WO2004016155A2 - Apparatus for multifocal deposition and analysis and methods for its use - Google Patents

Abstract

An multifocal apparatus for delivering an agent to and/or gathering information about a biological tissue. The apparatus includes a catheter (24) having a catheter lumen extending longitudinally at least partially therethrough and a deployment port within the distal portion of the catheter. A plurality of extendable-retractable needles (15) are housed within the catheter lumen and, when deployed, extend through the deployment port. A needle may be solid or hollow and may deliver an agent to the tissue, include a mechanism for gathering information about the tissue, or both.

Description

APPARATUS FOR MULTIFOCAL DEPOSITION AND ANALYSIS AND METHODS FOR ITS USE

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No.

60/403,875 filed August 16, 2002, which is incorporated herein by reference.

FIELD

This invention relates to apparatus and methods for delivering agents to and gathering information about a tissue of an animal body, including multifocal analysis and deposition of agents for diagnostic and therapeutic purposes.

BACKGROUND

Mj-nimally invasive therapies offer alternatives to traditional medical and veterinary surgical procedures for the treatment of disease or other physiological conditions. Open surgery poses many risks to the subject, such as a risk of post-surgical infection or complications resulting from anesthesia, and the trauma of surgery may require a long (and often painful) recovery.

Surgical options for the treatment of hypertrophy (the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells) and hyperplasia (the abnormal multiplication or increase in the number of normal cells in a normal arrangement of tissue) may be risky, while chemotherapeutic treatments may induce unwanted side-effects and systemic problems. Localized methods of treatment offer an attractive alternative to surgery or systemic treatments. For example, many types of cancer are treated by resection of the tumor or hyperthermia treatment of the tumor, both of which can be disruptive and may damage healthy tissue. In a resection procedure, care must be taken to avoid dissecting the tumor in a way that causes seeding of the tumor and metastasis. Hyperthermia procedures often result in heat damage to healthy tissue due to inadequate control over the localization of heat. Additionally, regardless of the procedure used to remove or destroy the tumor, identifying the margins of the tumor to minimize destruction or removal of healthy tissue may be difficult. Better methods of determining the margins of a tumor or neoplasm would allow more selective removal of unwanted tissue while minimizing damage to healthy tissue. Cancerous tumors (as well as other neoplastic disease) also may be treated through chemotherapy. However, systemic administration of a chemotherapeutic agent delivers the agent throughout the entire body of the subject, rather than localizing that agent to the tumor and immediately surrounding tissue. Since many chemotherapeutic agents target specific aspects of the cellular growth cycle, systemic administration of such agents can kill or damage both cancer cells and normal cells, especially quickly growing cells. Chemotherapeutic agents may induce renal toxicity, damage otherwise healthy tissues in addition to tumors, or cause unwanted side-effects, such as nausea, anemia, and hair loss. Targeting the chemotherapeutic agents to specific tissues would mmimize the damage to healthy cells and the resulting side-effects of chemotherapy.

SUMMARY An apparatus capable of multifocal, localized delivery of agents to a tissue of interest is disclosed; the apparatus also is capable of gathering spectroscopic data and other information useful for characterizing the tissue. The apparatus includes a catheter having a proximal end and a distal end, for example, the proximal end being closer to the operator and the distal end contacting the tissue. The catheter also includes a catheter lumen extending longitudinally at least partially through the distal end of the catheter. A deployment port is located in the catheter wall in the distal portion of the catheter, such as at its distal tip. The apparatus further includes a plurality of extendable-retractable needles capable of being transitioned between a deployed state and a nondeployed state. When nondeployed, the needles are housed within the catheter lumen. During deployment, the needles move relative to the catheter through the deployment port, for example, by being pushed through the deployment port via a deployment device, such as a spring. Alternatively, the distal portion of the catheter can be retracted along the needles, thus exposing the needles through the deployment port. In a fully deployed state, the collection of needles can adopt an outwardly everted configuration, such as a blossoming or "umbrella-like" configuration.

The needles can independently deliver an agent to the tissue or gather mformation from the tissue. The agent delivered by the apparatus can be a solid, fluid, liquid, gas, or radiation, including a pharmaceutical, chemical, biological, mechanical, or radiant energy agent that is therapeutic or diagnostic in nature. Information can be gathered by various sensors, including temperature sensors and optical devices.

Methods of using the apparatus include multifocal deposition of agents and retrieving information, such as spectroscopic data, about the tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of one embodiment of the apparatus in use. The distal end of the apparatus is shown within a neoplasm and the needles are in a deployed state.

FIG. 2 is an enlarged, longitudinal section through the distal end of an embodiment of the apparatus, showing several extendable-retractable needles in a non- deployed, or retracted, state.

FIG. 3 is a longitudinal section through the distal end of the embodiment illustrated by FIG. 2, showing the distal end portions of the needles extending from the tip of the catheter.

FIG. 4 is a further enlarged, longitudinal section through the distal end of one of the needles illustrated in FIGS. 2-3 in a region noted FIG. 4 in FIG. 3.

FIG. 5 is a further enlarged, longitudinal section through the distal end of a needle showing an alternative embodiment to the needle of FIG. 4.

FIG. 6 is an enlarged, schematic cross-section taken at line 6-6 in FIG. 2. FIG. 7 is an enlarged perspective view of an end portion of an embodiment of one of the needles shown in FIGS. 2-3 with portion broken away.

FIG. 8 shows an enlarged cross section taken generally along a line 8-8 of FIG. 7. FIG. 9 is a schematic block diagram illustrating an exemplary system that may be used to perform light-scattering spectroscopy utilizing a needle as shown in FIGS. 7 and 8.

DETAILED DESCRIPTION

As used herein, the singular forms of "a," "an," and "the," refer to both the singular as well as plural, unless the context clearly indicates otherwise. For example, the term "a needle" includes singular or plural needles and can be considered equivalent to the phrase "at least one needle." As used herein, the term "comprises" means "includes."

Disclosed is an apparatus for delivering an agent to a tissue, or gathering information about a tissue, within the body of a human or other animal. The apparatus includes a catheter having a proximal end, a distal end, and a catheter lumen extending longitudinally at least partially through the distal end of the catheter. The catheter lumen communicates with a deployment port in the distal portion of the catheter, for example a deployment port defined in the distal tip of the catheter.

A plurality of extendable-retractable needles are housed within the catheter lumen, and each needle has a proximal end and a distal end. A needle can have a needle lumen extending longitudinally at least partially therethrough, and the needle lumen can communicate with a delivery port located in the distal portion of the needle, such as at the distal tip of the needle. An agent can be delivered by a needle, for example, through the needle lumen of a hollow needle. Additionally, a deployment device for deploying the needle can be operably coupled to the needles for extending or retracting the needles through the deployment port of the catheter. Alternatively, the deployment device can deploy the needles by extending or refracting the distal portion of the catheter to expose the needles. Needles in a non-deployed state are housed within the catheter lumen. To deploy the needles, the deployment device causes the distal ends of the needles to emerge from the catheter lumen through the deployment port, for example, by pushing the needles out through the deployment port or retracting the distal portion of the catheter to expose the needles. The needles can be deployed individually or collectively. In particular embodiments, the needles assume an outwardly evert configuration after being deployed.

Any suitable procedure can be used to insert the catheter and/or needles into a target tissue. The catheter can be introduced percutaneously into the body of a subject (for example, through a small incision in the skin), can be introduced through some other surgical procedure (for example, open heart surgery or abdominal surgery), or can be introduced through a body orifice of the subject. The catheter can be a steerable catheter or a guideable catheter, such as a flexible catheter capable of being guided into the cavity of a body. For example, the catheter can be introduced through the nasal passages or mouth of a person and guided into the lungs. As another example, the catheter can be introduced into a blood vessel, such as being introduced percutaneously into a femoral artery by a cutdown of the artery or via the Seldinger technique, and guided through the cardiovascular system to a certain position within the body.

In alternative embodiments, however, the cathether has sufficient strength and rigidity to puncture tissue, for example, to puncture and penetrate the external body surface of an animal. Thus, such a rigid catheter can be considered a probe or an outer needle that houses the inner needles during a non-deployed state. In such embodiments, the distal end of the catheter can include a sharpened tip to assist in penetrating tissue. Additionally, the distal end of the catheter can contain a biocompatible plug, such as a dissolvable collagen-gel plug, to inhibit coring of tissue during puncture and penetration.

The catheter can be composed of any material, or combination of materials, providing the properties of strength, flexibility, and rigidity desired for a particular embodiment. For a flexible catheter, such as a steerable or guideable catheter, suitable materials are those that resist collapse by external forces, or forces imposed during bending or twisting; exemplary materials include (without limitation), polymers, such as polyethylene or polyurethane optionally reinforced with fibers of metal, carbon fiber, glass, fiberglass, a rigid polymer, or other high-strength material. For catheters requiring greater strength and rigidity, such as catheters intended for use in puncturing and penetrating tissue, suitable materials include (without limitation) carbon fiber, ceramics, high-strength plastics, or metals, such as Nitinol, platinum, titanium, tungsten, copper, or nickel. Additionally, composite materials can be used to construct the catheter.

Like the catheter, a needle also can be composed of materials providing the properties of strength, flexibility, and rigidity desired for a particular embodiment. In some embodiments, a needle will be made from a material having sufficient strength and rigidity to allow the needle to penetrate tissue. Exemplary materials include those used to construct the catheter. Like the catheter, the needle can include a sharpened tip at its distal end and/or a biocompatible plug to inhibit coring of tissue during puncture and penefration. In particular embodiments, a needle is composed of a conductive or semi-conductive metal having a shape memory, such as a nickel-titanium shape memory alloy. In such embodiments, the shape memory allows the needles to assume an outwardly everted configuration following deployment of needles beyond the distal end of the catheter. The catheter and needles can be made from the same or different materials. For example, an apparatus for delivering a diagnostic or therapeutic agent to a neoplasm within a lung can have a catheter composed of polymer reinforced by metal fibers (to provide sufficient flexibility to be guided through the nasal passages into the lungs) and needles composed of metal (to provide sufficient strength and rigidity to puncture the tumor).

Positioning the catheter and/or a needle can be accomplished by image enhancement. For example, the catheter and/or needle can contain radioopaque markers to aid in imaging, or can contain a visualization device, such as a laparoscope, for assisting the operator in determining the position of the catheter and/or needle within the body using X-ray, computed tomography (CT), computed axial tomography (CAT), magnetic resonance imaging (MRI) or other type of imaging. The catheter and/or needle can be constructed with markers that assist the operator in obtaining a desired placement via other types of imaging enhancement as well, such as ultrasound. For example, etchings or microgrooves can be added to the catheter and/or needle for enhancing ulfrasound imaging. As yet another example, radiographic contrast material can be injected through a lumen of the catheter or a needle, thereby enabling localization by fluoroscopy or angiography.

The apparatus also can comprise a handpiece at or adjacent to its proximal end. The handpiece can include a device for steering or guiding the apparatus, such as a guide collar. Various control mechanisms, including electrical, optical, or mechanical control mechanisms, can be attached to the apparatus via the handpiece. The handpiece can include additional operational features, such as a grip for aiding manual control of the apparatus, markers indicating the orientation of the catheter or needles, markers to gauge the depth of catheter or needle advancement, instruments to measure the operation of the apparatus (for example, a temperature guage to monitor radiofrequency or cryogenic ablation), or an injector control mechanism coupled to the catheter lumen and/or a needle lumen for delivering a small, precise volume of injectate.

The agent delivered by the apparatus can be a solid, fluid (liquid or gas), or radiation, and can be a pharmaceutical, chemical, biological, mechanical, or radiant energy agent. Suitable diagnostic and therapeutic agents include, but are not limited to, the particular agents disclosed herein.

Pharmaceutical agents include drugs commonly available to treat disease, such pain relievers, anti-cancer agents, antibiotics, anti-thrombotic agents, antivirals, and enzymatic inhibitors. Chemical agents include non-pharmaceutical chemicals, such as ethanol, phenol, chelating agents, and contrast agents for imaging particular structures of the body, including contrast agents for X-ray, fluoroscopy, ulfrasound, CT, MRI, and nuclear magnetic resonance (NMR) imaging. Biological agents include nucleic acids, amino acids, cells, viruses, prions, biochemicals, vitamins, and hormones. Mechanical agents include mechanisms for monitoring, visualizing, or manipulating internal portions of a body, including thermometers and other sensors, cameras, probes, knives, elecfrocautery snares, biopsy forceps, and suction tubes. Radiant agents include acoustic, thermal, and electromagnetic energies, such as infrared, ultraviolet, x-ray, microwave, radiofrequency, electricity, ultrasound, optical light, and laser.

In certain embodiments, the agent or mechanism delivered by the apparatus is capable of ablating tissue; thus, the apparatus can include means for ablating tissue using one of the pharmaceutical, chemical, biological, mechanical or radiant agents described above. Suitable means for ablating tissue include (without limitation): a needle with a distal end having a sharpened tip, or a mechanical cutting or boring apparatus; a hollow needle having an optical fiber for delivering laser energy, or a radiofrequency electrode for delivering radiofrequency energy, housed within the needle lumen; a hollow needle with a lumen capable of delivering a chemical ablative agent in the form of a solid, liquid, or gas; a solid needle capable of conducting thermal or radiofrequency energy; or a needle with a solid tip connected to a cryogenic source that functions as a cryogenically cooled probe. The apparatus can include devices that contain the agent delivered, or can be coupled to an appropriate source for delivering the agent. For example, the apparatus can include a syringe at its proximal end that contains a liquid or gas agent and is fluidly coupled to the lumens of the needles; the operator then depresses the plunger of the syringe to pressurize the syringe and deliver the agent through the lumens of the needles and the delivery ports. Alternatively, the apparatus can be operably connected to a power injector capable of providing high pressure delivery of the agent through a fluid connection to the needle lumens. Such power injectors are commercially available, such as the Medrad MCT Plus Front Load Auto-Injector available from Medrad, Inc. (Indianola, PA), and offer the advantage of controlling the amount of injectate with greater precision than can usually be accomplished by hand. For example, the predetermined hole sizes of the delivery ports in the needles can be correlated with the viscosity of the agent to be delivered and pressure exerted by the power injector to deliver a predictable amount of the agent.

Electromagnetic energy — including light and radiofrequency energy — can be delivered by operably coupling the needles to an appropriate power source. For example, and described in greater detail below, optical fibers can be placed in the needle lumens for delivering light through the delivery ports of the needles. In such embodiments, a light source is coupled to the proximal end of an optical fiber that has its distal end housed within the needle. Additionally, a lens can be mounted on the distal end of the same optical fiber for focusing or dispersing the light as it emerges from the optical fiber, such as a simple telescope lens assembly. The frequency of light emitted can be altered according to the desires of the operator. For example, optical spectroscopy and near-infrared light can be used to detect neoplastic and pre-neoplastic cells and tissues, identify the margins of a neoplasm or tumor, and identify the degree of tissue perfusion. See, e.g., U.S. Patent No. 5,769,081, herein incorporated by reference in its entirety; Wallace, M.B., et al., Gastroenterology 119:677-82 (2000); and Backman, V., et al., Nature 406:35-36 (2000). Additionally, laser energy of about 20 to 100 ml/mm² can be used to ablate tissue. Commercially available systems for emitting light or laser energy include the Axcis™ laser catheter system from CardioGenesis Corporation (Foothill Ranch, CA); and the OmniPulse™ MAX surgical laser system available from Trimedyne, Inc. (Irvine, CA).

Radiofrequency (RF) also can be used to ablate tissue. In such an embodiment, a needle includes an RF electrode electrically connected to an RF generator. Suitable RF generators are commercially available, such as the Surgifron^® model manufactured by Ellman International Inc. (Hewlett, NY). The electrode can be operated in a monopolar mode, in which case a patch electrode will be placed on the skin of the subject to complete the electrical pathway required for the RF electrode. Alternatively, the electrode can be provided with bipolar capability by placing a ground electrode in close proximity to the RF electrode. For example, two needles together may function as a bipolar electrode, or a ground electrode can be mounted on the catheter.

Cryogenic ablation offers another alternative means for ablating tissue. In such an embodiment, the needle includes a probe that is brought into contact with the tissue targeted for ablation and then cooled by a circulating refrigerant. The temperature of the probe is reduced to a level sufficient to induce ice crystals to form in the tissue. Infracellular ice crystals can induce cell lysis, thus leading to ablation of tissue. One such cryogenic probe is described in U.S. Pat. No. 6,237,355, herein incorporated by reference, and is commercially available as the Glacier™ Cardiac Ablation System from CryoGen, Inc. (San Diego, CA).

In some embodiments, plural agents are mixed or delivered together. As one, non-limiting example, the needles are deployed within a neoplasm and ethanol (an ablative agent) mixed with a contrast agent (such as rnicrobubbles for sonographic contrast, iodinated radiocontrast for X-ray contrast, or a metal chelate for MRI contrast) are delivered to the tissue. As another, non-limiting example, optical fibers within some needles can deliver different wavelengths of light to determine the margins of the neoplasm and gather information about the perfusion of normal tissue, while other ^λ needles deliver thermal ablative energy.

The dimensions of the device can depend on several factors, such as the needs of the user, the physical characteristics of the subject treated, the medical or veterinary status of the subject treated, and the methods used. In some embodiments, the catheter is from about 10 cm to about 125 cm long and about 5 mm to about 5 cm in diameter, while the needles are from about 3 cm to about 120 cm long and about 1 mm to about 10 mm in diameter. In particular embodiments, the catheter is from about 25 cm to about 100 cm long and about 5 mm to about 2 cm in diameter, while the needles are from about 5 cm to about 100 cm long and about 1 mm to 5 mm in diameter. For example, a catheter of about 15 cm to about 50 cm in length with a diameter of about 10 mm may be used to percutaneously deploy the needles into the underlying tissue of a human.

A deployment device can be used to control deployment of the needles during operation of the apparatus. Any suitable deployment device may be used, for example, a spring or a pneumatic cylinder. Exemplary deployment devices include the elecfrode actuators described in U.S. Pat. No. 6,221,071, herein incorporated by reference in its entirety. Additionally, the deployment device can be operationally coupled to a trigger that is part of a handle coupled to the proximal end of the catheter, thus allowing one- handed deployment of the needles. Needles can be deployed individually or as a group, and individual needles within the apparatus can be independently deployed.

Additionally, the needles can be controlled and manipulated along an axis other than the deployment axis. For example, the needles can be rotated after deployment. The speed of needle deployment can be adjusted according to various considerations, for example, the type of deployment device used, the type of tissue sought to be penetrated, or the physical characteristics and health of the subject. In particular embodiments, the needles rapidly deploy at an initial rate of from about 20 m/s to about 1.2 x 10⁴ m/s.

FIG. 1 illustrates one embodiment of the apparatus. The distal end of apparatus 10 with a group of needles 15 is deployed in an everted configuration within a neoplasm 20. The distal end 22 of catheter 24 has penetrated the skin 26 and underlying tissue 27 of the subject, and the collection of needles 15 has emerged from distal tip 26 of catheter 24.

FIG. 2 illustrates the distal end portion 22 of catheter 24 with the collection of needles 15 housed within the catheter lumen 28 in a non-deployed, or retracted, state, as further illustrated by FIG. 6, a cross-section through the apparatus taken at line 6-6 of FIG. 1. Catheter lumen 28 communicates with deployment port 30 located at distal tip 26 of catheter 24, and a biocompatible plug 32 covers deployment port 30. FIG. 3 illustrates the same embodiment of apparatus 10 with the group of needles 15 shown emerging through deployment port 30 at distal tip 26 of catheter 24. In the illustrated embodiment, the collection of needles 15 includes six individual needles 100, 200, 300, 400, 500, 600, each of which has a distal end portion 102, 202, 302, 402, 502, 602. The number of needles can vary according to factors such as the requirements of the operator, the type of tissue to be treated or analyzed, the size of the catheter, the size of the needles, and the type of agent to be delivered. Particular embodiments employ an apparatus having about 20 or fewer needles, such as about 15, 12, 9, 6, 4, or fewer needles, or any number of needles from about 2 to about 20. The needles can be arranged in any suitable manner, such as the regular array illustrated in FIG. 6. The needles within a collection can be of the same or different types. In some embodiments, the needles are all of a particular type, for example, all being capable of delivering an agent (the same agent or different agents) to a tissue or all being capable of gathering information about a tissue. For example (and without limitation), an apparatus can include a plurality of needles capable of delivering therapeutic agents to a tumor or other neoplasm. In alternative embodiments, the needles are of different types, for example, a collection of some needles capable of delivering an agent to a tissue and some needles being capable of gathering information about a tissue. In particular alternative embodiments, the collection of needles includes a first needle capable of delivering an agent, such as an ablative agent, to a tissue; a second needle capable of gathering information about the margin of a tissue, such as a thermometer; and a third needle capable of gathering information about the effects of the agent delivered (via the first needle) on the tissue, such as perfusion information useful for determining treatment margins. Of course, such embodiments can employ additional needles for delivering the same or different agents as the first needle, or gathering the same or different information as the second and third needles.

FIG. 4 is a close up view of distal end 102 of an exemplary needle 100. A delivery port 108 communicates with needle lumen 110 and is located at distal tip 112 of needle 100. Delivery port 108 can be located anywhere along the distal portion 102 of needle 100 and can be sized according to the needs of the operator.

In the embodiment of FIG. 4, optional additional delivery ports 109a-c (as well as other additional delivery ports shown in FIG. 4, but not referenced) are defined by the wall 114 of needle 100 and also are in communication with needle lumen 110. In alternative embodiments, delivery port 108 at the distal tip 112 of needle 100 is not present and needle wall 114 is substantially continuous around the distal tip 112. These additional delivery ports 109a-c are spaced apart longitudinally along wall 114 of the distal end portion of the needle. The additional delivery ports 109a-c may comprise small pores machined into the needle wall 114 that enhance the even distribution and delivery of a solid, liquid, or gas agent through the needle. A needle can contain an array of additional delivery ports regularly or irregularly spaced around the entire circumference of the needle, rather than along the two rows of ports illustrated in FIG. 4. Alternatively, the needle can contain a single delivery port in the wall of the needle or a collection of delivery ports grouped together at a location in the wall of the needle. This hollow needle is useful for a number of applications, for example, delivering a solid, liquid, or gas agent. In such embodiments, the deposition of the agent can be altered by changing the number of delivery ports 108, 109a-c at distal end portion 102 of needle 100; a needle 100 with a delivery port 108 only at its distal tip 112 will deliver the agent in a single, focused direction, while a needle 100 with multiple delivery ports 109a-c along its distal end portion 102 (in addition to, or in place of, the single delivery port 108 at the distal tip 112) will deliver the agent in multiple directions. For example, the apparatus can be used to deliver an imaging agent to a particular part of the body, such as a chamber of the heart. In such an embodiment, the catheter or probe 24 is inserted into the chest cavity of a subject, such as via a small incision in the chest wall. Distal tip of probe 26 is placed adjacent the wall of the heart outside the chamber of interest, and a needle 100 is deployed through the heart wall into the chamber. The imaging agent is then injected through the needle lumen 110 through delivery port 108 into the heart chamber. In other embodiments, it is desirable to direct an agent from the needle lumen

110 in multiple directions. For example, if the apparatus is used to deliver a therapeutic agent to a tumor or other neoplasm (in a manner similar to that illustrated in FIG. 1), then it may be desirable to deliver the agent in multiple directions at the same time to provide a diffuse dispersal of the agent throughout the tissue. In such embodiments, multiple delivery ports 109a-c (in addition to distal delivery port 108) are defined in the needle wall 114 distal end 102 of needle 100. The distal end 22 of catheter 24 is inserted into (or adjacent to) the tumor and needle 100 is deployed in a manner allowing distal end 102 of needle 100 to penetrate the tumor. After insertion of needle 100, the therapeutic agent — such as an ablative agent, a nucleic acid or chemotherapeutic agent — is delivered through needle lumen 110 and delivery ports 108, 109a-c. Like the distal delivery port 108 described above, delivery ports 109a-c can be sized according to the needs of the operator, and all delivery ports can be of a uniform diameter or different diameters. Delivery ports 109a-c can be located anywhere along the distal portion 102 of needle 100, though particular embodiments employ a needle 100 with delivery ports 109a-c defined in the most distal 1 cm to about 4 cm of the needle. As illustrated in FIGS. 1 and 4, needles 100 having multiple delivery ports 108, 109a-c allow delivery of an agent throughout an area of tissue, such as tumor 20, rather than directing delivery of the agent in a single direction.

Optionally, the distal tip 112 of needle 100 can be sharpened to facilitate puncturing and penetration of tissue, which is useful in certain embodiments. For example, the sharpened needle tips can be used to take small biopsy samples of tissue from an organ or neoplasm. In such an embodiment, distal end 22 of catheter 24 is inserted into or adjacent to the tissue or organ of interest (in a manner similar to that shown in FIG. 1), and a hollow needle 100 is deployed into the tissue. The sharpened distal tip 112 cuts through the tissue, allowing some of the tissue to enter delivery port 108 at the distal tip 112. This tissue is retained in the needle lumen 110 for later extraction after the apparatus has been removed from the subject. Optionally, a distal tip 112 of needle 100 can be capped by a biocompatible material (such as collagen-gel) that is allowed to melt after needles 100 are initially inserted into the tissue, thus allowing selective removal of tissue deeper within an anatomic site of interest.

Additionally, needle 100 optionally can comprise a device or feature that assists in biopsying tissue, such as biopsy forceps or internal grooves within needle lumen 110 to aid in retaining tissue inside the needle 100. This multifocal biopsy allows small tissue samples to be taken from different regions of an organ or tissue, such as a neoplasm, which individually may not be representative of the whole organ or tissue.

FIG. 5 illustrates yet another embodiment of needle 100a containing an optical fiber 150 and lens 152 for delivering light or laser energy through a delivery port 108a. Optical fiber 150 and lens 152 are shown housed within the needle lumen 110a, though other embodiments employ different configurations. For example, optical fiber 150 optionally can lack a lens; distal tip 112a of needle 100a can be composed of a material that functions as a lens, such as plastic or glass; or a portion of optical fiber 150 can extend through delivery port 108a outside of needle 100a. Additionally, needle lumen 110 can contain multiple optical fibers 150 and/or lenses 152.

Embodiments having a needle comprising an optical fiber 150 are useful for a number of applications. For example, optical fiber 150 and lens 152 can be part of a video recording system for imaging an internal cavity or tissue of a subject's body, similar to a laparoscope, or ablative laser energy can be delivered through optical fiber 150 and focused (or dispersed) by lens 152 to ablate tissue adjacent distal tip 112a of needle 100a. As another example, optical fiber 150 can be replaced with an electromagnetic or radiofrequency probe for delivering X-ray, microwave, or radio energy. Additionally, rather than a hollow needle (as illustrated in FIG. 5), the apparatus can be constructed with a solid needle (for example, a needle lacking a needle lumen and a delivery port) comprising an electromagnetic or radiofrequency probe. In particular embodiments, a needle 100a can contain an optical fiber 150 for light specfroscopy of tissue. As used herein, "light spectroscopy" includes all wavelengths of visible light, ultraviolet, and infrared within the electromagnetic spectrum, from about 900 angstroms to about 100 microns. In such embodiments, a needle (or multiple needles) 100a is inserted into a tumor or other neoplasm, as described above, and localized or mapped using image enhancement, such as CT, MRI, or ultrasound. Thus, the needle 100a illustrated in FIG. 5 can be considered a fiberoptic probe for gathering specfroscopic data from a tissue, including bioluminescence or sub- cellular data. Such information is useful for characterizing tissue, such as determining chromatin density tomography, tumor viability margins, tissue perfusions, or margins of a neoplasm. See, e.g., Wallace, M.B., et al. (2000) and Backman, V., et al. (2000). Additionally, such fiberoptic probes can be used to gather information about the location, volume, and density of deposition of an agent delivered to a tissue, such as a nucleic acid, cytotoxin, ablative agent, imaging agent or drug. For example, optical specfroscopic data can be gathered by a needle (functioning as a fiberoptic probe) to determine the margins of a tumor, a second needle can provide radiofrequency energy to ablate the tumor, and — following freatment — a third needle (also functioning as a fiberoptic probe) can gather near-infrared specfroscopic data to locate the treatment margins. Thus, the effectiveness of the freatment can be analyzed in real-time during a single percutaneous insertion of the apparatus.

FIG. 7 illustrates an exemplary embodiment of a needle 700 comprising a plurality of optical fibers that may be used for light spectroscopy. In particular, the needle 700, which is sometimes referred to as an optical probe needle or tine, may be used to perform light-scattering specfroscopy to obtain characterization information about the illuminated tissue. For example, the needle 700 may be used in vivo to measure changes in nuclear size, density, chromatin texture, hemoglobin concentration, and oxygen saturation in various epithelial tissues on a sub-cellular level. The epithelium observed may be on the surface of a number of different organs including, but not limited to, the intestine, esophagus, and prostrate. This information may then be used, for example, to detect and diagnose dysplastic growth of the epithelial tissue, which is often an early indicator of cancer. FIG. 7 shows a perspective view of the exemplary needle 700. A cylindrical needle wall 710 has a distal end portion 712 that surrounds a distal port 708. The distal end portion 712 can be beveled to allow for easier penefration of tissue layers and for better positioning of the needle relative to a tissue layer. The distal end portion 712 may be beveled, for example, to an angle between 30 and 45 degrees relative to a plane perpendicular to the longitudinal axis of the needle 700. A needle tip portion 720 is positioned inside the needle wall 710 adjacent to the distal end portion 712. The needle tip portion 720 comprises a suitable material that allows for the transmission of electromagnetic radiation within the interior of the needle wall 710. For example, the needle tip portion 720 may comprise glass. The needle tip portion 720 may also be beveled to match the distal end portion 712 or may have a rounded distal end.

Moreover, in certain embodiments, the distal end of the needle tip portion 720 may extend slightly beyond the distal end portion 712 of the needle wall 710.

In the illustrated embodiment, a lens portion 730 is positioned adjacent to the needle tip portion 720. Depending on the particular application for which the needle 700 is used, the lens portion 730 may comprise a variety of different optical lenses and/or filters. For example, as shown in FIG. 7, the lens portion 730 comprises two polarizing regions 732, 734 separated along a division line 736. The upper region 732 polarizes electromagnetic radiation along a first axis, whereas the lower region 734 polarizes radiation along a second axis substantially perpendicular to the first axis. The polarizing regions can be used to reduce the diffusive background in the reflected radiation and the effects of hemoglobin absorption. See, e.g., Perelman, L.T., et al., Phys. Rev. Lett. 80:627-630 (1998); Backman, V., et al., 7EEE, J. Selected Topics in Quantum Electronics on Lasers in Medicine and Biology 5 (1999). The needle tip portion 720 further may be selected to have a refractive index substantially identical to that of the lens portion 730, thereby preventing any of the transmitted light from being reflected.

In one particular embodiment, the needle tip portion 720 is affixed to the lens portion 730 via a suitable optical cement. In certain other embodiments, no lens portion 730 is provided. The specific lengths and sizes of the needle tip portion 720 and lens portion 730 may vary depending on the particular implementation. In one particular implementation, however, the needle tip portion 720 has a length of about 4.5 mm between the lens portion 730 and the beveled distal end portion 712, and the lens portion 730 has a length of about 0.5 mm. In this embodiment, the diameter of the needle 700 is about 1.2 mm.

As shown in FIG. 7, a plurality of optical fibers 750, 760 are also positioned within the needle 700. In the illustrated embodiment, the optical fibers are located adjacent to the lens portion 730 and oriented to transmit electromagnetic radiation to and receive reflected radiation from the distal port 708. It should be noted that FIG. 7 does not show a full needle 700, but only a portion of the needle as it teπninates at its distal end 712. Thus, the left end of the needle 700 in FIG. 7 includes a broken-away portion showing the interior of the needle.

As illustrated in FIG. 7, a transmission optical fiber 750 is positioned substantially centrally within the needle wall 710 and is used to transmit electromagnetic radiation, as denoted by dashed line 752, through the distal port 708. The elecfromagnetic radiation may be produced, for example, from a broadband source, such as a Xenon arc lamp, or other suitable light source (e.g., a laser-light source). In certain other embodiments, multiple optical fibers are used to transmit the electromagnetic radiation through the distal port 708. The transmission optical fiber 750 is surrounded by a plurality of reception optical fibers 760 used to receive electromagnetic radiation, as denoted generally by dashed lines 762, 764, and to transmit the radiation to the proximal end of a catheter, where it may be further transmitted to a specfrograph or computer for analysis. In some embodiments, the optical fibers 750, 760, lens portion 730, and/or needle tip portion 720 are adjustable within the needle 700. For example, the distal end portion 712 may be positioned adjacent a particular tissue area while the optical fibers 750, 760, lens portion 730, and needle tip portion 720 are selectively adjusted along the longitudinal axis of the needle 700. In certain embodiments, the needle wall 710 is constructed of a transparent material that enables the reception optical fibers 760, some of which may be outwardly oriented toward the needle wall 710, to collect a wider range (or cylinder) of data.

FIG. 8 shows an enlarged cross section of the needle 700 taken generally along line 8-8 of FIG. 7. As seen in FIG. 8, the transmission optical fiber 750 of the illustrated embodiment is positioned centrally within the needle wall 710 and is surrounded by multiple reception optical fibers 760. In FIG. 7, the reception optical fibers 760 are generally evenly distributed around the fransmission optical fiber 750 and allow a panoramic image of backscattered light to be collected. In certain embodiments, the reception optical fibers 760 have a diameter less than that of the transmission optical fiber 750. For example, the transmission optical fiber 750 may have a diameter of around 200 μm, whereas the reception optical fibers 760 may have a diameter of around 100 μm. The reception optical fibers 760 and the transmission optical fiber 750 may comprise optical fibers that have suitable flexibility and transmission characteristics for placement in the needle 700. For example, thermocoat- jacketed all-silica anhydroguide optical fibers from Fiberguide Industries (Stirling, NJ) may be used. The number of reception optical fibers 760 located within the needle skin 710 may vary from implementation to implementation. In one embodiment, for example, a needle 700 having a diameter of about 1.2 mm contains around fifty reception optical fibers 760 and one transmission optical fiber 750. FIGS. 7 and 8 show a division 736 that represents the division between the two polarizing regions of the lens portion 730. As can be seen, the division is located directly adjacent to the edge of the transmission optical fiber 750 such that the transmitted radiation passes through a single polarizing region. Thus, in the illustrated embodiment, the polarizing regions polarize approximately half of the reception optical fibers 760.

FIG. 9 is a schematic block diagram illustrating an exemplary system that may be used to perform light-scattering specfroscopy utilizing needles as discussed above with respect to FIGS. 7 and 8. A catheter 900 comprises one of needles 700 described above and may additionally include one or more of any of the other needles described herein (e.g., needles used to deliver ablative agents or radiation). The distal end portion 712 is positioned next to a selected epithelial area and illuminates and samples reflected radiation from a region of the area having a predetermined size (e.g., 1 mm²). The transmission optical fiber 750 of the needle 700 is coupled to a suitable light source 910. For example, in one particular implementation, the light source 910 is a Xenon arc lamp that delivers 10 W of radiation in a spectral interval between 400-800 nm. The polarized light transmitted onto the tissue sample and the polarized light reflected may have considerably less power than the light source output (e.g., about 100 μW and 0.1 μW, respectively). In certain embodiments, the light is delivered in a fixed pulse of time (e.g., 50 msec). The reception optical fibers 760 of the needle 700 are coupled to a specfrograph 920, which includes a charge-coupled device (CCD) 930. The specfrograph 920 and CCD 930 are used to collect and spectrally analyze the radiation scattered from the tissue sample and detected by the multiple reception optical fibers 760. The specfrograph 920 and/or the reception optical fibers 760 may be equipped with one or more filters used to isolate certain spectral regions of the collected radiation. Further, multiple and/or different filters may be used for different sets of optical fibers 760. For example, in one implementation, approximately ten filters are used to filter the collected radiation into multiple bandwidths of 20-40 nm that range from the visible light region (~ 550 nm) to the near infra-red region (~ 950 nm). The scattering characteristics of the reflected light may be determined by analyzing the light collected at each pixel of the CCD using known Mie-scattering analysis techniques. This analysis may be performed by a computer 950 coupled to the CCD 930 and configured to store the collected data. The computer 950 may also be used to operate a confroller 940 coupled to the specfrograph 920 and the CCD 930. Alternatively, the computer may directly control the specfrograph 920 and the CCD 930. As noted above, the scattering characteristics may be used to measure, among other things, changes in nuclear size, density, chromatin texture, hemoglobin concentration, and oxygen saturation in the observed tissue. In other particular embodiments, the apparatus includes both a needle or fiberoptic probe (as illustrated in FIG. 5) and a hollow needle for delivering a solid, liquid, or gaseous agent (as illustrated in FIG. 4). Thus, the apparatus is capable of both delivering an agent to a tissue and gathering information about that agent — such as its dispersal within the tissue or its effects on the tissue — once the agent is delivered. Additionally, some needles are capable of both delivering an agent to a tissue and gathering information from the tissue. For example, the needle illustrated in FIG. 5 can deliver a solid, liquid, or gaseous agent through lumen 110a and out through delivery part 108a, while optical fiber 150 can transmit specfroscopic data gathered through lens 152. Additionally, the apparatus can include a needle that delivers an ablative agent (for example, ethanol, phenol, or radiofrequency energy) and a fiberoptic probe for visualizing or gathering information about the ablative effects. As one non-limiting example, the apparatus illustrated in FIG. 3 includes hollow needles 100, 300, and 500 (similar to the needle illustrated in FIG. 4) operably connected to sources for delivering a confrast agent, a liquid suspension of nucleic acids, and a chemotherapeutic agent; needle 600 is capable of delivering thermal ablative energy; and needles 200 and 400 function as fiberoptic probes for gathering visual and other optical information from the surrounding tissue.

In other embodiments, the apparatus is capable of delivering an ablative agent and providing real-time information about the progress and effects of the tissue ablation. For example (and without limitation), the apparatus can include a first needle that functions as a thermal ablation probe, and a second needle containing an optical fiber capable of capturing visual images during ablation of the tissue.

Having illustrated and described the principles of the invention by several embodiments, it should be apparent that those embodiments can be modified in arrangement and detail without departing from the principles of the invention. Thus, the invention as claimed includes all such embodiments and variations thereof, and their equivalence, as come within the true spirit and scope of the claims stated below. WE CLAIM:

Claims

1. A multifocal surgical probe apparatus for delivering a therapeutic or diagnostic agent to a tissue, comprising: a catheter having a proximal end, a distal end, and a lumen extending longitudinally at least partially through the catheter and through the distal end of the catheter, thereby defining a deployment port; a plurality of extendable-retractable needles housed within the catheter lumen, wherein each needle has a proximal end and a distal end, and at least one needle has a delivery lumen extending longitudinally at least partially through the needle, defining a delivery port in the needle through which delivery port the agent may be delivered; and a deployment device operably coupled to the needles, the device capable of advancing the needles through the catheter lumen.

2. The apparatus according to claim 1 wherein said at least one needle has a side wall and said delivery port extends through said side wall and communicates with the delivery lumen of the needle.

3. The apparatus according to claim 2 wherein a plurality of delivery ports extend through said side wall and are spaced apart longitudinally of said at least one needle to provide lateral delivery ports, through which the agent may be delivered.

4. The apparatus according to claim 1 wherein said delivery port extends longitudinally through the distal end of said at least one needle to define a distal delivery port.

5. The apparatus according to claim 4 wherein the delivery lumen of each needle further communicates with a plurality of lateral delivery ports, through which lateral delivery ports the agent may be delivered.

6. The apparatus according to claim 1 wherein a distal portion of at least one of the needles, when deployed, extends in a direction transverse to the longitudinal axis of the catheter.

7. The apparatus according to claim 6 wherein the distal portion of the at least one needle is curved.

8. The apparatus according to claim 6 wherein individual distal portions of a majority of the needles, when deployed, extend in a direction transverse to the longitudinal axis of the catheter.

9. The apparatus according to claim 1 wherein the agent is a non-ablative fluid agent, solid agent, or radiant agent.

10. The apparatus according to claim 9 wherein the agent is a fluid agent.

11. The apparatus according to claim 9 wherein the agent is a radiant agent.

12. The apparatus according to claim 11 wherein the radiant agent comprises optical light.

13. The apparatus according to claim 11 wherein the radiant agent comprises infrared energy.

14. The apparatus according to claim 11 wherein the needle further comprises a radiant energy probe housed within the delivery lumen of the needle.

15. The apparatus according to claim 13 wherein the radiant energy probe is a fiber optic probe.

16. The apparatus according to claim 1 wherein the agent is an ablative agent.

17. The apparatus according to claim 16 wherein the ablative agent is a thermal ablative agent.

18. The apparatus according to claim 1 wherein the catheter or needle further comprises a visualization marker adjacent its distal end.

19. The apparatus according to claim 15 wherein the visualization marker is an etching, a microgroove or a radioopaque marker.

20. The apparatus according to claim 1, further comprising a biologically compatible plug adjacent the distal end of the catheter.

21. The apparatus according to claim 21 , wherein the biologically compatible plug comprises collagen gel.

22. A kit, comprising: the apparatus according to any of claims 1-20; and a thereapeutic or diagnostic agent.

23. The kit according to claim 22 wherein the agent comprises an ablative agent.

24. The kit according to claim 22, wherein the agent comprises a non- ablative fluid agent, solid agent, or radiant agent.

25. An apparatus for determining the margins of a neoplasm, comprising: a hollow catheter having a proximal end, a distal end, and a lumen extending longitudinally through the distal end of the catheter, thereby defining a deployment port; and a plurality of deployable needles housed within the catheter lumen and capable of being deployed by advancement through the distal end of the catheter, wherein each needle has a proximal end, a distal end, and at least one needle comprises an optical fiber.

26. The apparatus according to claim 25 wherein a plurality of needles comprise optical fibers.

27. The apparatus according to claim 25 wherein the at least one needle comprising an optical fiber also comprises a needle lumen extending longitudinally at least partially through the needle and the optical fiber is housed within the needle lumen.

28. An apparatus for multifocally introducing an agent into a tissue, comprising: a catheter having a proximal end, a distal end, and a lumen extending longitudinally through the distal end of the catheter and at least partially through the catheter, thereby defining a deployment port; and a plurality of extendable-retractable needles housed within the catheter lumen and capable of being deployed by advancement through the deployment port, wherein each needle has a proximal end, a distal end, and a delivery lumen extending longitudinally through a wall of the needle thereby defining a delivery port in the needle through which delivery port the agent may be delivered.

29. The apparatus according to claim 28 wherein the delivery port of at least one needle is defined adjacent the distal end of that needle.

30. The apparatus according to claim 29 wherein the delivery port of each needle is defined adjacent the distal end of each needle.

31. The apparatus according to claim 28 wherein at least one needle comprises plural delivery ports in communication with the delivery lumen.

32. The apparatus according to claim 31 wherein each needle comprises plural delivery ports in communication with its delivery lumen.

33. A method of multifocally delivering a therapeutic or diagnostic agent to a tissue within a subject, comprising: providing a multifocal delivery apparatus comprising an elongated deployment catheter and a deployment device operably coupled to a plurality of needles, wherein the catheter has a proximal end, a distal end, a deployment port defined by the distal end, and a deployment lumen extending longitudinally within the catheter and in communication with the deployment port, and wherein each needle has a proximal end and a distal end, and at least two needles each have a delivery lumen extending longitudinally through the wall of each needle, thereby defining a delivery port in each needle, through which delivery ports the agent may be delivered; advancing the distal end of the deployment catheter into a target tissue of a subject; deploying the needles; and infroducing the therapeutic or diagnostic agent through the delivery lumens of the needles into the target tissue.

34. The method according to claim 33 wherein the tissue is a neoplasm.

35. The method according to claim 33 wherein the agent is a non-ablative agent.

36. The method according to claim 33 wherein the agent is an ablative agent.

37. A method for determining at least one characteristic of a neoplasm, comprising: providing a multifocal fiber optic apparatus comprising an elongated deployment catheter and a plurality of tines, wherein the catheter has a proximal end, a distal end, a deployment port defined by the distal end, and a deployment lumen extending longitudinally within the catheter and in communication with the deployment port, and wherein each tine has a proximal end, a distal end, and a fiber optic probe, the tines housed within the deployment lumen of the catheter and capable of being deployed through the deployment port; advancing the distal end of the deployment catheter into a target neoplasm; deploying the tines; causing light to be emitted by the fiber optic probes, thereby generating specfroscopic information; and determining a characteristic of the neoplasm based on the resulting specfroscopic information.

38. The method according to claim 37 wherein the neoplasm is located within a subject.

39. A method for determining at least one characteristic of a neoplasm, comprising: providing a multifocal fiber optic apparatus comprising an elongated deployment catheter and a plurality of tines, _r wherein the catheter has a proximal end, a distal end, a deployment port defined by the distal end, and a deployment lumen extending longitudinally within the catheter and in communication with the deployment port, and wherein at least one of the tines has a proximal end, a distal end, a fransmission optical fiber, and a plurality of reception optical fibers, the at least one tine being housed within the deployment lumen of the catheter and capable of being deployed through the deployment port; advancing the distal end of the deployment catheter adjacent a target neoplasm; deploying the at least one of the tines; causing light to be emitted through the transmission optical fiber, thereby illuminating a portion of the target neoplasm; and collecting reflected light from the target neoplasm with the plurality of reception optical fibers.

40. The method according to claim 39 further comprising deteπriining a characteristic of the neoplasm based on the collected light.

41. The method according to claim 39 wherein the neoplasm is located within a subject.

42. The method according to claim 39 further comprising spectrographically analyzing the collected light.

43. The method according to claim 42 wherein spectrographically analyzing the collected light includes measuring intensities at different spectra of the collected light with a charge-coupled device.

44. The method according to claim 43 further comprising storing the measured intensities in a computer coupled to the charge-coupled device.

45. The method according to claim 39 further comprising determining a nuclear size, density, or chromatic texture of cells in the target neoplasm based on the collected light.

46. The method according to claim 39 further comprising determining a hemoglobin concentration based on the collected light.

47. The method according to claim 39 further comprising determining an oxygen saturation in the target neoplasm based on the collected light.

48. The method according to claim 39 further comprising polarizing the emitted light along a first axis, and polarizing the collected light along the first axis and a second axis substantially perpendicular to the first axis.

49. The method according to claim 39 wherein the collected light is filtered through one or more filters.

50. The method according to claim 39 wherein the emitted light is in a spectral interval substantially between 400 and 800 nm.

51. An apparatus for characterizing tissue in a subject, comprising: a hollow catheter having a proximal end, a distal end, and a lumen extending longitudinally through the distal end of the catheter, thereby defining a deployment port; and a plurality of deployable needles housed within the catheter lumen and capable of being deployed by advancement through the distal end of the catheter, wherein at least one of the deployable needles is an optical probe needle comprising: a transmission optical fiber coupled to a light source and configured to transmit a light pulse onto a sample region of the tissue; and a plurality of reception optical fibers coupled to an analysis system and configured to receive reflected light from the sample region and transmit the received light to the analysis system.

52. The apparatus of claim 51, wherein the optical probe needle further comprises a distal end portion that encloses a distal port, and wherein the distal end portion is beveled.

53. The apparatus of claim 51 , wherein the optical probe needle further comprises a lens portion and a needle tip portion that terminates at a distal end portion, the lens portion being positioned substantially between distal ends of the fransmission and reception optical fibers and the needle tip portion.

54. The apparatus of claim 51 , wherein the lens portion comprises at least two polarizing regions, a first polarizing region being configured to polarize light along a first axis, and a second polarizing region being configured to polarize light along a second axis substantially perpendicular to the first axis.

55. The apparatus of claim 51, wherein the light source is a Xenon arc lamp.

56. The apparatus of claim 51 , wherein the fransmission optical fiber is positioned substantially centrally within the optical probe needle and the reception optical fibers are distributed substantially evenly around the fransmission optical fiber.

57. The apparatus of claim 51 , wherein a diameter of the transmission optical fiber is less than a diameter of the reception optical fibers.

58. The apparatus of claim 51, wherein the analysis system comprises a specfrograph configured to spectrally separate the reflected light.

59. The apparatus of claim 58, wherein the analysis system further comprises a charge-coupled device coupled to the specfrograph and configured to measure intensities of the spectrally separated light.

60. The apparatus of claim 59, wherein the analysis system further comprises a computer coupled to the spectrograph and the charge-coupled device.

61. The apparatus of claim 58, wherein the specfrograph includes one or more filters for separating the collected light into multiple spectra.