WO2024226746A1 - Radiopaque biodegradable polymer for tracking breast tissue tumor cavity after lumpectomy - Google Patents

Abstract

Disclosed herein is a device made of biodegradable polymer and a radiopaque agent, wherein the device has a patterned shape with a high ratio of surface area to volume (e.g a scaffold, net, mesh, collapsible). A method for marking a post-operative cavity using a device made of biodegradable polymer and radiopaque agent is also disclosed.

Description

RADIOPAQUE BIODEGRADABLE POLYMER FOR TRACKING BREAST TISSUE TUMOR CAVITY AFTER LUMPECTOMY

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application 63/461,767, filed April 25, 2023, the contents of which are hereby incorporated in its entirety.

BACKGROUND

[0002] Around 40% of women diagnosed with breast cancer have a lumpectomy procedure performed. Typically, this operation is followed by radiation therapy to ensure the cancerous cells do not continue to grow, as they are more likely to reappear near the previous tumor. It is important to mark where the tumor was in the breast to better plan for the post-operative radiation treatment.

[0003] When performing the lumpectomy procedure, the surgeon typically inserts fiducial markers into the breast to mark the parameters of the cavity that remains after the tumor has been removed. These markers are made of titanium and remain in the body forever. They make it easier for radiation therapists, dosimetrists, and radiation oncologists to see the location of the tumor when preparing for and administering the radiation. The specificity of the treatment is very important to ensure that the oncologist is only targeting the area within the tumor cavity and that damage to the noncancerous tissue of the patient is minimized. The radiation therapists use the markers to evaluate the changes in the breast from treatment to treatment, so the further along the patient is in the treatment process the more important the markers are as more and more changes occur in the body during the course of treatment. The dosimetrists series of MRIs and CT scans along with advanced math and physics to calculate the distribution of the radiation dosage across the spread of the tumor cavity, as the higher risk area of the cavity gets a boosted treatment with higher levels of radiation. The lack of reliable markers hinders the efficiency of the treatments and puts the patient at more possible risk.

[0004] Currently, the markers that are used are known to either cause post-operational issues for the patients, like the accumulation of serous fluid underneath the skin, or they undergo geometric shifts with the natural post-operational changes that occur in the breast as a result of the radiation. This is a huge concern for the patient as seromas can lead to the formation of abscesses, which arc a collection of pus that could hinder radiation treatment and healing. Seromas can also cause cavity markers to shift and migrate. Current market options do not fit the needs and wants of stakeholders, including doctors, patients, radiation therapists, and more. The device needs to be biodegradable after 12 weeks — a timepoint in which most radiation treatments are done. The device needs to be radiopaque for precise radiation treatment from radiation therapists and dosimetrists. Additionally, the current options have the potential to be painful for patients and do not adequately mark the cavity for radiation planning.

[0005] An improved fiducial marker device should be biocompatible, mark the cavity, be distinguishable on imaging, easy to implant, reliable, comfortable, long-lasting, aid reconstruction of breast shape, and inexpensive.

SUMMARY

[0006] Provided herein are devices (fiducial markers) that can be formed from a biodegradable polymer having a radiopaque agent dispersed therein. The devices can exhibit a high surface area to volume ratio, so as to provide a desirable rate of biodegradation following implantation. For example, the devices can be an improvement as compared to existing devices that are formed from larger quantities of material, resulting in significantly longer persistence following implantation. The devices can have more surface area and a smaller volume to allow for quicker biodegradation in the cavity. Additionally, instead of incorporating non- biodegradable metal clips that will stay in the body forever, these devices can include a biocompatible radiopaque agent. This allows for the device to be viewed under a CT stan, which allows radiation therapists and dosimetrists to accurately know the boundaries of the tumor cavity and accurately treat the area with a proper radiation dosage.

[0007] In some aspects, the techniques described herein relate to a fiduciary marker including: a matrix including a biodegradable polymer and a radiopaque agent dispersed therein, wherein the fiduciary marker is patterned into a shape including contiguous matrix material and interspersed cavities (e.g a scaffold, net, mesh, collapsible).

[0008] In some aspects, the techniques described herein relate to a method for marking a post-operative cavity, the method including: inserting a fiduciary marker into a post-operative cavity, wherein the fiduciary marker includes a matrix including a biodegradable polymer and a radiopaque agent disposed therein, wherein the fiduciary marker is patterned into a shape including contiguous matrix material and interspersed cavities (e.g a scaffold, net, mesh, collapsible).

BRIEF DESCRIPTION OF THE FIGURES

[0009] Figure 1 depicts (left) a flat mesh with a thickness and (right) a hemispherical shape mesh.

[0010] Figure 2 depicts a collapsible scaffold 3D design.

[0011] Figure 3 depicts frontal plane results from a CT scan.

DETAILED SPECIFICATION

[0012] A fiducial marker for use in post-operative tissue, in particular human breast tissue after a lumpectomy, is described herein. The fiducial marker is designed to be biocompatible, to effectively mark the cavity, to be distinguishable on imaging (e.g. MRI, CT, X-Ray, etc), easy to implant, reliable (i.e. does not move within the tissue), comfortable, long-lasting (e.g at least 8 weeks), aid reconstruction of breast shape, and inexpensive.

[0013] In one embodiment, the fiducial marker is comprised of a matrix of biodegradable polymer and a radiopaque agent disposed therein. In one embodiment, the fiducial marker is patterned into a shape having contiguous matrix material and interspersed cavities, such as a scaffold, mesh, net, or other high- surface area shape, using a solution of polymer and radiopaque agent. In some instances, the radiopaque agent may be nanoparticulate. In some instances, the radiopaque agent is 30% by weight of the device and may be present as nanoparticles in a polymer matrix.

[0014] In some implementations, the biodegradable polymer can include polyesters, polycarbonates, poly anhydrides, polyamides, polyurethanes, polyketals, polyacetals, polydioxanones, polyesteramides, polyorthoesters, polyorthocarbonates, polyphosphazenes, polypeptides, polyvinyls, polyalkylene oxides, polysaccharides, copolymers thereof, and combinations thereof. In certain implementations, the biodegradable polymer can be poly(caprolactone), poly(glycolic acid), poly(lactic acid), poly (hydroxybutry ate); poly(maleic anhydride); poly(malic acid), poly(ethylene glycol), poly(vinylpyrrolidone), poly(methyl vinylether), hydroxycellulose; chitin; chitosan; alginate, hyaluronic acid, and copolymers thereof. Combinations of the aforementioned polymers may also be employed. [0015] In some implementations the biodegradable polymer can be poly(caprolactone), poly(glycolic acid), poly(lactic acid), a copolymer thereof, or a combination thereof. In some implementations the biodegradable polymer can be poly(caprolactone-co-glycolic acid), poly(caprolactone-co-lactic acid), or poly(lactic acid-co-glycolic acid). As used herein, poly(caprolactone-co-lactic acid) is used interchangeable with poly(caprolactone-co-lactide) and poly(lactide-co-caprolactone). In certain implementations, the poly (lactic acid) can be poly(L- lactic acid). In some implementations the poly (lactic acid) can be poly(L-lactic acid), in other implementations, the poly(lactic acid) can be poly(D-lactic acid), and in further implementations the the poly(lactic acid) can be poly(DL-lactic acid).

[0016] In certain implementations the biodegradable polymer is poly(L-lactic acid-co- caprolactone). In some implementations the biodegradable polymer is poly(D-lactic acid-co- caprolactone). In further implementations the biodegradable polymer is poly(DL-lactic acid-co- caprolactone).

[0017] The biodegradable polymer can have a MW_w that is from 10,000-2,500,000 g/mol, from 50,000-2,500,000 g/mol, from 100,000-2,500,000 g/mol, from 250,000-2,500,000 g/mol, from 100,000-2,000,000 g/mol, from 100,000-1,500,000 g/mol, from 100,000-1,000,000 g/mol, from 250,000-1,000,000 g/mol, from 500,000-1,000,000 g/mol, from 250,000-900,000 g/mol, from 50,000-250,000 g/mol, from 50,000-150,000 g/mol, from 100,000-500,000 g/mol, from 100,000-250,000 g/mol, or from 250,000-500,000 g/mol.

[0018] In some implementations the biodegradable polymer is poly(L-lactic acid-co- caprolactone) having a MW_w that is from 10,000-2,500,000 g/mol, from 50,000-2,500,000 g/mol, from 100,000-2,500,000 g/mol, from 250,000-2,500,000 g/mol, from 100,000-2,000,000 g/mol, from 100,000-1,500,000 g/mol, from 100,000-1,000,000 g/mol, from 250,000-1,000,000 g/mol, from 500,000-1,000,000 g/mol, from 250,000-900,000 g/mol, from 10,000-100,000 g/mol, from 10,000-50,000 g/mol, from 25,000-75,000 g/mol, from 50,000-250,000 g/mol, from 50,000-150,000 g/mol, from 100,000-500,000 g/mol, from 100,000-250,000 g/mol, or from 250,000-500,000 g/mol.

[0019] In certain implementations the fiducial marker is moldable upon application of heat. In certain implementations, the biodegradable polymer (separate from the radiopaque agent) can have a melting point from 30-70°C., from 30-50°C., from 30-40°C., from 35-50°C., from 35- 45°C„ from 40-50°C., from 45-55°C„ from 50-60°C„ from 55-65°C., or from 60-70°C. In certain implementations melting point can be determined according to ASTM D3418-99.

[0020] The radiopaque agent provides contrast for x-ray and other imaging modalities. In certain implementations, the radiopaque agent includes a barium salt, e.g., barium sulfate. In some implementations the radiopaque agent includes a ferrous ferric oxide compound. In certain implementations the radiopaque agent is an iodine-containing compound. In some implementations the radiopaque agent is gadolinium agent.

[0021] The radiopaque agent may be provided in the fiducial marker in particulate form. In certain implementations the radiopaque agent is barium sulfate having a particle size from 0.001- 100 pm, from 1-100 pm, from 25-100 pm, from 50-100 pm, from 1-25 pm, from 1-50 pm, from 25-50 pm, from 10-25 pm, from 1-10 pm, from 1-5 pm, from 5-10 pm, or from 5-15 pm. In some implementations the radiopaque agent is barium sulfate having a particle size from 1-1,000 nm, from 500-1,000 nm, from 1-500 nm, from 100-500 nm, from 100-250 nm, from 250-500 nm, from 1-50 nm, from 1-10 nm, from 1-25 nm, from 10-50 nm, from 25-75 nm, from 10-100 nm, from 50-150 nm, or from 250-750 nm.

[0022] In certain implementations, the radiopaque agent is present in the fiducial marker in an amount from 10-75 wt.%, from 10-50 wt.%, from 10-25 wt.%, from 20-40 wt.%, from 25-75 wt.%, from 25-50 wt.%, from 40-60 wt.%, or from 50-75 wt.%.

[0023] The patterned shape of the fiducial marker is chosen to increase the ratio of surface area to volume. The addition of the radiopaque agent allows for the device to be imaged by CT, MRI, X-Ray or other medical imaging.

[0024] An exemplary fiducial marker may have a three-dimensional shape, such as a flat lying mesh with a thickness, a curved three-dimensional shape, a spherical shape, or a hemispherical shape, as shown in Fig. 1. As used herein, a hemispherical does not refer only to perfect half-spheres but rather denotes a bowl shape. In a perfect half sphere, the radius of the top is the same length as the height of the bowl from the bottom to the top, but rather a bowl shape. In certain implementations, the fiducial marker is provided in a bowl shape in which the radius of the top has a length that is no more than 50% different that the height. In some implementations, the fiducial marker is provided in a bowl shape in which the radius of the top has a length that is no more than 25% different that the height. [0025] An exemplary fiducial marker may have a diameter of 1-7 cm, 1-6 cm, 1 -5 cm, 1-4 cm, 1-3 cm, 1-2 cm, 2-7 cm, 2-6 cm, 2-5, cm, 2-4 cm, 2-3 cm, 3-7 cm, 3-6 cm, 3-5 cm, 3-4 cm, 4-7 cm, 4-6 cm, 4-5 cm, 5-7 cm, 5-6 cm, or 6-7 cm. In certain implementations the fiducial marker can have the shape of a bowl wherein the diameter, at the widest point, has a length from 1-7 cm, 1-6 cm, 1-5 cm, 1-4 cm, 1-3 cm, 1-2 cm, 2-7 cm, 2-6 cm, 2-5, cm, 2-4 cm, 2-3 cm, 3-7 cm, 3-6 cm, 3-5 cm, 3-4 cm, 4-7 cm, 4-6 cm, 4-5 cm, 5-7 cm, 5-6 cm, or 6-7 cm.

[0026] An exemplary fiducial marker may have a thickness of 1.0-3.2 mm, 1.5-3.2 mm, 2.0- 3.2 mm, 2.5-3.2 mm, 1.0-3.0 mm, 1.5-3.0 mm, 2.0-3.0 mm, 2.5-3.0 mm, 1.0-2.5 mm, 1.5-2.5 mm, 2.0-2.5 mm, 1.0-2.0 mm, 1.5-2.0 mm, 1.0- 1.5 mm.

[0027] An exemplary fiducial marker may have a radiodensity that is substantially different than human tissue (-210 to -100 HU), preferably the device has a radiodensity of 0 to 3,000 Houndsfield Units, 0-2,000 HU, 0-1,000 HU, 0-500 HU, 0-100 HU, 100-3,000 HU, 100-2,000 HU, 100-1,000 HU, 100-500 HU, 500-3,000 HU, 500-2,000 HU, 500-1,000 HU, 1,000-3,000 HU, 1,000-2,000 HU, or 2,000-3,000 HU.

[0028] An exemplary fiducial marker may have a density of 812-4,500 kg/m³, 812-4,000 kg/m³, 812-3,500 kg/m³, 812-3,000 kg/m³, 812-2,500 kg/m³, 812-2,000 kg/m³, 812-1,500 kg/m³, 812-1,000 kg/m³, 1,000-4,500 kg/m³, 1,000-4,000 kg/m³, 1,000-3,500 kg/m³, 1,000-3,000 kg/m³, 1,000-2,500 kg/m³, 1,000-2,000 kg/m³, 1,000-1,500 kg/m³, 1,500-4,500 kg/m³, 1,500-4,000 kg/m³, 1,500-3,500 kg/m³, 1,500-3,000 kg/m³, 1,500-2,500 kg/m³, 1,500-2,000 kg/m³, 2,000- 4,500 kg/m³, 2,000-4,000 kg/m³, 2,000-3,500 kg/m³, 2,000-3,000 kg/m³, 2,000-2,500 kg/m³, 2,500-4,500 kg/m³, 2,500-4,000 kg/m³, 2,500-3,500 kg/m³, 2,500-3,000 kg/m³, 2,500-2,500 kg/m³, 3,000-4,500 kg/m³, 3,000-4,000 kg/m³, 3,000-3,500 kg/m³, 3,000-3,000 kg/m³, 3,500- 4,500 kg/m³, 3,500-4,000 kg/m³, 3,500-3,500 kg/m³, or 4,000-4,500 kg/m³.

[0029] In certain implementations, the fiducial marker can have an bending elastic modulus from 500-20,000 kPa, from 10,000-20,000 kPa, from 1,000-10,000 kPa, from 1,000-5,000 kPa, from 2,000-5,000 kPa, from 3,000-5,000 kPa, from 4,000-5,000 kPa, from 2,000-3,000 kPa, from 2,000-4,000 kPa, from 3,000-4,000 kPa, from 3,000-3,500 kPa, from 2,500-3,000 kPa, or from 2,500-3,500 kPa. In some implementations, bending elastic modulus may be determined by applying a load to a 1 cm diameter rod of fiducial marker and measuring the deflection, using the equation E = PL³/(36I), wherein P is the applied load, L is the length of material, 5 is the measured deflection and I is the calculated moment of inertia. [0030] An exemplary fiducial marker may be biocompatible as defined by the U.S. Food and Drug Administration ISO 10993. An exemplary device may be collapsible.

[0031] The exemplary fiducial marker as taught by any of the above exemplary devices may be used in an exemplary method for marking a post-operative cavity.

[0032] An exemplary fiducial marker may be implanted in a post-operative cavity, preferably a post-operative lumpectomy cavity in breast tissue.

[0033] Disclosed herein are methods of treating cancer in a patient in need thereof including the step implanting the fiducial marker disclosed herein in a cavity created by removal of cancerous tissue from the subject. In certain implementations the method includes the step of surgically removing cancerous tissue from the subject and implanting the fiducial marker in the space previously occupied by the cancerous tissue. In certain implementations the method includes the step of irradiating the tissue adjacent or near to the fiducial marker. In some implementations, a patient having the fiducial marker presents to a radiation oncologist (or similar physician) and the patient receives radiation therapy to tissues located near or adjacent to the fiducial market. The precise parameters and location of the irradiation can be determined by the clinician based on the individual needs of the patient. In certain implementations the cancer is breast cancer, ovarian cancer, cervical cancer, anal cancer, prostate cancer, skin cancer (including non-melanoma skin cancer) head and neck cancer, or non-small cell lung cancer.

[0034] The fiducial marker can persist in the body for a period of time post-implantation. As used herein, the persistence time relates to the period over which the shape of the fiducial marker can be resolved using the relevant imaging technique. In certain implementations, the fiducial marker persists for a period of at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, or at least 52 weeks. In certain implementations, the fiducial marker persists for a period of 2-52 weeks, of 4-52 weeks, of 8-52 weeks, of 12-52 weeks, of 16-52 weeks, of 20-52 weeks, of 24-52 weeks, of 2-24 weeks, of 4-24 weeks, of 8-24 weeks, of 12-24 weeks, of 16-24 weeks, of 20-24 weeks, of 2-12 weeks, of 4-12 weeks, of 8-12 weeks, of 2-8 weeks, or of 4-8 weeks.

EXAMPLES

[0035] The fiducial marker design was a collapsible polymer mesh. The mesh was made of Poly(L-lactide-co-e-caprolactone) (PLCL), which is a biodegradable polymer with a low melting point. The radiopaque agent was barium sulfate, an agent used extensively in digestive system marking. The mixture is 30% barium sulfate by weight. This was a desirable prospect because it has been used in clinical trials on rats where it was shown to degrade (Haim et al., 2020). Also, it was relatively easy to make due to PLCL’s low melting point. The materials were cheap, too, with PLCL being about $90 for 4 kilograms and barium sulfate being $18 for 500 grams. PLCL and barium sulfate are manufacturable and biocompatible, which makes it a desirable candidate to pursue.

[0036] The design fulfills multiple predetermined requirements. The scaffold would be made from a polymer with FDA approval, such as PLA, fulfilling the need for the design to be biocompatible and sterilizable (“Polylactide”). The scaffold would be made to look like a net, Figure 2, to increase the surface area of the polymer and improve its ability to biodegrade.

[0037] The polymer material is versatile and can be printed with nanoparticles. This is done by creating a solution of the polymer and nanoparticles prior to printing it into the shape shown in Fig. 2. The nanoparticles will be used so that the scaffold can be viewed under CT scan and MRI (Naim). They will have a low enough radiodensity to fit our specifications, and they will have a small surface area. The polymer is advertised to degrade within our given timeframe, but further in vitro and in vivo testing will have to be done to confirm that. The mechanical properties of the polymer resemble that of the breast tissue, allowing it to move with the breast tissue when it does collapse.

[0038] The following chart details the materials needed to create a successful prototype for the collapsible scaffold idea. Although there are more specific components of the nanoparticles that will be used in the final product, the list gives a baseline to start understanding how this device would work in practice.

[0039] The design allows for a biocompatible device that adheres to the surface of the cavity, mimics the mechanical properties of the breast tissue, and allows for the incorporation of nanoparticles to view the tumor cavity in CT scan and MRI.

[0040] One standard that will be applied to the device is ASTM F2579-18 - Standard Specification for Amorphous Poly(Lactide) and Poly(Lactide-Co-Glycolide) Resins for Surgical Implants. This standard addresses the material characteristics of PLA to ensure that it has the correct stereoisomeric specificity on a molecular- level and that it can fully solvate at 30°C using dichloromethane or trichloromethane. This standard confirms the device’s safety and efficacy (“ASTM F2579- 18"). Another standard that will be applied to the device is ASTM F2503-20 - Standard Practice for Marketing Medical Devices and Other Items for Safety in the Magnetic Resonance Environment. This standard confirms that the device can be used in a magnetic resonance environment by ensuring that the device does not overheat with differing magnetic field strengths. Additionally, this standard confirms that the device will not migrate in the tumor cavity when it experiences strong magnetic field forces (“ASTM F2503-20"). Finally, another standard that will be applied to the device is ATSM F640-20 - Standard Test Methods for Determining Radiopacity for Medical Use. This standard ensures that the device can be visible and locatable through X-Ray, fluoroscopy, and CT scan (“ATSM F640-20").

[0041] A test for determining radiopacity was conducted on three samples: a first sample PLCL-BaSCU mesh with BaSCE present at 30% by weight, a second sample PLCL-BaSCE thin wire, and a third sample PLCL mesh were imaged in a breast-tissue phantom. The results from the test for determining radiopacity showed the three samples appeared in the CT scan in the frontal plane Figure 3.

[0042] The mesh sample of PLCL with 30% by weight of barium sulfate appeared brightest and had a radiodensity of around 3200 HU. It is contemplated that a lower percentage of barium sulfate may be used to decrease the radiodensity because the object appeared too bright and introduced artifact in the CT scan. Next, the PLCL net without barium sulfate had a radiodensity of around 100 HU. This sample meets the acceptance criteria of being within 0-3000 HU.

Finally, the thin wire sample had a radiodensity of around 1800 HU, also meeting the acceptance criteria.

DISCUSSION

[0043] The exemplary device as shown in Fig. 1 could be sutured or medically stapled into the tumor cavity. Ideally, the device would adhere to the cavity without a secondary attachment method. The mesh device is made from a mixture of PLCL, which is a flexible, biodegradable polymer and barium sulfate, a radiopaque contrast agent. The exemplary device was made from a material 30% barium sulfate by weight. Once inserted, it should be visible on the patient’s tumor cavity CT scan, which allows the radiology team to direct radiation at the tumor cavity more accurately. [0044] When administering radiotherapy, the radiation therapist would like to know precisely where the tumor cavity is, ideally within a millimeter. This allows the radiation team to target the tumor cavity more accurately, which will increase the effectiveness of the treatment and reduce collateral damage to the rest of the body. Doctors are tasked with interpreting a CT scan to determine where they should administer radiation. After making that determination, the doctors draw contours along the scan, which tell the radiation therapists where to direct radiation. [0045] These contours are drawn in a manner that takes into account two main factors. One is that the tumor cavity fills with fluid after the operation, which is something that the surgeon cannot control or prevent. The other is the presence of an artificial body, inserted by the surgeon, in order to help locate the cavity on the CT scan. However, the current industry standard for the artificial body introduces some uncertainty, thus widening the contour. Moreover, when a reconstructive surgeon operates on the breast, the markers have even more uncertainty, which widens the contour even more. Currently, there is no device that painlessly, accurately, and consistently identifies the cavity on a CT scan, especially after reconstructive surgery.

[0046] Biocompatibility was the highest priority objective; the device should be biocompatible, and materials should be chosen to minimize implantation complications with the patient’s immune system. Marking the post-operative cavity is the purpose of the device and, therefore. The third-highest objective is that the device is easy to distinguish on CT scans, MRIs, and X-Rays. The fourth-highest objective is to make the device reliable in its ability to be seen on an imaging device and its ability to mark the cavity without migration. This would allow for better alignment of the device within the cavity and therefore allow radiation therapists to properly see and treat the area. The next objective is to make sure the device is easy to implant. Both the surgical oncologist and patient benefit if the device is easy to implant into the patient. Accomplishing this would allow for less time wasted within surgery and shorter lead times for the patient. The sixth objective is that the device should be comfortable. This would improve the patient's quality of life during the lumpectomy cavity marking process and make the post-operate recovery more pleasant. The seventh objective is that the device should be long-lasting. There could be 6-8 weeks between the lumpectomy and the last day of radiation, and the device should be able to last eight weeks to ensure radiation therapists can properly align the patient during the entire process. The second to last objective is that the device should be reconstructive. The breast tissue loses significant mass from the lumpectomy procedure, and the device should expand the breast tissue such that it sits in a similar position as before the surgery. Completing this objective would improve the patient’s quality of life during the lumpectomy cavity marking process. The final objective is that the device should be inexpensive. This would allow more hospitals to purchase the device to improve the lives of surgeons, radiation therapists, dosimetrists, and patients all over the country.

DEFINITIONS

[0047] Some references, which may include various patents, patent applications, and publications, are cited in a reference list and discussed in the disclosure provided herein. The citation and/or discussion of such references is provided merely to clarify the description of the present disclosure and is not an admission that any such reference is “prior art” to any aspects of the present disclosure described herein. In terms of notation, “[n]” corresponds to the n^lh reference in the list. All references cited and discussed in this specification arc incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.

[0048] Although example embodiments of the present disclosure are explained in some instances in detail herein, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the present disclosure be limited in its scope to the details of construction and arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or carried out in various ways.

[0049] It must also be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” or “5 approximately” one particular value and/or to “about” or “approximately” another particular value. When such a range is expressed, other exemplary embodiments include from the one particular value and/or to the other particular value.

[0050] By “comprising” or “containing” or “including” is meant that at least the name compound, element, particle, or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles, method steps, even if the other such compounds, material, particles, method steps have the same function as what is named. [0051] In describing example embodiments, terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the ait and includes all technical equivalents that operate in a similar manner to accomplish a similar purpose. It is also to be understood that the mention of one or more steps of a method does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Steps of a method may be performed in a different order than those described herein without departing from the scope of the present disclosure. Similarly, it is also to be understood that the mention of one or more components in a device or system does not preclude the presence of additional components or intervening components between those components expressly identified.

[0052] The expressions "ambient temperature" and "room temperature" as used herein are understood in the art and refer generally to a temperature from about 20 °C to about 35 °C. [0053] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.

[0054] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a mixture containing 2 parts by weight of component X and 5 parts by weight, components Y, X, and Y are present at a weight ratio of 2:5 and are present in such ratio regardless of whether additional components are contained in the mixture.

[0055] A weight percent (wt.%) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. [0056] It will be understood that when an element is referred to as being "connected" or "coupled" to another element, it can be directly connected or coupled to the other element, or intervening elements may be present. In contrast, when an element is referred to as being "directly connected" or "directly coupled" to another element, there are no intervening elements present. Other words used to describe the relationship between elements or layers should be interpreted in a like fashion (e.g., "between" versus "directly between," "adjacent" versus "directly adjacent," "on" versus "directly on").

[0057] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Furthermore, when numerical ranges of varying scope are set forth herein, it is contemplated that any combination of these values inclusive of the recited values may be used. Further, ranges can be expressed herein as from “about” one particular value and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value.

[0058] Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. Unless stated otherwise, the term “about” means within 5% (e.g., within 2% or 1%) of the particular value modified by the term “about.” [0059] Similarly, numerical ranges recited herein by endpoints include subranges subsumed within that range (e.g., 1 to 5 includes 1-1.5, 1.5-2, 2-2.75, 2.75-3, 3-3.90, 3.90-4, 4-4.24, 4.24-5, 2-5, 3-5, 1-4, and 2-4). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.”

[0060] It will be understood that, although the terms "first," "second," etc., may be used herein to describe various elements, components, regions, layers, and/or sections. These elements, components, regions, layers, and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below could be termed a second element, component, region, layer, or section without departing from the teachings of example embodiments.

[0061] As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance generally, typically, or approximately occurs. [0062] Still further, the term “substantially” can in some aspects refer to at least about 80 %, at least about 85 %, at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, or about 100 % of the stated property, component, composition, or other condition for which substantially is used to characterize or otherwise quantify an amount.

[0063] In other aspects, as used herein, the term “substantially free,” when used in the context of a composition or component of a composition that is substantially absent, is intended to refer to an amount that is then about 1 % by weight, e.g., less than about 0.5 % by weight, less than about 0.1 % by weight, less than about 0.05 % by weight, or less than about 0.01 % by weight of the stated material, based on the total weight of the composition.

[0064] As used herein, the terms “substantially identical reference composition,” “substantially identical reference article,” or “substantially identical reference electrochemical cell” refer to a reference composition, article, or electrochemical cell comprising substantially identical components in the absence of an inventive component. In another exemplary aspect, the term "substantially," in, for example, the context "substantially identical reference composition," or “substantially identical reference article,” or “substantially identical reference electrochemical cell” refers to a reference composition, article, or an electrochemical cell comprising substantially identical components and wherein an inventive component is substituted with a common in the art component.

[0065] The devices, systems, and methods of the appended claims are not limited in scope by the specific devices, systems, and methods described herein, which are intended as illustrations of a few aspects of the claims. Any devices, systems, and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the devices, systems, and methods, in addition to those shown and described herein, are intended to fall within the scope of the appended claims. Further, while only certain representative devices, systems, and method steps disclosed herein are specifically described, other combinations of the devices, systems, and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. [0066] Although several embodiments of the invention have been disclosed in the foregoing specification, it is understood by those skilled in the art that many modifications and other embodiments of the invention will come to mind to which the invention pertains, having the benefit of the teaching presented in the foregoing description and associated drawings. It is thus understood that the invention is not limited to the specific embodiments disclosed hereinabove and that many modifications and other embodiments are intended to be included within the scope of the appended claims. Moreover, although specific terms are employed herein, as well as in the claims which follow, they are used only in a generic and descriptive sense and not for the purposes of limiting the described invention nor the claims which follow.

[0067] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

[0068] While aspects can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of ordinary skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0069] In view of the described processes and compositions, hereinbelow are described certain more particularly described aspects of the inventions. These particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein, or that the “particular” aspects are somehow limited in some way other than the inherent meanings of the language and formulas literally used therein. [0070] The present invention may be understood more readily by reference to the following detailed description of various aspects of the invention and the examples included therein and to the Figures and their previous and following description.

Claims

CLAIMS What is claimed is:

1. A fiduciary marker comprising a biodegradable polymer and a radiopaque agent dispersed therein, wherein the fiduciary marker is patterned into a shape comprising contiguous matrix material and interspersed cavities.

2. The fiduciary marker of claim 1, wherein the fiducial marker comprises the radiopaque agent in an amount from 10-75 wt.%, from 10-50 wt.%, from 10-25 wt.%, from 20-40 wt.%, from 25-75 wt.%, from 25-50 wt.%, from 40-60 wt.%, or from 50-75 wt.%.

3. The fiduciary marker of claim 1 or 2, wherein the radiopaque agent comprises barium sulfate.

4. The fiduciary marker of any one of claims 1-3, wherein the fiduciary marker is about 1-7 cm in diameter.

5. The fiduciary marker of any one of claims 1-4, wherein the fiduciary marker has a thickness of about 1.0 mm - 3.2 mm.

6. The fiduciary marker of any one of claims 1-5, wherein the fiduciary marker has a radiodensity of about 0 to 3,000 Houndsfield Units.

7. The fiduciary marker of any one of claims 1-6, wherein the fiduciary marker has a density of about 812-4,500 kg/m³.

8. The fiduciary marker of any one of claims 1 -7, wherein the biodegradable polymer comprises poly(caprolactone), poly(glycolic acid), poly(lactic acid), a copolymer thereof, or a combination thereof.

9. The fiduciary marker of any one of claims 1-8, wherein the biodegradable polymer comprises poly(caprolactone-co-glycolic acid), poly(caprolactone-co-lactic acid), or poly (lactic acid-co-glycolic acid).

10. The fiduciary marker of any one of claims 1-9, wherein the biodegradable polymer comprises poly(caprolactone-co-glycolic acid), poly(caprolactone-co-lactic acid), or poly(lactic acid-co-glycolic acid), having a MW_w that is from 10,000-2,500,000 g/mol, from 50,000-2,500,000 g/mol, from 100,000-2,500,000 g/mol, from 250,000-2,500,000 g/mol, from 100,000-2,000,000 g/mol, from 100,000-1,500,000 g/mol, from 100,000- 1,000,000 g/mol, from 250,000-1,000,000 g/mol, from 500,000-1,000,000 g/mol, from 250,000-900,000 g/mol, from 10,000-100,000 g/mol, from 10,000-50,000 g/mol, from 25,000-75,000 g/mol, from 50,000-250,000 g/mol, from 50,000-150,000 g/mol, from 100,000-500,000 g/mol, from 100,000-250,000 g/mol, or from 250,000-500,000 g/mol.

11. The fiduciary marker of any one of claims 1-10, wherein the wherein the biodegradable polymer comprises poly(caprolactone-co-lactic acid) having a MW_w that is from 10,000- 250,000 or from 25,000-100,000.

12. The fiduciary marker of any one of claims 1-11, wherein the biodegradable polymer has a melting point from 30-70°C., from 30-50°C„ from 30-40°C., from 35-5O°C., from 35- 45°C., from 40-50°C., from 45-55°C., from 50-60°C., from 55-65°C., or from 60-70°C.

13. The fiduciary marker of any one of claims 1-12, wherein the fiduciary marker is collapsible.

14. The fiduciary marker of any one of claims 1-13, wherein the matrix is printed from a solution of biodegradable polymer and radiopaque agent.

15. The fiduciary marker of any one of claims 1-14, wherein the radiopaque agent is nanoparticulate.

16. The fiduciary marker of any one of claims 1-15, wherein the radiopaque agent has a particle size 1-1,000 nm, from 500-1,000 nm, from 1-500 nm, from 100-500 nm, from 100-250 nm, from 250-500 nm, from 1-50 nm, from 1-10 nm, from 1-25 nm, from 10-50 nm, from 25-75 nm, from 10-100 nm, from 50-150 nm, or from 250-750 nm.

17. The fiduciary marker of any one of claims 1-16, wherein the fiduciary marker is implanted in a post-operative cavity.

18. A method for marking a post-operative cavity in a subject, the method comprising: inserting the fiduciary marker according to any of claims 1-17 into a post-operative cavity.

19. The method of claim 18, furthering comprising the removal of tissue from the subject, and implantation of the fiducial marker in the space previously occupied by the removed tissue.

20. A method of treating cancer in a subject in need thereof comprising implanting the fiducial marker according to any of claims 1-17 in a cavity created by removal of cancerous tissue from the subject.

21. The method of any of claims 18-20, further comprising irradiating the tissue adjacent to the fiducial marker.

22. A method of treating cancer in a subject having an implanted fiduciary marker according to any of claims 1-17, comprising irradiating tissue in the subject located adjacent to the fiduciary marker.

23. The method of any of claims 18-22, wherein the subject has breast cancer, ovarian cancer, cervical cancer, anal cancer, prostate cancer, skin cancer (including nonmelanoma skin cancer) head and neck cancer, or non- small cell lung cancer.

24. The method of any of claims 18-21, wherein the fiducial marker persists in the subject for a period of at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, or at least 52 weeks.