Biodegradable fiducial markers and implants

Abstract

The invention generally concerns a biodegradable marker element for placement in a human or an animal body, the element may be used a mammography clip.

Description

[0001] BIODEGRADABLE FIDUCIAL MARKERS AND IMPLANTS TECHNOLOGICAL FIELD

[0002] The technology generally concerns biodegradable implantable devices.

[0003] BACKGROUND

[0004] Mammography plays a vital role in early breast cancer detection. Often, during the procedure, radiologists utilize 5mm metallic clips delivered via a needle to mark suspicious lesions. These clips serve as permanent landmarks, allowing for follow-up examination of the marked areas six months later. Studies indicate that in approximately 90% of cases, the marked lesion remains unchanged after six months, effectively mitigating the initial cancer risk. However, a critical drawback lies in the permanent nature of the metallic clip within the patient's body. Only in the remaining 10% of cases where the lesion exhibits concerning changes does the medical team proceed with surgical removal of the marked tissue.

[0005] Displacement and movement of metallic clips from the site of instillation is a further issue of concern as it may point-out. to a wrong location and movement into sensitive tissues. While metallic clips offer valuable aid in identifying suspicious sites, their permanent presence within sensitive organs raises legitimate concerns. Patients naturally harbor concerns about an enduring foreign object, and the risk of metal migration within tissue, with reported instances of inflammation, adds to the apprehension. Furthermore, in cases requiring radiation therapy, metal can hinder targeted treatment. These limitations underscore the need for alternative solutions that offer similar efficacy while minimizing patient concerns, eliminating migration risks, and ensuring unimpeded radiation therapy, ultimately leading to improved patient outcomes.

[0006] US Patent Application No. 2016 / 0151124 and International Publication No. WO / 2023 / 144826 describe solid blends of biodegradable polymers and Lipiodol- an iodinated poppyseed oil. These publications concern mainly the formation of marking clips using iodinated contrast agents, i.e. lipiodol and iodixanol, incorporated in the biodegradable polymer for CT visualization.SUMMARY OF THE INVENTION

[0007] Unlike metallic clips or other non-biodegradable clips that are implanted in a body tissue or organ of human or an animal subject, devices of the invention are not only biodegradable, but also demonstrate distinct and persistent visibility by methods such as MRI, CT, and ultrasound over long periods of time, typically at the months mark. The devices of the invention provide a novel solution to a substantial unmet need to replace current metallic clips with a resorbable alternatives for soft tissue marking for many indications. While the initial target is mammography, applications for such marker (such as for mammography) clips extend beyond this domain. Colorectal and lung tissues represent additional promising targets, while the technology could also be adapted for marking surgical sutures or other biodegradable devices within the human or animal body.

[0008] One of the features defining the technology disclosed herein is a provision of solidification of iodinated lipid markers such as Lipiodol by mixing in biodegradable polymeric particles, formed for example from polymers such as polylactic acid (PLA), poly(lactide-co-ε-caprolactone) (PLCL) or poly(lactic-co-glycolic acid) (PLGA), at a 40-60% w / w loading and incorporating these particles at different concentration and distribution into a continuous phase that can be a biodegradable polymer such as PLGA by melt or solvent mixing. The particles can be dispersed in water or in an oil for injection into a site. The continuous phase polymer may be a biodegradable polymer or a hydrogel or a solid wax or lipid.

[0009] Another aspect of this invention relates to the use of magnesium metal, alloys, blends and mixtures thereof with a biodegradable polymer where the magnesium serves as the contrast agent. Magnesium is a biodegradable material that degrades within a few months and it is biocompatible.

[0010] Another suitable contrast agent is barium sulfate powder that can be added to a biodegradable polymer such as PLA or PLCL at an amount of 5-50% for marking a site. Barium sulfate can also be mixed with a slow degrading hydrogel such as high molecular weight hyaluronic acid and dried to form a clip marker that is visible by CT, US and MRI. Independent of the contrast agent used, the agent can be evenly spread throughout the clip marker as a dissolved compound or dispersed particles, or can be non-evenly distributed to allow different visualizations such as strips along a rod.In most general terms, a marker clip element of the invention, being for example a mammography clip, independent of its intended use or site of instillation, can be of different shapes, structures and consistencies. For example, the marker may be shaped as a pin, a rod, a screw, a suture, a hernia mesh, a plate, or a filament.

[0011] The element can be a solid rod that is delivered to the site using a needle; a swellable hydrogel containing a contrast agent; an injectable hydrogel or polymer; a solution of a biodegradable polymer and a contrast agent, for example a dispersion of lipiodol, iron oxide nanoparticles and PLGA polymer carrier solution in N-methyl pyrrolidone; or in a form, size and shape that is visible or detectable by MRI, ultrasound (US), and CT. The preferred devices are those that are made of clinically used, FDA approved biodegradable polymers, such as PLGA, PLCL, hyaluronic acid and contrast agents such as lipiodol, iodixanol, gadolinium complexes, iron oxides, etc. The applicator for implementation can be similar to existing tools or system used for implanting metallic clips adjusted for the delivery of a marker device.

[0012] The marker clip element is, however, not an inflatable balloon or a bladder or any such object that is a container having an inner space for loading with liquids, or having an inflatable skin. Typically, the element of the invention does not comprise an external coating or a skin and is formed of a hydrogel that acts as a matrix material for holding a contrast agent or particles containing a contrast agent. Thus, in some cases, the element is formed of a hydrogel comprising a plurality of polymeric particles, each containing same or different contrast agents.

[0013] The clip may be a mammography clip also referred to as a tissue marker, configured for placement within breast tissue to identify the location of a biopsy site, lesion, or region of clinical interest. The mammography clip may be sized and shaped for delivery through a biopsy needle or introducer and is formed from biocompatible materials suitable for long-term implantation or controlled resorption. The clip may be detectable by one or more medical imaging modalities, including mammography, as further disclosed herein, thereby enabling subsequent localization of the marked site during follow-up imaging, surgical procedures, or therapeutic interventions. In some embodiments, the clip comprises a bioresorbable polymer and a hydrogel coating, as disclosed herein. The mammography clip may further be configured to resist migration within tissue and to maintain positional stability over time, while minimizing patient discomfort and interference with surrounding tissue.In a first of its aspects, there is provided a biodegradable marker element for targeted placement in a human or an animal body, said element being uncoated and formed of a non-hydrogel material and a hydrogel material comprising at least one contrast agent; the hydrogel is in its dry form suitable for placement in the human or animal body and a hydrated form when in the body, said hydrated form having a predetermined shape and size detectable by at least one imaging technique.

[0014] In some embodiments, and as further disclosed herein, the at least one imaging techniques may be magnetic resonance imaging (MRI), ultrasound (US) and / or computed tomography (CT), including mammography.

[0015] The invention further concerns a marker element for targeted placement in a human or an animal body, the element having a body formed of a non-hydrogel material and / or a hydrogel material that is adapted to absorb and retain water or a physiological medium following placement in the body, wherein said body comprising at least one contrast agent permitting detection by one or more of magnetic resonance imaging (MRI), ultrasound (US) and / or computed tomography (CT).

[0016] In some embodiments, the marker element is a marker clip, (or a clip). The clip may be a mammography clip.

[0017] Further provided is hydrogel-containing element comprising at least one contrast agent and configured for placement within a body of a human or an animal subject, the element having a first predefined shape and size adapted to allow placement thereof in the body, said first predefined shape and size being transformable into a second predefined shape and size upon absorption of water or a physiological medium or upon reaching body temperature following placement in the body or a mechanical shape memory element that is a rod like when in the needle used for deposition while changing into a spring or a loop shape upon release from the needle; said second predefined shape and size being detectable by one or more of magnetic resonance imaging (MRI), ultrasound (US) and / or computed tomography (CT).

[0018] The invention further provides a biodegradable marker element for placement in a human or an animal body, said element comprising a body formed of a non-hydrogel material, and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising at least one contrast agent; wherein said hydrogel material is transitionable between a dry form and a hydrated form such that the hydrogel becomes hydrated when placed in the human or animal bodyand wherein said marker element having a predetermined shape and size detectable by at least one imaging techniques.

[0019] In some embodiments or aspects of the invention, there is provided a biodegradable marker element for placement in a human or an animal body, said element comprising a body formed of a non-hydrogel material, and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising at least one contrast agent; wherein said hydrogel material is an anhydrous, dry or water-free element or is a hydrated water-containing form, and wherein said marker element having a predetermined shape and size detectable by at least one imaging techniques.

[0020] As used herein, the term “water-free” or “dry” refers to a state of the hydrogel in which free or bulk water is substantially absent. The terms do not require absolute absence of water, but rather indicate that the material contains no intentionally added water and is not in a swollen or hydrated state. Trace amounts of residual or bound water may be present, such as water associated with polymer chains, adsorbed moisture, or water introduced during manufacturing, provided that such water does not impart hydrogel swelling, softness, or gel-like mechanical behavior. It is to be understood that the hydrogel may include a residual amount of water in the dry or water-free state. In practical terms, a water-free hydrogel may contain residual water at levels typically below those required for network expansion or chain mobility. In some embodiments, a water-free or dry hydrogel may comprise a water content of less than about 10 wt%, less than about 5 wt%, less than about 2 wt%, or less than about 1 wt% relative to the total weight of the hydrogel. In some embodiments, residual water may be present at levels below 1 wt%, such as at equilibrium with ambient humidity.

[0021] Unlike the water-free form, the hydrated form or water-containing form of the hydrogel refers to a state of the hydrogel in which the polymeric network has absorbed a sufficient amount of water to form a swollen, gel-like structure exhibiting hydrogel properties. In the hydrated state, water is present as free or loosely bound water within the polymeric matrix, enabling polymer chain mobility, elasticity, and diffusion of solutes through the network. Hydration may occur through direct contact with water, exposure to an aqueous environment, or uptake of physiological fluids, and may be reversible or irreversible depending on the polymer composition and crosslinking. A hydratedhydrogel exhibits mechanical, transport, and functional characteristics distinct from its water-free state.

[0022] The hydrogels used according to the invention are said to be “transitionable” between the dry form and the hydrated form. This means that the hydrogels are selected to have the capability of changing from one state to another in response to exposure to an aqueous environment, such as bodily fluids. The transition from the a water-free form to the hydrated form may occur through absorption of water into the polymeric network, resulting in swelling, increased polymer chain mobility, and acquisition of hydrogel properties. This transition may occur gradually over time and may be influenced by factors including polymer composition, crosslink density, temperature, pH, and ionic strength of the surrounding environment. The hydrogel need not transition instantaneously or exhibit a complete conversion, but rather may demonstrate a partial, progressive, or region-specific hydration of the material. In some embodiments, the hydrogel may be further capable of transitioning back toward a less hydrated or dehydrated state upon removal from the aqueous environment, although reversibility is not required. Importantly, the non-hydrogel materials and hydrogel materials differ in that the hydrogels excludes materials that are permanently fixed in a single state, or which are not transitionable between the dry and hydrated forms.

[0023] In some embodiments, the element of the invention, as disclosed herein in any of the embodiments, is provided with a hydrogel component or region, such as a coating that is in a dry or water-free form. In some embodiments, the element of the invention, as disclosed herein in any of the embodiments, is provided with a hydrogel component or region, such as a coating that is in a hydrated or water-containing form.

[0024] Marking devices of different shapes are required to differentiate among different sites in the breast or other tissues that are marked at the same time or at different times.

[0025] The invention further provides a resorbable hydrophilic device configured for placement in a human or animal tissue site, the device comprising a biocompatible resorbable carrier, a mixture of biocompatible contrast agents visible by imaging devices, including CT, US and MRI, wherein the device is formed of a hydrogel or coated with a hydrogel.

[0026] As disclosed herein, elements of the invention are implantable marker devices that can undergo biodegradation in the body. The primary function of the devices is to assist in the identification of suspicious sites (of diseases tissues or organs) during medicalimaging procedures in mammography or for localization of tumors in soft tissues in e.g., colorectal and lung tissue. As such, the devices may be placed or instilled in the body of the subject by a minimally invasive procedure or during a surgical procedure carried out on the body of the subject. The placement of the device may be by any means known and may vary based, inter alia, on the size of the device, whether or not a surgical operation is involved, the tissue depth and other factors known to the medical practitioner. In some cases, the device may be delivered by a syringe. To enable such a delivery, as well as other modes of delivery, it is typically required that the device is shaped and sized so that its placement or delivery into the tissue is possible. Typically, in this initial delivery form, the device may be dry, or water free, so that its volume and size are minimized and the device can be compacted. The shape and size of the initial delivery form is typically predetermined so that its proper placement in the tissue can be monitored by external methods such as US, MRI, etc. Following placement in the tissue, the device will typically absorb fluids and undergo a structural change reflected both in its size and shape. This form of the device, now retaining water or a biological fluid, is too predetermined and can be visualized by external methods such as MRI, US and / or CT.

[0027] The transformation or conversion from one form to another is enabled by use of a hydrogel material that does not contain an external skin nor any coating that can prevent proper absorption and retention of fluids therein. The hydrogel may be pre-shaped in the dry form to afford a pre-shaped hydrated or swelled form, both having known shapes and sizes. This in situ swelling contributes to the fixation of the element in the site of insertion. As known in the art, a hydrogel is a network of polymer chains that are capable of holding large amounts of water within their structure, making them highly absorbent. As the hydrogel swells water or a physiological medium, it retains its solid-like form due to the cross-linked polymer network. Thus, when a hydrogel is used for making and using a device of the invention, its mechanical properties may be tailored, modified, or selected to provide a polymeric material with proper or desired mechanical characteristics. The hydrogel used may be synthetic or naturally derived.

[0028] Formed of a hydrogel material, the device may be shaped and sized without limitation. The rate of degradation may also be predefined so that the residence time in the body is limited. For example, hyaluronic acid hydrogels may retain in the body from a few months to over a year as a function of molecular weight and crosslinking.As stated herein, the hydrogel body of the device is provided skin-free. However, the hydrogel can be used as a skin material or a coating material for an element of a different material which placement in the body is desired. The hydrogel body of the device may be presented in a variety of forms and compositions. For instance, the hydrogel may comprise different hydrogel materials, each having a different residence time in the body. In other cases, the hydrogel material may be a carrier for micro or nano capsules that themselves act as delivery vehicles or marker elements.

[0029] Without limitation, the element may be formed of a non-hydrogel material, e.g., a biodegradable polymer made from lactic acid, glycolic acid, caprolactone, ethylene and propylene carbonates, dioxanone and mixtures thereof. Polyanhydrides based on sebacic acid, castor oil and ricinoleic acid may also be used. In some cases, the polymer may be selected from polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) and poly(lactide-co-caprolactone). The hydrogel component of the marking device may be made from polyethylene glycol (PEG), chitosan, alginate, gelatin, hyaluronic acid (HA), oxidized cellulose, gelatin, human or bovine serum albumin, fibrin, and others.

[0030] In some embodiments, the device is formed of a biodegradable polymer being or comprising lactic acid, glycolic acid, caprolactone, trimethylene carbonate, dioxanone and mixture thereof.

[0031] In some embodiments, the device is formed or comprises hyaluronic acid, gelatin, oxidized cellulose, and polyethylene glycol

[0032] In other embodiments, the device comprises a solid lipid composed of fatty acids, fatty alcohols, triglycerides and waxes.

[0033] The contrast agent may be distributed within the hydrogel, or within carriers such as nanoparticles, microparticles, microspheres, filaments and others. The distribution of the agent or the carriers may be uniform or non-uniform. The contrast agent may alternatively be chemical associated to the hydrogel material. The chemical modification may include direct substitution by a contrast agent or association via a ligand group or another functionality.

[0034] In some cases, the contrast agent is a chemical agent that is added to the hydrogel by any means known in the art. In some cases, water absorbed by the hydrogel and a plentiful of hydrogen bonding in the hydrogel suffice to permit external visualization of the device, e.g., by MRI.The selection of contrast agents may depend on the method used for visualization of the device. Contrast agents for CT may be selected amongst such substances that can enhance the visibility of internal structures and organs in the body. These agents improve the contrast between different tissues, making it easier for the radiologist to interpret the images. Non-limiting examples of contrast agents for CT imaging include iodine-based agents such as lipiodol, iohexol, iopamidol, iodixanol, ioversol and others. MRI contrast agents typically contain substances that affect the relaxation times of nearby hydrogen nuclei, thereby improving the contrast between different tissues. Non-limiting examples include gadolinium-based contrast agents (GBCAs), such as gadopentetate dimeglumine (Magnevist), gadobutrol (Gadavist), gadodiamide (Omniscan), gadoteridol (ProHance), gadofosveset trisodium (Ablavar), and others.

[0035] In some embodiments, the contrast agent is selected from Diatrizoic acid, Metri Zoic acid, lodamide, lotalamic acid, loxitalamic acid, loglicic acid, Acetrizoic acid, locarmic acid, Methiodal, Diodone, Metrizamide, Iohexol, loxaglic acid, Iopamidol, lopromide, lotrolan, loversol, lopentol, Iodixanol, lomeprol, lobitridol, loxilan, lodoxamic acid, lotroxic acid, loglycamic acid, Adipiodone, lobenzamic acid, lopanoic acid, locetamic acid, Sodium iopodate, Tyropanoic acid, Calcium iopodate, Iopy dol, Propyliodone, lofendylate, Lipiodol and non-iodinated salt, barium sulfate; Gadobenic acid, Gadobutrol, Gadodia mide, Gadofosveset, Gadolinium, Gadopentetic acid, Gadot eric acid, Gadoteridol, Gadoversetamide, Gadoxetic acid; Gadolinium oxide, carbonate, chloride, bromide fluoride, Sulfates and other gadolinium salts and gadolinium com plexes with organic and inorganic molecules; Iron oxide; Microspheres of human albumin, Microparticles of galac tose, Perflenapent, Microspheres of phospholipids, Sulfur hexafluoride and air entrapped bubbles; and short half-life radioactive agents selected from technetium and low hazard radioactive containing tritiated molecules.

[0036] In some embodiments, the device comprises a contrast agent or a coating comprising a contrast agent.

[0037] In some embodiments, the contrast agent is selected amongst iodinated compounds such as lipiodol, iohexol, and iodixanol.

[0038] In some embodiments, the contrast agent is iron oxide or a gadolinium complex. In some embodiments, the contrast agent is a magnesium-based material, such as a magnesium metal, a magnesium alloy, or blends and mixtures thereof with suitable biodegradable polymers.In some embodiments, the contrast agent is barium sulfate powder.

[0039] In some embodiments, the contrast agent, being one or both of a magnesium -based material and a barium sulfate, is provided into a polymeric carrier, as defined, present therein at a loading amount ranging between 5 and 50% w / w.

[0040] In some embodiments, the contrast agent is provided in a carrier formed of a biodegradable polymer at amounts ranging between 1 and 60% w / w, or between 1 and 50% w / w, or between 1 and 40% w / w, or between 1 and 30% w / w, or between 1 and 20% w / w, or between 5 and 50% w / w, or between 7 and 25% w / w, or between 10 and 60% w / w, or between 20 and 60% w / w, or between 30 and 60% w / w, or between 40 and 60% w / w, or between 50 and 60% w / w.

[0041] In some embodiments, the contrast agent is provided in any material component or part of the element or clip of the invention in an amount ranging between 1 and 60% w / w, or between 1 and 50% w / w, or between 1 and 40% w / w, or between 1 and 30% w / w, or between 1 and 20% w / w, or between 5 and 50% w / w, or between 7 and 25% w / w, or between 10 and 60% w / w, or between 20 and 60% w / w, or between 30 and 60% w / w, or between 40 and 60% w / w, or between 50 and 60% w / w.

[0042] In some embodiments, the contrast agent is provided in any material component or part of the element or clip of the invention in an amount ranging between 5 and 50% w / w, or between 7 and 25% w / w.

[0043] In some embodiments, where the contrast agent is barium sulfate or a magnesium-based material, the amount thereof may be between 5 and 50% w / w. In other embodiments, where the contrast agent is an iodinated material such as Lipiodol, the amount thereof may be between 1 and 50% w / w or between 1 and 20% w / w.

[0044] The invention further provides a marker element for placement within a body of a human or an animal subject, the element comprises a contrast agent permitting visualization of the element in the body by means of MRI, US and / or CT; the element having a dry compacted form suitable for delivery to the body and a hydrated form with a predetermined shape and size, wherein the dry form is transformable into the hydrated form by swelling with water in situ.

[0045] Elements or devices of the invention degrade and eliminate from the body shortly after the period of marking, being typically between 6 and 18 months after placing in the body, minimizing patient concerns and ensuring unimpeded radiation therapy. The biodegradation rate is controllable via tailored polymer composition, making it a versatileand clinically viable alternative for medical imaging. In some cases, the element or device of the invention is a theragnostic device, namely a device that combines both therapeutic and diagnostic functions. As such, the device may comprise a contrast agent as well as at least one therapeutic active agent that is selected to induce a therapeutic effect over the period of residence. Such therapeutic agents may be selected amongst anticancer agents, anti-inflammatory agents, and others.

[0046] Based on the above description, the invention further provides a theragnostic marker element for targeted placement in a human or an animal body, said element comprising a polymer, a contrast agent and at least one therapeutic drug; wherein upon delivery to the body, the polymer increases viscosity to be detectable by magnetic resonance imaging (MRI), ultrasound (US) and / or computed tomography (CT).

[0047] Also provided is an injectable liquid or pasty formulation comprising a polymer and contrast agents, said formulation, upon injection into the body, increases in viscosity to form in situ a marker of a certain shape and size.

[0048] In some embodiments, the polymer is a thermoresponsive polymer or a polymer soluble in a biocompatible organic solvent.

[0049] In some embodiments, the polymer has a water solubility at temperatures below body temperature.

[0050] In some embodiments, the polymer is selected from poly(propylene glycol-ethylene glycol), block copolymers of lactide, glycolide, caprolactone and polyethylene glycol.

[0051] In some embodiments, the polymer is PLA, PLGA, PCL, PLCL.

[0052] In some embodiments, the formulation comprises a solvent.

[0053] In some embodiments, the solvent is or comprises N-methyl pyrrolidone.

[0054] Further provide is a biodegradable device for placement in a human or animal body, the device being detectable by US, CT and / or MRI, and configured to treat or induce treatment of at least one disease or disorder.

[0055] In some embodiments, the device comprises a contrast agent.

[0056] In some embodiments, the device comprised at least one therapeutic agent.

[0057] In some embodiments, the device is shaped and sized to a predetermined structure. In some embodiments, the device has a shape and size capable of inducing a medical effect.

[0058] In some embodiments, the device is in a form of an inflatable device.In some embodiments, the inflatable device is an inflatable ballon for tissue separation.

[0059] In some embodiments, the device is a biodegradable hydrogel implant, an absorbable suture or filament, an orthopedic pin, a screw or a plate.

[0060] In some embodiments, the device is for controllably releasing at least one therapeutic agent.

[0061] Also provided is an implantable biodegradable device comprising at least one contrast agent for visualization by CT, US and / or MRI, and optionally at least one therapeutic agent; the device being in a form different from an inflatable balloon or bladder, e.g., may be in a form of a suture or filament, an orthopedic pin, a screw or a plate.

[0062] In some embodiments, the device is formed of polymers prepared from lactic acid, glycolic acid, caprolactone, ethylene and propylene carbonates, dioxanone, polyethylene glycol and mixtures thereof.

[0063] In some embodiments, the device is formed of a polyanhydride of sebacic acid, castor oil or ricinoleic acid.

[0064] In some embodiments, the device is formed of polymers selected from polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), chitosan, alginate, gelatin, hyaluronic acid (HA), oxidized cellulose, polycaprolactone (PCL), fibrin.

[0065] In some embodiments, the device is formed of a biodegradable polymer being or comprising lactic acid, glycolic acid, caprolactone, trimethylene carbonate, dioxanone and mixture thereof.

[0066] In some embodiments, the device is formed of or comprising hyaluronic acid, gelatin, oxidized cellulose, and polyethylene glycol.

[0067] In some embodiments, the device comprises a solid lipid composed of fatty acids, fatty alcohols, triglycerides and waxes.

[0068] In some embodiments, the contract agent is distributed within the hydrogel body or embedded therein either directly by absorption of the agents in the hydrogel, or by incorporation thereof in microspheres, filaments, or particles embedded in the hydrogel; or wherein the contrast agent is comprised in a coating formed of a hydrogel material.

[0069] In some embodiments, the hydrogel is modified chemically to associate to one or more contract agents.In some embodiments, the contrast agent is selected from iodine-based agents. In some embodiments, the agents are selected from lipiodol, iohexol, iopamidol, iodixanol, ioversol.

[0070] In some embodiments, the contrast agent is selected from gadolinium-based contrast agents (GBCAs).

[0071] In some embodiments, the agent is selected from gadopentetate dimeglumine (Magnevist), gadobutrol (Gadavist), gadodiamide (Omniscan), gadoteridol (ProHance), gadofosveset trisodium (Ablavar).

[0072] In some embodiments, the contrast agent is selected from Diatrizoic acid, Metri Zoic acid, lodamide, lotalamic acid, loxitalamic acid, loglicic acid, Acetrizoic acid, locarmic acid, Methiodal, Diodone, Metrizamide, Iohexol, loxaglic acid, Iopamidol, lopromide, lotrolan, loversol, lopentol, Iodixanol, lomeprol, lobitridol, loxilan, lodoxamic acid, lotroxic acid, loglycamic acid, Adipiodone, lobenzamic acid, lopanoic acid, locetamic acid, Sodium iopodate, Tyropanoic acid, Calcium iopodate, Iopy dol, Propyliodone, lofendylate, Lipiodol and non-iodinated salt, barium sulfate; Gadobenic acid, Gadobutrol, Gadodia mide, Gadofosveset, Gadolinium, Gadopentetic acid, Gadoteric acid, Gadoteridol, Gadoversetamide, Gadoxetic acid; Gadolinium oxide, Gadolinium carbonate, Gadolinium chloride, Gadolinium bromide, Gadolinium fluoride, Sulfates and other gadolinium salts and gadolinium complexes with organic and inorganic molecules; Iron oxide; Microspheres of human albumin, Microparticles of galactose, Perflenapent, Microspheres of phospholipids, Sulfur hexafluoride and air entrapped bubbles; and short half-life radioactive agents selected from technetium and low hazard radioactive containing tritiated molecules.

[0073] Further provided is an elongated or a tubular biodegradable device for placement in a human or animal body, the device having an external tubular body formed of a hydrophilic polymer and an internal cavity comprising a contrast agent and optionally at least one therapeutic agent, wherein the device is detectable by US, CT and / or MRI.

[0074] In some embodiments, the internal cavity comprising at least one polymer in which the contrast agent and the optionally present therapeutic agent are contained.

[0075] In some embodiments, the device is an absorbable suture or filament, an orthopedic pin, or a rod structure.

[0076] In some aspects of the invention, a CT-imageable biodegradable rod-shaped marker element for placement in a human or an animal body, said element comprising anelongated non-hydrogel polymeric body and a coating of hyaluronic acid (HA) formed on said body; one or both of said non-hydrogel polymeric material and said HA comprising lipiodol or magnesium metal; wherein said HA is in a dry form or a hydrated form; or is transitionable between a dry form and a hydrated form such that the HA becomes hydrated when placed in the human or animal body.

[0077] In other aspects, a CT-imageable biodegradable rod-shaped marker element for placement in a human or an animal body, said element comprising an elongated nonhydrogel polymeric body and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising lipiodol or magnesium metal; wherein said hydrogel material is in a dry form or a hydrated form.

[0078] As used herein, the term “elongated” refers to a geometric configuration of an element or a mammography clip in which one principal dimension (a length) is greater than at least one transverse dimension (such as width or thickness). An elongated element or mammography clip thus extends along a longitudinal axis and is not substantially spherical or equi dimensional. The elongated shape may be linear, curved, bent, or partially flexible, and may include straight segments, arcs, or folded portions, provided that the overall geometry exhibits a predominant lengthwise dimension. In the context of the present invention, the elongated element or mammography clip may facilitate delivery through a biopsy needle or introducer, enhance visibility or orientation under imaging, and / or improve positional stability within tissue. The term “elongated” does not require a specific length, aspect ratio, or cross-sectional shape, and includes clips having circular, oval, rectangular, polygonal, or irregular cross sections, so long as the longitudinal dimension exceeds the transverse dimensions.

[0079] Devices and elements of the invention are configured to exhibit prolonged residence in the body. Putting it differently, devices of the invention degrade and eliminate from the body 1 to 6 months after installation, or shortly after the period of functionality, being typically between 1 and 6 months has ended. This prolonged residence time and auto-degradation minimizes patient concerns and ensuring unimpeded radiation therapy. The degradation may involve time-dependent breakdown of the polymer(s) making up the device, leading to changes in the device size, shape, mass, composition, and mechanical properties, typically, the degradation is not or may not require external stimulation.The invention further provides methods of using a device or an element according to the invention. Accordingly, the invention provides a method of placing a device or a clip according to the invention in a tissue of a subject, the method comprising delivering said device of clip into a tissue or near a tissue or in a vicinity of a tissue that is to be treated, monitored or otherwise imaged. The delivery of the device or clip may be by injection, a planed surgery, a minimally invasive surgery or procedure. The tissue may be a tissue site from which a diseases tissue or one suspected of being diseased has been removed, a tissue site to monitor for changes and others.

[0080] The invention further concerns method of monitoring a tissue site implanted or provided with a device or a clip, as disclosed herein, the method comprises imaging the site or tissue by a method capable of providing visibility of said device or clip, wherein said method is MRI, CT, ultrasound or any other method as disclosed herein. The method capable of providing visibility will depend, at least partially, on the composition of the device or clip.

[0081] In some embodiments, the method is carried out several times over a time period to detect or monitor changes in the device or clip or in the tissue.

[0082] The invention further provides:

[0083] A biodegradable marker element for placement in a human or an animal body, said element comprising a body formed of a non-hydrogel material, and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising at least one contrast agent; wherein said hydrogel material is transitionable between a dry form and a hydrated form such that the hydrogel becomes hydrated when placed in the human or animal body and wherein said marker element having a predetermined shape and size detectable by at least one imaging techniques.

[0084] In some configurations of any element of the invention, the non-hydrogel material is selected from polymers comprising or selected from lactic acid, glycolic acid, caprolactone, ethylene or propylene carbonates, sebacic acid, ricinoleic acid, castor oil, dioxanone and mixtures thereof.

[0085] In some configurations of any element of the invention, the hydrogel material is selected from polyethylene glycol (PEG), chitosan, alginate, gelatin, hyaluronic acid (HA), oxidized cellulose, and fibrin.In some configurations of any element of the invention, the element comprises a solid lipid composed of fatty acids, fatty alcohols, triglycerides and waxes.

[0086] In some configurations of any element of the invention, the at least one contrast agent is present only in the hydrogel material.

[0087] In some configurations of any element of the invention, the at least one contrast agent is present only in the non-hydrogel material.

[0088] In some configurations of any element of the invention, the at least one contrast agent is distributed within the element or embedded by absorption in the materials, or by incorporation thereof in nanoparticles, microparticles, microspheres, or filaments embedded in the hydrogel material.

[0089] In some configurations of any element of the invention, the hydrogel is chemically associated with the at least one contrast agent.

[0090] In some configurations of any element of the invention, the at least one contrast agent is selected from iodine-based agents.

[0091] In some configurations of any element of the invention, the at least one contrast agent is selected from lipiodol, iohexol, iopamidol, iodixanol, and ioversol.

[0092] In some configurations of any element of the invention, the at least one contrast agent is lipiodol.

[0093] In some configurations of any element of the invention, the at least one contrast agent is selected from gadolinium-based contrast agents (GBCAs).

[0094] In some configurations of any element of the invention, the at least one contrast agent is selected from gadopentetate dimeglumine (Magnevist), gadobutrol (Gadavist), gadodiamide (Omniscan), gadoteridol (ProHance), gadofosveset trisodium (Ablavar).

[0095] In some configurations of any element of the invention, the at least one contrast agent is selected from Diatrizoic acid, Metri Zoic acid, lodamide, lotalamic acid, loxitalamic acid, loglicic acid, Acetrizoic acid, locarmic acid, Methiodal, Diodone, Metrizamide, Iohexol, loxaglic acid, Iopamidol, lopromide, lotrolan, loversol, lopentol, Iodixanol, lomeprol, lobitridol, loxilan, lodoxamic acid, lotroxic acid, loglycamic acid, Adipiodone, lobenzamic acid, lopanoic acid, locetamic acid, Sodium iopodate, Tyropanoic acid, Calcium iopodate, Iopy dol, Propyliodone, lofendylate, Lipiodol and non-iodinated salt, barium sulfate; Gadobenic acid, Gadobutrol, Gadodia mide, Gadofosveset, Gadolinium, Gadopentetic acid, Gadot eric acid, Gadoteridol, Gadoversetamide, Gadoxetic acid; Gadolinium oxide, carbonate, chloride, bromidefluoride, Sulfates and other gadolinium salts and gadolinium complexes with organic and inorganic molecules; Iron oxide; Microspheres of human albumin, Microparticles of galactose, Perflenapent, Microspheres of phospholipids, Sulfur hexafluoride and air entrapped bubbles; and short half-life radioactive agents selected from technetium and low hazard radioactive containing tritiated molecules.

[0096] In some configurations of any element of the invention, the at least one contrast agent is a magnesium-based contrast agent.

[0097] In some configurations of any element of the invention, the magnesium-based contrast agent is magnesium metal, a magnesium alloy or a combination thereof.

[0098] In some configurations of any element of the invention, the magnesium-based contrast agent is provided in a carrier that is embedded in the hydrogel material.

[0099] In some configurations of any element of the invention, the at least one contrast agent is barium sulfate.

[0100] In some configurations of any element of the invention, the at least one contrast agent is provided in an amount ranging between 1 and 60% w / w, or between 1 and 50% w / w, or between 1 and 40% w / w, or between 1 and 30% w / w, or between 1 and 20% w / w, or between 5 and 50% w / w, or 7 and 25% w / w, or between 10 and 60% w / w, or between 20 and 60% w / w, or between 30 and 60% w / w, or between 40 and 60% w / w, or between 50 and 60% w / w.

[0101] In some configurations of any element of the invention, the at least one contrast agent is barium sulfate and the amount thereof is between 1 and 60% w / w.

[0102] In some configurations of any element of the invention, the at least one contrast agent is provided in a carrier that is embedded in the hydrogel material.

[0103] In some configurations of any element of the invention, the element is a biodegradable marker element having a predetermined shape and size detectable by the at least one imaging technique.

[0104] In some configurations of any element of the invention, the element has a shape of a pin, a rod, a screw, a suture, spring, a hernia mesh, a plate, or a filament.

[0105] In some configurations of any element of the invention, the element is in a form of a pin or a spring, or in the form of a clip.

[0106] In some configurations of any element of the invention, the amount of the at least one contrast agent is varied with a distance from a surface of the element.In some configurations of any element of the invention, the amount of the at least one contrast agent reduces as a function of an increase in the distance from a surface of the element.

[0107] In some configurations of any element of the invention, the element is not an inflatable element, or is not a balloon or is not a bladder.

[0108] In some configurations of any element of the invention, the element is for placement in a tissue suspected of being cancerous.

[0109] In some configurations of any element of the invention, the element is for placement at a site of excision of a tissue suspected of being cancerous.

[0110] In some configurations of any element of the invention, the element is imageable by CT, MRI or ultrasound.

[0111] Also provided is a biodegradable rod-shaped marker element for placement in a human or an animal body, said element comprising an elongated body formed of a nonhydrogel material, and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising at least one contrast agent selected from lipiodol, magnesium metal and barium sulfate; wherein said hydrogel material is transitionable between a dry form and a hydrated form such that the hydrogel becomes hydrated when placed in the human or animal body, and wherein said marker element having a predetermined shape and size detectable by at least one imaging techniques.

[0112] In some configurations of any element of the invention, the at least one contrast agent is provided in the hydrogel.

[0113] In some configurations of any element of the invention, the at least one contrast agent is lipiodol.

[0114] In some configurations of any element of the invention, the at least one contrast agent is magnesium metal.

[0115] In some configurations of any element of the invention, the non-hydrogel material is a polymeric material selected from lactic acid, glycolic acid, caprolactone, ethylene or propylene carbonates, sebacic acid, ricinoleic acid, castor oil, dioxanone and mixtures thereof.

[0116] In some configurations of any element of the invention, the hydrogel material is selected from polyethylene glycol (PEG), chitosan, alginate, gelatin, hyaluronic acid (HA), oxidized cellulose, and fibrin.Also provided is a CT-imageable biodegradable rod-shaped marker element for placement in a human or an animal body, said element comprising an elongated nonhydrogel polymeric body and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising lipiodol or magnesium metal; wherein said hydrogel material is transitionable between a dry form and a hydrated form such that the hydrogel becomes hydrated when placed in the human or animal body.

[0117] In some configurations of any element of the invention, the element is deliverable to the human or animal body through a needle.

[0118] In some configurations of any element of the invention, the hydrogel material is HA.

[0119] In some configurations of any element of the invention, the contrast agent, being selected from iohexol, iopamidol, iodixanol, and ioversol, is chemically bound to the hydrogel network or polymerized or bound to a hydrophobic molecule optionally being a fatty acid.

[0120] In some configurations of any element of the invention, the element is a mammography clip.

[0121] In some configurations of any element of the invention, the element is a mammography clip formed of a biodegradable poly(L-lactide-caprolactone) (PLCL), containing between 7 and 25% Lipiodol (by weight), wherein the element is embedded or coated with a hydrogel.

[0122] Also provided is a CT-imageable biodegradable rod-shaped marker element for placement in a human or an animal body, said element comprising an elongated nonhydrogel polymeric body and a coating of hyaluronic acid (HA) formed on said body; one or both of said non-hydrogel polymeric material and said HA comprising lipiodol or magnesium metal; wherein said HA is transitionable between a dry form and a hydrated form such that the HA becomes hydrated when placed in the human or animal body.

[0123] Further provided is a mammography clip in a form of a biodegradable rod-shaped marker element for placement in a human or an animal body, said clip comprising an elongated body formed of poly(L-lactide-caprolactone) (PLCL), and a coating of a hydrogel formed on said body; one or both of said PLCL and said hydrogel comprising lipiodol in an amount between 7 and 25% w / w, wherein said hydrogel is in a dry form ora hydrated form; or is transitionable between a dry form and a hydrated form such that the HA becomes hydrated when placed in the human or animal body.

[0124] BRIEF DESCRIPTION OF THE DRAWINGS

[0125] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0126] Fig. 1: Illustration of hydrogel loading of contrast agent. The dry hydrogel is swelled in a dispersion of the contrast agents where upon drying, forms a composite of the contrast agent entrapped into the dry hydrogel. The dry hydrogel of different shapes and compositions are used for marking a tissue site in the body. The hydrophobic particles or contrast agent droplets or particles remain in the hydrogel and eliminates parallel to the hydrogel.

[0127] Fig. 2: different configurations on the marker implant

[0128] Fig.3: TEM lipiodol loaded PLGA (75:25) NPs.

[0129] Fig. 4: CT of localized and dispersed PLANP formulation in agarose gel.

[0130] Fig.5: Magnesium micro and nanoparticles were incorporated in PLGA or PLCL by either solvent cast or melt mixing and cast into a desired object such as rods, filaments or sheets which are biodegradable and visible by CT as white distinctive object.

[0131] Fig.6: Row 1 (upper, left to right): Blank PLCL; freshly prepared 20% Lipiodol in PLCL; 1 -month older sample; three months aged samples. Row 2 (middle, left to right): Barium sulfate containing PLCL samples; 5, 10, 15, 20 and 30% w / w in PLCL. Row 3 (bottom, left to right): 1% w / w Barium sulfate containing PLCL sample; blank PLCL; agar gel only.

[0132] DETAILED DESCRIPTION OF EMBODIMENTS

[0133] Example 1: Preparation of clip marker

[0134] The objective of this experiment is to make lasting markers based on hydrogel. Hydrogels are hydrophilic polymer, usually crosslinked or of high molecular weight or block copolymers of hydrophilic-hydrophobic segments, that upon immersion in water it absorbs water at an amount of up to 98% of the swollen sample. Hydrogels are not visibleto CT / mammography and thus must be stained with a contrast agent by either absorption, chemical binding or encapsulated marker into biodegradable polymer microparticles.

[0135] Absorption of a contrast agent: in a typical experiment, an emulsion of 20% w / w Lipiodol iodinated poppy seed oil is loaded into the gel by first fully or partially drying the gel and immerse the dried gel in the Lipiodol emulsion whereupon full absorption, the gel can be used for injection into the site of marking. Alternatively, the gel is loaded in a mold and dried or lyophilized to form a dry insert in a form of a thin cylinder that upon ejection in the marking site, swells to a certain shape which fixes the device in the site and degrades over time. The marker device can be of different concentrations of contrast agents, different contrast agents and different shapes and sizes which provides divers distinguishable markers. The loading of the gel with marker dispersion can be of the contrast agents or of the contrast agents loaded in a biodegradable polymer or lipid particles.

[0136] Another option is binding of contrast agent to the hydrogel polymer. In a typical experiment, iodixanol that contains 8 hydroxyl groups that are bound to hyaluronic acid carboxylic acids via an ester bond following the methods of esterification described in Sci Rep 6, 25925 (2016). https: / / doi.org / 10.1038 / srep25925. Iodixanol or iohexol is dissolved in ester coupling agent solution and loaded in the gel and left to react to form ester bonds. Di and tricarboxylic acids such as citric acid or oxalic acid as be added to improve the binding of the water soluble iodixanol. This binding can be prepared in hydrophilic solvents such as DMSO or DMF with DCC as coupling agent. The incorporation of contrast agents into hydrogel is illustrated in Fig. 1. The hydrogel is based on hyaluronic acid of different molecular weights and crosslinking, gelatin implant grade, oxidized cellulose or starch, PEG-PLA, crosslinked polyethylene glycol and more. In a typical experiment, Surgicel-oxidized cellulose sponge was cut into a rod shape and loaded with a 20% w / w aqueous dispersion of Lipiodol loaded PLA microparticles. After 10 minutes of absorption, the sponges were dried to form a rod shape device.

[0137] Example 2: Synthesis of hydrophobic iodexaol

[0138] Triiodobenzene is the active moiety in CT contrast agents it is not water soluble and thus preferred for incorporation in a biodegradable polymer or lipids for long term marking a body site. Iodixanol or iohexol are water soluble derivatives of triiodobenzene contain several hydroxyl groups which are partially esterified with various acids such aslactic acid, fatty acids, amino acids and polymerization of common biodegradable polymers based on lactide, glycolide, caprolactone and carbonates. Another possibility is to oligomerize iodixanol with carbonate bond, acetal and hemiacetal bonds, and ester bonds. The physical properties of the modified iodixanol is dominated by the side groups grafted onto the alcoholic groups of the contrast agent and the number of hydroxyl groups modified.

[0139] Example 3: Preparation of polymer rods and filaments loaded with contrast agents In a typical experiment, a molten blend of PLGA 75:25 and iodinated contrast agent such as Lipiodol or iodixanol at a 60:40 w / w ratio is passed through a spinning orifice of different cross-section patterns (circular, triangle, square, and tri-arm star) and diameter, to form filaments with different cross-sections that can be distinguished in tissue (Fig.2, top panel). Similarly, blends or mixtures of iodixanol in PLGA or PLCL at 20-40% w / w and 0.2% w / w of iron oxide or gadolinium complex are prepared by melt or solvent mixing of the contrast agents and spinning or molding into the desired shape. Another possibility is to inject-mold rods with different layers, the core contains a polymer loaded with 60% of one CT contrast agent, first layer with MRI contrast agents, iron oxide or gadolinium complex and a hydrogel is the outer layer (Fig.2, middle panel).

[0140] Rods or segments that contain a contrast agent and segments that do not contain contrast agent or different contrast agent are prepared by injection molding into a mold or by 3D printing. The segmented rod allows differentiation / distinction among different implantable markers required for monitoring different locations in the body and times of implantation (Fig. 2, bottom panel).

[0141] Shape memory marker with coil shape: To obtain a rod that upon ejection in tissue changes its shape into a coil shape, linear filaments composed of PLGA or PLCL and contrast agents such as lipiodol, triiodobenzene derivatives and gadolinium complex and iron oxide, prepared by melt spinning, are wrapped onto a hot metallic rod where upon cooling, provides a flexible coil shape. The coil is extended to a close to linear rod shape and pushed into a needle where upon releasing out from the needle, a coil shape of the original diameter is formed. Alternatively, biodegradable shape memory polymers based on PLGA-urethane are used to form rod shape implants that upon reaching body temperature changes its shape to a pre-determined shape. Another option for a rod implant that changes its visibility shape is to put together biodegradable rod shape solid fibers thatabsorbed a hydrogel at a certain point along the fibers where upon implantation in tissue, absorb water and expand at the point of the hydrogel to form a new shape.

[0142] Coating of the polymeric rods with hydrogels: The marker rods described in this example and any marker shape described in this invention, are coated with a hydrogel made from hyaluronic acid, gelatin, oxidized cellulose or starch, polyethylene glycol derivatives and more. The coatings are crosslinked to maintain them for periods or about 6 or 12 months. The crosslinking is performed by adding a multifunctional linker molecule or by self-crosslinking or denaturation. The coated hydrogel can be of different thicknesses and layers or different compositions or degree of crosslinking. One or more coating layers may contain a contrast agent loaded from a dispersion of the contrast agents. In a typical experiment, the solid rod is coated with hyaluronic acid by dipping into a viscous solution of the polysaccharide. The coated device is immersed in an aqueous solution of a crosslinker, such as: 1,4-butanediol diglycidyl ether (BDDE), poly (ethylene glycol) diglycidyl ether (PEGDE), divinyl sulfone (DVS), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 1,2,7,8-diepoxyoctane, and glutaraldehyde (GA) and left to cure at room temperature on in an oven at 40oC overnight. The degree of crosslinking is dependent on the concentration of crosslinker in the dipping solution, the temperature of the solution and the time of the dipping as well as the curing temperature and time. The coating may include a contrast agent where the hyaluronic acid dipping solution contains the contrast agent as a dispersion so when coating the coating contains the contrast agents. Alternatively, the coated rod with hyaluronic acid, before or after crosslinking, is immersed in a dispersion of contrast agent particles to allow absorption onto the coating where upon evaporation of the coating solvent, a dry surface containing the contrast agent is obtained. Another coating can be applied onto the first hydrogel coating by dip or spray coating with either a different polymeric hydrogel, different thickness or loaded with different contrast agents. Similarly, coating with gelatin and coating with multifunctional crosslinking agents are used.

[0143] Coating of solid devices is affected by dipping is a solution of PEG-PLA to form a hydrophilic surface without the need for crosslinking.

[0144] Example 4: theragnostic implantable markers

[0145] The devices described above may contain an active agent at a therapeutic amount for controlled release in the site of placement in tissue. For mammography clips, ananti cancer agent commonly used for treating breast cancer, including paclitaxel, cisplatin, etc. that are incorporated in the device during manufacturing and being released to the surrounding tissue while the polymer is degraded. In a typical experiment, paclitaxel powder is dissolved is dichloromethane containing lipiodol, iron oxide nanoparticles and poly(lactide-co-glycolide) 75:25 at a w / w ratio: 10:20:0.2:68.8. After solvent evaporation, the solid material was shaped into 5 mm rods of 1 mm in diameter. The rods were placed in phosphate buffer solution containing 1% Tween 80 (to increase paclitaxel solubility) and the release was monitored by HPLC. A constant release was obtained over 30 days. Other therapeutic agent can be included, including small molecule drugs, therapeutic proteins and nucleotide-based drugs.

[0146] Example 5: shape memory markers

[0147] To obtain a rod that upon ejection in tissue changes its shape into a coil shape, the linear filaments prepared by hot spinning are wrapped onto a hot metallic rod where upon cooling, provides a flexible coil shape. The coil is extended to a rod shape and pushed into a needle where upon releasing out from the needle, a coil shape of the original diameter is formed. No shape memory polymer is needed to form such a shape.

[0148] Example 6: biodegradable contrast agent particles

[0149] This experiment describes the formation of biodegradable particles that are visible by CT US and MRI. In this study, iodinated organic molecules and inorganic contrast agents were incorporated in a biodegradable polymer carrier to form nano- and microparticles. A precipitation in anti-solvent in an aqueous or an organic medium was used, to avoid leakage of the contrast agent from the formed particles. Poly(ε-caprolactone) (PCL) and poly(lactide-glycolide) (PLGA) were used as carriers and Lipiodol (iodinated poppyseed oil), lodixanol and iron oxide nanoparticles ere the contrast agents. Lecithin and polyvinyl alcohol PVA (30,000-70,000) were used as dispersing agents.

[0150] In a typical experiment, PCL (14000 molecular weight, 800 mg), Lipiodol-iodinated poppyseed oil (200 mg) and lecithin (100 mg) were dissolved in 10 mL chloroform. PVA aqueous solution (1% w / v) was prepared by dissolving 1 g in 100 mL water. To prepare the nanoparticles, organic solution mixture was added to the aqueous phase and homogenized at 13500 rpm for 15 minutes at room temperature. The pelletsobtained were re-dispersed in water and analyzed. DLS analysis of nanoparticles obtained was 350+ / -50 nm and Zeta potential of -44 mV. DSC analysis showed melting temperature of 60°C for the blank PCL particles and 58°C for the Lipiodol loaded particles.

[0151] When PLGA 75:25 and 50:50 were used, instead of the PCL, nanoparticles of 150+ / -50 nm and Zeta potential of -49 mV were obtained. The particles were spherical in shape within 150 nm in size as shown by TEM analysis and DLS measurements.

[0152] When PL A of 100000 molecular weight was used to prepare 20% Lipiodol loaded nanoparticles, 250+ / -50 nm particles were obtained with a Zeta potential of -40 mV. The Lipiodol content in the particles was determined by UV detection of an ethanolic solution of Lipiodol at 260nm using a calibration curve. The polymer loaded Lipiodol nanoparticles (20 mg) were added to ethanol and mixed overnight and the UV absorption at 260nm of the ethanolic solution was determined. The content of 20% Lipiodol was confirmed.

[0153] The particles were analyzed for visualization by Computed Tomography of polymer-Lipiodol NPs in agarose gel. PL A loaded 20%w / w lipiodol nanoparticles were embedded in agarose gel (1.2% w / v agarose in water).

[0154] As seen in Fig. 4, PLA-Lipiodol concentrated NPs on top of the agarose gel showed high resolution images (right 3 tubes) where the gel or the blank PLA particles do not show any contrast (left two tubes). When the nanoparticles were dispersed in agarose (60-150 mg in 1 ml gel) the dispersion can be seen where the contrast intensified with the nanoparticles’ concentration dispersed in the gel.

[0155] To increase the contrast of the particles, Lipiodol was incorporated in the nanoparticles at an amount of 35 and 50% w / w loading. The particles remain solid flowable powders.

[0156] Polymer-Lipiodol -Paclitaxel nanoparticles: Nanoparticles containing 10% paclitaxel and 20% lipiodol were prepared as described above where the paclitaxel was dissolved in the dichloromethane phase used for making the nanoparticles. PCL 14 kDa and PLA 100 kDa were used for making the nanoparticles. In a typical experiment, 100 mg Paclitaxel and 180 mg Lipiodol were mixed together to form a white pasty material which was dissolved in 10 mL dichloromethane containing 720 mg of PLA to form a transparent solution. Nanoparticles were prepared by adding to a water phase containing PVA as described above. Free flowing fine powder of 200 nm particles size wasobtaining. To obtain microparticles in the range of 20-100 microns, a concentrated solution of the polymer-Lipiodol and paclitaxel in di chloromethane was used, as well the mixing rate was reduced to about 1000 rpm.

[0157] In vitro release of Paclitaxel from the nanoparticles was determined in phosphate buffer pH7.4 solution containing 1% w / v Tween 80 to increase the solubility of paclitaxel in the release solution. A constant release of paclitaxel was obtained for at least 20 days.

[0158] Example 7: Injectable marker in water miscible organic solvents

[0159] In situ forming implant marker was prepared from poly(D, L-lactide) (PLA) and biocompatible solvents was used to obtain a solid implant upon tissue administration. N- m ethyl -2-pyrrolidone (NMP) was used to determine the implant properties, however, 2- pyrrolidone, triacetine and benzyl benzoate are also available for in situ forming implant. These solvents form a 30% w / v solution of PLGA of different viscosities and rate of solidification after injection in tissue. The polymer solutions were prepared by mixing the polymer powder into the solvent at 60°C with constant mixing and cooling to room temperature. To the polymer solution, contrast agents were added at an amount required for visibility by the imaging systems, CT, MRI or ultrasound. Typically, gadolinium complex or iron oxide needed for MRI are added in small amount, below 1% w / w to the polymer carrier while iodinated benzene derivatives or Lipiodol are added at an amount of 10 to 30% w / w per the polymer carrier. Polymer solution can vary from 10 to 40% w / v, depending on the miscibility and the viscosity of the polymer-contrast agent compositions. When anticancer agents are added to the solution, they should be compatible with the polymer-contrast agent solution to form a homogeneous injection. The release profile is dependent on the polymer carrier, the contrast agents, the solvent and the ratio of the formulation components. The release is usually for weeks with some bursting at the first few hours.

[0160] Example 8: Lipid based implantable markers

[0161] Solid lipids, including triglycerides, fatty acids and fatty alcohols, paraffines and waxes, are used for the incorporation of contrast agents and molded into rods and other shapes of inserts that may remain in the body for many months. In a typical example, carnauba wax is melted and lipiodol or iodixanol are mixed to form a uniform melt which is cast to form thin rods suitable for markers.Example 9: Lipid based implantable markers

[0162] Lipid based rods and other shapes are prepared by melt casting of a solid lipid such as waxes, high melting fatty acids, fatty alcohols and solid mono-, di- and triglycerides. The molten lipid is loaded with the contrast agent as liquid or solid particles and coated with a hydrophilic coating as described above.

[0163] Example 10: Thermoresponsive hydrogel markers

[0164] In this example, polymers that are water soluble at low temperature, solidify into a gel at body temperature are used. To the solutions of these polymers at low temperature, PLGA particles loaded with contrast agents (iodinated molecules, iron oxide or gadolinium complexes, etc) are added to an amount that is visible by US, MRI or CT. water soluble contrast agents like iodixanol or iohexol or a dispersion of Lipiodol and mixed in the polymer solution. The formed dispersions may be injected into the site of marking where-upon reaching body temperature, it solidifies at the injection point. Alternatively, the solutions are made with polymers that are soluble at low temperature such as below lOoC where at room temperature the solutions are solid gels where they are molded in a certain shape such as a rod or coil and left to dry so that when the dry shape is implanted, it absorbs water and gel. More specifically PGLA-PEG-PLGA copolymers that are water soluble at a range of temperatures and solidify at body temperature are used. The preparation and properties of these block copolymers are described in our publication in: J. Polym. Sci. A Polym. Chem. 57 (17), 1847-1847, 2019.

[0165] Another polymer is a block-copolymer of polypropylene oxide-polyethylene oxide such as Polyoxamer 407 and their mixtures with hydroxypropyl methylcellulose (HPMC) or sodium carboxymethylcellulose (NaCMC). These compositions are liquid at temperatures in the range of l-30°C and gel at body temperature. For both polymers, the viscosity of the liquid phase of the polymers and the gel hardness and temperature of gelling are affected by the properties of the polymers-composition and molecular weight, the concentration in the aqueous media, the ionic strength and pH and additives added to the solution.Example 11: Magnesium based resorbable clips

[0166] Absorbable clips containing magnesium metal are prepared from pure magnesium, magnesium alloys and mixtures of biodegradable polymers with magnesium particles. Magnesium metal is biodegradable and is in clinical use of orthopedic screws and nails which are visible by CT and MRI. Commercially available magnesium micro and nanoparticles were incorporated in PLGA or PLCL by either solvent cast or melt mixing and cast into a desired object such as rods, filaments or sheets which are biodegradable and visible by CT as white distinctive object.

[0167] Example 12: Barium sulfate contrast agent

[0168] Rods containing 5-30% w / w barium sulfates nanoparticles (700 nm) in PLCL were prepared by solvent cast of a fine and uniform dispersion of barium sulfate in 12.5% w / v solution of PLCL in dichloromethane (viscosity 80 cps at 22°C). The dry solid samples were stuck into solid agar tube and visualized by CT. As control, agar with no marker sample were used. For comparison, similar samples containing 20% w / w Lipiodol in PLCL were used. The CT results are given in Fig. 6.

[0169] As can be understood from Fig. 6, 20% Lipiodol containing polymers are visible by CT with no change in visibility with time. Polymer samples containing >5% barium sulfate are strongly visible by CT, while 1% still can be seen. Similarly, barium sulfate containing filaments and sheets were prepared by melt mixing barium sulfate or lipiodol or the mixture thereof in the polymer melt to form a uniform blend which then melt molded to various objects.

[0170] In another experiment, rods loaded with 5% w / w lipiodol were coated with a dispersion of barium sulfate to form a rod that contain lipiodol contrast agent in the inner rod and barium sulfate in the outside. Similarly, plain object that does not contain a contrast agent was coated with PLCL or another biodegradable polymer containing a contrast agent such as lipiodol or barium sulfate or both.

[0171] The lactide based biodegradable filaments containing contrast agents such as lipiodol, iohexol or barium sulfates have been used for 3D printing of objection that are visible by CT.Example 13: Preparation of medical implants by lipiodol absorption Biodegradable objects, including; clip rods of 7X1 mm, filaments, films, screens, microspheres and nanospheres, made from PLCL were immersed in net lipiodol oil or a lipiodol solution in ethanol (20%w / w) and samples were taken out at certain time points. Lipiodol was absorbed in all the PLCL devices as a function of time, the longer the time of immersion the more Lipiodol is absorbed and dipper in the device. Devices containing 5, 10 and 20% lipiodol were obtained by controlling the time, lipiodol concentration in ethanol and temperature. The higher the temperature the faster is the absorption into the polymer object.

[0172] Lipiodol loaded rods prepared by absorption of lipiodol from a net or lipiodol solution, having a gradient of lipiodol concentrations so that the outer layer contains high lipiodol content while the inner layers contain less and less lipiodol where the lipiodol content in the center of the rod is the least.

[0173] The absorption method of loading lipiodol contrast agent allows staining biodegradable elements at different locations or patterns, depending on the immersion site and immersion conditions.

[0174] It should be noted that this phenomenon of absorption into polymer is unique to lipiodol. When performing similar absorption experiments with non-iodinated vegetable oils such as sesame oil and corn oil, no weight gain into the PLA, PLCL or PLGA polymers was obtained.

[0175] In another experiment solid blends of polymer-oil were prepared by solvent mixing and evaporation of for example, PLCL and sesame oil at a 2:1 w / w ratio. The polymer blend was treated with ethanol to remove the oil to form a sponge-like polymer matrix. When adding this sponge to lipiodol or lipiodol solution in ethanol, lipiodol was absorbed in the polymer matrix in significant quantities which was controlled by the blend composition and the absorption conditions. A loading of up to 30% of lipiodol in PLCL was obtained.

[0176] Example 14: Hydrogel containing contrast agent coating of solid objects

[0177] A 2% w / v solution of hyaluronic acid suitable for injection to humans, was mixed with 2% w / v of glycerol and 20% PLCL microparticles loaded with 50% w / w lipiodol of a particle size below 10 microns. The uniform dispersion was deposited onto the surface of objects in the form of a sheet, a slab, a rod or films by either paining or sprayingthe hydrogel onto the surface or dipping or passing through the dispersion. Wet coated objects were left to dry for 3-7 days to form a dry flexible adhesive onto the surface. These coated objects were visible by CT, MTI and ultrasound.

Claims

1. CLAIMS:

1. A biodegradable marker element for placement in a human or an animal body, said element comprising a body formed of a non-hydrogel material, and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising at least one contrast agent; wherein said hydrogel material is transitionable between a dry form and a hydrated form such that the hydrogel becomes hydrated when placed in the human or animal body and wherein said marker element having a predetermined shape and size detectable by at least one imaging techniques.

2. The element according to claim 1, being a biodegradable marker element having a body formed of a non-hydrogel material, and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising at least one contrast agent; wherein said hydrogel material is water free or dry.

3. The element according to claim 1, being a biodegradable marker element having a body formed of a non-hydrogel material, and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising at least one contrast agent; wherein said hydrogel material is hydrated.

4. The element according to claim 1, wherein the non-hydrogel material is selected from polymers comprising or selected from lactic acid, glycolic acid, caprolactone, ethylene or propylene carbonates, sebacic acid, ricinoleic acid, castor oil, dioxanone and mixtures thereof.

5. The element according to claim 1, wherein the hydrogel material is selected from polyethylene glycol (PEG), chitosan, alginate, gelatin, hyaluronic acid (HA), oxidized cellulose, and fibrin.

6. The element according to any one of claims 1 to 5, comprising a solid lipid composed of fatty acids, fatty alcohols, triglycerides and waxes.

7. The element according to any one of the preceding claims, wherein the at least one contrast agent is present only in the hydrogel material.

8. The element according to any one of claims 1 to 6, wherein the at least one contrast agent is present only in the non-hydrogel material.

9. The element according to any one of the preceding claims, wherein the at least one contrast agent is distributed within the element or embedded by absorption in thematerials, or by incorporation thereof in nanoparticles, microparticles, microspheres, or filaments embedded in the hydrogel material.

10. The element according to any one of claims 1 to 9, wherein the hydrogel is chemically associated with the at least one contrast agent.

11. The element according to any one of claims 1 to 10, wherein the at least one contrast agent is selected from iodine-based agents.

12. The element according to claim 11, wherein the at least one contrast agent is selected from lipiodol, iohexol, iopamidol, iodixanol, and ioversol.

13. The element accoridng to claim 12, wherein the at least one contrast agent is lipiodol.

14. The device according to any one of claims 1 to 11, wherein the at least one contrast agent is selected from gadolinium-based contrast agents (GBCAs).

15. The device accoridng to claim 14, wherein the at least one contrast agent is selected from gadopentetate dimeglumine (Magnevist), gadobutrol (Gadavist), gadodiamide (Omniscan), gadoteridol (ProHance), gadofosveset trisodium (Ablavar).

16. The device according to any one of claims 1 to 11, wherein the at least one contrast agent is selected from Diatrizoic acid, Metri Zoic acid, lodamide, lotalamic acid, loxitalamic acid, loglicic acid, Acetrizoic acid, locarmic acid, Methiodal, Diodone, Metrizamide, Iohexol, loxaglic acid, Iopamidol, lopromide, lotrolan, loversol, lopentol, Iodixanol, lomeprol, lobitridol, loxilan, lodoxamic acid, lotroxic acid, loglycamic acid, Adipiodone, lobenzamic acid, lopanoic acid, locetamic acid, Sodium iopodate, Tyropanoic acid, Calcium iopodate, Iopy dol, Propyliodone, lofendylate, Lipiodol and non-iodinated salt, barium sulfate; Gadobenic acid, Gadobutrol, Gadodia mide, Gadofosveset, Gadolinium, Gadopentetic acid, Gadot eric acid, Gadoteridol, Gadoversetamide, Gadoxetic acid; Gadolinium oxide, Gadolinium carbonate, Gadolinium chloride, Gadolinium bromide, Gadolinium fluoride, Gadolinium fulfate, gadolinium complexes with organic and inorganic molecules; Iron oxide; Microspheres of human albumin, Microparticles of galactose, Perflenapent, Microspheres of phospholipids, Sulfur hexafluoride and air entrapped bubbles; and short half-life radioactive agents selected from technetium and low hazard radioactive containing tritiated molecules.

17. The element according to any one of claims 1 to 11, wherein the at least one contrast agent is a magnesium-based contrast agent.

18. The element according to claim 17, wherein the magnesium-based contrast agent is magnesium metal, a magnesium alloy or a combination thereof.

19. The element according to claim 17 or 18, wherein the magnesium-based contrast agent is provided in a carrier that is embedded in the hydrogel material.

20. The element according to any one of claims 1 to 11, wherein the at least one contrast agent is barium sulfate.

21. The element according to any one of the preceding claims, wherein the at least one contrast agent is provided in an amount ranging between 1 and 60% w / w, or between 1 and 50% w / w, or between 1 and 40% w / w, or between 1 and 30% w / w, or between 1 and 20% w / w, or between 5 and 50% w / w, or between 10 and 60% w / w, or between 7 and 25% w / w, or between 20 and 60% w / w, or between 30 and 60% w / w, or between 40 and 60% w / w, or between 50 and 60% w / w.

22. The element according to claim 21, wherein the at least one contrast agent is barium sulfate and the amount thereof is between 1 and 60% w / w.

23. The element according to claim 22, wherein the at least one contrast agent is provided in a carrier that is embedded in the hydrogel material.

24. The element accoridng to any one of the preceding claims, being a biodegradable marker element having a predetermined shape and size detectable by the at least one imaging technique.

25. The element according to any one of the preceding claims, having a shape of a pin, a rod, a screw, a suture, spring, a hernia mesh, a plate, a clip or a filament.

26. The element according to claim 25, in a form of a pin or a spring.

27. The element according to claim 25, being a mammography clip.

28. The element according to any one of claims 1 to 27, wherein the amount of the at least one contrast agent is varied with a distance from a surface of the element.

29. The element according to claim 28, wherein the amount of the at least one contrast agent reduces as a function of an increase in the distance from a surface of the element.

30. The element according to any one of the preceding claims, wherein the element is not an inflatable element, or is not a balloon or is not a bladder.

31. The element according to any one of the preceding claims, for placement in a tissue suspected of being cancerous.

32. The element according to any one of the preceding claims, for placement at a site of excision of a tissue suspected of being cancerous.

33. The element according to any one of the preceding claims, for placement at a site of a biopsy site, lesion, or region of clinical interest.

34. The element according to any one of the preceding claims, imageable by CT, MRI or ultrasound.

35. The element according to any one of the preceding claims, imageable by mammography.

36. A biodegradable rod-shaped marker element for placement in a human or an animal body, said element comprising an elongated body formed of a non-hydrogel material, and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising at least one contrast agent selected from lipiodol, magnesium metal and barium sulfate; wherein said hydrogel material is a dry form or a hydrated form, and wherein said marker element having a predetermined shape and size detectable by at least one imaging techniques.

37. The element according to claim 36, wherein the at least one contrast agent is provided in the hydrogel.

38. The element according to claim 36, wherein the at least one contrast agent is lipiodol.

39. The element according to claim 36, wherein the at least one contrast agent is magnesium metal.

40. The element according to claim 36, wherein the non-hydrogel material is a polymeric material selected from lactic acid, glycolic acid, caprolactone, ethylene or propylene carbonates, sebacic acid, ricinoleic acid, castor oil, dioxanone and mixtures thereof.

41. The element according to claim 36, wherein the hydrogel material is selected from polyethylene glycol (PEG), chitosan, alginate, gelatin, hyaluronic acid (HA), oxidized cellulose, and fibrin.

42. A CT-imageable biodegradable rod-shaped marker element for placement in a human or an animal body, said element comprising an elongated non-hydrogel polymeric body and a coating of at least one hydrogel material formed on said body; one or both of said non-hydrogel material and hydrogel material comprising lipiodol or magnesium metal; wherein said hydrogel material is in a dry form or a hydrated form.

43. The element according to any one of claims 36 to 42, deliverable to the human or animal body through a needle.

44. The element according to any one of claims 36 to 43, wherein the hydrogel material is HA.

45. The element according to any one of claims 1 to 35, wherein the contrast agent, being selected from iohexol, iopamidol, iodixanol, and ioversol, is chemically bound to the hydrogel network or polymerized or bound to a hydrophobic molecule optionally being a fatty acid.

46. The element according to any one of claims 1 to 45, being a mammography clip formed of poly(L-lactide-caprolactone) (PLCL), containing between 7 and 25% w / w Lipiodol, wherein the element is coated with a hydrogel.

47. The element according to claim 46, wherein the hydrogel is HA.

48. A CT-imageable biodegradable rod-shaped marker element for placement in a human or an animal body, said element comprising an elongated non-hydrogel polymeric body and a coating of hyaluronic acid (HA) formed on said body; one or both of said nonhydrogel polymeric material and said HA comprising lipiodol or magnesium metal; wherein said HA is in a dry form or a hydrated form; or is transitionable between a dry form and a hydrated form such that the HA becomes hydrated when placed in the human or animal body.

49. A mammography clip in a form of a biodegradable rod-shaped marker element for placement in a human or an animal body, said clip comprising an elongated body formed of poly(L-lactide-caprolactone) (PLCL), and a coating of a hydrogel formed on said body; one or both of said PLCL and said hydrogel comprising lipiodol in an amount between 7 and 25% w / w, wherein said hydrogel is in a dry form or a hydrated form; or is transitionable between a dry form and a hydrated form such that the HA becomes hydrated when placed in the human or animal body.

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