Patent Abstract:
In one embodiment, an IDDC system utilizes an intelligent therapeutic agent delivery system comprised of one, but more likely an array of “cells” containing therapeutic agent(s) and/or diagnostic agents(s); an integrated bio-sensing system designed to sample and analyze biological materials using multiple sensors that include both hardware and software components. The software component involves biomedical signal processing to analyze complex liquid mixtures and a microcontrollers) acts as interface to the biosensors, to the therapeutic delivery elements, and to a communications system(s) for the purpose of controlling the amount of therapeutic agent to deliver and also to provide information in a useful form to interested parties on the progress of therapy and compliance thereto. The synergistic effect of combining the above describe elements is expected to dramatically improve patient compliance with prescribed therapy, quality and timeliness of care provided by physicians, and at the same time reduce the cost of providing effective healthcare to IDDC system users, thereby improving profitability for Managed Care organizations and pharmaceutical companies utilizing the system.

Full Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application claims the benefit of U.S. patent application Nos. 61/014,184 and 61/023,972, each of which is hereby expressly incorporated by reference in its entirety. 
    
    
     TECHNICAL FIELD 
     The present invention relates generally to an integrated intra-dermal delivery, diagnostic and patient interface system and in particular, relates to a transdermal delivery system having micro/nano features suitable for delivery below the stratum corneum layer, to an integrated biosensing system that can be used with the transdermal delivery system, an integrated micro-controller and an integrated communication system. 
     BACKGROUND 
     The healthcare industry in the U.S. drives an annual health related spending of approximately $2 trillion. Goods and services are provided by manufacturers of drugs, medical devices, and other supplies, with combined revenue of $300 billion, and by care providers—doctors, hospitals, clinics, nursing homes, etc., with combined annual revenue of $1.5 trillion. Most of the costs for healthcare is funded by private health insurers and government health insurance programs such as Medicare and Medicaid, with the private sector funding approximately $700 billion annually and the government providing combined annual payments of $1 trillion. Of the $1.5 trillion care provider market, the Managed Healthcare segment makes up approximately $350 billion. 
     This segment of the industry provides various types of health insurance plans designed with means of controlling the cost of healthcare related spending. The major products include health maintenance organizations (HMO&#39;s), preferred provider organizations (PPO&#39;s), point of services plans, and indemnity benefit plans. 
     The industry has expanded over the last decade on the premise that the traditional way of delivering healthcare was financially wasteful. Managed care companies attempt to control costs in four ways: by providing financial incentives to providers and users to minimize the amount of care used, contracting for services at discounted rates, reviewing expenses to determine the legitimacy of costs, and establishing low-cost treatment protocols providers are expected to follow. They are in effect, administrative intermediaries between healthcare providers and users. 
     In addition to using financial incentives to limit unnecessary medical care, managed healthcare companies use “utilization management” to review and standardize care. Committees of doctors and administrators review the actual services used in the network to determine if they&#39;re being used appropriately, and to recommend standards of care that doctors and hospitals are expected to follow. Committees also determine drug formularies that specify which drugs should be used to treat specific conditions. The statistical information collected for utilization management is also used for risk management and underwriting, the process of determining what payments to offer providers and what premiums to charge consumers. Computerized information and communications systems are vital to managed healthcare companies to process claims and manage records, and for statistical collection and analysis. 
     What appears to be an underdeveloped set of opportunities is preventive care and healing process management. According to PricewaterhouseCoopers, preventative care and disease management programs have untapped potential to enhance health status and reduce costs, a win for managed care and for the consumer. 
     Delivering care involves complex inter-relationships among multidisciplinary providers of various services and products. Opportunities for waste are rife. HealthCast 2020 survey respondents said sustainability depends on incentivizing clinicians, hospitals, pharmaceutical companies and payers to integrate care and manage chronic conditions together. The present applicant believes there is another critical component in this complex set of relationships, the patient. Wellness, prevention, and treatment regime compliance ultimately begins and ends with the patient. Patients are notoriously ineffective in maintaining compliance with their treatment regimes. Effectively integrating delivery, diagnostics, and communication into a single patient friendly system is expected to dramatically improve patient treatment outcomes and at the same time reduce cost and improve profitability for healthcare providers. 
     The pharmaceutical dosage form that may best be utilized to achieve the above described integration of functionality and technology is a patch or transdermal system. The currently available patch and transdermal technologies do not possess these capabilities and there is thus a need for an improved product that addresses and overcomes these deficiencies. 
     A transdermal drug delivery system is a system that delivers a dose of medication through the skin, for either local or systemic distribution. Often this promotes healing to a specific injured area of the body. An advantage of a transdermal drug delivery system over other types of drug delivery systems, such as oral, topical, etc., is that is provides a controlled release of the medicament into the patient. A wide variety of pharmaceuticals can be delivered via a transdermal drug delivery system. 
     One commonly found transdermal drug delivery system is a transdermal patch. A typical transdermal patch includes the following components: (1) a liner that protects the patch during storage and is removed prior to use; (2) a drug solution in direct contact with the release liner; (3) an adhesive that serves to adhere the components of the patch together along with adhering the patch to the skin; (4) a membrane that controls the release of the drug from the reservoir and multi-layer patches; and (5) a backing that protects the patch from the outer environment. 
     There are at least four different types of transdermal patches. One type is a single-layer drug-in adhesive where the adhesive layer of this system also contains the drug. The adhesive layer is surrounded by a temporary liner and a backing. A second type is a multi layer drug-in adhesive in which both adhesive layers are also responsible for the releasing of the drug; however, in this system, another layer of drug-in-adhesive is added. This path also has a temporary liner-layer and a permanent backing. A third type of path is a reservoir type that has a separate drug layer that is a liquid or semi-solid compartment containing a drug solution or suspension separated by the adhesive layer. A fourth type of patch is a matrix system that has a drug layer of a semisolid matrix containing a drug solution or suspension. An adhesive layer surrounds the drug layer partially overlaying it. 
     The limitations of these passive systems is that they are typically only effective in delivering (i) low molecular weight (&lt;500 Da) compounds, (ii) lipophilic compounds, and (iii) potent compounds requiring low dosage (20-25 mg). 
     SUMMARY 
     According to one embodiment of the present invention, an intra-dermal delivery, diagnostic and communication (IDDC) system utilizes an intelligent therapeutic agent delivery system that includes at least one but more likely an array of “cells” containing therapeutic agent(s) and/or diagnostic agents(s). The IDDC system also includes an integrated bio-sensing system that is designed to sample and analyze biological materials to measure or determine a number of parameters including but not limited to i) clinical or therapeutic markers or surrogates thereof, e.g. blood pressure, blood or interstitial glucose level, histamine levels, cholesterol level, triglyceride level, etc., ii) circulating levels of therapeutic agent(s) using multiple sensors that include both hardware and software components, where the software component involves biomedical signal processing and/or pattern recognition to analyze complex liquid mixtures, etc. The IDDC system also includes at least one microcontroller to act as an interface to the biosensors, to the therapeutic delivery elements, and to the communications system(s) for the purpose of controlling the amount of therapeutic agent to deliver and also to provide information in a useful form to interested parties (patient, physicians, Managed Care Organization) on the progress of therapy and compliance thereto. 
     A communication system can be provided to manage the collection, storage and transmission of information from the above systems to a receiver system which may include ubiquitous communication devices, such as cell phones, PDA&#39;s, and infrastructure services such as WiFi, WiMax, cell towers, etc., with another role of the communication system(s) being initial configuration or ongoing modification of therapeutic agent delivery regimen (maximal dosage per unit of time, etc.). An energy storage and delivery subsystem(s) are included as part of the IDDC system for the purpose of providing other subsystems of the device with electric power which is stored in a battery, capacitor, transmitted through a communications link, including but not limited to a wireless link, an RF (radio frequency) link or by a combination of the above. The synergistic effect of combining the above described elements dramatically improves the potential for patient compliance with prescribed therapy, quality and timeliness of care provided by physicians, and at the same time reduces the cost of providing effective healthcare to IDDC system users thereby improving profitability for Managed Care organizations and pharmaceutical companies utilizing the system. 
     In one embodiment, an intra-dermal delivery, diagnostic and communication (IDDC) system includes a micro/nano sized cell containing drug that has at least one drug, therapeutic agent, etc., stored within a membrane of the cell. The cell also has a magnetic element associated therewith. The system also includes a drug delivery device in the form of a micro/nano lancet that has a drug delivery conduit defined by an entrance and an exit defined at a sharp distal end of the lancet. The lancet also has actuator, such as a magnetic or piezoelectric element associated therewith. At least one of the magnetic or piezoelectric elements is an element that is energized by a source of power. By energizing the electromagnetic or piezoelectric element, the lancet is driven toward and through drug containing cell so as to cause the drug or therapeutic agent in the membrane to flow into the inlet, through the lancet to the exit where it is discharged into the patient&#39;s body below the stratum corneum. Upon de-energizing the magnetic elements or piezoelectric elements after successful delivery of the drug or agent, the lancet can be removed. Alternatively, the electromagnetic or piezoelectric element can be energized with reverse polarity to retract the lancet. 
     In another embodiment, a micro/nano implant device includes a body that has a holding post and a magnetic or piezoelectric element. A micro/nano barbed implant that has the drug or agent incorporated therein is held at one end of the holding post (opposite the magnetic element). A magnetic membrane is positioned along the patient&#39;s skin and upon energizing the magnetic or piezoelectric elements, the barbed implant and holding post penetrate the stratum corneum and the implant is positioned at a desired depth below the skin. Upon de-energizing the magnetic or piezoelectric elements, the device can be withdrawn from the stratum corneum; however, the barbs of the implant engage the skin layer and thereby hold the implant in place at the desired location and depth below the patient&#39;s skin. 
     In still another embodiment, a micro/nano implant device includes a body that has a holding post supported by a first side of a substrate. A micro/nano barbed implant that has the drug or agent incorporated therein is held at one end of the holding post (opposite the substrate). The barbs are recessed or otherwise contained in a surrounding pliable material. The substrate is placed on the user&#39;s skin, with the barbs and pliable material facing the skin. A pressure applied to an opposite, second side of the substrate causes the pliable material to compress and permits the barbs to implant through the stratum corneum at a desired depth below the skin which is generally equal to the height of the barb off of the substrate. The barbs remain within the skin after the substrate is removed. The barbs are bio-absorbed over time. The pliable material may incorporate a skin contact layer including a topical anesthetic, which may be from but not limited to (benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine (Alcaine), proxymetacaine, and tetracaine (AKA amethocaine.) the anesthetic being incorporated in a gel layer which may be comprised of cross-linked polymers or other materials, preferably something inert such as silica. The gel layer may have adhesion properties to ensure proper surface to skin contact and also allow for pain free removal as required. 
     In yet another embodiment, microneedles with channels are mounted on an oscillating movable base. The contact between a surface of the device and the skin is managed by and at the same time limited by a fixed casing. The microneedles are oscillated at a frequency between about 0 kHz to about 3 MHz (preferably between about 5 kHz to about 2 MHz), with amplitudes of between about 0 to about 1000 microns preferably between about 5 microns to about 250 microns). Amplitudes of oscillations are varied for drilling/opening channels in stratum corneum (SC)/epidermis/dermis and/or pumping/suction of drug/blood/interstitial fluids. The oscillating microneedles (with respect to the fixed device casting) create holes with specified properties in the stratum corneum. The design of the microneedles varies for specific requirements and depending upon the particular application. The back pressure and/or the SC-device interface pressure drive the drug to the target level in the intra-dermal space. Negative back pressure (difference) is utilized to extract blood and or interstitial fluid from the intra-dermal region into the appropriate reservoir(s) and in contact with (a) sensor(s). Pressure oscillations and motion control are utilized to move fluid in and out of the reservoir and in and out of contact with the sensor(s). The pressurized reservoirs utilize a synchronization scheme. Frequency and duty cycles as well as synchronization are optimized for the maximum performance. The biological sample can be obtained using any number of different techniques, including operating the device to draw the sample therein as when a pressure differential is created within the device. 
     Biosensing of the biological material may be accomplished utilizing electrical/electrochemical detection. The system can utilize one or more of i) application of DC voltage and measuring the DC current response (amperometry), ii) application of a DC current and measuring the DC voltage response (potentiometry), or iii) application of an AC voltage and measuring the AC current response (capacitance or impedance). In all cases, three electrodes are incorporated into the intra-dermal delivery, diagnostic and communication device, the working, reference and counter electrodes. These electrodes are positioned as closely together as possible, with analyte detection occurring at the working electrode. Ideally, the electrodes are designed such that the voltage is applied between the working and reference electrodes, while current is detected through the counter electrode. 
     A further embodiment involves the use of an electrode array, sometimes referred to as an “electronic tongue,” to subtract out the signal from background or interfering species from those of the analyte(s) of interest. The electronic tongue includes hardware and software that will allow for accurate transdermal and or intra-dermal detection of an analyte in blood or in interstitial fluids. The hardware of an electronic tongue is an array of sensor electrodes at which distinct electrical/electrochemical signals are obtained. The individual electrodes are constructed from different materials, are coated with different membranes, or have different biomolecules immobilized at of near their surfaces. Each individual sensor electrode can employ amperometric, potentiometric, capacitance, or impedance detection, as described above. For an electronic tongue, reference electrodes may sometimes be shared by multiple working electrodes. The software of this type of system utilizes this array of electrodes to recognize patterns associated with an analyte of interest. By using an array of electrodes, a ‘pattern’ can be detected which is robust to selectivity issues with any one individual electrode. 
     For larger molecules that elicit an immune response, antibody electrodes can be used to construct an electrochemical immunosensor, which may also suffer from interference from other species beyond the analyte of interest. A number of U.S. patents, including U.S. Pat. Nos. 7,241,628; 7,241,418; 6,815,217; and 5,356,785 (each of which is hereby incorporated by reference in its entirety), describe methods to use reference channels to subtract out the effects of interfering species in antibody-, DNA-, and nucleic acid-based sensors; however, all of these methods suffer from interference arising from non-specific interactions and cross-reactivity and therefore have limitations and shortcomings. 
     Although these patents discuss the use of reference antibodies, nucleic acids, and DNA to subtract out the signals of interfering species, the patents discuss optical, not electrical/electrochemical methods, and none of the patents mentions intra-dermal or transdermal applications. The use of an ULSI sensor device allows more intricate methods for background subtraction, including an electronic tongue constructed from an array of electrochemical sensors. 
     The hardware of the electronic tongue also includes interfacing circuitry that allows interface between a microcontroller and individual sensors. The interfacing circuitry allows for individual reading of the signals from each of the sensors in the array, signal conditioning for shifting signal levels to ones interpretable by the microcontroller and digitization of the sensor signals for further processing by the software component. 
     The software component of an electronic tongue involves analyzing the collection of signals from this array of sensor electrodes by signal processing and pattern recognition algorithms. Pattern recognition methods are applied to the signals obtained by the sensor array for a large number of blood and/or interstitial fluid samples. This large data set is analyzed off-line to develop pattern recognition algorithms which recognize via the incorporated processor or transferred wirelessly to an external integrated processor to find patterns that allow subtraction of the signal from background or interfering species at each sensor electrode, allowing detection of only the species that each electrode is designed to detect. When antibodies or oxidoreductase enzymes are immobilized at or near a particular sensor electrode, that electrode will be designed to detect a specific, corresponding analyte. In general, the electronic tongue may also contain blank sensor electrodes that are present only for background subtraction through the use of pattern recognition algorithms. 
     In addition, pattern recognition can be performed via the incorporated processor or transferred wirelessly to an external integrated processor. Supervised pattern recognition algorithm, such as support vector machines, logistic regression, neural networks, may be utilized and include steps of preprocessing, feature extraction, and classification training. The large dataset is used to train the algorithm to recognize complex patterns. Sensing data is processed by an on-board electronic controller. Processed data and instructions are transmitted to/from the patient, physician and or a health care provider via the wireless communications. 
     The software component measures the quantity of interest (biomarker concentration) that is stored internally or reported via the communication subsystem, or establishes the presence of an event of interest (such as the above normal concentration of a certain biomarker) that may trigger delivery of a therapeutic agent or reporting of event detection via the communication subsystem. In the case of local processing and local delivery on the incorporated processor (microcontroller), the processor executes algorithms of the software component, establishes presence of an event of interest and delivers the therapeutic agent if necessary. In case of the remote processing by the software component of the biosensor data, the microcontroller receives the results through the wireless interface and then makes the delivery decision. Alternatively, the fact of detecting an event of interest is communicated to the user and the user makes a decision on therapeutic agent delivery communicated to the microcontroller via the wireless interface. The microcontroller initiates drug delivery by activating the delivery subsystem. 
     It will also be appreciated that microneedles with channels, microchannels, pumping units with controls, valves, pressure/motion actuators (acoustic, electric, etc.), reservoirs, dump sites (reservoirs), sensors (for biomarkers, etc.), ultrasound (low and high frequency), sonophoresis, vibration (flexural waves), thermal (thermophoretic, heat, burn, thermal oscillations, thermal skin/penetration), iontophoresis (electric field, polar molecule migration), electrical pulses (electromagnetic field), electroporation, magnetophoresis (magnetic field), and chemical permeation enhancers can be utilized. 
     Functionality is achieved when repeating pulsation of the needles creates a high pressure field in the holes of the stratum corneum for drug delivery either due to reservoir pressure and/or inertia/dynamic effects. For extraction of blood/interstitial fluids, the back-pressure is decreased. The reservoir pressure is oscillated and synchronized with the needle oscillations to increase the pumping action. 
     It will be appreciated that the systems and devices of the present invention as described herein can be used to deliver any number of different types (classes) of drugs. For example, the following drug classes and drugs are exemplary and can be incorporated into one or more devices and/or methods disclosed herein and in accordance with the present invention: cardiovascular agents and inotropic agents (e.g., cardiac glycosides); antiarrhythmic agents (e.g., quinidine); calcium channel blockers; vasodilators (e.g., nitrates and peripheral vasodilators); antiadrenergics/sympatholytics (e.g. beta-adrenergic blocking agents, alpha/beta-adrenergic blocking agents, antiadrenergic agents—centrally acting, antiadrenergic agents—peripherally acting, antiadrenergic agents—peripherally acting/alpha-1 adrenergic blockers); renin angiotensin system antagonists (e.g., angiotensin—converting enzyme inhibitors, angiotensin II receptor antagonists); antihypertensive combinations; agents for pheochromocytoma; agents for hypertensive emergencies; antihyperlipidemic agents (e.g., bile acid sequestrants, HGM-CoA reductase inhibitors, fibric acid derivatives); vasopressors used in shock; potassium removing resins; edentate disodium; cardioplegic solutions; agents for patent doctus arteriosus; sclerosing agents; endocrine/metabolic; sex hormones (e.g., estrogens, selective estrogen receptor modulator, progestins, contraceptive hormones, ovulation stimulants, gonadotrophins, including gonodotropin-releasing hormones, gonodotropin-releasing hormone antagonists, androgens, androgen hormone inhibitor, anabolic steroids); uterine-active agents (e.g., abortifacients, agents for cervical ripening); bisphosphonates; antidiabetic agents (e.g., insulin, insulin-high-potency, sulfonylureas, alpha-glucosidase inhibitors, biguanides, meglitinides, thiazolidinediones, antidiabetic combination products); glucose elevating agents; andrenocortical steroids (e.g., adrenal steroid inhibitors, corticotrophin, glucocorticoids, glucocorticosteroids/corticosteroid retention enemas, glucocorticosteroids/corticosteroid intrarectal foam, mineralocorticoids); thyroid drugs (e.g., thyroid hormones, antithyroid agents); growth hormone (e.g., posterior pituitary hormones, octreotide acetate); imiglucerase; calcitonin-salmon; imiglucerase; sodium phenylbutyrate; betaine anhydrous; cysteamine bitartrate; sodium benzoate/sodium phenylacetate; bromocriptine mesylate; cabergoline; agents for gout (e.g., uricosurics); antidotes (e.g., narcotic antagonists); respiratory agents; bronchodilators (e.g., sympathomimetics and diluents, xanthine derivatives, anticholinergics); leukotriene receptor antagonists; leukotriene formation inhibitors; respiratory inhalant products; corticosteroids; intranasal steroids; mucolytics; mast cell stabilizers; respiratory gases; nasal decongestants (e.g., arylalkylamines and imidazolines); respiratory enzymes; lung surfactants; antihistamines; alkylamines, non-selective; ethanolamines, non-selective; phenothiazine, non-selective; piperazine, non-selective; piperidines, non-selective; phthalazinone, peripherally-selective; piperazine, peripherally-selective; piperidines, peripherally-selective; antiasthmatic combinations; upper respiratory combinations; cough preparation; renal and genitourinary agents; interstitial cystitis agents. 
     Some suitable drugs that fall within the above classes include Rosiglitazone, Interferon α 2b, Omalizumab (Xolair), Cetirizine, Erythropoietin (EPO), and metoprolol tartrate. In generally, any number of different protein drugs can be delivered with the system of the present invention. In addition, the systems and devices of the present invention can use any number of different biomarkers depending upon the drug that is of interest. For example, some biomarkers of interest include but are not limited to glucose alanine, Hepatitis C virus, immunoglobulin E, histamine, ferritin, transferrin, and C-reactive protein. It will therefore be appreciated that the biomarker is selected in view of the drug that is selected for delivery or the disease selected for monitoring. 
     Moreover, the present invention offers significant improvements over conventional systems, including those that use an electronic tongue, where signal processing algorithms are applied to an array of electrodes to subtract out background or interfering signals. In particular, the conventional systems do not use antibodies immobilized on electrodes and further, the conventional systems do not use capacitance or impedance detection, both of which involve AC rather than DC signals. 
     The use of an “electronic nose”, which is a similar concept to the electronic tongue described hereinbefore is known. However, the electronic nose is designed for detecting species in the gas phase. In accordance with the present invention, gas phase or at least airborne particulate detection can be incorporated in the present system in the event that the user wishes to manage a biological response and/or drug delivery using one of the devices described hereinbefore based on signals from the ambient environment. In this event, the signals would not originate from a liquid medium but instead would originate from a gaseous or atmospheric medium (e.g., an ambient signal that is from pollen in the atmosphere). The electrodes and electrical/electrochemical methods that are employed in this situation are selected and customized based on the location of origination of the ambient signal (e.g., gaseous or atmospheric medium). 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWING FIGURES 
       The foregoing and other features of the present invention will be more readily apparent from the following detailed description and drawings figures of illustrative embodiments of the invention in which: 
         FIG. 1  is a side cross-sectional view of a micro/nano drug containing membrane or cell according to a transdermal delivery system according to one embodiment; 
         FIG. 2  is a side cross-sectional view of a micro/nano drug delivery device for use with the cell of  FIG. 1 ; 
         FIG. 3  is side cross-sectional view of the drug delivery device proximate the cell prior to delivery of the drug; 
         FIG. 4  is a side cross-section view of the drug delivery device inserted into the patient&#39;s skin after piecing the cell to deliver the drug to the patient; 
         FIG. 5  is a side cross-sectional view of a micro/nano implant according to a transdermal delivery system according to another embodiment; 
         FIG. 6  is a side cross-sectional view of a micro/nano implant according to another embodiment; 
         FIG. 7  is a side cross-sectional view of a micro/nano implant according to another embodiment; 
         FIG. 8  is a side cross-sectional view of a micro/nano implant according to yet another embodiment; 
         FIG. 9  is a top plan view of an array of micro/nano drug delivery devices that are part of a transdermal delivery system; 
         FIG. 10  is side cross-sectional view of an array of micro/nano barbed implants; 
         FIG. 11  is schematic diagram of a biofeedback system; 
         FIG. 12  is a side cross-sectional view of a micro/nano barb assembly with a protective gel coating; 
         FIG. 13  is a side cross-sectional view of an applicator for use with micro/nano drug delivery devices, including the one of  FIG. 12 ; 
         FIG. 14  is a cross-sectional view of an alternate micro/nano drug delivery device for use with the cell of  FIG. 1 ; 
         FIG. 15  is a cross-sectional view of an alternate micro/nano drug delivery device according to another embodiment; 
         FIG. 16  is a cross-sectional view of an alternate micro/nano needle according to another embodiment; 
         FIG. 17  is a cross-sectional view of an alternate micro/nano drug delivery device according to another embodiment; 
         FIG. 18  is a cross-sectional view of an alternate micro/nano drug delivery device depicting oscillatory movement and associated pressure differential according to another embodiment; 
         FIG. 19  schematic diagram of the drug delivery device interfaced with biosensors, control system hardware, and communication units; 
         FIG. 20  is a cross-sectional view of an alternate micro/nano drug delivery device depicting pressure and motion actuators; 
         FIG. 21  is a cross-sectional view of an alternate micro/nano drug delivery device depicting piezoelectric componentry; and 
         FIG. 22  is a cross-sectional view of an alternate micro/nano drug delivery device depicting biosensor interface with drug delivery sub-unit and control system. 
     
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     An optimal transdermal delivery system, for some applicants, is a topical patch, gel, cream, or similarly applied system that is easily applied by a patient or caregiver onto a convenient, but unobvious location. It will deliver its target drug(s), which may be either small molecules or biologics, with a predictable and programmable rate and absorption kinetics. The system in one form can be designed to deliver drugs for local or regional effect. In other embodiments, the system can be designed to achieve the predictability of an i.v. infusion, but with out the pain and inconvenience of having an installed port. The system should only produce a depot effect by design. In addition, the drug release kinetics should not be interrupted by normal use and should be difficult to intentionally disrupt. The duration and extent of delivery is controlled by a combination of release site, release rate, and surface area. It is an objective to provide controlled delivery from a single day application up to and including 10 days of therapy to accommodate most antibiotic prescription regimes. However, it will be appreciated and understood that the time period for use of the delivery systems described herein varies depending upon the condition to be treated. For example, the devices are intended for use as part of a chronic therapy and therefore, controlled delivery can be achieved for a single day through the end of a person&#39;s life depending upon the circumstances and the application. Thus, the time periods and length of treatment recited above is merely exemplary and not limiting. 
     In accordance with one embodiment of the present invention the above objectives are achieved by an intra-dermal delivery diagnostic and communication system  100  shown in  FIGS. 1-4 . The system  100  is of the type that includes one or more drug reservoirs or depots and includes a means for delivering the drug to a patient. The system  100  includes at least one drug containing member  110  that stores the drug that is to be delivered. The member  110  includes an actuator  112  that can be in the form of a magnetic membrane that is formed of a magnetic material and a drug containing cell  120  (other actuators can be used, such as a piezoelectric based actuator and therefore, the discussion herein of magnetic membrane  112  is intended to cover one embodiment and is not limiting of the invention since actuator  112  can be another type of actuator). The drug containing cell  120  is flexible but provides the necessary stability to provide a cell that contains the drug that can be in the form of a drug solution or suspension. The drug containing cell  120  thus defines an interior pocket or compartment that contains and stores the drug that is to be delivered. While, the term “drug” is used herein, it will be understood that other substances besides drugs can be stored in the cell. For example, the cell can contain therapeutic agents, vitamins, etc., and is not limited to a substance that is classified as a “drug” per applicable government guidelines. 
     As illustrated in  FIG. 1 , the magnetic membrane  112  is disposed over the cell  120 . The shape and size of the cell  110  can be tailored according to the given application, including the type of drug to be delivered and the quantity that is to be delivered over time. 
     The drug delivery system  100  also includes a drug delivery device  130  that is complementary to the drug containing member  110  and is designed to mate therewith for controlled delivery of the drug that is contained in the cell  120 . For example, the drug delivery device  130  can be in the form of a mechanically robust micro or nano lancet or the like that acts as a carrier portal and cell sealing device. The lancet  130  includes a first end  132  and an opposing second end  134 . At the first end  132 , the lancet  130  has a magnetic contact  140 . The magnetic contact  140  can be in the form of one or more pads or other type of structures. In the illustrated embodiment, the lancet  130  has a support structure  134  (planar surface) that supports the magnetic contact  140 . 
     The lancet  130  also has an elongated hollow body  150  through which the drug is delivered as described below. The hollow body  150  can be an elongated tubular structure (cylindrically shaped tube) that has an inlet  160  (drug entrance or orifice) that is formed between the first and second ends  132 ,  134  and is located along one side of the hollow body  150 . In other words, the hollow body  150  includes a main bore  152  and the inlet  160  is formed perpendicular to the main bore  152 . The second end  134  represents an open end of the hollow body  150  and thus represents a distal opening  135  of the main bore  152 . The distal opening  135  at end  134  serves as a drug delivering orifice or exit. It will be appreciated that the second end  134  of the lancet  130  is a sharpened end that permits the lancet to pierce an object, such as the skin of the patient. The second end  134  can thus be a sharp, beveled edge. 
     The lancet  130  also includes a biasing member  170  that is disposed between the hollow body  150  and the support structure  134 . The biasing member  170  serves to move the lancet  130  relative to the drug containing member  110  after delivery of the drug from within the cell  120 . In the illustrated embodiment, the biasing member  170  is in the form of a spring, such as a leaf spring, that is attached to an underside of the support structure  134  and bows outwardly toward and into contact with the hollow body  150  at a location proximately adjacent to the inlet  160  such that the biasing member  170  does not obstruct drug flow into the inlet  160 . 
     The biasing member  170  will thus store energy when the structure is compressed as shown in  FIG. 4  and as described below. In lieu of a biasing element, spaced electromagnets can be energized so as to attract and thereby compress an intervening space, and thereafter energized so as to repel and thereby restore the dimensions of the intervening space, if desired. 
     According to one embodiment and as shown in  FIG. 3 , the distance X is approximately equal to the stratum corneum, which is the outermost layer of the epidermis (the outermost layer of the skin). It is composed mostly of dead cells that lack nuclei. The thickness of the stratum corneum varies according to the amount of protection and/or grip required by a region of the body. For example, the hands are typically used to grasp objects, requiring the palms to be covered with a thick stratum corneum. Similarly, the sole of the foot is prone to injury, and so it is protected with a thick stratum corneum layer. In general, the stratum corneum contains 15 to 20 layers of dead cells. 
     The sequence of using the system  100  to administer one or more drugs to a patient in accordance with one method of the invention can be as follows. First, the proper drug containing member  110  is selected based on the needs of the patient and then it is arranged so that the drug containing cell  120  faces and is placed in contact with a target location of the patient&#39;s skin where the drug is to be administered. It will therefore be appreciated that the magnetic membrane  112  faces away from the patient&#39;s skin. The drug delivery device  130  is then positioned so that the second end  134  faces the magnetic membrane  112 . In other words, the sharp, piercing end of the lancet  130  faces the drug containing member  110  as shown in  FIG. 3  which is an illustration of the system just prior to administration of the drug to the patient. 
     Next, the magnetic elements, namely the magnetic membrane  112  and the magnetic contact  140  are energized using conventional techniques. For example, a microprocessor can include a circuit that is used to energize the magnetic membrane or other electric components (e.g., capacitors) can be used to energize the two magnetic elements. The energized magnetic elements  112 ,  140  close the gap therebetween resulting in the sharp second end  134  of the lancet  130  piercing first the magnetic membrane  112  and then piercing through both the top surface and the bottom surface of the cell or membrane  120 . The magnetic elements  112 ,  140  are in contact with one another as shown in  FIG. 4  and the second end  134  of the lancet  130  is located well below the bottom surface of the cell  120 . 
     At least one of the magnetic elements is an electromagnet; the other can be a permanent magnet or permanent magnet layer. The magnet system is energized when there are two electromagnets that are being driven by an energizing signal, or when there is one electromagnet being driven by an energizing signal in proximity to a permanent magnet. 
     The construction of the lancet  130  permits the drug within the cell  120  to be delivered therethrough to the patient and more specifically, the dimensions of the lancet  130  and the cell  120  are selected so that when the magnetic elements  112 ,  140  are in contact with one another ( FIG. 4 ), the drug inlet  160  is located within the cell  120  itself, thereby allows the drug contained therein to flow through the inlet  160  and into the main bore  152 . The drug then flows along the arrows shown in  FIG. 4  and flows from the inlet  160  down the main bore  152  toward and out of the outlet at the second end  134  and into the patient. As mentioned above, the length of the lancet  130  is selected so that the second end  134  is at a desired penetration depth. 
     Accordingly, the pressure from the lancet  130  on the drug containing member  110  forces the drug in the cell  120  to flow into the main bore  152  and into the target tissue. 
     Also, as the lancet  130  pierces the drug containing member  110 , the biasing member  170 , if provided, compresses and stores energy. 
     At least one of the magnetic elements  112 ,  140  can de-energize to allow the lancet  130  to be free and move relative to the drug containing member  110  and also to allow the biasing member  170  to release its energy and return to a relaxed state. This action results in the lancet  130  being withdrawn from the stratum corneum. 
     It will also be appreciated that the magnetic elements  110 ,  140  can be energized multiple times, e.g., in succession, and this will result in a pumping action to ensure that an optimal amount of the drug in the cell  120  is delivered to into the patient&#39;s skin. 
     The entire system  100  includes both macro and micro scale components. For example, the component of the system that is disposed within the body is constructed on a micro/nano scale so as to deliver the drug to the patient in an unobvious manner; however, in some embodiments, the structure in which the microscale components are incorporated, such as a path, are on a macroscale. When the system  100  is incorporated into a transdermal patch or the like, the means of adhering the system to the skin must be hypo-allergenic and substantially robust enough to withstand normal daily function including hygiene practice, athletic participation, sleeping, etc. 
       FIG. 5  shows an intra-dermal drug delivery system  200  according to another embodiment. The system  200  is similar to the system  100  in that it utilizes a similar lancet design to create a micro/nano implant that is delivered into the patient. In this embodiment, the system  200  includes an implant device  210  that includes a support structure having a base  212  at a first end  214  and an elongated holding post  216  that extends outwardly from an underside of the base  212 . The base  212  can be in the form of a planar surface, with the holding post  216  being oriented perpendicular thereto. An implant device  210  is broadly speaking any type of device that can be implanted into a patient (e.g., a member that enables intra-dermal installation). 
     The system  200  also includes a magnetic element  220  which can be in the form of a magnetic strip that is coupled to the base  212 . For example, the magnetic element can be a thin planar layer of magnetic material that seats on and is coupled to an upper surface of the base  212 . The magnetic element  220  thus represents one end of the implant device  210 . 
     Similar to the system  100 , the implant device  210  can include a biasing member  170 . In the illustrated embodiment, the biasing member  170  is in the form of a spring, such as a leaf spring, that is attached to an underside of the base  212  and bows outwardly toward and into contact with the holding post  216 . Alternatively, a magnetic system arrangement can be used as described above to compress and restore dimensions of the system  200  before and after the implant is deposited in the skin. 
     The system  200  also includes a drug carrying component  230  which in this case is in the form of micro/nano implant body with a barbed structure  232 . As illustrated in  FIG. 5 , implant body  230  is coupled to a second end  215  of the holding post  216 . The implant body  230  has one or more barbs  232  and terminates in a sharp end  234  that is intended to pierce the patient&#39;s skin. 
     The system  200  further includes a magnetic membrane  240  that is intended for placement on the patient&#39;s skin. The magnetic membrane  240  can thus be a planar magnetic layer (strip) that can lie against the patient&#39;s skin at a target location where the drug is to be administered. In order to hold the magnetic membrane  240  in position on the patient&#39;s skin, the magnetic membrane  240  can includes an adhesive or the like, such as an adhesive border that serves to temporarily attach the magnetic membrane  240  to the skin. 
     It will be appreciated that in this design, the implant  230  is the member that carries the drug that is to be administered into the patient&#39;s body. The implant  230 , including the barbs  232  can be formed of a number of different material, including a polymer matrix with biodegradable properties. In addition, the implant  230  should be imperceptible when in place and non hypo-allergenic and have a predictable disintegration where the disintegration rate controls the drug release rate since the drug is incorporated into the implant material. Alternatively, the implant  230  can be formed of a resorbable polymer matrix where the release rate is independent of resorption rate and resorption occurs after delivery of the drug content. 
     The system  200  is operated in the following manner to delivery the drug to the patient. First, the magnetic membrane  240  is placed on the patient&#39;s skin and the implant device  210  is positioned as shown in  FIG. 5  with the implant  230  facing the magnetic membrane  240 . The magnetic element  220  and the magnetic membrane  240  are energized to cause the magnetic elements  220 ,  240  to close the gap therebetween causing the device  210 , including the holding post  216  and implant body  230 , to penetrate the stratum corneum painlessly. The biasing member  170  compresses and stores energy. 
     When the magnetic elements  220 ,  240  are adjacent one another, the implant  230  has been delivered to the desired penetration depth. The magnetic elements  220 ,  240  are de-energized releasing the implant device  210  and allowing the biasing member  170  to release its stored energy and return to its relaxed position, thereby withdrawing the base  212  and holding post  216  from the stratum corneum. Upon this withdrawal action, the barbs  232  of the implant body  230  engages the skin layer resulting in only the holding post  216  to be withdrawn from the patient. This results in the implant body  230  being left behind at the desired location and at the desired depth. The dimensions of the implant body  230  and the dimensions and locations of the barbs  232  are selected to accomplish this and result in the implant body  230  and the drug therein to be left at the proper location within the patient&#39;s body. 
       FIG. 6  shows yet another embodiment for the barbed implant body and more specifically, an implant body  300  is shown for use with the system  200 . The implant body  300  is similar to implant body  230  in that includes barbs  302 ; however, in this embodiment, the implant body  300  has a drug containing reservoir  310  formed therein. The reservoir  310  can be simply a bore formed therein that is open only at a first (top) end  304  of the implant body  300 . 
     The implant body  300  and barbs  302  are fabricated out of a bioresorbable material that is formed to include the reservoir  310  that contains liquid, semi-solid or solid drug containing materials. The reservoir  310  is sealed with a sealing membrane  320  that extends across the open end  304  of the body  300  to seal the drug in place. The sealing membrane  320  can be formed of a material that penetrates or dissolves. 
     The release rate of the drug is controlled by the dissolution rate of payload (small or large molecules) and the surface area of the reservoir opening, as well as post membrane disruption/disintegration. 
       FIG. 7  shows an implant body  330  that is formed of a solid or porous matrix and includes a holding post cavity (bore)  332  for receiving the holding post  216  ( FIG. 5 ). The release rate is controlled by disintegration/dissolution of the matrix in interstitial fluids. 
     The shape of the barb in any of the above embodiments can be anything that allows for imperceptible penetration and a sufficient rear side surface to prevent the barb from backing out of the skin. 
       FIG. 8  shows another embodiment in which an implant body  340  has a drug containing reservoir  350  formed therein. The reservoir  350  can be simply a bore formed therein that is open at both a first (top) end  352  of the implant body  340  and at or near a second end  354  of the implant body  340 . The reservoir  350  is sealed with a first sealing membrane  360  that extends across the open first end  352  of the body  300  and with a second sealing membrane  362  that extends across the open second end  354  to seal the drug in place within the reservoir  350 . The sealing membranes  360 ,  362  can be formed of a material that penetrates or dissolves. 
       FIG. 9  illustrates a drug delivery system  400  that is in the form of an array of a plurality of drug delivery devices  410  that can be fired/triggered based on a prescribed time or response signal. For example, the system  400  can be linked to an energy source  420  that includes a time sequenced firing mechanism. In other words, each of the individual drug delivery devices  410  is linked to the energy source  420  and a controller (microprocessor) can be programmed depending upon the patient&#39;s needs to sequentially fire a prescribed number of the drug delivery devices  410  over a period of time to delivery the drug at set time intervals and over the period of time. It will also be appreciated that the array can include more than one drug in that some of the drug delivery devices  410  thereof can contain one drug, while others contain other drugs. By linking each drug delivery device  410  to the energy source, different drugs can be delivered at different times and in proper sequence relative to one another. 
     It will be appreciated that the drug delivery devices  410  can be one of the systems previously described herein. For example, the drug delivery devices  410  can be of a lancet structure ( FIGS. 1-4 ) or a barbed implant structure ( FIG. 5-7 ).  FIG. 10  shows the array being formed of a lancet structure. 
     In yet another embodiment illustrated in  FIG. 11 , any of the previous embodiments, including the array  400  can be linked to a biofeedback system  500  that includes a microprocessor, a programmable input, etc. to control delivery of the drug(s) in the array  400 . The biofeedback system  500  includes at least one sensor  510  that is in communication with the biofeedback system  500 . During biofeedback, special sensors  510  are placed on or in the body and may be incorporated in the lancet structure  130  or the holding post  216 . These sensors  510  measure the clinically relevant materials that may be used to detect, diagnosis, monitor or demonstrate control over bodily function or surrogates thereof that is causing the patient&#39;s problem symptoms, such as heart rate, blood pressure, muscle tension (EMS or electromyographic feedback), brain waves (EEC or electroencophalographic feedback), respiration, and body temperature (thermal feedback), etc. and delivers the information to the biofeedback system  500  where it is translated and can be displayed as a visual and/or audible readout. Optionally, the biofeedback sensor can be part of the transdermal drug delivery systems  100 ,  200 ,  300 ,  400  that have been described hereinbefore or it can be one of the delivery systems described hereinafter. 
     The biofeedback system  500  is in communication with a controller  520  that is linked to each of the drug delivery devices  410  of the array  400  and is configured to actuate (energize) each of the drug delivery devices  410  at a specific point in time or to actuate only a portion of the drug delivery devices  410  rather than all of them as a function of the person&#39;s requirements relative to a target value using the biofeedback information. As described above, this allows for controlled release of drug to the patient and since it is part of a biofeedback system, the information detected by the sensors  510  is used to decide when and how to trigger release of the drug. For example, if the sensor  510  is measuring a property of the patient&#39;s blood, and the measured values fall outside of an acceptable range, the sensor  510  will send a signal to the biofeedback system  500  which in turn signals the control system  520  to actuate one or more devices  410  that contain the specific drug(s) that is to be administered to correct and combat the detected condition. The information from the biofeedback system  500  may also be sent to the control system  520  where it may be stored in memory  531  and/or displayed  530  or transmitted for display immediately or in an appropriate time and manner to patient and or others, including physicians and/or mange care organizations, to demonstrate effectiveness and or progress of therapy. Memory  531  can be internal memory that is associated with the master controller  520  or it can external memory that is located remote from the inter-dermal delivery device and is accessed using the communication network described below. 
     A communication subsystem  537  is provided for communicating information from the controller  520  to another device, such as an external device (e.g., handheld unit or a computer that is connected over a network to the communication subsystem  537 ). The means for sending information (communication subsystem  537 ) can include use of a radio frequency transmitter or other appropriate mechanism. 
     An external device  539  (ubiquitous device) is in communication with the subsystem  537  to allow information and control signals to flow between the intra-dermal device (e.g., the subsystem  537  thereof) and the external device  539 . The external device  539  thus includes a receiver which can be incorporated or may be a standalone device such as a handheld device, e.g., a cellular phone, a Personal Digital Assistant (PDA), a media player (e.g., an I-POD) or similar electronic device that contains its own energy source, a CPU, and interface software. In other words, the means for sending information can be provided in a handheld unit that has a receiver and it can be provided either be a unit that is dedicated to performing the function described herein or it can be supplied as part of and a feature of another device, such as a cellular phone. Alternatively the receiver  539  may be a part of common communication infrastructure services, such as WiFi, WiMax, cellular communication towers, etc. It will be understood that the interface should include signal transmission that is appropriate to Health Maintenance Organizations, Insurance Companies, and or Managed Care companies, as well as patients and physicians already described. In this manner, information can be readily transmitted from the intra-dermal delivery device to a person at a remote location via the use of external communications devices. A physician or the like can thus monitor, over an external device  539 , the measurements (bio-properties) taken at the intra-dermal delivery device and since the external device  539  communicates with the intra-dermal delivery device, the physician can send control signals to the controller  520  to cause immediate release of drug or the like. 
     Once again, it will be understood that the present device has both macro and micro/nano sized features and in particular, the features (e.g., microneedles, barbs, etc. as disclosed herein) that are moved into the intra-dermal space are micro/nano sized, while the structure (e.g., a patch or casing as disclosed herein) that supports these are on a macro-scale since this placed on the user&#39;s skin. 
     A power source or energy subsystem  541 , such as a battery, is provided for powering the microcontroller  520  and any other electronic components that may need powering. A charger or other means for energy delivery  543  for charging power source  541  or otherwise powering the energy subsystem  541  is provided. 
     It will also be appreciated that the array of drug delivery devices  410  can be part of a cartridge-based delivery system in which an applicator is used. The applicator includes a compartment that removably receives the array cartridge and properly positions the drug delivery devices  410  relative to the electronics of the applicator. The electronics, including a controller, communication subsystem(s) and the energy subsystems, can be part of a permanent interface device that is adjacent the compartment that receives the cartridge (as by inserting the cartridge through a slot). The user thus simply inserts the cartridge into the applicator and this results in proper alignment with the firing mechanism that causes the implants to be selectively and controllably delivered to the patient since the controller of the applicator (microprocessor) can be programmed depending upon the patient&#39;s needs to sequentially fire a prescribed number of the drug delivery devices  410  over a period of time to delivery the drug at set time intervals and over the period of time. The patient can simply insert a fresh array cartridge once a day/week/month, etc. 
       FIG. 12  illustrates a transdermal delivery system  600  according to yet another embodiment. The system  600  includes a micro/nano removable barb assembly  610  and a protective gel layer  620 . In particular, the assembly  610  includes a plurality of barbs  612  (can be arranged as an array) that extend from a flexible substrate  614  and contain a sharp, pointed end  616 . The barbs  612  protrude from the substrate  614  and can be oriented perpendicular thereto. The protective gel layer  620  is disposed opposite the substrate  614  in that the protective gel layer  620  is located along the pointed ends  616  of the barbs  612 . 
     The barb configuration operates in the same manner as the barb configurations described above in that the drug to be delivered is incorporated into the barb (implant) structure. However, in this embodiment, the implant force comes from manually applying pressure to the top surface of the flexible substrate  614  or via pressure applied by an applicator. The protective gel layer  620  provides: a stable protective environment for the micro/nano structures; a pleasant skin contact surface and potentially the ability to incorporate a local anesthetic agent/antimicrobial agent to provide a benefit during barb insertion. 
     When a force is applied to the top plane of the flexible substrate  614 , the micro/nano sized barb structures  612  penetrate through the protective gel layer  620  and pierce/enter the skin to the desired depth. The dimensions of the barbs  612  are thus selected so that the barbs  612  are delivered to the desired location underneath the patient&#39;s skin. Once the force being applied to the substrate  614  is removed, the barbs  612  disengage from the holding posts  216  and remain in the desired location for dissolution/disintegration/resorption per application design for a given treatment. 
     The flexible substrate  614  can be formed of any number of different materials and can have any number of different constructions. For example, the flexible substrate  614  can be form of a pliable material that can be comprised of a plurality of functional layers, including an chemically “inert” barb protective layer, an anesthetic layer and an adhesive layer, where the layers may be separate an distinct from each other or where they may be formulated in combination. The skin contact layer including a topical anesthetic, which may be from but not limited to (benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine (Alcaine), proxymetacaine, and tetracaine (AKA amethocaine). The anesthetic is incorporated in a gel layer which may be comprised of cross-linked polymers or other materials, preferably something inert such as silica. The gel layer may have adhesion properties to ensure proper surface to skin contact and also allow for pain free removal as required. 
     This type of system  600  can be used for drug or cosmetic applications. 
       FIG. 13  illustrates an applicator  700  that can be used in combination with the system  600 . The applicator  700  has a body  710  that contains an interior compartment  720  that includes a first supply section  722  and a second section  724 . The interior compartment  720  stores a feedstock of drug delivery devices that contain the drug(s) to be delivered. For example, a roll of the micro/nano removable barb assembly  610  and protective gel layer  620  can be disposed about a spindle or gear  726  that permits unwinding of the barb/gel assembly. The body  710  can include one or more guide members  730  that serve to route the barb/gel assembly through the interior compartment  720  as it is unwound. 
     Along one surface  712  of the body  710 , an applicator window  730  is formed for delivering the drug containing structures (barb/gel) to the patient. The roll of barbs/gel is routed so that it passes adjacent the window  730  such that the gel layer  620  faces the window and the pointed ends of the barbs face the window  730  to permit them to be implanted into the patient. To implant the barbs  612  into the patient, the applicator can be actuated to cause a force to be applied to the substrate  614  to cause the barbs  612  to be advanced through the window  730  and into the patient&#39;s skin as described above. 
     After implanting a predetermined number of barbs  612  (e.g., the ones visible through the window  730 ), the applicator  700  is manipulated to cause the roll to be advanced and the spent micro/nano barbs  612  are taken up on a spindle or gear  740 . For example, the applicator  700  can include a knob that causes advancement of the feedstock of barbs when it is rotated. Other mechanism can equally be used. The barbs  612  and gel layer  620  can be routed in the body  710  such that it is fed to the window  730  in a manner that causes the barbs  612  and gel layer  620  to protrude beyond the surface  712  and thus when the applicator  700  is pressed against the skin to position surface  712 , into contact with the skin, the barbs  612  are implanted. Alternatively, the applicator can have some type of firing mechanism that applies a force to the substrate  614  to cause the barbs  612  to be implanted. 
     It will also be appreciated that the roll of the micro/nano removable barb assembly  610  and protective gel layer  620  can be part of a cartridge and thus, the applicator  700  can be a cartridge based system. Electronics, including controllers, etc., of the applicator  700  are located on a more permanent interface device. The patient simply inserts a fresh array cartridge once a day/week/month, etc. 
     Example 
     One application for a drug delivery system is the human ear. More specifically, the barbed implant design of  FIGS. 5-7  can be configured as an anti-infective implant formulation for use prophylactically or as a curative agent in middle ear infections. The barbed implants are coupled to a topical application (e.g., similar to a swab (Qtip) or a film) and the barbed-based formulation is applied to the outer surface of the eardrum allowing the micro/nano barbs to penetrate the membrane and enter the region of the middle ear where the barbs with anti-infective agents (antibiotics) are deposited to pre-condition or treat an already infected ear space. The applicator may take the form of a gel, or multi-layer film which could include a topical anesthetic to facilitate application to areas where nerves have been sensitized. 
     Example 
     Another example is for the barbed implant design of  FIGS. 5-7  can be configured as an anti-infective or anti-allergic implant formulation for use prophylactically or as a curative agent in nasal infections or rhinitis. The barbed implants are coupled to a topical application (e.g., similar to a swab (Qtip) or a film, or spray) and the barbed-based formulation is applied to the nasal mucosa allowing the micro/nano barbs to penetrate the membrane and enter the region of the middle ear where the barbs with anti-infective agents (antibiotics), anti-allergic agents (anti-histamines, etc.) are deposited to pre-condition or treat an already effected nasal space. The applicator may take the form of a gel, spray or multi-layer film which could include a topical anesthetic to facilitate application to areas where nerves have been sensitized. 
     Example 
     Another application is for a tumor/organ wrap that is configured to directly infuse sustained release agents. The wrap is formed of a “fabric” or shrinking polymer skin to drive “barb” open portals and allow for active transfer of agent to the target tissue. The wrap can be applied laproscopically by spray or roll on. 
     In yet another embodiment, the transdermal delivery systems disclosed above can be part of a system that provides a visual indicator to the person using the system that the application of drug was or was not successful. For example, the applicator and the barbs can be constructed so that a color change occurs on release (implant) of the barb into the patient&#39;s skin, thereby providing a visual indicator or confirmation that a successful delivery resulted. In other words, when the barbs are removed from the holding posts or other supporting structure, a color change results. This could occur by having the distal tip of the holding post be formed of a material that upon discharge of the surrounding barbed implant and upon exposure to air, changes color. Alternatively, the end of the holding post may have a color that is initially covered up by the barbed implant but upon implanting the barbed implant into the patient, the color is exposed. 
     The user of such a system will thus be able to readily determine how many barbed implants were successfully delivered into the patient. For example, when the barbed implant are located at the end of a swab, after the swab is pressed against the patient&#39;s skin, it will readily be apparent what areas of the swab successfully delivered their barbed implants by simply looking at the surface of the swab. The user will see regions of no color (or a first color) indicated implants still intact and regions of another color indicated successful implantation. 
     Yet another delivery system application includes systems as described hereinabove in which a substance is delivered locally and below the stratum corneum and has a composition that swells after implantation so as to apply pressure to the stratum corneum from below the surface. One application of such a topical application is to reduce the appearance of wrinkles or to tighten the surface of skin. 
     For example, the barbed implant disclosed herein can be part of a cosmetic wrinkle reduction system. The system enables anyone desiring to reduce or temporarily eliminate facial wrinkles (around the mouth, nose, eyes, etc.) typically associated with aging by easily and painlessly implanting an appropriate amount of swelling barbed implants between the stratum corneum and the stratum germinativum where interstitial fluids will cause the barbs to expand and apply appropriate pressures to the stratum corneum to fill in the valleys that cause wrinkles. The barbed implants may be formed from materials that are endogenous in the body and that can be complexed to form swelling hydro-gel type matrix. As with the other embodiments, the barbed implants will be absorbed and eliminated without potential accumulation. 
     Now referring to  FIGS. 14-22  in which other embodiments are illustrated. In  FIG. 14 , a device  800  that is part of a micro/nano transdermal delivery system and includes at least one and preferably a plurality of microneedles  810  with channels  820  formed therein. The microneedle(s) is mounted on an oscillating movable base  830 . The device  800  includes a fixed casing  802  that is open along a bottom  804  thereof. In the illustrated embodiment, the fixed casing  802  has a top portion  804  that closes off the fixed casing  802 . The movable base  830  is located proximate the top portion  804  and extends across side walls  805  of the casing  802 . 
     The contact between a surface of the device (e.g., a bottom surface  807 ) and the skin is managed by and at the same time limited by the fixed casing  802 . The microneedles  810  are oscillated at a frequency between about 0 kHz to about 3 MHz (preferably between about 5 kHz to about 2 MHz), with amplitudes of between about 0 to about 1000 microns (preferably between about 5 microns to about 250 microns) as a result of the base  830  being movable. Amplitudes of oscillations are varied for drilling/opening channels in the stratum corneum/epidermis/dermis and/or pumping/suction of drug/blood/interstitial fluids. The oscillating microneedles  810  (with respect to the fixed device casing  802 ) create holes with specified properties in the stratum corneum. The design of the microneedles  810  varies for specific requirements and depending upon the particular application. The creation of the back pressure and/or the interface pressure between the stratum corneum and the device  800  interface pressure drive the drug to the target level in the intra-dermal space. 
       FIG. 14  shows a basic device  800  for both delivery of a drug and extraction of a fluid, such as blood and/or interstitial fluid.  FIG. 14  shows the device  800  in a normal rest position where the microneedles  810  are not extended into an out-of plane delivery or extraction position.  FIG. 15  shows the device  800  in an activated condition where the base  830  has oscillated relative to its position in  FIG. 14  and this results in the microneedles  810  being moved out of the plane such that the distal tips  812  of the microneedles  810  extend below the bottom surface  807  of the device  800  (casing  802 ).  FIGS. 14 and 15  show two channels  820  being formed therein. The channels  820  can have the same construction or they can contain different constructions as shown.  FIG. 15  thus shows an out-of-plane oscillation where the distal tip  812  advances into the skin to the desired depth as described herein. 
     In  FIG. 15 , each of the channels  820  includes a flow control device  850 ,  852  (such as directional valves/pumps) that are included in the respective channels  820  to control flow within the channel  820  to be controlled. The flow control component  850 ,  852  is in communication with the master controller/processor of the device  800  to allow control thereof depending upon the precise application and state of the microneedle  810 . Additional flow control devices can be provided in the device in locations remote from the actual channels to control flow of fluid within the device. 
       FIG. 16  shows a device  900  that includes a number of different types of microneedle constructions and in particular, channel constructions. It will be understood that the device  900  that is shown can include one type of microneedle construction or it can include a combination of different types of microneedle constructions. For example,  FIG. 16A  shows a microneedle  810  that has a passive free-flow channel construction. In particular, the microneedle  810  includes a single channel  820  that has a main section  822  that is open at the top and bottom of the microneedle  810  and includes a side or secondary section  824  that is open along the side of the microneedle  810  prior to the distal tip  812 . Fluid flows freely in both directions within the channels.  FIG. 16B  shows a microneedle  810  of a different construction where there is a single channel  820  with flow control. In particular, the single channel  820  is similar to the channel shown in  FIG. 16A  in the channel  820  that has a main section  822  that is open at the top and bottom of the microneedle  810  and includes a side or secondary section  824  that is open along the side of the microneedle  810  prior to the distal tip  812 . At or near the top end of the main section  822 , a directional valve/pump  850  is included to control flow within the channel  820  to be controlled. The flow control component  850  is in communication with the master controller/processor of the device  800  to allow control thereof depending upon the precise application and state of the microneedle  810 . 
       FIG. 16C  shows a microneedle  810  that is similar to those in  FIGS. 16A and 16B ; however, in this embodiment, the microneedle  810  has a multi-channel construction. More specifically, the microneedle  810  includes a first channel  820  and second channel  821 . The first channel  820  is open at the top end and is open at the distal end. The second channel  821  is open at the top end and opens along the side of the microneedle  810 . At or near the top end of both the first section  820  and the second channel  821 , directional valves/pumps  850 ,  852  are included in the respective channels to control flow within the channel  820 ,  821  to be controlled. The flow control component  850  is in communication with the master controller/processor of the device  800  to allow control thereof depending upon the precise application and state of the microneedle  810 . 
       FIG. 16D  shows a microneedle  810  that includes a back pressure channel. More specifically, the microneedle  810  includes a main channel  815  that has a top end and a bottom end that is open at the distal end of the microneedle  810 . A side or back channel  831  is provided in the microneedle  810  such that one end of the side channel  831  is open along the side of the microneedle  810  and the other end communicates with the main channel  815 . At a location above the juncture between the side channel  831  and the main channel  815 , a directional valve/pump  850  is included in the respective channels to control flow within the channel to be controlled. The flow control component  850  is in communication with the master controller/processor of the device  800  to allow control thereof depending upon the precise application and state of the microneedle  810 . The arrows shown in  FIG. 16D  reflect fluid flow. 
       FIG. 17  shows the backpressure microneedle embodiment of  FIG. 16D  installed in a device for use in a micro/nano transdermal delivery system. In  FIG. 18 , there are two flow control components  850  that allow control over the fluid as it flows within the device, such as when the drug to be delivered flows into the microneedle  810 . In  FIG. 17 , the microneedle  810  is in a normal, rest position where the distal tip of the microneedle  810  does not extend beyond the bottom of the device (casing).  FIG. 18  shows the microneedle  810  in an actuated state (oscillated out-of-plane) where the microneedle  810  extends beyond the casing resulting in the distal tip of the microneedle  810  being driven into the skin. 
       FIG. 19  shows a sub-unit  1000  constructed in accordance with the present invention. The unit  1000  includes a body  1010  that has a drug containing reservoir  1020  that is contained between a pair of substrates or layers  1022 . The layers  1022  can be in the form of an actuator that is configured to selectively fire one or more microneedles  810 . For example, the layers  1022  can be formed of piezoelectric strips that, as is known, change shape when powered by small amounts of electricity. The layers  1022  can be other types of actuators, such as a pressure actuator and/or motion actuator, which under select conditions, causes deformation of the unit  1000  in a manner described below resulting in controlled release of the drug contained in the reservoir  1020 . 
     The unit  1000  includes at least one and preferably a plurality of microneedles  810  that are in selective communication with the reservoir  1020 . The precise structure and interface between the reservoir  1020  and the microneedles  810  can vary depending upon the particular application and other considerations. For example, there can be a main channel  1030  that is in selective communication with the reservoir since a valve/pump  1040  is provided within or at the end of the main channel  1030  to control flow of the drug from the reservoir  1020 . The main channel  1030  is also in communication with an internal channel network that delivers the fluid from the reservoir to a number of channels that directly feed the microneedles  810  and allow the drug to be discharged through the distal tips of the microneedles  810 . 
     The unit  1000  further includes biofeedback system  500  that is in communication with a controller  520  that is linked to each of the drug delivery devices (microneedles  810  in this case) of the array and is configured to actuate (energize) each of the microneedles  810  at a specific point in time or to actuate only a portion of the microneedles  810  rather than all of them as a function of the person&#39;s requirements relative to a target value using the biofeedback information. As described above, this allows for controlled release of drug to the patient and since it is part of a biofeedback system, information detected by the sensors  510  is used to decide when and how to trigger release of the drug. For example, if the sensor  510  is measuring a property of the patient&#39;s blood, and the measured values fall outside of an acceptable range, the sensor  510  will send a signal to the biofeedback system  500  which in turn signals the control system  520  to actuate one or more microneedles  810  that contain the specific drug(s) that is to be administered to correct and combat the detected condition. 
     The information from the biofeedback system  500  may also be sent to the control system where it may be stored and or displayed  530  or transmitted for display immediately or in an appropriate time and manner to patient and or others, including physicians, to demonstrate effectiveness and or progress of therapy. The means for sending information may include use of radio frequency transmitter or other appropriate mechanism, generally shown as communication subsystem  505  in  FIG. 19 . As previously mentioned, the receiver can be incorporated or may be a standalone device such as a handheld device, e.g., a cellular phone, a Personal Digital Assistant (PDA), a media player (e.g., an I-POD) or similar electronic device that contains its own energy source, a CPU, and interface software. In other words, the means for sending information can be provided in a handheld unit that has a receiver and it can be provided either be a unit that is dedicated to performing the function described herein or it can be supplied as part of and a feature of another device, such as a cellular phone. Alternatively the receiver may be a part of common communication infrastructure services, such as WiFi, WiMax, cellular communication towers, etc. It will be understood that the interface should include signal transmission that is appropriate to Health Maintenance Organizations, Insurance Companies, and or Managed Care companies, as well as patients and physicians already described. 
     It will also be appreciated that the biofeedback system  500  disclosed herein is not limited to being used as a part of a larger drug delivery device or in combination therewith. Instead, all of the drug delivery devices disclosed herein can be modified so as to not include the drug delivery component (e.g., reservoir) or if this component is present, the communication from the feedback system  400  to the control system can be for diagnostic purposes only and not related to signals or instructions relating to release of drug. In other words, the biofeedback system can communicate with the control system which can store and/or display the received information irrespective of drug delivery. 
     Now referring to  FIG. 20  in which another sub-unit  1100  is shown. The sub-unit  1100  includes the fixed casing  802  that houses the drug containing reservoir  110 , the microneedles  810  and the other components. In the illustrated embodiment, the reservoir  110  is in communication with at least one actuator. For example, one or more pressure actuators  1110  can be provided for applying a select force to a local area of the unit. In the illustrated embodiment, the pressure actuators  1110  are located along the top of the reservoir  110 . In addition, one or more motion actuators  1120  can be provided and in the illustrated embodiment, a plurality of motion actuators  1120  are located along the bottom of the reservoir  110  and are spaced apart from one another. The motion actuators  1120  are located so as not to obstruct the flow of the drug from the reservoir  110  into the top of the main channel  821  in the microneedle  810 . The combination of these actuators provides a means for actuating select microneedles  810  to cause advancement (“firing”) of the microneedle  810  into the skin of the patient and to permit the microneedles to resume their normal retracted, rest positions. 
     As with the other embodiments, one or more valves/pumps  1130  can be provided for controlling the flow of fluid within the device. For example, one valve/pump  1130  can be provided in a line that communicates between the reservoir  110  and sensor  510  and one or more valves/pumps  1130  can be provided between the reservoir  110  and the channel architecture. As with other embodiments, the microneedles  810  can be extended beyond the casing and into the skin. 
       FIG. 21  shows another sub-unit  1200 . This embodiment is similar to the other embodiments; however, in this embodiment, there are piezoelectric strips  1210  located along both the top and bottom of the reservoir  110 . The strips  1210  thus define the interior of the reservoir  110 . Actuation of the piezoelectric strips  1210  causes selective firing (deformation) of certain microneedles  810 . 
       FIG. 22  discloses an alternate micro/nano drug delivery device  1300  depicting biosensor interface with drug delivery sub-unit and control system. 
     The device  1300  includes the sub-unit  1200  shown in  FIG. 21  and further includes biofeedback system  500  that is in communication with a controller  520  that is linked to each of the drug delivery devices (microneedles  810  in this case) of the array and is configured to actuate (energize) each of the microneedles  810  at a specific point in time or to actuate only a portion of the microneedles  810  rather than all of them as a function of the person&#39;s requirements relative to a target value using the biofeedback information. As described above, this allows for controlled release of drug to the patient and since it is part of a biofeedback system, information detected by the sensors  510  is used to decide when and how to trigger release of the drug. For example, if the sensor  510  is measuring a property of the patient&#39;s blood, and the measured values fall outside of an acceptable range, the sensor  510  will send a signal to the biofeedback system  500  which in turn signals the control system  520  to actuate one or more microneedles  810  that contain the specific drug(s) that is to be administered to correct and combat the detected condition. 
     In the illustrated embodiment, the sensor  510  is disposed proximate (adjacent) a reservoir  511  that is in selective communication with the reservoir  110  via a conduit or passage  111 . A pump/valve  850  is disposed along the conduit  111  to permit flow between the reservoirs  511 ,  110 . Other pumps/valves  850  are disposed in communication with the microneedle channels to selectively allow fluid to flow between reservoir  110  and the microneedles  810 . A pressure actuator  1310  is provided and is located in reservoir  511  that is adjacent the sensor  510 . 
     As shown in  FIG. 22 , the electronic controller  520  is in communication with the working components of the device including the pumps/valves  850 , sensor  510 , pressure actuator  1310 , etc. 
     The information from the biofeedback system  500  may also be sent to the control system where it may be stored and or displayed or transmitted for display immediately or in an appropriate time and manner to patient and or others, including physicians, to demonstrate effectiveness and or progress of therapy. The means for sending information may include use of radio frequency transmitter or other appropriate mechanism. As previously mentioned, the receiver can be incorporated or may be a standalone device such as a handheld device. 
     The devices of  FIGS. 14-22  are configured to perform any number of different operations. For example, in one embodiment, a negative back pressure (difference) is utilized to extract blood and/or interstitial fluid from the intra-dermal region into the appropriate reservoir(s) (e.g.,  511  in  FIG. 22 ) and in contact with a sensor(s)  510 . Pressure oscillations and motion control (e.g., using the disclosed actuators, piezoelectric strips, etc.) are utilized to move fluid in and out of the reservoir  511  and in and out of contact with the sensor(s)  510 . The pressurized reservoirs utilize a synchronization scheme. Frequency and duty cycles as well as synchronization are optimized for the maximum performance. The biological sample can be obtained using any number of different techniques as described hereinbefore. 
     Biosensing of the biological material can be accomplished utilizing electrical/electrochemical/mass detection. The system can utilize one or more of i) application of DC voltage and measuring the DC current response (amperometry), ii) application of a DC current and measuring the DC voltage response (potentiometry), or iii) application of an AC voltage and measuring the AC current response (capacitance or impedance). In all cases, three electrodes are incorporated into the intra-dermal delivery, diagnostic and communication device, the working, reference and counter electrodes. These electrodes are positioned as closely together as possible, with analyte detection occurring at the working electrode. Ideally, the electrodes are designed such that the voltage is applied between the working and reference electrodes, while current is detected through the counter electrode. Mass deposition on a functionalized surface can be detected by inertia based methods such as the resonance frequency shift of a cantilever beam due to its change of mass. 
     Example 
     The following is a general description of how one of the devices of  FIGS. 14-22  can be used as a drug delivery application. In a first step, the back pressure is increased or the back pressure is oscillated out-of-phase with the microneedle motion. This results in the stratum corneum being pecked for a duty cycle (defined by a frequency, amplitude, and duration) and the creation of multiple holes in the stratum corneum. Large drug molecules are forced through the stratum corneum due to the (oscillating) back-pressure motion. In a subsequent step, the “pecking motions” are stopped and the (static) back-pressure is kept until the holes in stratum corneum are closed/healed. 
     In accordance with one embodiment, a mode of operation diagnostic includes decreasing the back-pressure (or oscillate the back pressure out-of-phase with the needle motion); peck the stratum corneum for a duty cycle (frequency, amplitude, and duration; thereby creating multiple holes in the stratum corneum. This forces blood/fluid from these holes thorough the stratum corneum due to the (oscillating) negative back-pressure into the sensor(s) reservoir(s) that contains the drug. 
     The pecking motions are stopped and the back-pressure is increased to the internal body pressure until the holes in stratum corneum are closed/healed. There are a number of advantages that can be realized with the device and method of the present invention, including but not limited to the following: the required contact time with the top of the stratum corneum is very short (micro-seconds since the operation time-scale is short (kHz-MHz)); no need for long contact periods with the top of the stratum corneum since the device can be activated as the contact is established; only a brief period of contact with the stratum corneum is required (i.e., microseconds); large molecules can be delivered through “large holes” in the stratum corneum (due to the microneedle size); multi-drug delivery is possible due to modular design of reservoirs/sensors and rapid operations; provides time for the stratum corneum to heal due to micro-second operations and hours of usage (off) times; it is minimally invasive; rapid blood/fluids extraction leading to multiply tests/monitors; large number of control parameters (amplitude, frequency, duration, etc.) provides flexibility in device design, operations, and uses; very rapid dosage alterations on-the-fly (as needed) are possible due to short operation times; can be programmed for continuous, patterned, on-demand or feedback-controlled drug delivery/monitoring; novel microneedle designs can be integrated and this provides further flexibility in delivery design and utilization regimes; active process control is possible due to the large number of control parameters; short operation times minimize energy consumption; modular design allows the dispersion of chemical permeation enhancer and the integration of thermal/ultrasonic/electrical enhancing components. 
     It will be understood that the components, including the sensors and drug delivery devices, shown in  FIGS. 14-22  are suitable for use in the system generally illustrated in  FIG. 11 . 
     While the invention has been described in connection with certain embodiments thereof, the invention is capable of being practiced in other forms and using other materials and structures. Accordingly, the invention is defined by the recitations in the claims appended hereto and equivalents thereof.

Technology Classification (CPC): 0