Patent US6484052B1 successfully refreshed from Google Patents.
US6484052B1
Expired / Lapsed
US
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Optically generated ultrasound for enhanced drug delivery
Assignee: University of California
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Filing: 1999-03-30
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Granted: 2002-11-19
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Expires: 2019-03-30
Abstract
Abstract High frequency acoustic waves, analogous to ultrasound, can enhance the delivery of therapeutic compounds into cells. The compounds delivered may be chemotherapeutic drugs, antibiotics, photodynamic drugs or gene therapies. The therapeutic compounds are administered systemically, or preferably locally to the targeted site. Local delivery can be accomplished through a needle, cannula, or through a variety of vascular catheters, depending on the location of routes of access. To enhance the systemic or local delivery of the therapeutic compounds, high frequency acoustic waves are generated locally near the target site, and preferably near the site of compound administration. The acoustic waves are produced via laser radiation interaction with an absorbing media and can be produced via thermoelastic expansion, thermodynamic vaporization, material ablation, or plasma formation. Acoustic waves have the effect of temporarily permeabilizing the membranes of local cells, increasing the diffusion of the therapeutic compound into the cells, allowing for decreased total body dosages, decreased side effects, and enabling new therapies.
Inventors
- 👤 Steven R. Visuri
- 👤 Heather L. Campbell
- 👤 Luiz Da Silva
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 18:44
CPC Classifications
A; A61; A61M; A61M37/00; A61M37/0092; A61B; A61B18/00; A61B18/18; A61B18/20; A61B18/22; A61B18/26; A61B2018/263; A61M2037/0007
Claims Analysis
Total Claims: 91
Claim 1
Independent Claim
187 words
A method for enhancing drug delivery, comprising: inserting a fiber optic to a drug delivery point within a medium, wherein said fiber optic comprises a proximal end and a distal end, wherein said medium is selected from a group consisting of a portion of a human body and a portion of an animal body; delivering a drug to said drug delivery point; and coupling laser light into said proximal end, wherein said laser light has (i) a pulse frequency within the range of 100 Hz to 1 MHz, (ii) a wavelength within the range of 200 nm to 5000 nm, (iii) a pulse duration within the range of 1 fs to 1 ms and (iv) a-fluence within the range of 0.01 J/cm 2 to 25 J/cm 2 , wherein said laser light emerges from said distal end and generates an acoustic radiation field within said medium, wherein said acoustic radiation field is generated through one or more mechanisms selected from a group consisting of thermoelastic expansion within said medium and superheated vapor expansion within said medium, wherein said acoustic radiation field enhances drug delivery to surrounding cells.
Claim 2
Independent Claim
187 words
A method for enhancing drug delivery, comprising: inserting a fiber optic to a drug delivery point within a medium, wherein said fiber optic comprises a proximal end and a distal end, wherein said medium is selected from a group consisting of a portion of a human body and a portion of an animal body; delivering a drug to said drug delivery point; and coupling laser light into said proximal end, wherein said laser light has (i) a pulse frequency within the range of 100 Hz to 1 MHz, (ii) a wavelength within the range of 200 nm to 5000 nm, (iii) a pulse duration within the range of 1 fs to 1 ms and (iv) a-fluence within the range of 0.01 J/cm 2 to 25 J/cm 2 , wherein said laser light emerges from said distal end and generates an acoustic radiation field within said medium, wherein said acoustic radiation field is generated through one or more mechanisms selected from a group consisting of thermoelastic expansion within said medium and superheated vapor expansion within said medium, wherein said acoustic radiation field enhances drug delivery to surrounding cells.
Claim 3
Independent Claim
101 words
A method for enhancing drug delivery, comprising: inserting a fiber optic to a drug delivery site within a medium, wherein said fiber optic comprises a proximal end and a distal end, wherein said medium is selected from a group consisting of a portion of a hum an body and a portion of an animal body; and delivering a drug to said drug delivery site; and generating an acoustic radiation field with said medium near said drug delivery site by coupling laser light into said proximal end of said fiber optic, wherein said acoustic radiation field enhances drug delivery to surrounding cells.
Claim 4
Independent Claim
101 words
A method for enhancing drug delivery, comprising: inserting a fiber optic to a drug delivery site within a medium, wherein said fiber optic comprises a proximal end and a distal end, wherein said medium is selected from a group consisting of a portion of a hum an body and a portion of an animal body; and delivering a drug to said drug delivery site; and generating an acoustic radiation field with said medium near said drug delivery site by coupling laser light into said proximal end of said fiber optic, wherein said acoustic radiation field enhances drug delivery to surrounding cells.
Claim 5
Dependent Claim
36 words
The method of claim 2 , wherein said acoustic radiation field is generated through at least one mechanism selected from a group consisting of thermoelastic expansion within said medium and superheated vapor expansion within said medium.
Claim 6
Dependent Claim
64 words
The method of claim 3 , wherein said laser light has (i) a pulse frequency within the range of 100 Hz to 1 MHz, (ii) a wavelength within the range of 200 nm to 5000 nm, (iii) a pulse duration within the range of 1 fs to 1 ms and (iii) a-fluence within the range of 0.01 J/cm 2 to 25 J/cm 2 .
Claim 7
Dependent Claim
24 words
The method of claim 2 , wherein said drugs are selected from a group consisting of chemotherapeutic drugs, antibiotics, photodynamic drugs, and gene therapies.
Claim 8
Dependent Claim
22 words
The method of claim 5 , wherein said chemotherapeutic drugs are selected from a group consisting of Taxol, 5-Aminoaleuvenic acid and anthracyclines.
Claim 9
Dependent Claim
21 words
The method of claim 5 , wherein said photodynamic drugs are selected from a group consisting of psoralans and porphyrin derivatives.
Claim 10
Dependent Claim
22 words
The method of claim 5 , wherein said gene therapies are selected from a group consisting of RNA therapies and DNA therapies.
Claim 11
Dependent Claim
23 words
The method of claim 2 , wherein the step of delivering a drug to said drug delivery site includes administering therapeutic compounds systemically.
Claim 12
Dependent Claim
28 words
The method of claim 2 , wherein the step of delivering a drug to said drug delivery site includes administering therapeutic compounds locally to said drug delivery site.
Claim 13
Dependent Claim
43 words
The method of claim 10 , wherein the step of administering therapeutic compounds locally to said drug delivery site is accomplished by delivering a drug through a delivery mechanism selected from a group consisting of a needle, a cannula and a vascular catheter.
Claim 14
Dependent Claim
32 words
The method of claim 10 , wherein the step of administering therapeutic compounds locally to said drug delivery site includes utilizing natural barriers within the vasculature to limit diffusion of said compounds.
Claim 15
Dependent Claim
29 words
The method of claim 10 , wherein the step of administering therapeutic compounds locally to said drug delivery site includes utilizing mechanical barriers to limit diffusion of said compounds.
Claim 16
Dependent Claim
22 words
The method of claim 13 , wherein said mechanical barriers comprise a balloon catheter to dam said drug within a blood vessel.
Claim 17
Dependent Claim
29 words
The method of claim 2 , wherein said acoustic radiation field is generated through at least one mechanism selected from a group consisting of material ablation and plasma formation.
Claim 18
Dependent Claim
40 words
The method of claim 2 , wherein said acoustic radiation field is generated by absorption of laser radiation in at least one medium selected from a group consisting of native tissues, native fluids, applied absorbing dyes and a therapeutic compound.
Claim 19
Dependent Claim
30 words
The method of claim 2 , wherein said acoustic radiation field temporarily, but non-toxically permeabilizes the membranes of local cells, increasing the diffusion of a therapeutic compound into said cells.
Claim 20
Dependent Claim
23 words
The method of claim 2 , wherein said acoustic radiation field comprises a pressure within the range of 0.1 bar to 100 bar.
Claim 21
Dependent Claim
15 words
The method of claim 2 , wherein said fiber optic is located within a catheter.
Claim 22
Dependent Claim
19 words
The method of claim 19 , wherein said drug is delivered through a working channel located within said catheter.
Claim 23
Dependent Claim
81 words
The method of claim 2 , wherein the step of generating an acoustic radiation field acts as a drug delivery enhancer by disrupting the lipid bilayer membrane of cells near said drug delivery site to cause temporary channels to form in the membrane of said cells, wherein said acoustic radiation field transiently disorders said membrane to allow passage of drug molecules through said lipid bilayer, wherein the temporary disruption of a said membrane increases intracellular concentrations or diffusion rates of compounds.
Claim 24
Dependent Claim
16 words
The method of claim 2 , wherein said fiber optic is coupled to a laser system.
Claim 25
Dependent Claim
61 words
The method of claim 2 , wherein said laser light that emerges from said distal end of said fiber optic is absorbed by at least one medium selected from a group consisting of native fluids, such as blood, an exogenous absorber, such as a biological saline solution containing an absorbing dye, and a solid absorber such as a plastic or metal.
Claim 26
Dependent Claim
12 words
The method of claim 23 , wherein said native fluids comprise blood.
Claim 27
Dependent Claim
19 words
The method of claim 23 , wherein said exogenous absorber comprises a biological saline solution containing an absorbing dye.
Claim 28
Dependent Claim
20 words
The method of claim 23 , wherein said solid absorber is selected from a group consisting of plastic and metal.
Claim 29
Dependent Claim
52 words
The method of claim 2 , wherein the step of generating an acoustic radiation field includes producing acoustic waves by a method selected from a group consisting of electrically stimulating piezoelectric material, discharging an electrical current across a spark gap and delivering pulses of electromagnetic energy from a laser into an absorber.
Claim 30
Dependent Claim
36 words
The method of claim 4 , wherein the step of generating an acoustic radiation includes producing acoustic waves by a method selected from a group consisting of plasma formation, material ablation, thermoelastic expansion and thermodynamic vaporization.
Claim 31
Dependent Claim
35 words
The method of claim 4 , wherein the step of generating an acoustic radiation field is accomplished by delivering said laser light to a transducer tip affixed to said distal end of said fiber optic.
Claim 32
Dependent Claim
27 words
The method of claim 29 , wherein said transducer comprises material selected to match the acoustic impedance of said ambient medium for optimal transmission of acoustic energy.
Claim 33
Dependent Claim
23 words
The method of claim 29 , wherein said transducer comprises material selected to produce large impedance mismatches to reflect greater amounts of energy.
Claim 34
Dependent Claim
61 words
The method of claim 4 , wherein the step of generating an acoustic radiation field is accomplished by delivering said laser light through a plurality of fiber optics, wherein each fiber optic of said plurality of fiber optics comprises a distal end, wherein a transducer tip is affixed to each distal end to cover broad areas, within a lumen or organ.
Claim 35
Dependent Claim
22 words
The method of claim 29 , wherein waste heat produced at said distal end is mitigated by duty cycling said laser light.
Claim 36
Dependent Claim
32 words
The method of claim 29 , wherein waste heat produced at said distal end is mitigated by a convective cooling system in which air or fluid flows over or through said transducer.
Claim 37
Dependent Claim
27 words
The method of claim 29 , wherein coolant is pumped from a proximal position through said catheter, to said transducer tip and returned to a reservoir pump.
Claim 38
Dependent Claim
24 words
The method of claim 4 , wherein an absorbing fluid filled optically-powered mechanical transducer is attached to said distal end of said fiber optic.
Claim 39
Dependent Claim
33 words
The method of claim 36 , wherein said absorbing dye filled optically-powered mechanical transducer is a cylinder-shaped diaphragm which expands and contracts with the formation and collapse of bubbles within said absorbing dye.
Claim 40
Dependent Claim
17 words
The method of claim 36 , wherein said absorbing dye filled optically-powered mechanical transducer comprises a bellows.
Claim 41
Dependent Claim
40 words
The method of claim 4 , wherein said drug is located within an optically-powered mechanical transducer which comprises pores, wherein said drug is driven out of said transducer with the increased pressure caused by bubbles produced by said laser light.
Claim 42
Dependent Claim
22 words
The method of claim 2 , further comprising monitoring and controlling the magnitude of said acoustic radiation field with a feedback system.
Claim 43
Dependent Claim
26 words
The method of claim 40 , wherein said feedback system comprises piezoelectric materials in which an electrical signal is generated proportional to said acoustic radiation field.
Claim 44
Dependent Claim
69 words
The method of claim 2 , further comprising illuminating with a continuous wave laser a thin film mounted on said distal end of said fiber optic to produce laser reflections having an amplitude, wherein said thin film comprises an optical pathlength, wherein said acoustic radiation field alters said optical pathlength thereby altering said amplitude of said laser reflections, wherein said method further comprises monitoring said amplitude with a photodetector.
Claim 45
Dependent Claim
25 words
The method of claim 29 , further comprising monitoring the reflections of two surfaces of a thin film mounted at the end of said transducer.
Claim 46
Dependent Claim
30 words
The method of claim 2 , further comprising delivering an echo contrast agent near said drug delivery site, wherein said echo contrast agent further enhances the absorption of said drug.
Claim 47
Dependent Claim
27 words
The method of claim 44 , wherein said echo contrast agent is delivered to said drug delivery site prior the step of generating said acoustic radiation field.
Claim 48
Dependent Claim
27 words
The method of claim 44 , wherein said echo contrast agent is delivered to said drug delivery site during the step of generating said acoustic radiation filed.
Claim 49
Dependent Claim
45 words
The method of claim 19 , further comprising delivering an echo contrast agent near said drug delivery site, wherein said echo contrast agent further enhances the absorption of said drug, wherein said echo contrast agent is delivered through a working channel located within said catheter.
Claim 50
Dependent Claim
40 words
The method of claim 19 , further comprising delivering an echo contrast agent near said drug delivery site, wherein said echo contrast agent further enhances the absorption of said drug, wherein said echo contrast agent is delivered through a needle.
Claim 51
Dependent Claim
26 words
The method of claim 44 , wherein said echo contrast agent is selected from a group consisting of albumin-stabilized microbubbles, stabilized sulfur hexafluoride and galactose/palmitic acid.
Claim 52
Dependent Claim
23 words
The method of claim 44 , wherein said echo contrast agent comprises gas bubbles having a diameter within the range of 0.1-100 μm.
Claim 53
Independent Claim
195 words
An apparatus for enhancing drug delivery, comprising: a fiber optic for insertion into to a drug delivery point within a medium, wherein said fiber optic comprises a proximal end and a distal end, wherein said medium is selected from a group consisting of a portion of a human body and a portion of an animal body; means for delivering a drug to said drug delivery point; and means for coupling laser light into said proximal end, wherein said laser light has (i) a pulse frequency within the range of 100 Hz to 1 MHz, (ii) a wavelength within the range of 200 nm to 5000 nm, (iii) a pulse duration within the range of 1 fs to 1 ms and (iv) an energy density within the range of 0.01 J/cm 2 to 25 J/cm 2 , wherein said laser light emerges from said distal end and generates an acoustic radiation field in said medium, wherein said acoustic radiation field is generated through one or more mechanisms selected from a group consisting of thermoelastic expansion within said medium and superheated vapor expansion within said medium, wherein said acoustic radiation field acts as a drug delivery enhancer.
Claim 54
Independent Claim
195 words
An apparatus for enhancing drug delivery, comprising: a fiber optic for insertion into to a drug delivery point within a medium, wherein said fiber optic comprises a proximal end and a distal end, wherein said medium is selected from a group consisting of a portion of a human body and a portion of an animal body; means for delivering a drug to said drug delivery point; and means for coupling laser light into said proximal end, wherein said laser light has (i) a pulse frequency within the range of 100 Hz to 1 MHz, (ii) a wavelength within the range of 200 nm to 5000 nm, (iii) a pulse duration within the range of 1 fs to 1 ms and (iv) an energy density within the range of 0.01 J/cm 2 to 25 J/cm 2 , wherein said laser light emerges from said distal end and generates an acoustic radiation field in said medium, wherein said acoustic radiation field is generated through one or more mechanisms selected from a group consisting of thermoelastic expansion within said medium and superheated vapor expansion within said medium, wherein said acoustic radiation field acts as a drug delivery enhancer.
Claim 55
Independent Claim
105 words
An apparatus for enhancing drug delivery, comprising: a fiber optic for insertion to a drug delivery site within a medium, wherein said fiber optic comprises a proximal end and a distal end, wherein said medium is selected from a group consisting of a portion of a human body and a portion of an animal body; and means for delivering a drug to said drug delivery site; and means for coupling laser light into said proximal end of said fiber optic for generating an acoustic radiation field within said medium near said drug delivery site, wherein said acoustic radiation field enhances the absorption of said drug.
Claim 56
Independent Claim
105 words
An apparatus for enhancing drug delivery, comprising: a fiber optic for insertion to a drug delivery site within a medium, wherein said fiber optic comprises a proximal end and a distal end, wherein said medium is selected from a group consisting of a portion of a human body and a portion of an animal body; and means for delivering a drug to said drug delivery site; and means for coupling laser light into said proximal end of said fiber optic for generating an acoustic radiation field within said medium near said drug delivery site, wherein said acoustic radiation field enhances the absorption of said drug.
Claim 57
Dependent Claim
66 words
The apparatus of claim 52 , wherein said laser light has (i) a pulse frequency within the range of 100 Hz to 1 MHz, (ii) a wavelength within the range of 200 nm to 5000 nm, (iii) a pulse duration within the range of 1 fs to 1 ms and (iii) an energy density within the range of 0.01 J/cm 2 to 25 J/cm 2 .
Claim 58
Dependent Claim
24 words
The apparatus of claim 52 , wherein said drugs are selected from a group consisting of chemotherapeutic drugs, antibiotics, photodynamic drugs, and gene therapies.
Claim 59
Dependent Claim
22 words
The apparatus of claim 54 , wherein said chemotherapeutic drugs are selected from a group consisting of Taxol, 5-Aminoaleuvenic acid and anthracyclines.
Claim 60
Dependent Claim
21 words
The apparatus of claim 54 , wherein said photodynamic drugs are selected from a group consisting of psoralans and porphyrin derivatives.
Claim 61
Dependent Claim
21 words
The apparatus of claim 54 , wherein said gene therapies are selected from up consisting of RNA therapies and DNA therapies.
Claim 62
Dependent Claim
52 words
The apparatus of claim 52 , wherein said means for delivering a drug to said drug delivery site includes means for administering therapeutic compounds locally to said drug delivery site by delivering a drug through a delivery mechanism selected from a group consisting of a needle, a cannula and a vascular catheter.
Claim 63
Dependent Claim
40 words
The apparatus of claim 52 , wherein said means for delivering a drug to said drug delivery site includes means for administering therapeutic compounds locally to said drug delivery site by utilizing mechanical barriers to limit diffusion of said compounds.
Claim 64
Dependent Claim
22 words
The apparatus of claim 59 , wherein said mechanical barriers comprise a balloon catheter to dam said drug within a blood vessel.
Claim 65
Dependent Claim
36 words
The apparatus of claim 52 , wherein said means for generating an acoustic radiation field comprise means for generating pressure within said medium, wherein said pressure is within a range of 0.1 bar to 100 bar.
Claim 66
Dependent Claim
19 words
The apparatus of claim 52 , further comprising a catheter, wherein said fiber optic is located within said catheter.
Claim 67
Dependent Claim
42 words
The apparatus of claim 62 , further comprising a working channel within said catheter, wherein said working channel may deliver to said drug delivery site at least one deliverable selected from a group consisting of a drug and an echo contrast agent.
Claim 68
Dependent Claim
29 words
The apparatus of claim 53 , wherein said means for generating an acoustic radiation field comprise a laser system, wherein said fiber optic is coupled to said laser system.
Claim 69
Dependent Claim
49 words
The apparatus of claim 53 , further comprising at least one medium selected from a group consisting of native fluids, an exogenous absorber and a solid absorber, wherein said laser light that emerges from said distal end of said fiber optic is absorbed by said at least one medium.
Claim 70
Dependent Claim
12 words
The apparatus of claim 65 , wherein said native fluids comprise blood.
Claim 71
Dependent Claim
22 words
The apparatus of claim 65 , wherein said exogenous absorber comprises a bio-compatible solution, such as saline solution, containing an absorbing dye.
Claim 72
Dependent Claim
20 words
The apparatus of claim 65 , wherein said solid absorber is selected from a group consisting of plastic and metal.
Claim 73
Dependent Claim
29 words
The apparatus of claim 52 , wherein said means for generating an acoustic radiation field comprise means for delivering pulses of electromagnetic energy from a laser into an absorber.
Claim 74
Dependent Claim
42 words
The apparatus of claim 50 , wherein said means for generating an acoustic radiation field include means selected from a group consisting of means for plasma formation, means for material ablation, means for producing thermoelastic expansion and means for producing thermodynamic vaporization.
Claim 75
Dependent Claim
27 words
The apparatus of claim 53 , wherein said means for generating an acoustic radiation field comprise a transducer affixed to said distal end of said fiber optic.
Claim 76
Dependent Claim
27 words
The apparatus of claim 71 , wherein said transducer comprises material selected to match the acoustic impedance of said ambient medium for optimal transmission of acoustic energy.
Claim 77
Dependent Claim
23 words
The apparatus of claim 71 , wherein said transducer comprises material selected to produce large impedance mismatches to reflect greater amounts of energy.
Claim 78
Dependent Claim
54 words
The apparatus of claim 53 , further comprising a plurality of fiber optics, wherein said acoustic radiation field is produced by delivering said laser light through said plurality of fiber optics, wherein each fiber optic of said plurality of fiber optics comprises a distal end, wherein a transducer is affixed to each distal end.
Claim 79
Dependent Claim
13 words
The apparatus of claim 71 , further comprising means for cooling said transducer.
Claim 80
Dependent Claim
41 words
The apparatus of claim 75 , wherein said means for cooling said transducer comprise a convective cooling system, wherein waste heat produced at said distal end is mitigated by said convective cooling system, wherein a coolant removes heat from said transducer.
Claim 81
Dependent Claim
24 words
The apparatus of claim 52 , further comprising an absorbing fluid filled optically-powered mechanical transducer attached to said distal end of said fiber optic.
Claim 82
Dependent Claim
32 words
The apparatus of claim 77 , wherein said absorbing fluid filled optically-powered mechanical transducer is a cylinder-shaped diaphragm which expands and contracts with the formation and collapse of bubbles within said transducer.
Claim 83
Dependent Claim
17 words
The apparatus of claim 77 , wherein said absorbing fluid filled optically-powered mechanical transducer comprises a bellows.
Claim 84
Dependent Claim
36 words
The apparatus of claim 53 , further comprising an optically-powered mechanical transducer which comprises pores, wherein said drug is driven out of said transducer with the increased pressure caused by bubbles produced by said laser light.
Claim 85
Dependent Claim
24 words
The apparatus of claim 52 , further comprising means for monitoring and controlling the magnitude of said acoustic radiation field with a feedback system.
Claim 86
Dependent Claim
26 words
The apparatus of claim 81 , wherein said feedback system comprises piezoelectric materials in which an electrical signal is generated proportional to said acoustic radiation field.
Claim 87
Dependent Claim
40 words
The apparatus of claim 52 , further comprising a thin film mounted at the end of said fiber optic, wherein the reflections of two surfaces of said thin film are monitored to determine the amplitude of said acoustic radiation field.
Claim 88
Dependent Claim
39 words
The apparatus of claim 71 , further comprising a thin film mounted at the end of said transducer, wherein the reflections of two surfaces of said thin film are monitored to determine the amplitude of said acoustic radiation field.
Claim 89
Dependent Claim
31 words
The apparatus of claim 52 , further comprising an echo contrast agent for delivery near said drug delivery site, wherein said echo contrast agent further enhances the absorption of said drug.
Claim 90
Dependent Claim
26 words
The apparatus of claim 85 , wherein said echo contrast agent is selected from a group consisting of albumin-stabilized microbubbles, stabilized sulfur hexafluoride and galactose/palmitic acid.
Claim 91
Dependent Claim
23 words
The apparatus of claim 85 , wherein said echo contrast agent comprises gas bubbles having a diameter within the range of 0.1-100 μm.
References Cited (Backward Citations)
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