gray Halliburton

Submitted in partial compliance with the requirements for the Master’s Degree in Technology: Chiropractic, Durban University of Technology, 2014.<br>Background: Myofascial Pain and Dysfunction (MPD) is a diagnosis commonly encountered by practitioners, hence, there are several treatment approaches employed by various practicing physicians. Practitioners are required to perform evidence-based protocols on patients; however, such intervention becomes increasingly difficult with the increasing volume of evidence available with regards to treatment of MPD. A systematic review provides a well-structured, critical analysis of the available protocols, and as such, provides practitioners with an evidence-based summary of the available modalities and the effectiveness of these modalities. Thus, the aim of the study was to systematically review and evaluate the literature to determine the effects of various non-invasive modalities on MPD. Objectives: Studies investigating various non-invasive modalities were identified, evaluated against the inclusion criteria and then reviewed against PEDro criteria to present current available evidence regarding their effectiveness as a source of treatment for MPD. Methods: A literature search was conducted, based on key terms including: active and latent myofascial trigger points, manual therapy, manipulation, acupressure, massage, muscle stretching, ultrasound, transcutaneous electric nerve stimulation, electric stimulation therapy, magnetic field therapy, and exercise therapy. Databases searched were: PubMed, EBSCOhost, Medline, CINAL, Proquest, Health Source, Sport Discus, Science Direct, Springer Link, Google Scholar and Summons. The articles were screened according to inclusion and exclusion criteria, after which a secondary hand and reference searches were performed. Thereafter, the articles were reviewed by four independent reviewers and the researcher. The PEDro Scale was used to determine methodological rigor of the included studies. The results were then analysed and ranked. Results: Following the screening process during data collection for this study, a total of 25 studies were identified and included. The review and ranking of these studies revealed a moderate level of evidence present for the effectiveness of Topical Agents. A limited level of evidence was noted for TENS, Ischemic Compression, Ultrasound, Laser and Other Modalities. Approximately 25% of the reviewed studies involved combination therapies; hence their outcomes cannot be applied to the effectiveness of individual modalities. Conclusion: Upon comparison of the quality of evidence available for the various types of modalities present for the treatment of MPD, it was noted that Topical Agents were supported by a stronger level of evidence than TENS, Ischeamic Compression, Ultrasound, Laser and Other Modalities. However, due to a lack of strong overall evidence for any of these modalities it has been concluded that more research is required to establish which modality is in fact the most effective.