WO2014031760A1

WO2014031760A1 - System for the treatment of collagen structural abnormalities

Info

Publication number: WO2014031760A1
Application number: PCT/US2013/056012
Authority: WO
Inventors: Blaine SCHNEIDER; James C. KROCAK; Felicity PINO; John E. Ferguson
Original assignee: Regents Of The University Of Minnesota
Priority date: 2012-08-21
Filing date: 2013-08-21
Publication date: 2014-02-27

Abstract

A system for restructuring collagen in tissue includes a transducer including an emitter configured to emit energy proximate the tissue, a therapeutic compound including a collagenase configured to be delivered from a first location relative to the tissue to a second location different than the first location in response to the emitted energy, and a computing device communicatively coupled to the transducer and configured to control the emitter. Devices and methods associated with the system are also contemplated.

Description

SYSTEM FOR THE TREATMENT OF COLLAGEN STRUCTURAL ABNORMALITIES

CLAIM OF PRIORITY

This application claims the benefit of priority under U.S. Provisional Patent Application Serial Number 61/691,658, filed on August 21, 2012, which is herein incorporated by reference in its entirety.

BACKGROUND

Collagen is a naturally occurring protein found in animals and is a major component of flesh and connective tissue. In tissues, collagen frequently functions as a scaffold, or matrix, to preserve shape, structure, and functionality. Over time, however, the collagen matrix in tissues may change, increasing in collagen content, and consequently, reducing tissue compliance or leading to geometric changes. Alterations in tissue compliance include a reduction in vascular compliance, which can indicate arteriosclerosis, along with numerous other age-related vascular conditions. Collagen associated geometric changes can give rise to numerous medical ailments, such as Nerve Entrapment

Syndrome (NES).

Treatment methods for NES can include collagen restructuring to alleviate the underlying problem. Such restructuring is typically artificial, and frequently involves cutting and tissue removal, which can result in a lengthy or painful recovery.

Previous treatments for NES include braces, which help to relieve pressure on the affected nerve by forcing a specific geometric conformation, oral drugs, corticosteroid injections, and surgery. Braces, however, can be inconvenient for the user, due to the restriction they put on mobility, and they generally fail to cure the underlying geometric abnormality that is the ultimate cause of the NES. Drugs, such as aspirin, ibuprofen, and non-steroidal antiinflammatories (NSAIDs), do not generally solve the underlying problem associated with NES. Corticosteroids have associated problems such as pain, infection, shrinking of soft tissue, and loss of color in the skin. Additionally, corticosteroids must be administered at a medical facility, and physicians typically limit the number of injections to 3-4 a year, making corticosteroids a temporary solution while failing to address the underlying cause of the condition. Surgical procedures, such as a release, are frequently associated with substantial morbidity and can involve substantial recovery periods up to 14 weeks.

SUMMARY

The inventors recognize the need for treatment systems, devices, and methods, such as restructuring of collagen abnormalities, which reduce or eliminate the disadvantages described above, including, but not limited to, tissue morbidity, invasive nature of treatment, failure to address the underlying cause of the abnormality, or recovery time. In various embodiments, a system for restructuring collagen in tissue includes a transducer including an emitter configured to emit energy proximate the tissue; a therapeutic compound including a collagenase configured to be delivered from a first location relative to the tissue to a second location different than the first location in response to the emitted energy; and a computing device communicatively coupled to the transducer and configured to control the emitter.

The present inventors have also recognized a non-invasive collagen treatment sysem is needed. The present disclosure includes a system, device, and method without incisions to treat the patient. This reduces recovery time, scaring, and tenderness following the procedure, allowing the patient to return to work and normal life more quickly.

The present inventors have also recognzied that a means of more accurately targeting collagen structures of interest is needed. Systems described herein reduce the risk of damage to surrounding tissue such that recovery time reduced. Additionally, the disclosed method may utilize therapies that modulate cellular properties without invoking an inflamatory response. Therefore, inflamation due to the treatment itself may be reduced which may improve recovery time. The systems, devices, and methods described herein can be used to relieve, treat, or cure the symptoms or consequences relating to nerve entrapment syndrome (NES), Peyronie's disease, Dupuytren's contracture, uterine fibroids, cosmetic skin conditions, or any other condition that can be treated by targeting collagen containing structures, wherein said emitted energy modifies or manipulates said tissue through the application of a therapeutic compound including collagenase.

BRIEF DESCRIPTION OF THE DRAWING

In the drawings, which are not necessarily drawn to scale, like numerals may describe similar components in different views. Like numerals having different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

FIG. 1 is a perspective view of a system for restructuring collagen, in accordance with at least one embodiment of the present disclosure;

FIG. 2 is a partial cut-away of a transducer, in accordance with at least one embodiment of the present disclosure;

FIG. 3A is a perspective view of a transducer including a linear array of emitters, in accordance with at least one embodiment of the present disclosure;

FIG. 3B is a bottom surface of the transducer illustrated in FIG. 3A including a cartridge, in accordance with at least one embodiment of the present disclosure;

FIG. 4A is a perspective view of a transducer including a non- linear array of emitters, in accordance with at least one embodiment of the present disclosure;

FIG. 4B is a bottom surface of the transducer illustrated in FIG. 4A including a cartridge, in accordance with at least one embodiment of the present disclosure;

FIG. 5A is a perspective view of a substantially cylindrical transducer, in accordance with at least one embodiment of the present disclosure; FIG. 5B is a perspective view of an interior surface of the transducer illustrated in FIG. 5 A including a cartridge, in accordance with at least one embodiment of the present disclosure;

FIG. 6 is a perspective view of a system for restructuring collagen, in accordance with at least one embodiment of the present disclosure;

FIG. 7 is a perspective view of a transducer in a first mode, in accordance with at least one embodiment of the present disclosure;

FIGS. 8A-C are transducers in a second mode, in accordance with at least one embodiment of the present disclosure; and

FIG. 9 is an exemplary method for restructuring collagen in tissue, in accordance with at least one embodiment of the present disclosure.

DETAILED DESCRIPTION

In the following detailed description, reference is made to the accompanying drawings that form a part hereof, and in which is shown by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that other

embodiments may be utilized. It is also to be understood that structural, procedural, chemical and system changes may be made without departing from the spirit and scope of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present invention is defined by the appended claims and their equivalents. Collagen Abnormalities

In addition to NES, the present inventors have recognized a variety of collagen disorders that can be addressed by the present invention. For example, NESs can include carpal tunnel syndrome (CTS), Anterior Interosseous

Syndrome, Sciatica, Bulged or Herniated Disc, Pronator Syndrome, Cubital Tunnel Syndrome, Guyon's Canal, Radial Tunnel Syndrome, Posterior

Interosseous Syndrome, Wartenberg' s Syndrome (Cheiralgia Paresthetica), De Quervain's Disease, Tarsal Tunnel Syndrome, and Morton's Entrapment (Neuroma).

In various embodiments, the present systems, devices, and methods can treat Peyronie's disease, Dupuytren' s Contracture, keloid, nephrogenic systemic fibrosis, scleroderma, systemic sclerosis, cellulite, uterine fibroids, hammer toe, etc. Each of these disorders suffers from similar challenges - namely ineffective drugs and excessive recovery time and/or scarring associated with surgical options. Collagenase

As used herein, collagenase, such as collagenase Clostridium

histolyticum, is part of a class of proteolytic enzymes that can catalyze the hydrolysis of collagen by weakening or breaking its peptide bonds. Treatment with collagenase according to the systems, devices, and methods described herein can cause collagenous tissue to weaken, stretch, relax, or break, while leaveing other tissue, such as nervous tissue, relatively unaffected.

Previous approaches for use of collagenase, such as injections, are limited by the area in which they can treat. For example, certain NESs, such as CTS, can have a relatively large affected area, as compared to the narrow, collagen-rich chords in Dupytren' s Contracture. Consequently, injections poorly serve this patient base or at least complicate the medical procedure, as several injections would be needed that would have to continously cover the affected area. Additionally, the penetration depth of the delivery needles will dictate which tissue is ultimately affected. Further, injection for certain conditions, such as Peyronie' s disease, are complicated due to uncomfortable nature of multiple injections in the penis, the injections can be painful and inaccurate in targeting the built up collagen.

Figure 1 is a perspective view of a system 10 for restructuring collagen in tissue. As described herein, restructuring can include at least one of cell death, ablation, stretching, elongation, weakening, cutting, tearing, tissue remodeling, tissue modulation, softening, and/or modification of permeability and other physical attributes, such as tensile strength, compliance, elasticity, electrical properties, rheological properties. The system 10 can be configured to restructure the collagen in a minimally invasive way, such as by sonophoresis, sonoporation, irreversible sonoporation, electroporation, irreversible electroporation, high intensity focused ultrasound (HIFU), ultrasound, thermal warming, radio frequency, micro-needle application, or laser therapy. The system 10 can include a transducer 16 including an emitter configured to emit energy 18 proximate the tissue 26. The energy 18 can include at least one of acoustic, electrical, thermal, electromagnetic, optical, chemical, or mechanical energy.

In various embodiments, the transducer 16 can be configured to be be held, set on a table top, stand-alone, attached to a garment, or a combination thereof. As illustrated in Figure 1, the transducer 16 is configured to be held in hand and placed proximate, such as adjacent, touching, above, or below, the tissue 26. As shown, a hand 20 can be placed on a table 21 and stabilized, such as by a strap 22. Although the hand 20 is illustrated with the palm side on the table 21, embodiments are not so limited. For example, the therapeutic compound 24 can be applied to the palm of hand 20 when it is strapped to the table 21 such that the back of the hand on the table 21. That is, the hand 20 can be orientated in any direction suitable to provide a path for the energy 18 to target the tissue 26. Such embodiments, provide the benefit of reducing the chances of a patient moving during restructuring of the collagen in the tissue 26 and potentially inccuring adverse affects. As shown in Figure 1, and discussed herein, the tissue 26 can include a transverse carpal ligament (TCL), such as in the treatment of CTS.

The system 10 can include a therapeutic compound 24 including a collagenase configured to be delivered from a first location 11 relative to the tissue to a second location 15 different than the first location in response to the emitted energy 18. The first location 11 can include a location proximate the tissue, such as on top of the skin, adjacent the tissue, below the tissue, or above the tissue. The second location 15 can include a location within the tissue, such as a location including the collagen structural abnormality. The therapeutic compound 24 can include at least one of a solid, a liquid, a gel, a lotion, an aqueous solution, a cream, an oitment, a micro-particle, a microsphere, a nanoparticle, and a liposomal encasulation. As shown in Figure 1, the therapeutic compound 24 is a topoical treatment, but embodiments are not so limited.

In various embodiments, the system can be used as a diagnostic device when the therapeutic agent is not present, such as determining tissue characteristics, and as a therapeutic device when the agent is present, such as delivering the agent to the targeted tissue. This system may include diagnostic, pre-treatment, therapeutic, and post-treatment capabilities and may remain as separate components or combined.

Figure 2 is a partial cut-away of a transducer 16, in accordance with at least one embodiment of the present disclosure. As shown, the system 10 can include a computing device 12 communicatively coupled, such as wirelessly coupled, to the transducer 16 and configured to control at least one emitter 32. In such an embodiment, the transducer 16 can be battery powered. Further, as shown in Figure 1, the transducer 16 can be communicatively coupled to the computing device 12 by a wire 14, which can provide power to the transducer 16. The computing device 12 can be configured to modify a transducer parameter including, but not limited to, duty cycle, amplitude, duration, power delivery, and frequency. In various embodiments, the computer can be configured to modify the transducer parameter to deliver the collagenase to a predetermined depth of the tissue. As shown in Figure 2, the transducer 16 is targeting a tissue of the hand 20 placed atop the table 21 and held by the strap 22.

The system can include a cartridge 34 including the therapeutic compound. In such embodiments, the transducer 16 can include a cartridge holder 28 on a surface of the transducer configured to retain the cartridge 34 proximate the emitter 32, such as in a position to be at least partially disposed between the emitter 32 and the tissue. The energy 18 can be emitted from the emitter 32 through the cartridge 34 and directed toward the tissue. That is, the energy 18 can be applied to the cartridge including the therapeutic compound. In various embodiments the system can include an

activation/deactivation compound 35. Although the activation/deactivation compound is shown as a topical treatment, embodiments are not so limited. In an embodiment, the cartridge 34 can include the activation/deactivation compound 35. The activation/deactivation compound 35 can be configured to deactivate the collagenase after the collagenase is delivered to the predetermined depth of the tissue. For example, when the activation/deactivation compound 35 is used as a deactivation mechanism, it can be applied following delivery of the collagenase via sonophoresis, such that the deactivation compound 35 can penetrate to the tissue to the predetermined depth without penetrating further. The deactivation compound 35 can include deactivation compound includes at least one of a chelating agent, β-mercaptoehtanol, cysteine, 8-hydroxyquinoline- 5 -sulfonate.

Figure 3A is a perspective view of a transducer 16 including a linear array of emitters 32. The transducer 16 can include a cartridge holder 28, such that a cartridge can be retained proximate the linear array of emitters 32. For example, the emitter or linear array of emitters 32 can be on a surface 30A configured for a particular application, such as a particular tissue. In various embodiments, the emitter 32 can include a single emitter spanning substantially a length of the surface 30A. Each of the emitters 32 can be capable of delivering the energy 18 to the targeted tissue. Further, each emitter 32 can, for example, unit can be controlled independently, such as by a computing device 12.

As shown in Figure 3B, the cartridge 34 can include a plurality of pores 36 configured to permit passage of the collagenase from the cartridge 34 to the second location, such as the tissue. The cartridge 34 can be retained, such as by a snap fit or press fit, proximate the array of emitters 32 by the cartridge holder 28. As shown by the arrow in Figure 3B, the cartridge 34 can be positioned and retained on the transducer 16, such as transducer surface 30 A, by the cartridge holder 28. In various embodiments, the transducer 16 can include more than one linear array of emitters 32 so as to form a grid pattern of arrays. The transducer 16, when positioned over the targeted tissue and when activated, can drive the collagenase to the targeted tissue by sonophoresis.

Figure 4A is a perspective view of a transducer 16 including a non- linear, for instance a circular array, of emitters 32, such as on a surface 30B of the transducer 16. Each of the emitters 32 can be capable of delivering the energy 18 to the targeted tissue. Further, each emitter 32 can, for example, be controlled independently, such as by a computing device 12. As described herein, the transmitter 16 can include a cartridge holder 28 configured to retain a cartridge, such as cartridge 34 illustrated in Figure 4B. The cartridge holder can, for example, flex so as to compression fit, clip, snap fit, or press fit, the cartridge 34 to the surface 30B. As shown by the arrow in Figure 4B, the cartridge 34 can be positioned and retained on the transducer 16, such as transducer surface 30B, by the cartridge holder 28. Although Figure 4B illustrates cartridge 34 with pores 36, embodiments are not so limited. In an example, the transducer 16 can include a single emitter 32 configured to substantially cover surface 30B.

Figure 5A illustrates a substantially cylindrical transducer^, such that the transducer 16 can be positioned over an arm, leg, penis, finger, ankle, toe, or other appendage of a patient. The transducer 16 can include an interior surface 38 including at least one emitter 32. In various embodiments, the emitter 32 can substantially cover inner surface 38. The transducer 16 can include, for example, an array of emitters 32. Each emitter 32 can, for example, be controlled independently, such as by a computing device 12. The transducer 16 can, as discussed herein, include a cartridge holder 28 configured to retain a cartridge, such cartridge 34 of Figure 5B. In various embodiments, the cartridge 34 can include pores 36. As shown by the arrow, cartridge 34 can be positioned and retained within the transducer 16. For example, the transducer 16 and cartridge 34 can form concentric circle cross sections, such that the cartridge 34 can be nested at least partially within the transducer 16. That is, an outer diameter of the cartridge can be less than an inner diameter of the transducer 16. Further, the array of emitters 32 can be configured to emit energy 18 toward a central axis A of the transducer 16. Each of the emitters 32 can be capable of delivering the energy 18 to the targeted tissue. For example, the transducer 16 can utilize "triangulation" of the energy 18 in order to specifically target a particular tissue or tissue component. The ability to triangulate can assist in bypassing or avoiding activation energy or compound delivery to tissue not targeted; specified positioning of energy delivery can enable minimizing energy or compound exposure of non-targeted surrounding tissue. The array of emitters 32 can, in an example, be configured to emit the energy 18 toward a

predetermined location disposed, such as the second location or the targeted tissue, within the semi-cylindrical transducer 16. In an example, the transducer 16 can include an air pressurized cuff, similar to a blood pressure cuff, in order to restrain the body part that contains the target tissue.

Figure 6 illustrates a system 60 for restructuring collagen tissue. The system can include a transducer, including an emitter 32, configured to be affixed to a garment 40 and configured to be placed at least proximate the tissue. As shown, the garment 40 in Figure 6 includes a brace, configured to restrict movement of the wrist or hand 20. In various embodiments, the garment 40 can include a glove, a sleeve, a sheath, a splint, a boot, among others. For example, a glove can be used to treat collagen abnormalities such as Dupuytren' s

Contracture, so as to focus on cords of collagenous plaque located around the fingers of the hand. A sheath can, in an example, be used to treat collagen abnormalities such as Peyronie's Disease, so as to fit on a penis and proximate collagenous plaque. In an example, the system 10 can include a computer 42 affixed to the garment 40, however embodiments are not so limited. That is, the computer can be a standalone unit communicatively coupled to the transducer via a wire or wirelessly. The computer 42 can be communicatively coupled via 43 to at least one emitter 32.

As shown in Figure 6, an array of emitters 32 can be located proximate the target tissue, such as a tissue in the hand 20. The computer 42 can be configured to determine a path 33 along the array of emitters 32 based on diagnosis of the tissue. For example, the computer 42 can utilize the array of emitters, such as by emitting low frequency energy waves, to diagnose the target tissue, a cartridge 34, including the therapeutic compound, can be inserted below the array of emitters 32 by slot 44, which provides access to a cavity 46 within the garment 40. In various embodiments, the cartridge 34 can include pores 36 to aid in delivery of the collagenase.

Figure 7 illustrates a transducer 50A in a first mode configured for uterine application. For example, the therapeutic compound 24, including collagenase, can be applied directly to a surface of the uterus 47, such as where a fibroid 48 is present. The transducer 50A is illustrated in first configuration, such as a collapsed configuration, so as to be capable of insertion in the uterus 47, or a lumen of a tube to be inserted in the uterus 47. Figures 8A-C show the transducer in various deployed configurations 50B, 50C, and 50D. For example, 50B can be described as a tear drop configuration, 50 C can be described as a V- configuration, and 50D can be described as an umbrella configuration. In each configuration 50B-D, the transducer include an emitter 32 configured to emit energy toward at least the collagenase 24. In various embodiments, the transducer 50A does not deploy into a second configuration, rather it remains in the first mode. For example, the transducer 50A can include a straight transducer with at least one emitter configured to emit energy toward the therapeutic compound.

Method of Restructuring Collagen

The present subject matter includes methods for restructuring collagen, such as delivering collagenase for treatment of various collagen structural abnormalities by implementing sonophoresis, phonophoresis, or acoustic waves. Moreover, specific device embodiments are described for treatment of specific diseases.

An exemplary method 90 is shown in Figure 9. At, 92 a therapeutic compound is placed proximate a tissue having a collagen structural abnormality, such as Dupuytren's Contracture, Peyronie's disease, and Nerve Entrapment Syndrome (NES), including Carpal Tunnel Syndrome (CTS), Anterior

Interosseous Syndrome, Pronator Syndrome, Cubital Tunnel Syndrome, Guyon's Canal, Radial Tunnel Syndrome, Posterior Interosseous Syndrome, Wartenber' s Syndrome, De Quervain's Disease, Tarsal Tunnel Syndrome, and Morton's Entrapment. Tissue can include ligament, tendon, muscle, fascia, bone, tumor, soft tissue, connective tissue, skin, dermis, cutaneous tissue, subcutaneous tissue, vessels, plaques, and organ tissue. As described herein, the thereapeutic compound can include collagenase. The therapeutic compound can include at least one of solid, a liquid, a gel, a lotion, an aqueous solution, a cream, an ointment, a micro-particle, a microsphere, a nanoparticle, and a liposomal encapsulation. For example, placing the therapeutic compound 92 can include rubbing an ointment on the skin of a patient proximate the tissue. In another example, placing the therapeutic compound 92 can include snap or press fitting a cartridge into a transducer, such that when the transducer is placed proximate the skin of the patient, the cartridge is also proximate the tissue, as illustrated and discussed in connection with the system.

In an example, the method 90 can further include identifying the tissue to be treated. For example, if the patient is suffering from CTS, the TCL can be identified. Further, the method can include determining a characteristic of the identified tissue, including at least one of depth of the tissue, length of the tissue, and width of the tissue. Determining the characteristic can include a technique such as ultrasound, magnetic resonance imaging (MRI), Doppler velocimetry, thermal mapping, electrical mapping, resistance gradient mapping, or optical. Identifying the tissue can further include pretreating the identified tissue with acoustic, thermal, chemical, mechanical, or optical means. For example, the transducer can be placed proximate, such as at or near, surface of the tissue of interest. A prompt can be initiated, such as through the computer, to use ultrasound to map and record the location of the tissue.

In order to reduce the potential risk of damage to local nerves, line of fire tissues, or major blood vessels, the method 90 can include means for identifying such structures. For instance, the method can utilize a prompt for low level electrical impulses or acoustic signals to determine the location of nerves running through the targeted area including the tissue. A map of electrodes can be placed on the patient's skin, over the area to be treated. By determining which electrodes on this map lie proximate the nerve (as can be determined by the lowest amplitudes to elicit a neural response), the path of the nerve may be determined and avoided. At 94 an emitter can be aligned with the therapeutic compound, such as by placing the emitter above, on, below, or proximate the therapeutic compound. At 96, energy from the emitter can be applied to the therapeutic compound to deliver 98 the therapeutic compound to the tissue, such as by sonophoresis, sonoporation, irreversible sonoporation, electroporation, irreversible

electroporation, ultrasound, including high intensity focused ultrasound, thermal warming, radio frequency, micro-needle application, and laser therapy. In an embodiment, the method includes sonophoresis, such as where energy includes sound waves, including low-frequency ultrasound, to increase permeability of skin to allow for fast, targeted, or painless delivery of collagenase through the skin. Sonophoresis, phonophoresis, or ultrasound methods can increase untreated skin's permeability by 3000-5000 times, through one or more process, such as cavitation, micro streaming, and heating. In various embodiments, the application 96 of energy can be synchronized with specific emitters to enhance tissue permeability.

The depth of energy penetration can be controlled by varying the frequency, intensity, or duration of the ultrasound waves. In addition to rapid delivery, depth control, and being painless, sonophoresis avoids the

gastrointestinal system, such that collaganease can be given in lower doses, reducing systemic side-effects.

Sonophoresis can topically delivery macromolecules, such as collagenase to underlying tissue. For example, collagenase can include a mixture of enzymes that have a molecular weight of approximately 115 kiloDaltons (KDa). In an example, the method can include sonophoresis parameters with a duty cycle of about 0 % to about 80 %, power delivery of about 10 mW/cm2 to about 3 W/cm2, or frequency of about 20 kHz to about 2.4 MHz.

Delivering the therapeutic compound to the tissue can include treating the abnormality of the tissue, such as by cell death, ablation, stretching, elongation, weakening, cutting, tearing, remodeling, softening, and modification of a physical attribute of the tissue, including permeability, tensile strength, compliance, elasticity, an electrical property, and a rheological property. In various embodiments, the method can include applying an activation or deactivation compound. For example, an activation compound can be applied to a therapeutic compound including a deactivated collagenase. In an example, a deactivation compound can be applied to neutralize or cease the effects of the collagenase on the tissue.

By way of illustration and not limitation a method for treating NES is now described. Such an embodiment can modulate the ligament that is restricting tissue expansion and causing increased neural pressure. Treatment will therefore alleviate pressure on the entrapped nerve by allowing the tissue surrounding the nerve to expand. This will reduce the pressure on the nerve and, in turn, relieve entrapment symptoms. In the instance of CTS, this method may be used to modulate the transverse carpal ligament to reduce the pressures on the median nerve.

In order to reduce the risk of damage to local nerves or major blood vessels, the disclosed device may also incorporate means for identifying such structures. For instance, the device may utilize low level electrical impulses in order to determine the location of major nerves running through the targeted area. A map of electrodes could be placed on the patient's skin, over the area to be treated. By determining which electrodes on this map lie most near the nerve (as can be determined by the lowest amplitudes to elicit a neural response), the path of the nerve may be determined and avoided.

Similarly, the major vessels in the area may be localized by utilizing ultrasound, optical, Doppler velocimetry, thermal, or other means. Again, if the vessels can be mapped by the device, they can be avoided during the procedure and therefore reduce the risk of injury to the patient.

Treatment from the device will therefore alleviate pressure on the entrapped nerve by allowing the tissue surrounding the nerve to expand. This will reduce the pressure on the nerve and, in turn, relieve entrapment symptoms. In the instance of CTS, this device may be used to modulate the transverse carpal ligament to reduce the pressures on the median nerve.

Various Notes & Embodiments The present invention provides for the following exemplary

embodiments, the number of which is not to be construed as designating levels of importance:

Embodiment 1 provides a system for restructuring collagen in tissue, comprising: a transducer including an emitter configured to emit energy proximate the tissue; a therapeutic compound including a collagenase configured to be delivered from a first location relative to the tissue to a second location different than the first location in response to the emitted energy; and a computing device communicatively coupled to the transducer and configured to control the emitter.

Embodiment 2 provides the system of Embodiment 1, wherein the computing device is configured to modify a transducer parameter including at least one of duty cycle, amplitude, duration, power delivery, and frequency.

Embodiment 3 provides the system of at least one of or any combination of Embodiments 1-2, wherein the computer is configured to modify the transducer parameter to deliver the collagenase to a predetermined depth of the tissue.

Embodiment 4 provides the system of at least one of or any combination of Embodiments 1-3, further comprising a deactivation compound configured to deactivate the collagenase after the collagenase is delivered to the predetermined depth of the tissue.

Embodiment 5 provides the system of at least one of or any combination of Embodiments 1-4, wherein the deactivation compound includes at least one of a chelating agent, β-mercaptoehtanol, cysteine, 8-hydroxyquinoline-5 -sulfonate.

Embodiment 6 provides the system of at least one of or any combination of Embodiments 1-5, wherein the emitter is configured to emit low level electrical impulses to produce a nerve map.

Embodiment 7 provides the system of at least one of or any combination of Embodiments 1-6, wherein the computer is configured to control the emitter based on the nerve map indicating nerves proximate the tissue.

Embodiment 8 provides the system of at least one of or any combination of Embodiments 1-7, further comprising: a cartridge including the therapeutic compound; and a cartridge holder on a surface of the transducer configured to retain the cartridge proximate the emitter.

Embodiment 9 provides the system of at least one of or any combination of Embodiments 1-8, wherein the cartridge includes a plurality of pores configured to permit passage of the collagenase from the cartridge to the second location.

Embodiment 10 provides the system of at least one of or any

combination of Embodiments 1-9, further comprising an activation compound at the first location configured to activate the collagenase.

Embodiment 11 provides the system of at least one of or any

combination of Embodiments 1-10, wherein the therapeutic compound includes at least one of solid, a liquid, a gel, a lotion, an aqueous solution, a cream, an ointment, a micro-particle, a microsphere, a nanoparticle, and a liposomal encapsulation.

Embodiment 12 provides the system of at least one of or any

combination of Embodiments 1-11, wherein the emitted energy is acoustic energy.

Embodiment 13 provides the system of at least one of or any

combination of Embodiments 1-12, wherein the emitter is configured to deliver the collagenase by sonophoresis.

Embodiment 14 provides the system of at least one of or any

combination of Embodiments 1-13, wherein the system is configured to weaken the tissue.

Embodiment 15 provides the system of at least one of or any

combination of Embodiments 1-14, further comprising an array of emitters.

Embodiment 16 provides the system of at least one of or any

combination of Embodiments 1-15, wherein the array of emitters is a linear array or a circular array.

Embodiment 17 provides the system of at least one of or any

combination of Embodiments 1-16, wherein the transducer is configured to be held in hand and placed proximate the first location under guidance of the hand. Embodiment 18 provides the system of at least one of or any combination of Embodiments 1-17, wherein the transducer is affixed to a garment and configured to be placed at least proximate the tissue.

Embodiment 19 provides the system of at least one of or any combination of Embodiments 1-18, wherein the transducer is has a semi- cylindrical form having a central axis and the emitter is configured to emit the energy in a direction toward the central axis.

Embodiment 20 provides the system of at least one of or any combination of Embodiments 1-19, further comprising an array of emitters configured to emit the energy toward a predetermined location disposed within the semi-cylindrical transducer.

Embodiment 21 provides the system of at least one of or any combination of Embodiments 1-20, wherein the predetermined location includes the second location.

Embodiment 22 provides the system of at least one of or any combination of Embodiments 1-21, wherein the transducer includes a glove.

Embodiment 23 provides the system of at least one of or any combination of Embodiments 1-22, wherein the computer is mounted to the glove.

Embodiment 24 provides the system of at least one of or any combination of Embodiments 1-23, wherein the transducer includes a brace.

Embodiment 25 provides the system of at least one of or any combination of Embodiments 1-24, wherein the computer is configured to determine a path along the array of emitters based on diagnoses of the tissue, wherein the path is configured to bypass at least one nerve.

Embodiment 26 provides the system of at least one of or any combination of Embodiments 1-25, wherein the determined path is based on a patient's anatomy.

Embodiment 27 provides the system of at least one of or any combination of Embodiments 1-26, wherein the transducer is configured to power emitters along the path so as to emit the energy along the path. Embodiment 28 provides the system of at least one of or any combination of Embodiments 1-27, wherein the transducer is configured in a first mode for at least partial insertion into a patient.

Embodiment 29 provides the system of at least one of or any combination of Embodiments 1-28, wherein the transducer is configured in a second mode including a deployed configuration.

Embodiment 30 provides the system of at least one of or any combination of Embodiments 1-29, wherein the deployed configuration is a v- bend, a tear drop shape, or an umbrella shape.

Embodiment 31 provides the system of at least one of or any combination of Embodiments 1-30, wherein the system is configured to restructure the collagen associated with Nerve Entrapment Syndrome (NES).

Embodiment 32 provides a method for treating a collagen structural abnormality comprising placing a therapeutic compound including collagenase proximate a tissue, aligning an emitter with the therapeutic compound, applying energy from the emitter to the therapeutic compound, and delivering the therapeutic compound to the tissue.

Embodiment 33 provides the method of Embodiment 32, further comprising sensing a depth of penetration of the collagenase.

Embodiment 34 provides the method of at least one of or any combination of Embodiments 32-33, further comprising determining a therapeutic parameter, including at least one of duration, amplitude, and frequency, by a feedback loop.

Embodiment 35 provides the method of at least one of or any combination of Embodiments 32-34, further comprising deactivating the collagenase with a deactivating compound.

Embodiment 36 provides the method of at least one of or any combination of Embodiments 32-35, further comprising delivering the deactivating compound to at least a depth of the collagenase.

Embodiment 37 provides the method of at least one of or any combination of Embodiments 32-36, further comprising activating the collagenase with an activating compound, wherein the collagenase is a deactivated collagenase.

Embodiment 38 provides the method of at least one of or any combination of Embodiments 32-37, further comprising post-treating the tissue with at least one of acoustic energy, thermal energy, chemical energy, mechanical energy, optical energy, a collagenase neutralizing agent, and an antibiotic agent.

Embodiment 39 includes a method or system of at least one of or any combination of Embodiments 1-38.

The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention can be practiced. These embodiments are also referred to herein as "examples." Such examples can include elements in addition to those shown or described.

However, the present inventors also contemplate examples in which only those elements shown or described are provided. Moreover, the present inventors also contemplate examples using any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof), or with respect to other examples (or one or more aspects thereof) shown or described herein.

In the event of inconsistent usages between this document and any documents so incorporated by reference, the usage in this document controls.

In this document, the terms "a" or "an" are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of "at least one" or "one or more." In this document, the term "or" is used to refer to a nonexclusive or, such that "A or B" includes "A but not B," "B but not A," and "A and B," unless otherwise indicated. In this document, the terms "including" and "in which" are used as the plain-English equivalents of the respective terms "comprising" and "wherein." Also, in the following claims, the terms "including" and "comprising" are open-ended, that is, a system, device, article, composition, formulation, or process that includes elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim. Moreover, in the following claims, the terms "first," "second," and "third," etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.

Method examples described herein can be machine or computer- implemented at least in part. Some examples can include a computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device to perform methods as described in the above examples. An implementation of such methods can include code, such as microcode, assembly language code, a higher- level language code, or the like. Such code can include computer readable instructions for performing various methods. The code may form portions of computer program products. Further, in an example, the code can be tangibly stored on one or more volatile, non- transitory, or non- volatile tangible computer-readable media, such as during execution or at other times. Examples of these tangible computer-readable media can include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random access memories (RAMs), read only memories (ROMs), and the like.

The above description is intended to be illustrative, and not restrictive.

For example, the above-described examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments can be used, such as by one of ordinary skill in the art upon reviewing the above description. The Abstract is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features may be grouped together to streamline the disclosure. This should not be interpreted as intending that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the Detailed Description as examples or embodiments, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments can be combined with each other in various combinations or permutations.

Claims

What is claimed is:

1. A system for restructuring collagen in tissue, comprising:

a transducer including an emitter configured to emit energy proximate the tissue;

a therapeutic compound including a coUagenase configured to be delivered from a first location relative to the tissue to a second location different than the first location in response to the emitted energy; and

a computing device communicatively coupled to the transducer and configured to control the emitter.

2. The system of claim 1, wherein the computing device is configured to modify a transducer parameter including at least one of duty cycle, amplitude, duration, power delivery, and frequency.

3. The system of claim 2, wherein the computer is configured to modify the transducer parameter to deliver the coUagenase to a predetermined depth of the tissue.

4. The system of claim 3, further comprising a deactivation compound configured to deactivate the coUagenase after the coUagenase is delivered to the predetermined depth of the tissue.

5. The system of claim 4, wherein the deactivation compound includes at least one of a chelating agent, β-mercaptoehtanol, cysteine, 8-hydroxyquinoline- 5 -sulfonate.

6. The system of claim 3, wherein the emitter is configured to emit low level electrical impulses to produce a nerve map.

7. The system of claim 6, wherein the computer is configured to control the emitter based on the nerve map indicating nerves proximate the tissue.

8. The system of claim 1, further comprising:

a cartridge including the therapeutic compound; and

a cartridge holder on a surface of the transducer configured to retain the cartridge proximate the emitter.

9. The system of claim 8, wherein the cartridge includes a plurality of pores configured to permit passage of the collagenase from the cartridge to the second location.

10. The system of claim 1 , further comprising an activation compound at the first location configured to activate the collagenase.

11. The system of claim 1 , wherein the therapeutic compound includes at least one of solid, a liquid, a gel, a lotion, an aqueous solution, a cream, an ointment, a micro-particle, a microsphere, a nanoparticle, and a liposomal encapsulation.

12. The system of claim 1, wherein the emitted energy is acoustic energy.

13. The system of claim 1 , wherein the emitter is configured to deliver the collagenase by sonophoresis.

14. The system of claim 1, wherein the system is configured to weaken the tissue.

15. The system of claim 1 , further comprising an array of emitters.

16. The system of claim 15, wherein the array of emitters is a linear array or a circular array.

17. The system of claim 1 , wherein the transducer is configured to be held in hand and placed proximate the first location under guidance of the hand.

18. The system of claim 1, wherein the transducer is affixed to a garment and configured to be placed at least proximate the tissue.

19. The system of claim 18, wherein the transducer is has a semi-cylindrical form having a central axis and the emitter is configured to emit the energy in a direction toward the central axis.

20. The system of claim 19, further comprising an array of emitters configured to emit the energy toward a predetermined location disposed within the semi-cylindrical transducer.

21. The system of claim 20, wherein the predetermined location includes the second location.

22. The system of claim 18, wherein the transducer includes a glove.

23. The system of claim 20, wherein the computer is mounted to the glove.

24. The system of claim 18, wherein the transducer includes a brace.

25. The system of claim 20, wherein the computer is configured to determine a path along the array of emitters based on diagnoses of the tissue, wherein the path is configured to bypass at least one nerve.

26. The system of claim 25, wherein the determined path is based on a patient's anatomy.

27. The system of claim 25, wherein the transducer is configured to power emitters along the path so as to emit the energy along the path.

28. The system of claim 1 , wherein the transducer is configured in a first mode for at least partial insertion into a patient.

29. The system of claim 28, wherein the transducer is configured in a second mode including a deployed configuration.

30. The system of claim 29, wherein the deployed configuration is a v-bend, a tear drop shape, or an umbrella shape.

31. The system of claim 1, wherein the system is configured to restructure the collagen associated with Nerve Entrapment Syndrome (NES).