Patent Description:
Use of ultrasonic energy in the treatment of wounds has become more common in recent years as its benefits are better understood and this type of therapy becomes more widely utilized. In general, ultrasonic waves of various frequencies and intensities have been used in medical applications for a long time, including diagnostics, therapy, and industrial applications.

A number of innovative ultrasound therapy systems and devices have previously been developed. These systems and devices have been widely used for medical treatments in medical facilities around the world. See, for example, <CIT>, entitled ULTRASONIC METHOD AND DEVICE FOR WOUND TREATMENT. Unlike most conventional wound therapies that are limited to treatment of the wound surface, this patent discusses therapies in which ultrasound energy and atomized normal saline solutions were used to stimulate the cells within and below the wound bed to aid in initiating or promoting the healing process.

Although these ultrasound therapies have been effective, devices, systems and methods providing improved ultrasonic therapies that are more accessible, safer and easier to administer to patients, and more efficient in delivery of ultrasound energy have been desired.

Biologic products, including extracellular matrices, naturally occurring proteins, growth factors and adherent cell populations, are important components in the healing process. Additionally, further administration of biologic materials, either taken from autologous or allogenic sources, are capable of covering, supporting and/or enhancing the healing progress of partial- or full-thickness wounds. Moreover, some biologic materials are capable of being administered topically. Administration of some biologic components may result in modulation of inflammation that is additive or synergistic with that of ultrasound energy.

However, the effectiveness of biologic treatment of wounds is often limited because many of the healing components are unable to penetrate the epidermal, dermal or subcutaneous tissues. Most topically applied agents or cellular materials cannot normally penetrate the skin (intact or disrupted) with current methods and cannot be transported into the dermis. <CIT>, <CIT>, <CIT>, <CIT> and <CIT> refer to prior art relevant for the present invention.

The present invention is defined by appended claim <NUM>.

Embodiments relate to biologic and/or cellular material delivery and non-contact, low-frequency, highly efficient ultrasound therapy devices, and systems that deliver ultrasonic and biologic therapy treatments via a mist to a patient wound to promote wound healing. One embodiment is directed to a non-contact, medical ultrasound therapy system for generating and controlling low frequency ultrasound alongside delivery of biologic for promoting wound healing. The ultrasound therapy system includes a treatment wand including an ultrasonic transducer, a generator unit, a cable coupling the treatment wand to the generator unit, and a biologic and cellular material delivery mechanism. The generator unit generates electric power output to drive the ultrasonic transducer and includes a digital frequency generator, wherein the generator unit digitally controls energy output at resonance frequency of the ultrasonic transducer.

The disclosure also provides methods, presently not claimed, for treating a skin, mucosa, or other condition. In some embodiments, these methods involve using an ultrasound delivery device to apply to an area of skin, mucosa or other tissue affected by the condition a mist that comprises a micronized cellular or biological material. The skin or other condition can be, for example, a wound, ulcer, or other condition. The cellular or biological material is, in some embodiments, a placental extracellular matrix composition or a placental connective tissue matrix composition. These compositions can be prepared from, for example, whole placental, placental deciduas, placental amniotic membrane, or placental chorionic membrane. In some embodiments, the biological material includes a population of adherent cells, or a mixture of adherent and non-adherent cells. The cellular or biological material can also include platelet-rich plasma or placental perfusate. The cellular or biological material is micronized in some embodiments of the invention.

According to the invention, medical ultrasound devices are provided for delivering non-contact ultrasound therapies to a skin or other condition. These devices include at least one treatment wand that includes an ultrasonic transducer, at least one reservoir that contains a fluid or suspension that includes a micronized cellular or biological material; and a pump that is in fluid communication with the reservoir and the treatment wand to deliver the fluid to the treatment wand such that the ultrasonic transducer atomizes the cellular or biological material as the cellular or biological material passes through the treatment wand for delivery to the area of skin or other tissue that is affected by the condition. In some embodiments, the devices of the invention have a plurality of treatment wants and/or a plurality of reservoirs. Each treatment wand can be in fluid communication with one reservoir, or a treatment wand can be in fluid communication with more than one reservoir. In some embodiments, at least one of the reservoirs contains a fluid for cleaning or disinfecting a wound or other tissue. A fluid for debriding a wound or tissue, or a fluid for providing a protective or other coating on a wound or other tissue, can also be contained within one or more of the reservoirs. The reservoir(s) are sterile, in some embodiments, and the fluid that is contained in the reservoir(s) can also be sterile.

The medical ultrasound devices of the invention, in some embodiments, further include an applicator configured to be coupled to the treatment wand, wherein the applicator has a radio frequency identification (RFID) tag and the treatment wand has a RFID transceiver that is used to identify the RFID tag on the applicator to ensure that the applicator is limited to a single use.

The devices of the invention also include, in some embodiments, a microprocessor that is configured to control operation of the device. The treatment wand can include, in some embodiments, a plurality of tubes and a plurality of reservoirs, each tube in fluid communication with a different one of the plurality of reservoirs, and a microprocessor that is configured to control a delivery pattern of fluids from the plurality of reservoirs. For example, the delivery pattern can be, in some embodiments, sequential delivery of individual fluids or simultaneous delivery of at least two fluids. The devices can also include at least one valve that is configured to selectively couple at least one of the reservoirs to a treatment wand. The valve can include, for example, a static mixer. The microprocessor can be configured to control operation of the valve(s) and the device. The valve can also be manually controllable.

The disclosure may be more completely understood in consideration of the following detailed description of various embodiments of the invention in connection with the accompanying drawings, in which:.

Various embodiments may be embodied in other specific forms without departing from the essential attributes thereof, therefore, the illustrated embodiments should be considered in all respects as illustrative and not restrictive.

Skin and/or mucosal ulcers or wounds, which are breaks in the skin/mucosa located anywhere on the surface of the body or its cavities, are a common occurrence. Healing of these wounds may be complicated by concomitant disease states, making them difficult or slow to heal (i.e., chronic). Wounds may be acute but difficult to treat because of location or association with concomitant conditions or injuries and require more innovative treatment than simple or routine good wound care to accomplish a functional regenerative repair or significant pain relief. Acute wounds are usually the result of accidental (e.g., burn or trauma) or iatrogenic (e.g., surgery) injuries. Chronic wounds afflict certain patient populations, particularly the elderly, immobile, obese, under-exercised, or with comorbidities like diabetes, atherosclerosis or autoimmune/inflammatory conditions, while acute wounds are ubiquitous. Chronic wounds may initiate as acute wounds that are complicated by the presence of a disease state or become infected, causing them to require more than four to six weeks to heal. Chronic wounds are persistent, non-healing or slow-healing wounds in which the body's healing process becomes stalled. They require treatment of the underlying disease state in parallel to treatment of the wound to achieve healing. In order to maximize the potential for a functional outcome, a regenerative healing process is desired. To reduce scarring or fibrotic repair of wound, application of human tissue components that maintain their architecture and/or biochemical construct have been shown to increase the likelihood of a regenerative repair that minimizes fibrosis and maximizes the functional and aesthetic outcomes.

Skin ulcers, particularly leg ulcers (especially venous stasis and diabetic foot ulcers), have been treated by application of a variety of skin substitutes or dressings, such as xenografts, which can include extracellular matrix products derived from porcine/bovine/equine/ovine/piscine sources. Conventional products include living bi-layered skin substitutes comprised of dermal layer and epidermal layers with a synthetic and/or animal-derived matrix, human acellular dermal matrix products that are derived from donated human skin, or donated human skin that is cryopreserved to maintain living cells in the bilayer construct. Dressings that are considered skin substitutes include the products that include plant-sourced advanced matrices. The skin substitutes, however, have disadvantages that include difficulty in handling, storing, sourcing or manufacturing challenges and size limitations. Thus, despite the prevalence of skin wounds, particularly chronic ulcerations, and the availability of different types of graft materials, there exists a need for a method of supporting or promoting the healing of wounds using a flexible, readily-available, customizable, easily applied durable material that can facilitate healing of the ulcerated or wounded area. Other needs also exist, including for treating conditions other than wounds (e.g., psoriasis, eczema, and other rashes and skin conditions that significant inflammation associated therewith). Thus, while wounds may be used as examples herein throughout, treatment areas need not comprise wounds per se and can comprise areas of the skin or body afflicted by some condition or otherwise viewed by a medical professional as potentially responsive to therapy or treatment.

These and other needs for more accessible and effective biologic and cellular material delivery and therapy for patients have been recognized in this disclosure. In embodiments, these needs can be substantially addressed or met by a low-frequency ultrasound therapy device and system configured for use with biologic and cellular material delivery and therapy. Many of the substantial technical obstacles to providing such a device based on the requirements of conventional ultrasound therapy devices are recognized and overcome by this disclosure. Specifically, making devices more readily accessible to additional patient populations by treating a more diverse set of ailments or conditions with new materials and techniques has been a significant challenge now met, at least in part, by embodiments discussed in this disclosure.

An additional challenge associated with conventional ultrasound therapy devices is the very high voltage necessary to operate conventional devices. For example, some conventional ultrasound therapy devices have operated at about <NUM> Volts (V) and <NUM> Watts (W) of energy. This has necessitated qualified oversight of therapy provision, as allowing untrained users to operate such a high voltage machine on their own might otherwise present a significant safety risk. The energy requirements have made the possibility of a portable battery powered device, which could be used in a homecare or other nonclinical environment, unfeasible.

Further, many patients cannot tolerate conventional topical applications of biologic or cellular materials due to direct physical contact with the wound and surrounding area during the procedure, and/or those conventional applications are less effective than desired. Delivery of biologic or cellular and biologic materials using ultrasound therapy systems described herein, however, address many or all of the technological, patient tolerance, and clinical effectiveness obstacles of the past and provide a lower-power, safer, more efficient, and more accessible ultrasound system for delivery of and therapy by biologic or cellular materials. Even battery powered systems are possible in certain embodiments. In embodiments, treatment, acceleration, and support or promotion of healing may be achieved by providing an optimal selection of ultrasound parameters such as frequency, intensity, pulse length, beam characteristics, and application time on the skin to enhance the transportation of biological cellular agents into the epidermal, dermal and subcutaneous tissues. Thus, topical agents of cellular materials that cannot normally penetrate the skin or mucosa with current methods may be transported into the dermis or submucosa. Accordingly, designs for new biologic and cellular material delivery and medical ultrasound devices, systems and methods incorporating various features, concepts and improvements, are discussed in the following pages.

Cellular and/or biological materials suitable for use in embodiments can be prepared and delivered in many formats. Biologic materials or viable tissue can be harvested and processed via several methodologies in order to create a fine particulate. In some embodiments, micronized or particulate cellular or biological materials are created through an aseptic mechanical milling process that creates a desired or appropriate size of particle. Examples of suitable milling processes include ball milling, jet milling, impact milling and friction milling. Other milling or processing methodologies to micronize the cellular or biological material can be used in other embodiments, such as grinding.

In embodiments, and regardless of the processing methodology used, the particles of cellular or biological material can be sized to be smaller than a delivery orifice of a delivery mechanism of the ultrasound device, or the delivery orifice can be selected for use according to a known particulate size in a specific application. In embodiments, the particle size is less than about <NUM> micrometers (µm), for example less than about <NUM> in some embodiments, or between about <NUM> and <NUM> in one embodiment. The particle size also can be considered relative to atomized droplet size, when a fluid in which undissolved particles are suspended is atomized. In one embodiment, the particle size is less than or about <NUM>/<NUM> of the size of the atomized droplet. Particle size also can affect or depend upon the viscosity of the fluid in which the particles are suspended or dissolved, and fluids with viscosities of less than or about <NUM> centipoise can be advantageous in some embodiments, though fluids with higher viscosities still may be used in other embodiments. Because atomized droplet size depends on fluid viscosity and frequency, adjustments can be made to one or more characteristics, for different applications or situations.

In some aspects, various tissues and cells can be combined to create a mixture of biologics that are optimized for a particular application, therapy, patient or other characteristic. Additionally, characteristics of the fluid for atomization and/or the device that atomizes the fluid can be adjusted or optimized for a particular application, therapy, patient or other characteristic.

The cellular or biological material can comprise a population of an adherent cells, such as fibroblasts or mesenchymal stem cells (MSCs). The cells can be a mix of different cell types or a homogenous population. In some embodiments, cells can be derived from the patient or placental sources. Patient-sourced cells can be taken from a biopsy of skin or other tissue, and the tissue can be homogenized. The cells can be separated using a variety of commercial methods including plating cells on a tissue culture plate to enrich an adherent cell population. In other embodiments, the cellular or biological material can comprise a mixture of adherent and non-adherent cells.

There are two typical placental cell sources. First, perfusate sources contain a mix of adherent and non-adherent cell types. The perfusate can be plated on tissue culture plates, populated and later removed using a variety of well-known methods, including the use of a collagenase solution. The cells can be diluted into an appropriate pH balanced buffer, such as phosphate-buffered saline. An additive can be added to the cell buffer to improve cell viability and passage through the ultrasound device. Second, the placenta tissue itself can serve as a source of cells. Cells can be derived from an umbilical cord, the Wharton's jelly or the placental decidua. The tissue can be scraped and partly homogenized using mechanical or chemical methodologies, followed by plating the cells upon a tissue culture plate. The cells can be removed from the plate and mixed with a benign buffer. Cells can be autologous or allogeneic with immunomodulatory properties.

Biologic materials also can be derived from the placenta via the connective tissue matrix or the placental extracellular matrix to form a placental connective tissue matrix composition or a placental extracellular matrix composition. The connective tissue matrix can be derived from part of the placenta and processed within the guidance of the current good tissue practices (CGTPs). Once excised from the placenta, the materials can be ground and washed with salt and a detergent, such as deoxycholic acid, in order to produce a paste. The paste can then be lyophilized and jet-milled to a particle size of below that of the delivery mechanism aperture. Another method of preparing a connective tissue matrix includes preparing a soluble form. The connective tissue matrix can be dissolved using hydrochloric acid in solution around a pH of <NUM>. Phosphate-buffered solution can then be applied immediately following application of the connective tissue matrix at a pH about <NUM>.

Whole placental extracellular matrix can be generated using the full or whole placenta before or after removal of the amnion and the umbilical cord. The whole placental tissue can be ground and repeatedly washed with salt and water and then with deoxycholic acid. The tissue can be exposed to a low pH (e.g., pH = <NUM>) and a high pH (e.g., pH = <NUM>). The tissue can be washed with salt and water, forming a paste. The paste can be jet milled or ground. The tissue can be dissolved in hydrochloric acid solution with a pH of about <NUM>.

Placental extracellular matrix or placental connective tissue matrix also can be prepared from placental amniotic membrane or placental chorionic membrane.

The cellular or biological materials can be prepared in different forms, such as, for example, being micronized by grinding, milling (e.g., jet milling), freeze drying, or heat drying. The materials also can be solubilized. The cellular or biological material can be solubilized or otherwise made compatible for delivery via an ultrasound system in advance of or at the time of delivery and ultrasound therapy, when the material can be applied as part of a fluid, mist, or topical treatment. In some embodiments, the material application can be followed by administration of a solvent, application of further ultrasound therapy, or other treatments.

For example, in one embodiment a connective tissue matrix or extracellular matrix can be suspended in a solution and jet milled with saline or another fluid to a particle size below that of the aperture of the ultrasound delivery systems. In another embodiment, a biologic material can be applied as a powder to the wound or other area of patient anatomy where it is desired or necessary. Saline solution then can be applied to the powder, followed by ultrasound therapy provided by the ultrasound system to facilitate an even distribution and penetration of the biological material into deeper tissue levels, e.g., the dermis and subdermal levels of skin. In yet another embodiment, a biologic material can be freeze-dried or heat-dried. The dried material then can be applied to a wound or other area of patient anatomy where it is desired or necessary as a sheet or layer, followed by treatment with saline solution or another compatible fluid and ultrasound treatment to facilitate an even distribution and penetration of the biologic material into deeper tissue levels. In still another embodiment, a biologic material can be an acid solubilized solution of connective tissue matrix or extracellular matrix, treated with saline, phosphate buffered saline or another fluid, and delivery using ultrasound therapy.

In some embodiments, the cellular or biological material can comprise a platelet rich plasma or placental perfusate. Platelet rich plasma can be autologous and can be isolated using known methods. In one embodiment, the plasma is applied prior to ultrasound treatment, with or without saline treatment. Placenta perfusate can be generated, for example, by passing normal saline through the placenta via the umbilical cord blood vessels. The perfusate can be collected as a mix of proteins and cells in saline. The proteins can include blood proteins, growth factors and cytokines, although these may not be characterized. The cells can be a mix of CD34 hematopoietic progenitors, stems cells and adherent cell types. The cell composition of the perfusate need not be well characterized. Cell size can be a size capable of passing through the aperture of the delivery mechanism. In use, biological fluids such as platelet-rich blood plasma, autologous blood plasma, and placenta perfusate can be applied via the delivery device with or without saline treatment.

Still other materials and combinations thereof can be used in other embodiments. Thus, for example, materials comprising or containing, together or separated (i.e., purified), alone or combined, any of amnion, chorion, umbilical cord/cord blood derivatives, placental decidua, epithelium, basement membrane, extracellular matrix (ECM), connective tissue matrix (CTM, such as INTERFYL™), scaffold protein, plasma, collagen, elastin, platelet-rich plasma (PRP), glycosaminoglycan (GAG), proteoglycan (PG), laminins, fibronectin, cytokines, hemagglutinin (HA), coated fibers, other molecules with placental-derived components, antibiotics, anti-inflammatories, antifungals, and other cellular or biologic materials or combinations thereof can be used in various embodiments. As appreciated by those having skill in the art, the handling, storage, sterilization and combination, as well as the therapeutic delivery using ultrasound as discussed herein, of these materials can vary.

<FIG> shows an example of a medical ultrasound device <NUM> of an ultrasound therapy system <NUM> (refer, e.g., to <FIG>) for delivering non-contact ultrasound therapies to patient wounds via a low-frequency ultrasound mist. Medical ultrasound device <NUM> comprises both a console/generator unit <NUM> for generating power and a treatment wand <NUM> for administering therapies. In general, generator unit <NUM> supplies power to an ultrasonic transducer within the treatment wand <NUM>. Treatment wand <NUM> is generally and ergonomically pistol-shaped and may be conveniently positioned by a user to direct ultrasonic energy to a treatment area via atomized saline mist emitted from the end of treatment wand <NUM>. Generator unit <NUM> further comprises one or more external pumps <NUM> to pump saline, cellular/biologic and/or other materials through a tube or tubes <NUM> (see, e.g., <FIG>) attached to the end of treatment wand <NUM>. Pumps <NUM> depicted in <FIG> are peristaltic pumps but can comprise other suitable pump types or mechanism in other embodiments, such as rotary/gear pumps, positive displacement syringe pumps, or other pumps.

In some aspects of the invention, the system can have multiple treatment wands <NUM> and/or multiple flow channels. These configurations can allow for sequenced or simultaneous delivery of various materials, different treatment modalities or characteristics, expanded treatment areas, and other advantages.

One such embodiment is depicted in <FIG>. In the embodiment of <FIG>, system <NUM> can comprise a plurality of treatment wands <NUM> (one wand 40a is depicted in <FIG>), each of which can be coupled to a single generator unit <NUM> of device <NUM> by respective cables 90a, 90b and 90c. In use, the plurality of treatment wands <NUM> can be operated simultaneously or sequentially, and each wand <NUM> can be used to deliver a different material or fluid, operate according to different characteristics (e.g., different ultrasound frequencies), or have different features (e.g., a larger or smaller ultrasound horn, different delivery options).

Another such embodiment is depicted in <FIG>, in which a single treatment wand <NUM> interfaces with or comprises a plurality of tubes 120a, 120b, 120c for delivering different fluids or materials. While three tubes 120a-c are depicted in <FIG>, more or fewer tubes <NUM> can be included in treatment wand <NUM> in other embodiments. Having a plurality of tubes <NUM> enables different fluids or materials to be delivered by a single treatment wand <NUM>. System <NUM> can comprise hardware (e.g., valves, manifolds and/or pumps) along with a microprocessor and software and/or firmware to control delivery of the fluids sequentially, simultaneously (e.g., by mixing), or according to other delivery patterns. The microprocessor and other control elements and features of system <NUM> and device <NUM> are discussed in more detail herein below.

An example of a valve suitable for use with treatment wand <NUM> of <FIG> is depicted in <FIG>. Referring to <FIG>, an example valve <NUM> is depicted. Valve <NUM> comprises a rotary valve with stop cock-type sealing or an O-ring, though other valve types can be used in other embodiments. In some embodiments, all or a portion of valve <NUM> can be disposable. Valve <NUM> includes a static mixer <NUM> and can be driven by a servo motor, solenoid or stepper motor <NUM>, or some other actuator that allows for discreet positioning of the valve.

In the embodiment of <FIG>, valve <NUM> comprises three inputs InA, InB and InC, and one output Out. Valve <NUM> can be controlled manually or automatically (e.g. by a microprocessor of device <NUM> in generator unit <NUM> controlling motor <NUM>, as discussed in more detail below) to selectively couple one or more inputs InA, InB and/or InC with output Out as depicted in <FIG>, depending on a rotational position of a center valve portion <NUM> within a housing portion <NUM> with which inputs InA, InB and InC and output Out interface. One or more pinch valves (see, e.g., <FIG>) can be used with valve <NUM> to selectively control the fluid(s) or other materials by occluding fluid flow through compression of tubing placed in the pinch valve. Like valve <NUM>, the pinch valve(s) can be controlled by solenoids, stepper motor(s) or some other mechanical actuator. Thus, valve <NUM> can selectively control mixing and/or delivery of different media. In some embodiments, one media can be a cleaning or disinfecting solution. In another embodiment, one media can be a biologic or cellular material containing fluid. In yet another embodiment, the media can be a fluid for providing a protective coating, a biologic activating coating, or some other coating on a wound, ulcer or other tissue.

In some embodiments, mixing also can be accomplished using a vibrating plate, which can be incorporated in a heater block (discussed below) or separate holder. Vibration of the plate can be provided by solenoids or some other mechanical actuator, including an ultrasonic device.

While valve <NUM> is generally configured to deliver fluid media, in other embodiments system <NUM> can facilitate applying a powder, such as one comprising cellular or biologic material, directly to a wound or other patient tissue. This powder application can be followed by ultrasound delivery of saline or another fluid or material in some embodiments. In these embodiments, a different type of valve or system can be used to facilitate application of a powder.

In another embodiment, and referring to <FIG>, a nozzle or applicator <NUM> can be configured for use with of treatment wand <NUM> of <FIG>. As shown in <FIG>, applicator <NUM> facilitates coupling of three tubes 120a-c with treatment wand <NUM> to deliver one or more fluids to tip <NUM> of ultrasonic transducer <NUM>. <FIG> is a perspective view of applicator <NUM>, <FIG> is an end view showing an orifice <NUM> of applicator <NUM>, <FIG> is a cross-sectional view through orifice <NUM>, and <FIG> is a perspective view in which a portion of a housing <NUM> of treatment wand <NUM> is included. In some embodiments, only a single fluid is delivered at any time, via one of tubes 120a-c. Thus, a plurality of fluids can be delivered sequentially or in some other order. This can be controlled by a microprocessor controlling, e.g., a series of pumps each coupled with tubes 120a-c and discussed in more detail below. In other embodiments, two or more fluids or materials can be delivered simultaneously to applicator <NUM> for mixing at orifice <NUM>.

To assist the flow of fluid and help prevent clumping or aggregation of the biomaterials or other particulate, one or more coatings can be applied to the inner surface of the tubing. These coatings can comprise hydrophilic or hydrophobic coatings, such as those available commercially from Surmodics, Harlan Medical, or BioCoat. In some embodiments, the coatings can comprise specially developed or formulated material to interact with the biomaterial being dispensed.

In embodiments discussed above, one or more pumps can interface with tubing <NUM> to control delivery of fluids to treatment wand <NUM>. <FIG> depicts an example fluid pump configuration that can be used in embodiments. In particular, <FIG> depicts a stackable head peristaltic pump <NUM>. Pump <NUM> comprises a plurality of pump units 50a, 50b, 50c each arranged along or interfacing with a tubing 120a, 120b, 120c, respectively, between a fluid source (e.g., container(s) <NUM> discussed below) and treatment wand <NUM> to provide and/or control delivery of fluid or other material. In other embodiments, pump <NUM> can comprise more or fewer pump units, or a different type of pump (e.g., syringe or plunger pump). <FIG> show additional views of pump units 50a-c.

Pump <NUM> can be controlled by a microprocessor of device <NUM>, as discussed below. In operation, pump <NUM> can be controlled to operate one or more of pump units 50a-c at any time to deliver a fluid other material in tubing 120a-c to treatment wand <NUM>. Pump units 50a-c can operate sequentially to deliver different materials in sequence, or one or more of pump units 50a-c can operate simultaneously to provide one or more fluids for mixing or concurrent delivery. Pump <NUM> can operate in conjunction with valving (e.g., valve <NUM>) in embodiments.

Additional active or passive valving also can be incorporated into system <NUM> and device <NUM>. For example, it may be desired or required to heat or cool one or more of the materials to be delivered. Referring to <FIG>, some embodiments of system <NUM> can comprise at least one temperature control unit <NUM>. Temperature control unit <NUM> can comprise a Peltier effect heat/cool device, a resistive foil heater, or some other heating and/or cooling device. In some embodiments, a bottle warmer-type device <NUM> can be used for heating or cooling, such as on an IV bag, a sterile container, or some other source of the material to be delivered by system <NUM>. Temperature control unit <NUM> can comprise one or more valves, such as pinch valves <NUM> or another type of valve or arrangement, for controlling fluid or material flow in tubing <NUM>, which is arranged in or otherwise passes through temperature control unit <NUM>. This arrangement heats or cools the material in tubing <NUM> as it flows or passes through temperature control unit <NUM>. In some embodiments, a first cooling unit <NUM> can be provided along with a second heating unit <NUM>. In other embodiments, a single unit <NUM> can provide both heating and cooling. In still other embodiments, one or more units <NUM> can be combined with a bottle-based temperature control device <NUM>. Still other temperature control types and configurations also are possible, including infrared, dissipative and passive temperature control arrangements (e.g., insulative materials arranged around portions of system <NUM>, heat generating portions of system <NUM> arranged around or proximate to portions of system <NUM> to be heated, etc.). Temperature control unit <NUM>, device <NUM> and valves <NUM> can be controlled by a microcontroller of device <NUM>, discussed in more detail below.

In other embodiments, valves <NUM> (or any other valves discussed herein) can be passive rather than active. For example, in some embodiments as already discussed the valves can be controlled by a microcontroller. In other embodiments, however, the valves can comprise springs or other mechanisms that are passive and controlled by fluid flow speed or some other property.

<FIG> and <FIG> are high-level block diagrams of components of ultrasound therapy system <NUM>. In general, as depicted in <FIG>, system <NUM> comprises generator unit <NUM>; treatment wand <NUM>; fluid management pump <NUM>; an ultrasonic driver <NUM>; an ultrasonic transducer <NUM>; and an applicator <NUM>.

Generator unit <NUM> and treatment wand <NUM> are connected by a cable <NUM>. Ultrasonic driver <NUM> comprises hardware mounted inside generator unit <NUM>. A basic function of the ultrasonic driver <NUM> is to generate electric power output to drive ultrasonic transducer <NUM>. Ultrasonic transducer <NUM> includes an acoustic horn <NUM> and related assembly mounted inside treatment wand <NUM>. Ultrasonic transducer <NUM> converts and transfers input electrical power into vibrational mechanical (ultrasonic) energy that will be delivered to the treatment area (i.e. to a patient wound area via atomized saline). Treatment wand <NUM> is configured to appropriately position and hold applicator <NUM> relative to acoustic horn <NUM> for proper delivery of fluid or other another material, such as a biologic or cellular material, to be delivered during operation.

Appropriate positioning of applicator <NUM> also depends on appropriate positioning of treatment wand <NUM> by a user during use. Therefore, in embodiments treatment wand <NUM> can comprise a motion processing unit <NUM> to assist a user with proper positioning of treatment wand <NUM>. Motion processing unit <NUM> can comprise at least one of an accelerometer, a gyroscope, a magnetometer and/or another device that can determine an attitude, position and/or orientation of treatment wand <NUM> during use. One example of a motion processing unit that may be suitable for use in system <NUM> is a BNO055 Application Specific Sensor Node (ASSN) available from BOSCH SENSORTEC, but this is but one example, and other units or sensors can be used in other embodiments. Motion processing unit <NUM> may be able to achieve levels of resolution that allow for determining treatment distance and provide more detailed information on the actual therapy to generator unit <NUM> and the user (i.e., treatment coverage area, distance from the skin, etc.).

Motion processing unit <NUM> can interface with user interface <NUM> (discussed below) to provide feedback or alerts to a user during operation of system <NUM>. For example, a treatment area or patient position may lead a user to operate treatment wand <NUM> at an angle or in a position that interferes with proper operation (i.e., one that causes fluid to flow away from or build up on and overload transducer <NUM>), and an audible, haptic or visual alert to a user can cause them to take corrective action and reposition treatment wand <NUM> relative to the treatment area. In some embodiments, an effective treatment angle between wand <NUM> and a treatment area is about +/- <NUM> degrees, and while other angles are possible, motion processing unit <NUM> can assist a user in maintaining a most effective position. In some embodiments, the effective or preferred angle can vary, and motion processing unit can comprise customized algorithms that correspond to different treatments, therapies, types of wounds and/or other characteristics related to treatment and assist a user in achieving or maintaining an appropriate treatment position of wand <NUM>.

Treatment wand <NUM> also contains the system's user interface <NUM> and controls for parameters of the treatment, though in other embodiments an additional or alternative user interface can be incorporated in generator unit <NUM>. For example, user interface <NUM> can provide a way for a user to select various ultrasound parameters, including frequency, intensity, pulse length, beam characteristics, and application time on the skin. Selection and customization of these parameters can be used to provide or enhance the transportation of biological cellular agents into the epidermal, dermal and subcutaneous tissues in embodiments in which materials comprising these agents are used. Further, selection and customization of these parameters can be associated with a patient characteristic, wound or type of tissue to be treated, or other factor related to treatment, in addition to the type of material to be delivered.

The configuration also provides appropriate atomization of the fluid or other media to be delivered from sterile reservoir(s) or container(s) <NUM> and delivery of the resulting mist and ultrasound energy to a wound or other treatment area. Sterile container(s) <NUM> can include one or more reservoirs containing biologic materials and various fluids. Cells or subcellular biologic materials of many types may be loaded into a liquid, for example one having the viscosity of or similar to water and placed in a sterile container <NUM>.

A fluid containing a biologic, cellular or other biomaterial can be provided within a deliverable solution or as a separate component stored within a separate reservoir (<NUM>). A fluid containing a biologic can have a suitably high concentration such that it can be mixed to make the liquid concentration of cells homogeneous, maintain suspension of the particles of the biologic in the fluid, and ensure the fluid is ready for insertion in and application by the delivery apparatus. This mixing can be done before or at delivery, such as via an arrangement of sterile containers <NUM> containing the various materials and fluids for mixing, along with associated tubing and pump(s) <NUM> (see, e.g., <FIG>). This configuration, and pump(s) <NUM> in particular, can create a precise and controllable flow that allows for sterile delivery of the media to the patient via applicator <NUM> and transducer <NUM>. In embodiments, two or more independent streams can be mixed via a static mixer (e.g., <NUM> in <FIG>), a vibration mixer, or other mixing device, and the streams flow rates can be independently controlled, providing a specific mixed concentration or a continuously variable rate of flow. Mixing also can be performed by one or more of the aforementioned mixing devices to prepare a single fluid for delivery (i.e., mixing a particulate material with a fluid) or to mix fluids prior to or during treatment. For example, some fluids may require vibration or other mixing of container <NUM> during treatment in order to maintain desired characteristics of the fluid. The mixing (e.g., type, timing) and flow rates can be set or adjusted according to a particular material to be provided, therapy to be delivered, patient characteristic, or other factor(s).

In other embodiments, these mixings and delivery methodologies can be accomplished by mixers, as previously mentioned, and/or flow channel and valving configurations. In one embodiment, these hardware components are provided with or coupled to pump(s) <NUM>. For example, generator unit <NUM> and/or treatment wand unit <NUM> can open and close various valves (e.g., each valve associated with a container <NUM> or other supply of fluid or material) during operation to provide mixing, staged delivery of different fluids, materials, or concentrations, other techniques. Refer, for example, to <FIG>, <FIG> and <FIG>.

For example, in one embodiment a first fluid is delivered to clean or disinfect the wound or other patient tissue, then a second material for additional cleaning or preparation can be delivered, then a third material comprising the desired biologic material. Finally, a fourth or last material can be delivered to provide a protective or other coating on the tissue (e.g., to activate the cells and provide a barrier). The valving and/or pumping to accomplish this can be automatic according to a programming of settings, which in one embodiment itself can be automatic according to a scanning of a machine-readable code (discussed below) or manual by user programmable settings.

In other examples, a biologic fluid is delivered prior to saline and ultrasound treatment. In another embodiment, the biologic fluid is delivered simultaneously with saline and ultrasound therapy. In these or any other case, system <NUM> can be automatically or manually set, adjusted and/or used according to the desired delivery and treatment or therapy type.

In some embodiments, surfaces that the fluid comes into contact with (e.g., within containers <NUM>, pumps <NUM>, valve <NUM>, tubing <NUM>, applicator <NUM>, etc.) can be coated with various compounds or materials that either positively interact with the fluid or provide a neutral surface that does not interact with the material. For example, the coating can contain a component material that activates the cells as they come in contact with the coating. The coating can be dry or wet.

In some embodiments, the solution can be mixed and placed into a single use sterile container. This container can be directly coupled to as container <NUM> in some embodiments, or this container can interface with container <NUM> (e.g., be placed within a holding container <NUM>) in system <NUM>. Given the cellular and biologic nature of the material in some embodiments, the container can be specially marked to ensure use with the proper patient. For example, bar coding, Quick Response (QR) coding, radio frequency identification (RFID) tagging, or other wirelessly, electrically or mechanically readable technologies can be used to label the container. System <NUM> can include corresponding reading technology (e.g., a bar code reader, an RFID reader, etc.), such that system <NUM> can require that a patient identification (e.g., wrist band, medical chart, biometric identifier, etc.) is read, then the corresponding container is read and confirmed to match the patient before treatment via system <NUM> can begin. System <NUM> can additionally or alternatively confirm that the fluid is for use with a particular patient; confirm a content of the reservoir; or receive device programming information from the machine-readable label. In other embodiments, system <NUM> can comprise a reader configured to read a machine-readable component, such as a bar code, QR code, RFID tag, or the like, on a component or accessory of system <NUM> to confirm that the component or accessory is usable with system <NUM>.

This scanning also can provide programming information for operation of system <NUM>, which then can be automatically set by system <NUM>. In some embodiments, user confirmation of these settings can be required, or some manual entering or interaction with system <NUM> can be implemented. The settings can include intensity, intensity variation via electronic controlling signal (wave shaping), flow rate(s) of fluid(s), duty cycle of the output, variations in frequency within a defined range (i.e., large variation can require a separate transducer <NUM> to resonate at the desired frequency, and in embodiments system <NUM> can accommodate various different transducers <NUM>), and other settings. For example, in one embodiment saline is delivered first at a first, lower intensity, then the cellular material is delivered via a second, higher intensity. During delivery of the cellular material, the intensity can be further adjusted (e.g., increased or decreased) so that treatment ends at a third, even higher intensity. In embodiments, settings, including those made automatically, can be adjusted on the fly during operation, such as in the case of patient discomfort with or intolerance of a higher frequency or other setting. In one embodiment, this can be done via user interface <NUM>. In another embodiment, this can be done via treatment wand unit <NUM>, which instead of providing a two-state, on/off trigger can comprise variable or proportional trigger that increases or decreases with displacement thereof by the user (i.e., more force applied to or displacement of the trigger applied by a user increases intensity or rate of fluid delivery, etc., while less force or displacement decreases intensity, rate of fluid delivery, etc.). In some embodiments, the characteristic that is variable in this manner is user-selectable via user interface <NUM>, while in other embodiments the characteristic is automatically selected or set.

In some embodiments, the machine-reading components can be provided in treatment wand unit <NUM>. In other embodiments, these components can be implemented elsewhere in system <NUM>, such as generator unit <NUM>.

In some aspects the biologic or cellular material containing fluid may be provided in kit or as a separate component from saline or other fluids. In one embodiment, the kit can comprise one or more sterile containers <NUM> or containers that can be coupled to or with sterile containers <NUM> and/or pumps <NUM> and comprising a fluid or material for mixing and/or delivery; tubing <NUM> for coupling pumps <NUM> and applicator <NUM>; and applicator <NUM>. In such an embodiment, tubing <NUM> and applicator <NUM> can be single use and disposable, which can be required or convenient when the fluid delivered by these components includes biologic or cellular material. In other embodiments, the kit can additionally or instead comprise a detergent or cleaning agent, such as one provided in a container <NUM> for coupling with and running through system <NUM> after use with a biologic or cellular material to ensure no material remains in system <NUM> for use with the next patient. Other cleaning methodologies can be used in other embodiments and can comprise manual or automatic cleanings.

In other embodiments, kits can additionally or instead comprise disposables to form a disposable kit, such as a single-use applicator <NUM> coupleable to treatment wand <NUM>, tubing to convey the fluid from container <NUM> to treatment wand <NUM>, and a spike to pierce container <NUM> to couple the tubing to container <NUM>. A kit can additionally comprise at least one of a valve or a disposable mixer. Kits of disposables can be convenient for facilities using system <NUM> while also reducing the risk of cross-contamination of system components and/or reuse of components with multiple patients.

Fluid management pump(s) <NUM> (see also <FIG>) can provide a fixed flow rate of saline or other fluid and biologic and cellular materials for delivery (i.e., "the material for delivery" will be used herein generally and can comprise any of the fluids, biologic/cellular materials, or other liquids, powders, suspensions, gases, or other materials, as discussed herein) via tube(s) <NUM> to the distal tip <NUM> of ultrasonic transducer <NUM> from one or more sterile container(s) <NUM> and/or fluid reservoirs or other sources, as appropriate. Container(s) <NUM> can comprise one or more bags, bottles, packs, cups, or other packages suitable for holding the material for delivery and coupling with or in system <NUM>. The material in container(s) <NUM> is delivered to the radial surface of transducer horn near its tip <NUM> by one or more tube(s) <NUM> and applicator <NUM>. The material is dispensed through an orifice (e.g., <NUM> in <FIG>) on a superior surface of the horn <NUM>, and a portion of the material is displaced forward to the face of horn <NUM> and atomized by horn <NUM> when horn <NUM> is energized and operating. The remaining volume of material for delivery is fed to an inferior surface of ultrasonic transducer <NUM> via gravity and capillary action. When a sufficient volume of material is accumulated, transducer tip <NUM> atomizes the material into a plume. The atomized material spray plume emanates from two points on the ultrasonic transducer <NUM>, i.e., generally at the <NUM> o'clock and <NUM> o'clock positions given normal positioning of treatment wand <NUM> in operation, forming intersecting spray paths at approximately <NUM> from the front face of ultrasonic transducer <NUM> in some embodiments. Depending on the location of orifice(s) <NUM>, the spray plume may be varied or modified. While single-point dispensing has been discussed, multi-point dispensing also can be used in some embodiments. Additionally, the configuration of the shroud <NUM> (see <FIG>) also can contribute to controlling the spray plume, as shroud <NUM> acts as a reflective surface. In other embodiments, treatment wand <NUM>, transducer <NUM>, orifice <NUM>, horn <NUM>, tip <NUM>, applicator <NUM> and/or other components can be designed to provide a differently sized or configured spray plume and paths, such as one customized for a particular material to be delivered, wound or patient anatomy to be treated, therapy to provided, or other characteristic. In still other embodiments, these components of device <NUM> can vary in size or other characteristics, and a user can select (or device <NUM> can prescribe) a particular combination of the components, selectable from a kit comprising the components with various characteristics, to use with device <NUM> according to a particular treatment or therapy to be provided, a fluid to be delivered, a patient or condition to be treated, or some other factor. Instead of or in addition to varying the physical characteristics or specifications of one or more components of device <NUM>, one or more operating characteristics can be varied in order to alter the spray pattern, such as the flow rate, frequency, angle of delivery, delivery distance, delivery pattern (e.g., the way in which a user manipulates wand <NUM> during treatment), or some other characteristic.

<FIG> is a block diagram of a more detailed schematic of generator unit <NUM> and treatment wand <NUM> of ultrasound device <NUM>. As can be understood from the following description, parameter control of voltage, current, duty cycle and phase angle is enabled, in some embodiments.

Treatment wand <NUM> houses ultrasonic transducer <NUM> and includes a microprocessor <NUM>, various interface and sensing components, and an OLED display <NUM>. Treatment wand <NUM> is pistol-shaped in embodiments to provide an improved ergonomic design, though other configurations can be implemented as may be advantageous in some applications. Treatment wand <NUM> comprises an acoustic horn assembly (e.g., piezo elements, back mass, horn and booster), ultrasonic transducer <NUM>, microprocessor (MCU2) <NUM>, user control key pad <NUM> and trigger <NUM>, and an LCD screen display <NUM> that displays operational information and enables control and programming of the treatment therapy (see, e.g., <FIG>). Treatment wand <NUM> also includes an RFID transceiver <NUM> in some embodiments, and RFID transceiver <NUM> can be used to identify applicator <NUM>. This feature can be used to ensure that there is only a single use of a particular applicator <NUM> and to thereby deter unwanted reuse across multiple patients and/or treatments. This feature can be particularly advantageous in embodiments in which patient-specific cellular and biologic materials, information, data and/or characteristics are used in system <NUM>. Thus, in embodiments the RFID chips read by transceiver <NUM> can contain information about the specific treatment, which is conveyed to system <NUM> by this reading, providing inputs for the specific therapy to be administered by device <NUM>.

Treatment wand <NUM> connects to generator unit <NUM> through cable <NUM>. Cable <NUM> includes ultrasonic driver output power, RS488 communication and +5V power in an embodiment, though other power and/or communications features can be implemented or facilitated by cable <NUM> in other embodiments. In one embodiment, <NUM>. 3V and 13V power will be generated from the 5V power provided by generator unit <NUM> for the electronics in the treatment wand <NUM>. These example power characteristics can vary and are merely examples of one embodiment.

User interface <NUM> on treatment wand <NUM> includes key pad <NUM>, trigger <NUM>, and screen display <NUM>. In some embodiments, display <NUM> can be a full-color OLED display, and key pad <NUM> can be a four button display, as shown in <FIG>. The operator can configure and control device and system operation via key pad <NUM> and initiate the delivery of therapies by depressing a trigger switch <NUM>.

Microprocessor <NUM> that controls user input requirements can also measure the internal temperature of treatment wand <NUM>, or of transducer <NUM> or horn <NUM> more specifically, from ultrasonic transducer sensor <NUM> and treatment wand temperature sensor <NUM>. In embodiments, temperature sensors <NUM> and/or <NUM> or additional temperature sensors in treatment wand <NUM> or elsewhere in system <NUM> can be used to provide active thermal control. For example, in embodiments the material to be delivered (e.g. from container(s) <NUM>) can be heated or cooled for delivery. Temperature sensors throughout system <NUM> can monitor the temperature of the material at various places in system <NUM> (e.g., in treatment wand <NUM> by sensor <NUM>, and/or at container(s) <NUM>, pump(s) <NUM>, tube(s) <NUM> and elsewhere by additional sensors at those places) to ensure it is as desired. For example, in one embodiment, a sensor can monitor a temperature of the tissue, and system <NUM> can adjust the fluid dispensing temperature as needed. In some embodiments, heating or cooling elements can be provided, such as along tubing <NUM> and/or around container(s) <NUM>. In still other embodiments, heat generated during normal operation of system <NUM> can be used to heat the material, and/or this heat can be dissipated by cooling effects of the material, such as via selective arrangements of tubing <NUM> proximate heat sources. Still other sensors can be incorporated in or communicatively (e.g., wirelessly) coupled to treatment wand <NUM> for assessing and monitoring the tissue during operation of system <NUM>. Based on this assessing and monitoring, system <NUM> can adjust or regulate the therapy being provided. For example, wand <NUM> can comprise an infrared sensor to sense patient tissue temperature during treatment and provide feedback to an operator, who can adjust settings to provide heating or cooling or adjust other settings to increase patient comfort and therapeutic response. Still other types of non-contact sensing - or contact, such as via wireless sensors applied to a patient's skin - can be used in other embodiments, including imaging techniques, which can provide information regarding the size of a wound or lesion for use in determining optimum settings and therapies. Microprocessor <NUM>, or another processor in system <NUM>, can monitor and control these sensors and elements in operation, in various embodiments.

Microprocessor <NUM> also sends read/write information to applicator <NUM>. Microprocessor <NUM> communicates with generator unit <NUM> via an RS488 transceiver <NUM> and writes information to EEPROM <NUM>. This information is stored and can be retrieved for understanding the use and performance of the system. Accordingly, greater detail can be given on data stored, how much, how long and how retrieved (USB upload/download by the user, service or other).

RFID transceiver <NUM> of treatment wand <NUM> can be used to communicate with an RFID tag (not shown) for applicator detection, as previously mentioned. The RFID tag can be located on applicator <NUM>, and microprocessor <NUM> in treatment wand <NUM> can serve as an RFID reader and writer of the signals received via RFID transceiver <NUM>. Specifically, an RFID controller can be used in treatment wand <NUM> for a Read/Write RF tag on applicator <NUM> and/or container(s) <NUM>. In each new treatment, system <NUM> will require a new applicator <NUM> and container(s) <NUM>. The RFID controller can read the ID tag of applicator <NUM> and container(s) <NUM>, as well as a patient identifier on a bracelet, chart or other location, to identify if that particular applicator <NUM> is new or used, whether that applicator <NUM> is suitable for use with the material in container(s) <NUM> (e.g., according to particle and aperture sizes), and/or whether the material in container(s) <NUM> is suitable for the particular patient to be treated. The RFID controller also can obtain information related to specifics of the biologic or cellular material in container(s) <NUM>, a suitable or suggested therapy for use with that material or for a patient condition, time usage, and other therapeutic and treatment characteristics. For example, in one embodiment the RFID controller can read diagnostic information, obtain usage or other information about a disposable (e.g., applicator <NUM>), and use this data and information for system review and diagnostics if a user reports errors or problems, if a device or disposable is returned as being inoperable or defection, or for other purposes. In embodiments, the RFID controller also can write information to the tag for treatment monitoring and reporting. After a particular applicator <NUM> is used for a specified period of time, the RFID controller can write the information to an ID tag to identify that applicator <NUM> has been used to avoid reuse. As previously mentioned, treatment wand <NUM> also can comprise other machine-readable hardware (e.g., bar code reader), instead of or in additional to RFID transceiver <NUM>, and bar codes or other machine readable devices can be arranged on other components of system <NUM>.

Microprocessor <NUM> of treatment wand <NUM> can be used to control all inputs and output functions and perform all control loops, and calculations. Features of some embodiments can include: an <NUM> maximum frequency; <NUM> DMIPS/MHz (Dhrystone <NUM>) performance; an operating voltage range of <NUM>. 3V to <NUM>. 6V; a <NUM> flash memory (plus an additional <NUM> KB of Boot Flash); a <NUM> SRAM memory; a USB <NUM>-compliant full-speed device and On-The-Go (OTG) controller; up to <NUM>-channel, <NUM>-bit Analog-to-Digital Converter; six UART modules with RS-<NUM>, RS-<NUM> and LIN support; and up to four SPI modules. These features are merely examples of one embodiment and can vary in other embodiments.

Ultrasonic transducer <NUM> generally comprises a piezoelectric ceramic element and metal horn <NUM> mounted in a sealed housing. The ultrasonic transducer input can be an AC voltage or AC current, and the waveform can be a square form or sine form. The ultrasonic transducer output is mechanical vibration of the tip of transducer <NUM>. The amount of energy output depends on tip <NUM> displacement, operation frequency, size and driver load (e.g., air or liquid mist). The ratio of output to input energy is referred to as the electromechanical coupling factor. There are many variables that affect coupling factor, including operation frequency. In theory, it would be advantageous to operate an ultrasound transducer (UST) by keeping the operating frequency in the resonance frequency (Fr) or anti-resonance frequency (Fa) region because its electrical power factor is <NUM>. However, due to the related, very unique impedance-frequency characteristics of these transducers, which can vary from transducer to transducer, drive circuit design is very difficult. In previously designed ultrasonic drivers, Phase Loop Lock (PLL) techniques were widely used. Because of the nature of analog performance, keeping a highly accurate and stable frequency output was very difficult. In theory, a UST that operates at Fr or Fa has a high efficiency output. In practice, operating a UST at Fr or Fa is almost impossible with PLL technology. This is why most ultrasonic drivers with a PLL design only can operate in Fr or Fa regions rather than at Fr or Fa points, and the operational phase typically must be more than <NUM> degrees. For most systems with rapidly changing load impedance, operation at frequencies close to Fa or Fr will cause the system to be unstable. Alternatively, a system can be kept running stable by setting the operation frequency lower than Fr or higher than Fa points, as in past designs. In embodiments discussed herein, however, the ultrasonic driver can be monitored and controlled to operate at or very near Fr, a significant advantage over conventional systems.

Ultrasonic transducer <NUM> is operated at relatively large displacements and a low load condition, thereby reducing loading effects and electrical impedance. Accordingly, ultrasonic medical applications use a constant current control algorithm because of the following performance advantages: increased electrical safety due to lower operating voltage; proportional current to tip velocity (displacement if frequency is held constant); and the capability to limit excessive power surges by setting the voltage rail to an appropriate value, among others.

As discussed elsewhere herein, in embodiments system <NUM> can be compatible with or comprise more than one ultrasound transducer <NUM>. This plurality of USTs <NUM> can be operated sequentially or even simultaneously in embodiments, or an operator can select a single UST <NUM> from among the plurality for use in system <NUM>. In embodiments, microprocessors <NUM> and/or <NUM> can automatically adjust for a selected UST <NUM> or multiple USTs <NUM>, which can be implemented in multiple treatment wands <NUM> in embodiments.

Generator unit <NUM> includes a power entry module and AC/DC power supply <NUM> as well as an ultrasonic driver <NUM>. Delivery pump(s) <NUM> are mounted on generator unit <NUM> in one embodiment and are controlled by a pump driver located on ultrasonic driver <NUM>. In another embodiment, a pump(s) <NUM> can be provided in a separate pumping unit, such as one that additionally couples with or comprises mixing and valving components as previously discussed. Communications ports <NUM>, <NUM>, and <NUM> are also located on the generator unit <NUM>, though the number and arrangement of communications ports can vary from those depicted. For example, in other embodiments more or fewer ports are provided, and one or more of the ports can comprise a wireless communications port (e.g., infrared, RF, BLUETOOTH, WIFI or some other wireless technology). These ports provide an information exchange between generator unit <NUM> and treatment wand <NUM> as well as information exchange between device <NUM> and user.

With respect to the Power Entry Module & AC/DC Power Input, in some embodiments the local AC MAINS is connected to an appliance inlet with a hospital grade detachable power cord. In some embodiments, two power cords will be used, 15A with a 125V rate and 10A with a 250V rate. In some embodiments, the appliance inlet is a power entry module listed for medical applications with an 10A current rating, <NUM>/250VAC voltage input, MAINS switch, integral fuse holder (<NUM>¼ x1 <NUM>/<NUM>" / 5x20mm fuses), EMC line filter for medical applications, and is mounted on the rear panel of the chassis. Although not depicted in the figures, embodiments are contemplated that use battery power as the power source in the system's design. The battery would be located within generator <NUM> in various embodiments. Battery power is made possible due to the extremely efficient design discussed herein.

In some embodiments, system <NUM> can have a universal AC power input capability accepting a range of power input from 90V to 265VAC. The local AC MAINS are connected to an appliance inlet component (IEC <NUM> C14) with a hospital grade detachable power cord. The appliance inlet is a power entry module listed for medical applications with an 115V / 230V voltage input, MAINS switch, integral fuse holder (<NUM> -5x20mm fuses), and an EMC line filter for medical applications that is mounted on the rear panel of the chassis. The MAINS switch output is connected to two AC/DC switching power modules. The two AC/DC (24V output) switching power supply modules are serially connected together to provide +/-24V power to AB type amplifier use. All DC power sources +5V, +<NUM>. 5V, -<NUM>. 5V and <NUM>. 3V are generated from +24VDC - power source via DC/DC converter. The +5VDC will provide 5V power to treatment wand <NUM> through the detached cable and medical grade connector <NUM>.

In some embodiments, two identical AC/DC (24V output) switching power supply modules are serially connected together to provide +/-24V power to AB type amplifier use. The power supply can be medical grade, Class II, BF rated with 45W output with conventional cooling. A dual color (Red/Green) LED <NUM> can be mounted at the front of generator unit <NUM>. The green color indicates normal power on without errors, and the red color indicates a system error or failure. Error detail information can also display on the interface display screen <NUM> of treatment wand <NUM>.

In some embodiments, there is a plurality of, such as three, communication ports in the on generator <NUM>. The first port is a RS488 communication port <NUM>, with 5V power and XD outputs. This port <NUM> is connected to treatment wand <NUM> through cable <NUM>. Port <NUM> can be configured for full duplex communications in both directions at the same time. This port <NUM> can handle information exchange between generator unit <NUM> and treatment wand <NUM>. In operation, both sets of microcontrollers <NUM> and <NUM> can check each other to ensure none has failed to operate through this port <NUM>. The second port can be a USB-<NUM> type A port, referred to herein as port <NUM>. It can be designed for user download of information stored at the EEPROM memory <NUM> by using flash key device. This port <NUM> can be used for uploading software from flash key device. A third port can be an RS232-<NUM>. 3V serial port, referred to herein as port <NUM>. Port <NUM> can be designed for use with a PC, so the PC can communicate to the system <NUM> for download, upload, system debug and calibration. Also included in generator unit <NUM> and connected to the microcontroller are RTC DS1306 at numeral <NUM>, audible signal generator <NUM> and generator temperature sensor <NUM>. Additional sensors can be included in generator unit <NUM> in other embodiments, as discussed elsewhere herein.

A microcontroller controlled pump delivery system <NUM> can be used for fluid and material delivery. Delivery system <NUM> comprises pump(s) <NUM> and pump driver with controls <NUM> for pump speed and pump doors monitoring and can deliver fluid, such as saline or another fluid enriched with a biologic or cellular material, through a tube <NUM> and applicator <NUM> to the tip of ultrasonic transducer <NUM>. Microcontroller (MCU1) <NUM> of generator unit <NUM> can control peristaltic pump speed to control fluid flow rate for a fixed tubing size. Pump delivery system <NUM> generally operates at constant flow rate for all operating conditions. A cooling fan <NUM> is mounted in the back of generator unit <NUM>. It is controlled by microcontroller <NUM> of ultrasonic driver <NUM>.

Ultrasonic driver <NUM> includes a microprocessor <NUM> that controls, measures and monitors the drive electronics and communicates with the hardware and software of the treatment wand <NUM>. In some embodiments, ultrasonic driver <NUM> includes a microprocessor <NUM> (such as Microchip Technology Inc. PIC32) with an <NUM> clock and <NUM>. 56DMIPS/MHz performance, though some other suitable microprocessor can be used in other embodiments. The drive electronics contain a digital frequency generator (DDS) <NUM>, AC amplifier <NUM> and voltage and current phase detection circuits <NUM> and <NUM>. Digital frequency generator <NUM> generates accurate frequencies set by microprocessor <NUM> to AC amplifier <NUM> that are output via impedance match <NUM> to ultrasonic transducer <NUM>. Voltage and current phase detection circuits <NUM> and <NUM> continually monitor the phase difference sensed at <NUM>. In operation, microprocessor <NUM> can adjust the digital frequency generator output frequency based on voltage and current phase angle so that the frequency is locked at the resonance frequency Fr of ultrasonic transducer <NUM>. The resonance frequency Fr is not a fixed frequency, however, as it can drift with temperature and other changes. This is discussed herein below in additional detail.

Ultrasonic driver <NUM> also includes a digital frequency generator <NUM>, a resonance frequency control loop <NUM>, and an output current control loop <NUM>. Microcontroller <NUM> can be of sufficiently high speed so as to handle all input measures and output settings, especially for phase comparison of cycle by cycle frequency adjustment in real time. Ultrasonic driver <NUM> generates electrical output with an ultrasonic frequency and a required power.

At Fr and Fa, the impedance phase is <NUM> degrees, which means that ultrasonic transducer <NUM> can achieve the highest power efficiency at those points. Accordingly, it is recognized that keeping the output frequency close to Fr or Fa would be desirable, if possible. However, it is very difficult for any control systems to operate at Fr and Fa, as at those points any small increase or decrease of frequency will cause a large impedance increase or decrease. Accordingly, most ultrasonic drivers either operate at frequencies higher than Fa or lower than Fr because frequencies are relatively stable when they are farther from Fr or Fa.

For example, some conventional systems have been designed to operate in the Fa region. These designs were relatively stable and delivered effective treatment, but output power efficiency was very low and a very high operating voltage was required. Accordingly, in order to meet regulatory safety requirements, wires with high isolation and earth protection were required, adding cost and restricted user ergonomics due to a stiffer and heavier cable.

An example comparing the voltage required by a past device operating at Fa compared to an embodiment of the currently disclosed system, operating at Fr, is set forth below:
A conventional ultrasonic transducer was operated at anti-ultrasonic region which is approximately 1KΩ~8KΩ impedance. To deliver the required power to the transducer the driver must output very high voltage (300V) to the transducer. The power calculation is: <MAT>.

If the transducer requires 7W power, ϕ =<NUM>°, Z=1500Ω, from Equation <NUM> the current will be: <MAT> Accordingly, a power supply voltage would be: (230mA* 1500Ω) = 347V.

An embodiment of system <NUM>, in contrast, operates at Fr with constant current output control. Its impedance is about <NUM>-<NUM>Ω and voltage current phase angle close to <NUM> degrees. The power efficiency is almost <NUM>%. An example with Fr impedance is 50Ω.

If the transducer requires 7W power, ϕ =<NUM>°, Z=50Ω, the current will be: <MAT> and the power voltage will be: 370mA *50Ω = <NUM>.

Accordingly, embodiments of system <NUM>, with a low voltage operation condition, can be much more efficient and safer than conventional designs. Any voltage surges resulting when transducer impedance is increased can be limited by setting the voltage rail to an appropriate value.

Microcontroller <NUM> of the ultrasonic driver controls all input and output functions and performs all control loops and calculations. Certain embodiments of microcontroller <NUM> may include one or more of the following: a <NUM> maximum frequency; <NUM> DMIPS/MHz (Dhrystone <NUM>) performance; an operating voltage range of <NUM>. 3V to <NUM>. 6V; a <NUM> flash memory (plus an additional <NUM> KB of Boot Flash); a <NUM> SRAM memory; USB <NUM>-compliant full-speed device and On-The-Go (OTG) controller; up to <NUM>-channel, <NUM>-bit Analog-to-Digital Converter; six UART modules with RS-<NUM>, RS-<NUM> and LIN support; and up to four SPI modules. These characteristics are merely examples and can vary in other embodiments.

The ultrasonic frequency generator is a digital frequency generator <NUM> that provides numerous advantages over conventional designs. In some conventional designs, PLL technology was used with a voltage control oscillator (VCO) for generating a fixed ultrasonic frequency. However, this produced an output frequency that is low resolution and not flexible for wide frequency range applications without hardware changes. Further, the frequency stability was imprecise since the VCO is affected by temperature, noise and power ripple.

In the current ultrasonic therapy system <NUM>, a Direct Digital Synthesis programmable frequency generator (DDS) is used as part of the frequency generator <NUM>. Because a DDS is digitally programmable, the phase and frequency of waveform can be easily adjusted without the need to change the external components that would normally need to be changed when using traditional analog-programmed waveform generators. DDS permits simple adjustments of frequency in real time to locate resonance frequencies or compensate for temperature drift. The output frequency can be monitored and continually adjusted by microcontroller <NUM> at real time speed. Advantages of using DDS to generate frequency include: digitally controlled micro-hertz frequency-tuning and sub-degree phase-tuning capability; extremely fast speed in tuning output frequency (or phase); and phase-continuous frequency hops with no overshoot/undershoot or analog-related loop setting-time anomalies, among others.

The digital architecture of DDS eliminates the need for the manual tuning and tweaking related to components aging and temperature drift in analog synthesizer solutions, and the digital control interface of the DDS architecture facilitates an environment where systems can be remotely controlled and optimized with high resolution under processor control. <FIG> shows the system's digital frequency generation using microcontroller <NUM> and DDS <NUM>. Specifically, frequency set <NUM> and amplitude set <NUM> are received by DDS <NUM> which generates an output frequency <NUM> (fout).

<FIG> sets forth the frequency control loop <NUM> for system <NUM>. Frequency control loop <NUM> includes a digital frequency generator (DDS) <NUM>, D/A converter <NUM>, phase detector <NUM> and microprocessor <NUM>. The drive electronics utilize the digital frequency generator <NUM>, AC amplifier <NUM> and voltage and current phase detection circuits <NUM> and <NUM>. Digital frequency generator <NUM> generates a high accuracy and precision frequency signal, set by the microprocessor <NUM>, to AC amplifier <NUM> that outputs across a transducer load <NUM> to ultrasonic transducer <NUM>. At start-up, system <NUM> performs a Power On Self-Test (POST) and communicates with ultrasonic transducer <NUM> to gather information on characteristics of ultrasonic transducer <NUM> and determine that treatment wand <NUM> is functioning properly.

Specifically, when initially energized, microprocessor <NUM> can be programmed to perform a frequency sweep using a sine wave to determine the resonant frequency by evaluating and looking for a relative minimum impedance of ultrasonic transducer <NUM>. The sweep is confined to a smaller defined interval based on the information embedded in treatment wand <NUM> regarding the operating characteristics of ultrasonic transducer <NUM>. This includes the information stored in ultrasonic transducer <NUM> at the time of manufacture or otherwise programmed or updated. During the system start, digital frequency generator <NUM> can scan frequencies from a start frequency (min <NUM>, adjustable) to an end frequency (max <NUM>, adjustable) to find the resonance frequency (Fr). Microprocessor <NUM> can adjust the digital frequency generator output frequency based on voltage and current phase angle so that the frequency lockup is maintained at the resonance frequency of ultrasonic transducer <NUM> (i.e., at a <NUM>° phase angle). Because the frequencies continually shift due to temperature change and other factors, the phase of output voltage and current will change as well. The voltage and current phase detection circuits are continually monitored for the phase difference and adjusted accordingly. Resonance frequency is not a fixed frequency. This is due to heating and other factors causing a slight drift change with temperature. Specifically, increased temperature can cause decreased resonant frequency.

In order to keep output frequency lockup at resonance frequency, frequency control loop <NUM> can operate at the real time monitoring output voltage and current phase angle and continually adjust operating frequency to match the current resonance frequency. In some embodiments, microprocessor <NUM> can maintain Δϕ (as illustrated at <NUM>) to less than about <NUM> degree inaccuracy and provide sufficient capabilities to achieve accuracy of about <NUM> or better. In some embodiments, resonance frequency is digitally controlled to better than about <NUM> while maintaining constant energy output.

<FIG> sets forth output current control loop <NUM> for system <NUM>. Output current control loop <NUM> is designed to provide a constant current output. Since the transducer output displacement is a function of transducer current, the control output current (not voltage) will control output displacement. Displacement determines the amount of ultrasound energy delivered/output. Microprocessor <NUM> monitors the output current via a sensing resistor then adjusts the digital frequency generator <NUM> output signal level to maintain constant current output thus maintaining a constant output displacement from the tip of the horn. Current sensing circuit <NUM> will sense peak current, then convert peak value to an RMS value. Any waveform distortion will cause converter errors causing current control errors and ultimately displacement errors. To avoid this situation, embodiments of the system can use RMS sensing technology to reduce the errors. This may be implemented if the waveform has considerable distortion, for example.

In system <NUM>, the digital frequency generator <NUM> can be used to allow for selection and use of different frequencies via software implementation. Configurations having frequencies ranging from about <NUM>-<NUM> are possible. Digital frequency generator <NUM> is digitally programmable. Accordingly, the phase and frequency of a waveform can be easily adjusted without the need to change hardware (frequency generating components), as would normally be required to change when using traditional analog-programmed waveform generators. Digital frequency generator <NUM> permits simple adjustments of frequency in real time to locate resonance frequencies or compensate for temperature drift or other deviations in the resonant frequency. The output frequency can be monitored and continually adjusted by microcontroller <NUM> at real time speed.

There are many advantages to using digital frequency generator <NUM> to generate frequency. For example, this provides a digitally controlled, <NUM>-Hertz frequency-tuning and sub-degree phase-tuning capability as well as extremely fast speed in tuning output frequency (or phase). The digital frequency generator <NUM> also provides phase-continuous frequency loops with no overshoot/undershoot or analog-related loop setting-time anomalies. The digital architecture of the digital frequency generator <NUM> eliminates the need for the manual tuning and tweaking related to components aging and temperature drift in analog synthesizer solutions, and the digital control interface of the digital frequency generator architecture facilitates an environment where systems can be remotely controlled and optimized with high resolution under processor control.

In this system, ultrasonic driver <NUM> outputs a sine waveform through a class AB power amplifier <NUM>. It can operate at frequency from <NUM> to <NUM>, constant current mode. The ultrasonic driver <NUM> outputs current from <NUM> to <NUM>. 5A, voltage from <NUM> to 30Vrms, Max power to 15W. The ultrasonic driver output can scan resonance frequencies from the <NUM> to <NUM> range, detect minimum impedance (<NUM>° degree phase angle of voltage and current), and then lock operational frequency to resonance frequency of the ultrasonic transducer <NUM> at a ±<NUM> accuracy level. Parameters may vary in various embodiments. In certain embodiments, the drive voltage requirements are less than 50Vrms for the system.

The technology of system <NUM> is unique in that sees an essentially constant load. The no-load condition is similar to the operational load. Being a non-contact treatment and dispensing only a small amount of fluid onto the horn does not create a significant variation in the load/output allowing the system to be run at resonance (Fr). Running and controlling the system at Fr allows greater efficiency, as previously discussed. Typical ultrasound applications such as welding, mixing, cutting, and cleaning have significant variation in the load, e.g., going from a no-load to full load condition. The variation makes control of the output very difficult and requires greater power at the cost of efficiency.

<FIG> is a graph that helps to illustrate advantages of using system <NUM>'s ultrasonic driver based on the impedance and frequency characteristics of ultrasonic transducer <NUM>. Specifically, the dramatic change in impedance magnitude <NUM> and phase <NUM> is seen for changes in frequency <NUM> for even small deviations from the resonance frequency <NUM> and anti-resonance frequency <NUM>. Ultrasonic transducer <NUM> is a component that converts electrical energy to mechanical energy. Its impedance and frequency characteristics create significant drive circuit design challenges, especially if trying to optimize for low power input and accuracy. Traditional ultrasonic driver designs typically use Phase Loop Lock (PLL) frequency control technology. However, analog system performance generally does not allow for accuracy and stable frequency output. Accordingly, make it difficult to control the system precisely with analog systems. In theory, an ultrasonic transducer operating at resonance frequency Fr or anti-resonance Fa frequency has a high efficiency output. In practice, when ultrasonic transducers operate at resonance frequency or anti-resonance frequency, it is almost impossible using PLL technology to maintain elegant control. Most other ultrasonic drivers utilize an analog PLL based design for control. The PLL based designs operate close to resonance frequency or anti-resonance frequency points, but due to their inherent inaccuracy, these often operate at some phase angle away from Fr or Fa leading to inefficiencies.

In system <NUM>, a constant current control algorithm can be used. It can operate at resonance frequency, rather than just close to resonant frequency. The difference between anti-resonance and resonance is anti-resonance with highest impedance and resonance with lowest impedance. The high impedance can be range at 5KΩ~50KΩ and lowest impedance can be at 20Ω~100Ω in certain embodiments, for example.

Since ultrasonic transducer <NUM> is operated with relatively large displacements and a low load condition, there is a significant reduction in loading effects and electrical impedance variation. Many ultrasonic medical applications use a constant current control algorithm because of the following performance advantages: electrical safety (due to a lower operating voltage); current that is proportional to tip velocity (displacement if frequency is held constant); and fewer excessive power surges (by setting and maintaining the voltage rail to an appropriate value).

In some embodiments, and referring again to <FIG>, system <NUM> can comprise more than one treatment wand <NUM>, and microprocessor <NUM> can be programmed to sequentially operate the more than one treatment wands <NUM>. In <FIG>, treatment wand 40a is coupled to generator unit <NUM> by cable 90a. Second and third treatment wands (not depicted) can be coupled to generator unit <NUM> by cables 90b and 90c, respectively. In operation, a first transducer <NUM> in first treatment wand 40a can be used to atomize a first material (e.g., a liquid), and a second transducer <NUM> can atomize another material, thereby allowing for dispensing of two different cellular or other solutions, or the same solutions with different ultrasound characteristics (e.g., differently sized transducers). In such an embodiment, an operator can use one wand <NUM> in each hand, sequentially use one then the other wand <NUM>, or have multiple operators so that each wand is operated by its own operator. Multiple transducer embodiments can provide advantages, including being able to treat larger areas more quickly, allowing for dispensing different fluids and materials and treating with different ultrasound energies simultaneously, dispensing a first fluid without ultrasound and a second with ultrasound, among other advantages.

Some embodiments of system <NUM> have three modes of operation: a TREATMENT mode; an INFORMATION mode; and a TERMINAL mode. If the user enters the TREATMENT or normal operating mode upon power up, the user can select the length of time for a treatment and energize the acoustic output to treat a patient. In some embodiments, a user can select one or more additional parameters specific to a treatment to be provided, including parameters associated with a material to be delivered or otherwise used, including a cellular or biologic material. These parameters can include frequency, intensity, pulse length, beam characteristics, and application time on the skin. If the INFORMATION mode is entered on power up with a flash key plug to the USB port, user information can be downloaded that has been stored in the memory to flash or new software can be uploaded from the flash key to the system. Finally, a TERMINAL mode can be selected that is an engineering mode for internal device calibration, system characterization, and system evaluation.

System <NUM> may also save all information of the device hardware and software as well as the user's input and treatments during operation. In some embodiments, system <NUM> has enough memory storage for all information saved for at least one year of operation. For example, system <NUM> may implement 2MB bits EEPROM and flexible size memory in some embodiments.

<FIG> combine to provide a flow diagram operational method <NUM> of ultrasonic system <NUM>. Operation begins by first powering on the system at <NUM>, followed by conducting a system self-test at <NUM>.

<FIG> shows the steps of self-test <NUM>. First, system <NUM> can verify the integrity of the executable code and verifies RTC at <NUM>. Next, at <NUM>, if the self-test is passed, operation continues on to <NUM>. If the self-test is not passed, an error message is displayed at <NUM> on display <NUM> and the system is shut down at <NUM>.

If <NUM> is reached (in <FIG>), the number of wounds and size of wounds are input. If a new applicator <NUM> is present at <NUM>, operation proceeds, if not, a new applicator <NUM> is loaded at <NUM>. Next, at <NUM>, tuning mode commences.

<FIG> shows tuning mode <NUM>. First, the tuning mode voltage is set at <NUM>. Next the current loop is set off at <NUM>, followed by a search for the resonance frequency Fr of ultrasonic transducer <NUM> at <NUM>. If the resonance frequency is found at <NUM>, the system continues on to <NUM>. If the resonance frequency is not found, the system will try again for a set number of times at <NUM>. If resonance frequency is not found, after these attempts, an error is displayed on the system display <NUM> at <NUM>, followed by system shutdown at <NUM>.

If <NUM> is reached (in <FIG>), treatment is started following a successful tuning mode. Next, at <NUM>, the system checks the RFID tag on the applicator <NUM> to ensure that the treatment has proceeded for less than ninety minutes. If not, treatment is stopped at <NUM> and a new applicator is loaded at <NUM> before reengaging the operation at <NUM>. If the RFID tag indicates treatment of less than <NUM> minutes at <NUM>, then operation continues on to pump control at <NUM>.

<FIG> shows the pump control <NUM>. First, the system <NUM> checks that the pump doors of the peristaltic pumps <NUM> located on the exterior of the console / generator unit <NUM> are closed at <NUM>. If not, the display <NUM> indicates a message to close the pump doors at <NUM>. If the pump doors are closed, operation continues to <NUM> where the pump speed is set. The system then checks the pump speed at <NUM>, and the pump speed is set again if necessary, before proceeding on to <NUM> when the pump controls is complete.

When <NUM> is reached (<FIG>), the current is set for the ultrasonic transducer <NUM>. Next, the operation frequency is set at <NUM> and the voltage and current phase is measured at <NUM>. Next, monitoring the system commences at <NUM>.

<FIG> shows monitoring the system at <NUM>. First the system monitors: the temperature of the generator unit <NUM>; the temperature of the treatment wand <NUM>; the temperature of the case of the ultrasonic transducer <NUM>; the output voltage of the ultrasonic transducer <NUM>; the current of the pump <NUM>; and the communication between the two microprocessors <NUM> and <NUM> (MCU2 and MCU1). As previously mentioned, additional sensing (e.g., tissue temperature) also can be monitored and controlled by the system in various embodiments. Next, error codes are generated and communicated at <NUM> before returning to <NUM>.

When <NUM> is reached (<FIG>), if the system is not determined to be in order, an error message is communicated on the display <NUM> at <NUM> and the system is shut down at <NUM>. If, however, the system is determined to be ok at <NUM>, the system checks to ensure the voltage/current phase angle is <NUM>° at <NUM>. If not, operation reverts to <NUM> in which the operation frequency is adjusted to so that a voltage/current phase angle of <NUM>° can be achieved. If voltage/current phase angle is set to <NUM>° at <NUM>, the system checks to ensure the current sensed is equivalent to the current that was set for the system at <NUM>. If the current does not match, operation reverts to <NUM> and the transducer sets the current again before continuing. If the current is appropriate at <NUM>, the system then tests to see if the treatment has timed out at <NUM>. If it has not timed out, operation reverts to <NUM> and the test of <NUM> minute RFID time limit is conducted. If treatment has timed out at <NUM>, the treatment is stopped at <NUM> followed by the option to add a further treatment at <NUM>. If another treatment is desired, another treatment is added at <NUM> and operation reverts to the tuning mode at <NUM>. If no further treatment is desired, information is saved at <NUM>.

<FIG> shows saving information <NUM> in greater detail. First, the system collects device setup information, device operation information, and user treatment information at <NUM>. Next, at <NUM>, information is saved to EEPROM before continuing to system shutdown at <NUM>.

As understood by the various system checks and protocols in this operational explanation, the operation of the system can be suspended at many points. Advantageously, in certain embodiments, both microprocessor <NUM> and microprocessor <NUM> are configured to individually suspend operation of the ultrasonic system in fault condition situations. This arrangement provides enhanced safety not present in other types of designs.

As previously discussed, embodiments relate to or include the application of and treatment with biologic/cellular material(s) and ultrasound therapies. At a high level, there can be three stages of therapy in some embodiments: (<NUM>) preparation, (<NUM>) treatment, and (<NUM>) post-treatment. <FIG> are flowcharts that illustrate examples related thereto. In all cases, what is depicted in the figures and discussed herein is but an example embodiment, and other embodiments may include additional tasks not specifically depicted or discussed, omit tasks that are depicted or discussed, or reorder tasks. Additionally, tasks or features from different figures may be combined in other embodiments.

As depicted in <FIG>, a biologic/cellular material is prepared at <NUM>. The material is solubilized into a liquid solution at <NUM>. In some embodiments the material can be solubilized in sterile saline solution, phosphate buffered saline, acidic solutions (e.g., having pH of greater than about <NUM>), basic solutions (e.g., having a pH of less than about <NUM>) or combinations thereof or other solutions. The solution can be loaded into a sterile container <NUM> at <NUM>. At <NUM>, the solution is applied to the wound or treatment area via e.g., system <NUM>. In other embodiments, the solution or other biologic material can be applied to the wound or treatment area manually and then treated by system <NUM>. For example, a biologic in, e.g., powder form can be manually applied, such as by sprinkling, to a treatment area and then treated by system <NUM>.

Another example depicted in <FIG> relates to embodiments in which a plurality of biologic/cellular materials is prepared and applied to a wound other area for treatment. At <NUM>, a first biologic/cellular material is prepared. At <NUM>, a second biologic/cellular material is prepared. In one embodiment, multiple biologics are combined or mixed at <NUM>. This can be accomplished, for example, by valving or other features of system <NUM>, or the materials or solutions can be mixed and combined in a container or combined in some other way. At <NUM>, the mixture is applied to the wound or other treatment area by system <NUM>.

In another embodiment, the first and second materials can be applied via system <NUM> sequentially, as shown at <NUM> and <NUM>. For example, a liquid solution, such as saline or phosphate buffered saline, can be applied following biologic/cellular material application to the wound or treatment area. In other embodiments not depicted, a third or other additional materials can be applied, or different combinations of the tasks at <NUM>, <NUM>, <NUM> and/or <NUM> can be carried out in other embodiments. Delivery of the various materials and/or solutions can be accomplished and controlled by pumps, valving, multiple treatment wands and/or other features of various embodiments of system <NUM>, as discussed above.

Another example embodiment is depicted in <FIG>. At <NUM>, a biologic/cellular material can be prepared as a topical application <NUM>. In some embodiments the topical application can be a cellular sheet, powderized/lyophilized material, jet milled, a cream, liquid solution, or any combination thereof, as previously discussed. After topical application of the biologic/cellular material at <NUM>, sterile saline solution, other liquid solutions, or other treatments or therapies can be applied to the wound or treatment area via system <NUM> at <NUM>.

In the example embodiment of <FIG>, additional tasks can be included. For example, at <NUM> a cleaning or disinfectant substance can be applied to the treatment area prior to application of the biologic/cellular material. A biologic/cellular material can then be prepared at <NUM> and applied to the wound or treatment area at <NUM>. A liquid solution or second biologic/cellular material optionally can be applied at <NUM> to the wound or treatment area. Following either task <NUM> or task <NUM>, a protective coating or biologic enhancing or activating material can be applied to the wound or treatment area at <NUM>.

Thus, a variety of wounds, skin and other tissue conditions, and other issues can be treated by application of one or more biologic and/or cellular materials with an ultrasound system. These materials and the system can promote healing in a variety of ways, such as with faster healing, reduced pain, modulation of factors that affect healing processes (e.g., inflammation) and/or reduced likelihood of infection. For example, broad application of a biomaterial may reduce likelihood of adhesions when applied intraoperatively before closing a surgical site. This can minimize patient risk by being able to treat with material from one human donor rather than requiring more material and, hence, the potential for more than one donor (which multiplies the potential risk). In another example, penetration of some biologic and/or cellular materials can be enhanced (e.g., in the treatment of deep wounds or conditions) when administered by or with ultrasound. In yet another example, the systems, materials and methods disclosed herein can be used for debriding wounds or tissue areas, which also can promote wound healing. In a further example, embodiments can provide more effective ways to deliver topical treatment of defects associated with inflammatory conditions, which may allow drug therapy doses (and their side effects) to be decreased. In an even further example, embodiments can be used to deliver biologic drugs to bypass use of the gastrointestinal (GI) tract or injections (e.g., intravenous or intramuscular). Additionally, embodiments can reduce the aesthetic insult of scarring and provide more functional (regenerative) benefits than fibrotic results from an impaired healing process. Also, embodiments may be used to activate a bioglue or other molecule or material that can form an effective "new skin" barrier to a wound or tissue. These are only some examples, and many other examples have been given herein throughout. Still other examples and potential uses of the materials, systems, devices and/or methods discussed herein will be appreciated by those having skill in the art.

In an embodiment, a method of treating a skin, mucosa, or other condition comprises using an ultrasound delivery device to apply to an area of skin, mucosa or other tissue affected by the condition a mist that comprises a micronized cellular or biological material. The cellular or biological material can comprise a placental extracellular matrix composition or a placental connective tissue matrix composition. The placental extracellular matrix composition or placental connective tissue matrix composition can be prepared from whole placenta, placental deciduas, placental amniotic membrane, or placental chorionic membrane. The cellular or biological material can comprise a population of adherent cells. The cellular or biological material can comprise a mixture of adherent and non-adherent cells. The cellular or biological material can comprise platelet rich plasma or placental perfusate. The cellular or biological material can be micronized by grinding, milling, freeze drying, or heat drying. The skin condition can comprise a wound.

In an embodiment, a medical ultrasound device for delivering non-contact ultrasound therapies to a skin or other condition comprises at least one treatment wand comprising an ultrasonic transducer; at least one reservoir that contains a fluid or suspension comprising a micronized cellular or biological material; and a pump that is in fluid communication with the reservoir and the treatment wand to deliver the fluid to the treatment wand such that the ultrasonic transducer atomizes the cellular or biological material as the cellular or biological material passes through the treatment wand for delivery to the wound or other tissue. The the device can comprise a plurality of treatment wands and a plurality of reservoirs, wherein each treatment wand is in fluid communication with one of the reservoirs. The at least one of the plurality of reservoirs can contain a fluid for cleaning or disinfecting the area of skin or other tissue that is affected by the condition. The fluid can be for debriding a wound or tissue. The at least one of the reservoirs can contain a fluid for providing a protective or other coating on a wound or other tissue. The at least one reservoir can be sterile. The device can further comprise an applicator configured to be coupled to the treatment wand, wherein the applicator comprises a radio frequency identification (RFID) tag and the treatment wand comprises a RFID transceiver that is used to identify the RFID tag on the applicator to ensure that the applicator is limited to a single use. The device can further comprise a microprocessor configured to control operation of the device. The at least one treatment wand can comprise a plurality of tubes and the device comprises a plurality of reservoirs, each tube in fluid communication with a different one of the plurality of reservoirs, and wherein the microprocessor is configured to control a delivery pattern of fluids from the plurality of reservoirs. The delivery pattern can be sequential delivery of individual fluids or simultaneous delivery of at least two fluids. The medical ultrasound device can comprise one treatment wand and a plurality of reservoirs, wherein the device further comprises at least one valve configured to selectively couple at least one of the plurality of reservoirs to the treatment wand The at least one valve can comprise a static mixer. The device can comprise a microprocessor configured to control operation of the device and the at least one valve. The at least one valve can be manually controllable. The medical ultrasound device can further comprise a nozzle coupled to the treatment wand and configured to provide fluid from the at least one reservoir to the at least one treatment wand. The medical ultrasound device can further comprise a temperature control unit configured to heat or cool the fluid from the at least reservoir before the fluid is delivered to the treatment wand. The medical ultrasound device can further comprise a temperature control device configured to be coupled with the at least one reservoir to heat or cool the fluid contained therewithin. The treatment wand can comprise a motion processing unit and a user interface, wherein the user interface is configured to receive data from the motion processing unit and provide feedback to a user regarding positioning of the treatment wand during use of the device. The motion processing unit can be configured to adjust a characteristic of the device based on the received data related to positioning of the treatment wand during use of the device. The characteristic can be at least one of a flow rate of the fluid or a frequency of the ultrasonic transducer. The feedback can be at least one of visual feedback, audible feedback or haptic feedback. The at least one reservoir can comprise a machine-readable component, and the device can comprise a reader configured to read the machine-readable component and do at least one of: confirm that the fluid is for use with a particular patient; confirm a content of the reservoir; prompt a user to read, using the reader, a corresponding machine-readable patient identifier before use of the device; or receive device programming information from the machine-readable label. The machine-readable component can be a wirelessly machine-readable component, a radio frequency identification (RFID) tag, a bar code, or a Quick Response (QR) code. The medical ultrasound device can further comprise a reader configured to read a machine-readable component on a component or accessory of the device to confirm that the component or accessory is usable with the device. The medical ultrasound device can further comprise at least one mixer to mix the fluid in the at least one reservoir. The at least one mixer can mix the micronized cellular or biological material and the fluid. The at least one mixer can mix the fluid in a first one of the at least one reservoir with the fluid in at least a second one of the at least one reservoir. The at least one mixer can be a static mixer or a vibration mixer. At least one characteristic of the device can be variable to produce a variable spray pattern for delivery to the wound or other tissue. At least one characteristic of the device can be a size of an orifice of an applicator of the treatment wand, a shape of the orifice of the applicator of the treatment wand, a characteristic of the applicator of the treatment wand, a characteristic of a tip of an ultrasonic transducer of the treatment wand, or a flow rate of the fluid. The medical ultrasound device can further comprise a disposable kit comprising a single-use applicator coupleable to the treatment wand, tubing to convey the fluid from the reservoir to the treatment wand, and a spike to pierce the reservoir to couple the tubing to the reservoir. The kit can further comprise at least one of a valve or a disposable mixer.

In an embodiment, a method of promoting wound healing comprises providing a micronized cellular or biological material to be applied to the wound as a mist formed by an ultrasound delivery device. The cellular or biological material can comprise a placental extracellular matrix composition or a placental connective tissue matrix composition. The placental extracellular matrix composition or placental connective tissue matrix composition can be prepared from whole placenta, placental desidua, placental amniotic membrane, or placental chorionic membrane. The cellular or biological material can comprise a population of adherent cells. The cellular or biological material can comprise a mixture of adherent and non-adherent cells. The cellular or biological material can comprise platelet rich plasma or placental perfusate. The cellular or biological material can be micronized by grinding, milling, freeze drying, or heat drying.

In an embodiment, a method of promoting wound healing comprises providing a micronized cellular or biological material to be applied to the wound manually followed by a mist formed by an ultrasound delivery device. The cellular or biological material can comprise a placental extracellular matrix composition or a placental connective tissue matrix composition. The placental extracellular matrix composition or placental connective tissue matrix composition can be prepared from whole placenta, placental amniotic membrane, or placental chorionic membrane. The cellular or biological material can comprise a population of adherent cells. The cellular or biological material can comprise a mixture of adherent and non-adherent cells. The cellular or biological material can comprise platelet rich plasma or placental perfusate. The cellular or biological material can be micronized by grinding, jet milling, freeze drying, or heat drying.

In embodiments, system <NUM> and/or its components or systems include computing devices, microprocessors, modules and other computer or computing devices, which can be any programmable device that accepts digital data as input, is configured to process the input according to instructions or algorithms, and provides results as outputs. In an embodiment, computing and other such devices discussed herein can be, comprise, contain or be coupled to a central processing unit (CPU) configured to carry out the instructions of a computer program. Computing and other such devices discussed herein are therefore configured to perform basic arithmetical, logical, and input/output operations.

Computing and other devices discussed herein can include memory. Memory can comprise volatile or non-volatile memory as required by the coupled computing device or processor to not only provide space to execute the instructions or algorithms, but to provide the space to store the instructions themselves. In embodiments, volatile memory can include random access memory (RAM), dynamic random access memory (DRAM), or static random access memory (SRAM), for example. In embodiments, non-volatile memory can include read-only memory, flash memory, ferroelectric RAM, hard disk, floppy disk, magnetic tape, or optical disc storage, for example. The foregoing lists in no way limit the type of memory that can be used, as these embodiments are given only by way of example and are not intended to limit the scope of the invention.

In embodiments, the system or components thereof can comprise or include various modules or engines, each of which is constructed, programmed, configured, or otherwise adapted, to autonomously carry out a function or set of functions. The term "engine" as used herein is defined as a real-world device, component, or arrangement of components implemented using hardware, such as by an application specific integrated circuit (ASIC) or field-programmable gate array (FPGA), for example, or as a combination of hardware and software, such as by a microprocessor system and a set of program instructions that adapt the engine to implement the particular functionality, which (while being executed) transform the microprocessor system into a special-purpose device. An engine can also be implemented as a combination of the two, with certain functions facilitated by hardware alone, and other functions facilitated by a combination of hardware and software. In certain implementations, at least a portion, and in some cases, all, of an engine can be executed on the processor(s) of one or more computing platforms that are made up of hardware (e.g., one or more processors, data storage devices such as memory or drive storage, input/output facilities such as network interface devices, video devices, keyboard, mouse or touchscreen devices, etc.) that execute an operating system, system programs, and application programs, while also implementing the engine using multitasking, multithreading, distributed (e.g., cluster, peer-peer, cloud, etc.) processing where appropriate, or other such techniques. Accordingly, each engine can be realized in a variety of physically realizable configurations, and should generally not be limited to any particular implementation exemplified herein, unless such limitations are expressly called out. In addition, an engine can itself be composed of more than one sub-engines, each of which can be regarded as an engine in its own right. Moreover, in the embodiments described herein, each of the various engines corresponds to a defined autonomous functionality; however, it should be understood that in other contemplated embodiments, each functionality can be distributed to more than one engine. Likewise, in other contemplated embodiments, multiple defined functionalities may be implemented by a single engine that performs those multiple functions, possibly alongside other functions, or distributed differently among a set of engines than specifically illustrated in the examples herein.

Claim 1:
A medical ultrasound device (<NUM>) for delivering non-contact ultrasound therapies to a skin, mucosa, or other tissue affected by a wound, ulcer, or other condition, the device comprising:
at least one treatment wand (<NUM>) comprising an ultrasonic transducer (<NUM>);
at least one reservoir (<NUM>) that contains a fluid comprising a micronized cellular or biological material; and
a pump (<NUM>) that is in fluid communication with the reservoir and the treatment wand to deliver the fluid to the treatment wand such that the ultrasonic transducer forms the fluid including the cellular or biological material into a mist as the fluid passes through the treatment wand for delivery to the skin, mucosa, or other tissue.