Microbubble medical devices

Abstract

Method and medical devices for generating and stabilizing micro or nano bubbles, and systems and methods for therapeutic applications using the bubbles, is provided. Two novel bubble generating means are provided: in-line capillary tubes and mix chambers flow focusing, and cross flow bubble generation with optimized bubble detachment means. A method and medical device to stabilize bubble sizes and improve bubble size homogeneity through rectified diffusion is disclosed. A method and system to facilitate acoustic activation of therapeutic agents using ultrasound energy is provided. Methods, systems, selected additives, and devices to permit therapeutic benefits such as ultrasound-guided precision drug delivery and real-time verification, acoustic activation of large tumour masses while avoiding acoustic shadowing, enhanced acoustic activation through longer retention of therapeutic agents at the point of interest, on demand means to combine inertial and non-inertial acoustic activation in a single treatment, enhancement of high intensity focused ultrasound treatments, light activation of photodynamic drugs at a depth within a patient using extracorporeal light sources, probes, or sonoluminescence, and initiation of time reversal acoustics focused ultrasound to permit highly localized treatment, are provided.

1 . A device for generating bubbles for introduction into a body comprising: a generator syringe having a plunger slidably disposed within the generator syringe, the generator syringe preloaded with a preload of a liquid carrier component and a gas component in a predetermined liquid to gas ratio determined to provide bubbles of preselected size; a generator assembly that connects to the generator syringe; the generator assembly including an in-line flow focusing system having longitudinally spaced and interconnected first, capillary tube and second, mix chamber respectively of comparatively smaller and comparatively larger cross-sections cooperative to provide bubbles as a result of travel of said preload of a liquid carrier component and a gas component in a predetermined liquid and gas ratio through said longitudinally spaced and interconnected first, capillary tube and second, mix chamber respectively of comparatively smaller and comparatively larger cross-sections of said in-line flow focusing system; and said plunger applying a pressure to the generator syringe causing the preload of liquid carrier component and gas component in said predetermined liquid to gas ratio to travel from the generator syringe through the comparatively smaller and comparatively larger capillary tube and mix chamber of said in-line flow focusing system of the generator assembly to an outlet of the generator assembly resulting in said bubbles of said preselected size. 
     
     
         2 . The device according to  claim 1 , further comprising: a second syringe for supplying a second fluid to the generator assembly. 
     
     
         3 . The device according to  claim 1 , wherein the carrier component further comprises one member selected from the group consisting of: a therapeutic agent, a carrier, an additive, a stabilizer, a bioadhesive, a targeted agent, and a combination thereof. 
     
     
         4 . The device according to  claim 3 , wherein the therapeutic agent includes one or more of: a liquid drug, organic or inorganic; a solid drug suspended in a fluid; an acoustically activated drug delivery system, suspended in a fluid; a therapeutic chemical including ethanol or acid; an embolization fluid, gel, or gel suspension; a photodynamic drug; a radioisotope labelled drug or particle; and an imaging system contrast agent for imaging systems including CT scans, MRI, ultrasound, or X-ray. 
     
     
         5 . The device according to  claim 1 , wherein the device is a handheld device. 
     
     
         6 . The device according to  claim 2 , wherein the second fluid is an additional therapeutic agent. 
     
     
         7 . The device according to  claim 6 , further comprising an injection means communicating with the outlet. 
     
     
         8 . The device according to  claim 1 , further comprising means for stabilizing transient bubbles at a desired bubble size comprising: means for directing the bubbles to a stabilizing chamber; and means for transmitting an ultrasonic pulse at the bubbles for a sufficient time period for the bubbles to shrink to and stabilize at a size corresponding to the resonant frequency, or a harmonic, of the ultrasonic pulse. 
     
     
         9 . The device according to  claim 1 , further comprising temperature control means for modulating a temperature of the preload. 
     
     
         10 . The device of according to  claim 1 , further comprising a storage vessel positioned downstream of the generator assembly for receiving the bubbles. 
     
     
         11 . A system for acoustically activating bubbles comprising: a device according to  claim 1 ; and acoustic activation means for generating acoustic pulses; wherein the acoustic activation means is selected from the group consisting of an ultrasound transducer, and a transducer array for transmitting pulses; and wherein acoustic activation of the bubbles induces a member selected from the group consisting of inertial cavitations, non-inertial cavitations, bubble resonance, and bubble destruction and a combination thereof. 
     
     
         12 . A system for enhancing high intensity focussed ultrasound (HIFU) treatment comprising: a device according to  claim 1 ; and HIFU means for generating high intensity focused ultrasound pulses; wherein the HIFU means is selected from the group consisting of a HIFU probe for minimally invasive tumour ablation, an extracorporeal, high intensity ultrasound transducer, and a transducer array for transmitting pulses; wherein the high intensity focused ultrasound means comprises means for focusing the pulses; and wherein the HIFU energy applied to the bubbles induces a member selected from the group consisting of inertial cavitations, non-inertial cavitations, bubble resonance, bubble destruction, and a combination thereof. 
     
     
         13 . A method for acoustically activating bubbles comprising: using a device according to  claim 1  to generate bubbles; introducing the bubbles to a point of interest in a body; and applying acoustic pulses at the bubbles; wherein the acoustic pulses are generated by acoustic activation means, selected from the group consisting of an ultrasound transducer, and a transducer array for transmitting pulses; and wherein the acoustic activation of the bubbles induces a member selected from the group consisting of inertial cavitations, non-inertial cavitations, bubble resonance, bubble destruction, and a combination thereof. 
     
     
         14 . A method for enhancing high intensity focussed ultrasound (HIFU) treatment comprising: using a device according to  claim 1  to generate bubbles; introducing the bubbles to a point of interest in a body, and applying HIFU pulses at the bubbles; wherein the HIFU means is selected from the group consisting of a HIFU probe for minimally invasive tumour ablation, an extracorporeal, high intensity ultrasound transducer, and a transducer array for transmitting pulses; wherein the HIFU means comprises means for focusing the pulses, and wherein the HIFU energy applied to the bubbles induces a member selected from the group consisting of inertial cavitations, non-inertial cavitations, bubble resonance, bubble destruction, and a combination thereof. 
     
     
         15 . A method of treatment of cancers and tumours, including retinoblastoma, esophageal and liver cancers, vascular disease, or neurological disease comprising: using a device according to  claim 1  to generate bubbles; introducing the bubbles to a point of interest in a body; generating acoustic pulses; and applying the acoustic pulses at the bubbles; wherein the acoustic activation means is selected from the group consisting of an ultrasound transducer, and a transducer array for transmitting pulses; and wherein the acoustic activation of the bubbles induces a member selected from the group consisting of inertial cavitations, non-inertial cavitations, bubble resonance, bubble destruction, and a combination thereof. 
     
     
         16 . A method for inducing cell necrosis in diseased tissue comprising: using a device according to  claim 1  to generate bubbles; introducing the bubbles to a point of interest in a body; and applying high intensity focused ultrasound (HIFU) pulses at the bubbles; wherein the high intensity focussed ultrasound is applied using means selected from the group consisting of a HIFU probe for minimally invasive tumour ablation, an extracorporeal, high intensity ultrasound transducer, and a transducer array for transmitting pulses; wherein the pulses are focused using a time reversal acoustics array, and wherein the HIFU pulses applied to the bubbles induces a member selected from the group consisting of inertial cavitations, non-inertial cavitations, bubble resonance, bubble destruction, and a combination thereof. 
     
     
         17 . The device according to  claim 1 , wherein the gas component further comprises one member selected from the group consisting of: air, a perflorocarbon, and a combination thereof.