Medical implants used to mark surgical sites

Abstract

We provide a reabsorbable three-dimensional reference marker that can be used to more accurately deliver radiotherapy to the tissue margins of tumor resection cavities. [Solution] An implantable reference marker device 300 having a predetermined shape deforms when stress is applied in vivo and recovers its shape when the stress is removed, thereby reducing patient discomfort and palpability. Using this device, irregular tumor resection cavities can be shaped into a more ideal form for radiotherapy, enabling more accurate treatment. After treatment, the device is reabsorbed, eliminating unnecessary examinations that may occur if the clinician is unaware of the implanted reference marker device. Internal tissue growth within the device can also lead to improved aesthetic results when the device is implanted in the breast after mammary gland tumor removal. The device preferably comprises poly-4-hydroxybutyrate or poly(butylene succinate) or copolymers thereof.

Description

Technical Field

[0001] The present invention generally relates to the field of surgery, and more specifically, the present invention relates to a medical implant that can be used to delineate the margins of a surgical site during radiotherapy.

Background Art

[0002] Radiotherapy is often performed after resection of a tumor to destroy the remaining cancer cells and reduce the risk of cancer recurrence. However, it may be difficult to delineate the tissue margins of the tumor cavity postoperatively for radiotherapy. Conventionally, clinicians have relied on the presence of a surgical scar site or seroma to identify the site of radiotherapy and the radiation target volume. However, these identification methods are not the most accurate, and may not only reduce the effectiveness of radiotherapy, but also increase the likelihood of damage to healthy tissue around the cavity. The cavity may have an irregular shape, and in some tissues, the shape may change over time, so it may also be very difficult to accurately identify the position of the margins of the tumor resection cavity. For example, the tumor cavity may expand or contract during respiration, and may even change in size and shape as a result of continuous radiotherapy treatment.

[0003] To address these problems, clinicians often use a fiducial marker device to better define the position of the cavity and make the target of external beam radiotherapy clearer. A fiducial marker device is a marker or set of markers placed in the imaging field as a reference point. The fiducial marker device can be used for the planning of the target volume (PTV) for radiotherapy, as well as for targeting a specific position and shape within the body. The PTV is determined by measurement of the gross tumor volume (GTV), and a margin related to the spread of the disease that cannot be fully imaged is added to reach the clinical target volume (CTV), and an additional margin around the CTV is further added to ensure that radiotherapy is actually delivered to the CTV.

[0004] The initial reference markers were typically small metal objects, such as metal clips or pellets, used in the treatment of breast, abdominal, liver, lung, and prostate cancers. While these small metal objects can be useful as reference markers, they are known to move, resulting in larger target volumes required for radiotherapy. Their ability to accurately define the volume of tumor resection cavities, which may have irregular shapes, can also be limited.

[0005] To more accurately pinpoint the location of the radioactive target volume after tumor resection and to prevent the movement of metal clips, a three-dimensional reference marker is disclosed.

[0006] U.S. Patent Application to Stubbs No. 20090024225 discloses a bioabsorbable, three-dimensional, spherical, implantable reference marker that has a lower density than soft tissue and allows for postoperative imaging. The density of the bioabsorbable material used to prepare the marker is 1.03 g / cc or less.

[0007] U.S. Patent Nos. 9,014,787 and 9,199,092 to Stubbs disclose a rigid, bioabsorbable, three-dimensional reference marker that includes a metallic element having an arm extending from the center of the device.

[0008] U.S. Patent Nos. 9,615,915 and 9,980,809 to Lebovic, U.S. Patent No. 10,500,014 to Hermann, and U.S. Patent Applications 20130289389 and 20130289390 to Hermann disclose a three-dimensional reference marker device comprising an absorbable material and an X-ray-visible element that visualizes the device when placed within a surgical resection cavity.

[0009] Wiens, N. et al., "Effect of BioZorb® surgical marker placement on post-operative radiation boost target volume," J Radiat Oncol, 7:175-179, (2018) discloses a three-dimensional helical reference marker with six metal clips. This marker is a rigid device made from polylactic acid. Srour and Chung, "Utilization of BioZorb implantable device in breast-conserving surgery," Breast J, 2019;00:1-6, evaluated the palpability of this reference marker in the breast and found that the marker remained palpable in the breast for many years after placement. They reported that the marker was present in the body for 2.8 years after implantation and remained palpable. The palpability of this device is particularly problematic in the treatment of breast cancer for several reasons. Firstly, the presence of the marker device in the breast can be painful and may cause discomfort, especially when any stress or tension is applied to the breast. Because BioZorb devices are manufactured from polylactic acid, a polymer with an elastic modulus exceeding 3 GPa, the devices are rigid and therefore do not deform under stress and do not recover their original shape. Srour and Chung 2019 disclosed that the presence of a BioZorb device caused sufficient pain in one patient to necessitate surgical removal. Secondly, the prolonged presence of a foreign mass in a patient's breast can cause anxiety, especially in breast cancer patients. Thirdly, clinicians who are unaware that a device is implanted in the breast may perform unnecessary examinations on patients to investigate the foreign mass, thereby increasing patient anxiety. Srour and Chung 2019 reported that clinicians ordered additional imaging tests in 8.8% of patients examined because they were unaware of the marker device. Fourthly, because the device reabsorbs slowly and remains palpable for a long period, it may limit clinicians' ability to detect breast cancer recurrence.See also U.S. Patent No. 10,500,014 to Hermann and U.S. Patent No. 9,014,787 to Stubbs.

[0010] Despite the foregoing, there is still a need for three-dimensional reference markers, such as those described herein, which can be used to model the surgical margins around irregularly shaped tumor sacs into more clearly defined volumetric shapes in order to provide clear targets for radiotherapy. In particular, there is a need to develop three-dimensional reference markers that degrade more rapidly in vivo. Such markers would ideally not be palpable when implanted in the breast, and would have a lower elastic modulus than existing reference markers, allowing them to deform under stress or tension without causing pain after implantation. There is also a need to develop reference markers that allow internal tissue growth to fill the cavity of the tumor sac. These markers are particularly desirable in breast treatment because internal tissue growth into the cavity of the tumor resection improves aesthetic outcomes. Furthermore, there is a need to develop three-dimensional reference markers containing one or more bioactive agents such as chemotherapeutic agents, antitumor agents, immunomodulators, hormonal agents, anti-angiogenic agents, antibiotics, radiosensitizers, and immunotherapeutic agents. Reference markers can be used in the treatment of soft tissue cancers, including cancers of the breast, abdomen, liver, muscle, kidney, lung, and prostate. [Overview of the project] [Problems that the invention aims to solve]

[0011] This specification describes a reabsorbable three-dimensional reference marker which can be used to more accurately deliver radiotherapy to the tissue margins of a tumor resection cavity by conforming the irregular shape of the tissue resection cavity to the shape of the marker. In embodiments, the reference marker is formed into a predetermined shape desirable for radiotherapy and is embedded in the tumor resection cavity to shape the cavity into a shape more ideal for radiotherapy, such as a spherical or elliptical shape. The reference marker allows for more accurate definition and targeting of the volume of the tumor resection cavity during radiotherapy. The reference marker reduces the dose of radiation received by the normal tissue surrounding the tissue resection cavity and reduces the size of the margins around the cavity that needs to be treated with radiation. [Means for solving the problem]

[0012] In the embodiment, the reference marker is not palpable at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after implantation, particularly in the patient's breast. In the embodiment, the reference marker is not palpable immediately after implantation, particularly in the patient's breast. In the embodiment, a predetermined shape of the reference marker deforms under stress or tension. In the embodiment, a predetermined shape of the reference marker is flexible or compressible, and the shape is not rigid. In the embodiment, a predetermined shape of the reference marker deforms under stress or tension and recovers its predetermined shape when the stress or tension is removed. By recovering its predetermined shape when the stress or tension is removed, the marker can be used to accurately define the boundary of the target volume for radiotherapy. The ability of the reference marker to deform under stress or tension reduces or eliminates the palpability of the marker, particularly in the breast. The ability of the reference marker to deform under stress or tension in the breast also reduces or eliminates the possibility that the device will cause pain in the breast. In the embodiment, the reference marker device has an elastic modulus of less than 50 MPa, more preferably less than 10 MPa, but greater than 0.5 kPa.

[0013] The reference marker has a predetermined shape having an outer region that defines the peripheral boundary of the device. In an embodiment, the outer region of the three-dimensional marker is defined by a convex surface. In an embodiment, the peripheral boundary of the marker is defined by a spherical, helical, elliptical, scalene elliptical, cylindrical, oblong, or oblate spherical shape. In another embodiment, the peripheral boundary of the marker is defined by a parallelepiped or oval shape. In an embodiment, the marker device comprises a three-dimensional frame, skeleton, or scaffold that defines its predetermined shape and the outer region of the device. In an embodiment, the three-dimensional frame, skeleton, or scaffold may be an elliptical helix, a spherical helix, a cylindrical helix, or another helix that defines the outer region. In another embodiment, the three-dimensional frame, skeleton, or scaffold that defines the outer region of the reference marker may be a skeletal polyhedron, a skeletal sphere, a skeletal ellipsoid, a skeletal cylinder, or a skeletal parallelepiped.

[0014] In some embodiments, the outer region of a reference marker defining the boundary of the apparatus may have a longitudinal axis having a first end and a second end, a length (l), and a diameter (d) or width (w) at the midpoint of the longitudinal axis between the first end and the second end. In some embodiments, the length (l) of the marker is 1 to 6 cm, and the diameter (d) or width (w) is 1 to 5 cm. In these embodiments, the marker may have dimensions of (l) × (d) such as 2 × 2 cm, 2 × 3 cm, 3 × 3 cm, 3 × 4 cm, 4 × 4 cm, or 4 × 5 cm. In other embodiments, the outer region of a reference marker defining the boundary of the apparatus may have a longitudinal axis having a first end and a second end, a length (l), and a width (w) and height (h) at the midpoint of the longitudinal axis between the first end and the second end. In these other embodiments, the marker length (l) is 1 to 4 cm, the marker width (w) is 1 to 3 cm, and the marker height (h) is 1 to 2 cm. In these other embodiments, the marker may have dimensions of (l) × (w) × (h) of, for example, 3 × 2 × 1 cm, 3 × 3 × 1 cm, 1 × 1 × 2 cm, 2 × 1 × 2 cm, and 1 × 2 × 2 cm.

[0015] In the embodiment, the reference marker is porous or has an open framework, skeleton, or scaffold that allows for internal tissue growth. In the embodiment, the reference marker has a porous structure that allows for internal tissue growth. Internal tissue growth can help fix the device in place and fix the position of the visualization marker on the device. In the embodiment, the reference marker can maintain its predetermined shape or take its predetermined shape in a stress-free or tension-free state until internal tissue growth into the device fixes the visualization marker in place. Internal tissue growth can also fill the cavity of a tumor resection cavity, resulting in improved aesthetic results in some treatments, such as breast cancer. In the embodiment, the reference marker can be used as a void filler.

[0016] In embodiments, the reference marker is used as an oncoplastic device. In embodiments, the reference marker is used to reliably mark the surgical site. In embodiments, the reference marker is used to define the planned target volume (PTV) for radiotherapy. The reference marker may also be used for X-ray disease monitoring.

[0017] In embodiments, the reference marker comprises multiple visualization markers. The visualization markers can be used to determine the planned target volume (PTV) for radiotherapy and to concentrate radiation on the target site. The visualization markers provide high contrast when imaging the tissue containing the markers. The visualization markers can be imaged by one or more of the following methods: ultrasound, X-ray, MRI (magnetic resonance imaging), CT (computed tomography), or mammography. In embodiments, the visualization markers are made from titanium, stainless steel, gold, or composite polymer materials, such as a polymer mixed with barium sulfate. In embodiments, the visualization markers are coated with a hydrogel. In embodiments, the visualization markers are radiopaque clasps attached to the outer region of the reference marker to provide an imageable three-dimensional target. In embodiments, the visualization markers are attached to the outer region of the reference marker to prevent clasp movement and excessive radiation exposure. In the embodiment, visualization markers are positioned at the first and second ends of the longitudinal axis of the device so that the length (l) of the device can be imaged in vivo, and also around the circumference at the midpoint of the longitudinal axis between the first and second ends so that the diameter or width of the device can be imaged.

[0018] In one embodiment, the predetermined shape of the reference marker, or the framework of the reference marker, is formed from a radiolucent material. In another embodiment, the predetermined shape of the reference marker, or the framework of the reference marker, is formed from a radiopaque material, or from both radiolucent and radiopaque materials.

[0019] In this embodiment, the reference marker has integrated X-ray contrast properties.

[0020] The predetermined shape of the reference marker is reabsorbable. In the embodiment, the visualization marker attached to or incorporated into the predetermined shape is permanent or reabsorbable.

[0021] In the embodiment, the predetermined shape of the reference marker is reabsorbable. In the embodiment, the reabsorbable reference marker maintains its predetermined shape in vivo in a stress-free state for a sufficiently long period of time for radiotherapy treatment to be completed. In the embodiment, the reference marker maintains its predetermined shape for a period of 1, 2, 3, 4, 5, 6, 7, 8, or 9 months after implantation, or can assume its predetermined shape in a stress-free state. In the embodiment, the predetermined shape of the reference marker is reabsorbed in vivo in less than 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, or 9 months after implantation. Reabsorption of the predetermined shape eliminates the need for secondary surgical intervention to remove the marker. Reabsorption also eliminates the possibility that the device may cause any pain or discomfort, eliminates the possibility that an unaware clinician might order unnecessary tests to investigate the presence of the device, and eliminates any patient anxiety, especially in cancer patients, due to the presence of a marker in the breast.

[0022] In the embodiment, the three-dimensional framework, skeleton, or scaffold of the reference marker can be formed from one or more filaments and can optionally incorporate one or more support columns.

[0023] In the embodiment, the reference marker includes a polymer strut, fiber, coil, or spring having one or more of the following characteristics: (i) a diameter of 0.025 to 3 mm, more preferably 0.1 to 2 mm, and even more preferably 0.15 to 1 mm; (ii) a breaking load of 0.1 to 200 N, more preferably 1 to 100 N, and even more preferably 2 to 50 N; (iii) a breaking elongation of 22% to 1,000%, more preferably 100% to 700%; and (iv) an elastic modulus of 0.05 to 3 GPa, more preferably 0.1 to 1 GPa, and even more preferably 0.2 to 0.8 GPa. In the embodiment, the reference marker comprises a unit cell formed from the polymer strut, fiber, coil, or spring having these characteristics. In the embodiment, the unit cell is part of the framework, skeleton, or scaffolding of the reference marker. In the embodiment, the unit cell may have the same or different characteristics. In the embodiment, the polymer strut, fiber, coil, or spring is reabsorbent. In the embodiment, the reference marker is formed from a polymer column, fiber, coil, or spring having an elastic modulus less than 50 MPa, more preferably less than 10 MPa, but greater than 0.5 kPa, and possessing one or more of the following characteristics: (i) a diameter of 0.025 to 3 mm, more preferably 0.1 to 2 mm, and even more preferably 0.15 to 1 mm; (ii) a breaking load of 0.1 to 200 N, more preferably 1 to 100 N, and even more preferably 2 to 50 N; (iii) a breaking elongation of 22% to 1,000%, more preferably 100% to 700%; and (iv) an elastic modulus value of 0.05 to 3 GPa, more preferably 0.1 to 1 GPa, and even more preferably 0.2 to 0.8 GPa.

[0024] In one embodiment, the reference structure marker device comprises a reabsorbable porous scaffold having a predetermined 3D shape that defines the periphery of the device, the predetermined shape being deformable under stress and recovering its shape when the stress is removed, and the scaffold includes visualization markers at individual positions around the device. In another embodiment, the reference marker device has a predetermined 3D shape and has shape memory.

[0025] In an embodiment, a predetermined shape of a fiducial marker is formed from a resorbable polymer. A resorbable polymer can be used to form an outer region of the fiducial marker and a three-dimensional framework, skeleton, or scaffold that defines its predetermined shape. In an embodiment, the predetermined shape or framework of the fiducial marker is formed from poly-4-hydroxybutyrate (P4HB) or its copolymer, or from poly(butylene succinate) (PBS) or its copolymer.

[0026] In an embodiment, the fiducial marker is prepared by 3D printing including fused deposition modeling, fused filament fabrication, fused pellet deposition, selective laser melting, printing of slurries and solutions using a coagulation bath, and printing using binding solutions and powders or granules. In an embodiment, the fiducial marker is prepared by injection molding and by injection molding using a multi-part mold.

[0027] In an embodiment, the fiducial marker can be fixed to a tumor bed or surgical resection cavity using a permanent suture, a resorbable suture, staples, or other fixation means. Fixation helps prevent any subsequent movement of the device. In an embodiment, the fiducial marker includes one or more suture eyelets for fixing the device in place. To prevent movement of the device after implantation, a suture can be passed through the eyelet and fixed to the tissue.

[0028] In an embodiment, the fiducial marker is implanted after a breast tumor excision and is used in the planning target volume (PTV) for radiation therapy and the delivery of a postoperative radiation boost to the breast.

[0029] In an embodiment, the fiducial marker includes one or more of the following: chemotherapeutic agents, antineoplastic agents, antiangiogenic agents, immunomodulatory agents, hormonal agents, immunotherapeutic agents, antibiotics, and radiosensitizers.

[0030] In an embodiment, the polymer used to prepare the fiducial implant has a weight average molecular weight of 50 to 1,000 kDa, more preferably 90 to 600 kDa, and even more preferably 200 to 450 kDa.

[0031] In the embodiment, the reference marker implant has an endotoxin content of less than 20 endotoxin units per implant. In the embodiment, the reference marker is sterilized by ethylene oxide, electron beam, or gamma irradiation.

[0032] In embodiments, the reference marker can be used to treat soft tissue cancers, including cancers of the breast, abdomen, liver, muscle, kidney, lung, and prostate.

[0033] In embodiments, a method for implanting a reference marker device includes creating a cavity in a patient by removing soft tissue through an incision made by surgery from a location within the body, inserting a reference marker device into the cavity having a reabsorbable porous scaffold having a predetermined shape defining the periphery of the device, the predetermined shape having shape memory, inserting, and closing the surgical site. The method may further include suturing the device within the cavity. Optionally, the creation step is performed in the patient's breast, and the device is implanted in the cavity of the patient's breast. In preferred embodiments, the method includes creating the cavity during a mammary gland tumor excision procedure.

[0034] In the embodiment, the method includes determining the planned target volume (PTV) for radiotherapy for a patient based on a reference marker device implanted in the patient.

[0035] In the embodiment, the method includes forming a reference marker device by 3D printing.

[0036] In embodiments, the method includes the steps of forming a reference marker device based on a 3D model and optionally generating a 3D model based on image data from a patient. Examples of image data include 3D image data resulting from a CT or MRI scan. In fact, embodiments include generating 3D image data of a tumor or lesion or tissue volume and creating (optionally 3D printing) a reference marker device based on the 3D image data.

[0037] In one embodiment, the physician-customizable reference marker kit comprises at least one reference marker device having a 3D body and a plurality of fixed, spaced-apart visualization marker engagement features, and a plurality of visualization markers, each having a fitting feature for connecting to the visualization marker engagement features, so that one or more of the visualization markers can be fixed to the 3D body of the reference marker device as desired by the physician.

[0038] In this embodiment, the visualization marker engagement feature is a hole, and the visualization marker fitting feature is a column.

[0039] Therefore, taking the foregoing into consideration, the object of the present invention is to provide a reabsorbable reference marker.

[0040] Another object of the present invention is to provide a reference marker that is not palpable and does not cause pain after implantation.

[0041] Another object of the present invention is to provide a method for manufacturing a reference marker that is flexible and does not cause pain after implantation.

[0042] Another object of the present invention is to provide a method for embedding a reference marker.

[0043] These and other objects, aspects, and advantages of the present invention will become apparent upon consideration of the following description with reference to the accompanying drawings. [Brief explanation of the drawing]

[0044] [Figure 1A-1B] The front view and isometric view of a porous reference marker device (100) having an open porous honeycomb scaffold structure according to one embodiment of the present invention are shown, respectively. The device (100) has an elliptical sphere with the bottom diameter or length (l) and height (h) shown in Figure 1A. [Figure 2A-2B]Front and isometric views of a porous reference marker device (200) having an open porous honeycomb scaffold structure and six titanium clips (210a-f) arranged in the outer region around the structure are shown, respectively, to enable imaging of the dimensions of the device according to one embodiment of the present invention. The device (200) has the bottom diameter or length (l) and height (h) shown in Figure 2A. [Figure 3A] This is an exploded view of a porous, reabsorbable reference marker (300), showing a column or pin holder (310) designed to receive a visualization marker, which is a radiopaque column or pin (320), according to one embodiment of the present invention. [Figure 3B] Figure 3A shows a cross-sectional view along the line "3B-3B" of the porous reabsorbability reference marker (300). [Figure 3C] Figure 3A is a perspective view of a porous reabsorbable reference device (300) shown, which has multiple columns or pin holders (310) located on the surface of the device, and radiopaque columns or pins (320) on the columns or pin holders. [Modes for carrying out the invention]

[0045] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific variations described herein, as various changes or modifications can be made to the described invention and equivalents can be substituted without departing from the spirit and scope of the invention. As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and shown herein has individual components and features that can be readily separated or combined with features of any of several other embodiments without departing from the scope or spirit of the invention. Furthermore, many modifications can be made to adapt specific situations, materials, compositions, processes, process actions or steps to the object, spirit or scope of the invention. All such modifications are intended to fall within the scope of the claims made herein.

[0046] The methods enumerated herein may be performed in any logically possible order of the enumerated events, and in the order in which the events are enumerated. Furthermore, where a range of values ​​is provided, it is understood that all intervening values ​​between the upper and lower limits of that range, and any other stated or intervening values ​​within that stated range, are encompassed in the invention. In addition, any optional feature of any variation of the invention described herein may be described and claimed independently or in combination with any one or more features described herein.

[0047] All existing subject matter referenced herein (e.g., publications, patents, patent applications, and hardware) is incorporated herein by reference in its entirety, unless such subject matter may conflict with the subject matter of the present invention (in which case the subject matter present herein shall prevail).

[0048] A reference to a single item implies the possibility of multiple identical items existing. More specifically, as used herein and in the appended claims, the singular forms “a,” “an,” “said,” and “the” refer to multiple objects unless the context explicitly indicates otherwise. It should be further noted that the claims may be constructed to exclude any optional element. This statement is therefore intended to serve as a prerequisite for using exclusive terms such as “simply,” “only,” etc., in relation to the description of elements in the claims or the use of “negative” limitations. Finally, unless otherwise defined, all technical and scientific terms used herein should be understood to have the same meaning as that generally understood by those skilled in the art to which the invention pertains.

[0049] In embodiments of the present invention, a reabsorbable three-dimensional reference marker is embedded in a tumor resection cavity to shape the cavity to form a target volume for radiotherapy with more precisely demarcated tissue margins, reducing the size of the tissue margins around the cavity to be irradiated, thereby reducing the exposure of healthy tissue to radiation, and deforms under stress or tension in vivo, so as not to be palpable and not to cause pain, and returns to its original shape in vivo when the stress or tension is removed during the course of radiotherapy. The reference marker is available in sizes for use in tumor resection cavities of different sizes. The reference marker is porous and allows for internal tissue growth. In embodiments, the reference marker has an internal scaffold structure that promotes internal tissue growth. Internal tissue growth can also improve aesthetic results by fixing the device in place and filling tissue cavities. After radiotherapy, the three-dimensional structure of the reference marker is reabsorbed.

[0050] In the embodiment, the implant comprises an outer surface or peripheral structure (e.g., a shell) and an internally organized structure that can support and interconnect the peripheral structure, providing a porous structure.

[0051] In the embodiment, the reference marker has a predetermined three-dimensional shape that is not palpable after implantation, particularly in the patient's breast. When stress or tension is applied to the reference marker in vivo, the marker deforms, and when the stress or tension is removed, for example during imaging, it returns to its predetermined shape. In the embodiment, the reference marker has shape memory that allows the reference marker to deform from a predetermined shape when stress is applied and to return to that predetermined shape when the stress is removed. In a preferred embodiment, the marker is flexible and not rigid like existing reference marker devices, and can be compressed. When the compressive force is removed, the marker returns to its predetermined shape. In the embodiment, the reference marker has an elastic modulus of less than 50 MPa, more preferably less than 10 MPa, and even more preferably less than 1 MPa, which allows the device to deform and return to its original shape.

[0052] In embodiments, the reference marker has a predetermined three-dimensional shape having a longitudinal axis with a first end and a second end, and a diameter or width at the midpoint between the first end and the second end. The reference marker has a three-dimensional outer region that defines the periphery of the device. When the outer region is embedded in a tumor resection cavity, it shapes the cavity so that the tissue margins of that shape can be easily irradiated. In embodiments, the outer region is shaped so that the periphery of the device has a spherical, elliptical, scalene elliptical, cylindrical, oblong, flattened spheroid, oval, or parallelepiped shape. In embodiments, the outer region of the reference marker is formed from a framework, skeleton, or scaffold. In embodiments, the framework, skeleton, or scaffold is formed from one or more filaments and may optionally incorporate one or more supports. In the embodiment, the framework, skeleton, or scaffolding may be spiral or spiral in shape that defines the peripheral boundary of the marker, and may include elliptical spirals, spherical spirals, cylindrical spirals, or skeletal polyhedra, skeletal spheres, skeletal ellipsoids, skeletal cylinders, or skeletal parallelepipeds.

[0053] In the embodiment, the reference marker is porous or an open framework, skeleton, or scaffold that allows for internal tissue growth within the reference marker. Internal tissue growth fixes the device to the tumor bed so that it cannot move, and the visualization marker is fixed to the margin of the excised cavity. In the embodiment, the three-dimensional structure of the reference marker disintegrates after the visualization marker is fixed in place by internal tissue growth.

[0054] In this embodiment, the reference marker also functions as a void filler. Internal tissue growth into the void of the tumor resection cavity can improve aesthetic outcomes in the treatment of certain cancers, such as breast cancer, by eliminating visible defects.

[0055] In embodiments, the reference marker includes a plurality of visualization markers placed on the marker, which are used to plan the radiation target volume and to concentrate radiation to the target site, thereby allowing imaging of the marker volume after implantation. The visualization markers are radiopaque and, in embodiments, are fixed to the outer region of the reference marker to allow visualization of the outer region of the marker. Attaching the visualization markers to the outer region of the marker prevents the visualization markers from moving. In embodiments, the visualization markers can be imaged by one or more of the following methods: ultrasound, X-ray, MRI, CT, mammography, positron emission tomography, and single-photon emission computed tomography.

[0056] In the embodiment, the visualization marker is made from a composite polymer material such as titanium, stainless steel, gold, or a polymer mixed with barium sulfate.

[0057] In the embodiment, the visualization marker or device is coated with a hydrogel. The hydrogel may be used to improve the visibility of the device. Preferably, the hydrogel is absorbent.

[0058] In the embodiment, the reference marker further comprises one or more suture eyelets. The marker can be fixed to the tumor resection cavity by suturing the device in place using the suture eyelets. The eyelets can also easily shape the tumor resection cavity to the shape of the marker.

[0059] In the embodiment, the integrity of the three-dimensional structure of the reference marker remains intact during the course of radiotherapy, but subsequently decomposes. After the decomposition of the three-dimensional structure, only the non-degradable visualization marker remains in vivo. In the embodiment, the three-dimensional structure of the reference marker is reabsorbed in vivo within 6 to 24 months. A second procedure to remove the reference marker after radiotherapy is not required.

[0060] In the embodiment, the three-dimensional shape of the reference marker includes a reabsorbable polymer. In the embodiment, the three-dimensional shape includes P4HB or a copolymer thereof, or PBS or a copolymer thereof.

[0061] In this embodiment, the reference marker may include one or more of the following: chemotherapeutic agents, antitumor agents, anti-angiogenic agents, immunomodulators, hormones, immunotherapeutic agents, antibiotics, and radiosensitizers.

[0062] In the embodiment, the three-dimensional shape of the reference marker is 3D printed. In the embodiment, the marker is 3D printed from a composition containing a reabsorbable polymer. In the embodiment, the three-dimensional shape of the reference marker is prepared by injection molding, including injection molding using a multi-part mold.

[0063] In embodiments, the reference marker is used in radiotherapy for patients with soft tissue cancers, including cancers of the breast, abdomen, liver, muscle, kidney, lung, and prostate. In preferred embodiments, the reference marker is used in the treatment of breast cancer and is implanted after mammography to facilitate breast radiation boosting therapy.

[0064] In the embodiment, the embedded reference marker is sutured in vivo to prevent migration. The marker can be sutured in place with reabsorbable or permanent sutures. These sutures may be monofilament or multifilament.

[0065] I. Definition In this specification, “bioactive agent” is also used to mean therapeutic agents, prophylactic agents or diagnostic agents, preferably agents that promote the healing and regeneration of host tissue, as well as therapeutic agents that prevent, inhibit or eliminate infection. “Agent” includes a single such agent, but is also intended to include multiple such agents.

[0066] As used herein in general, “biocompatibility” means a biological response to a material or device that is suitable for the intended use of the device in vivo. Any metabolites of these materials must be biocompatible.

[0067] As used herein in general, "blend" refers to a physical combination of different polymers, as opposed to a copolymer formed from two or more different monomers.

[0068] As used herein, “clinical target volume,” or “CTV,” refers to the gross tumor volume (GTV), plus a margin around the GTV with respect to the extent of the disease that cannot be fully imaged.

[0069] As used herein generally, “poly(butylene succinate) copolymer” means any polymer containing 1,4-butanediol units and succinic acid units together with one or more different diol, diacid, or hydroxycarboxylic acid units, and containing one or more hydroxycarboxylic acid groups or hydroxy acid groups. The copolymer may also contain chain extenders, coupling agents, crosslinking agents, or branching agents.

[0070] As used herein in general, “poly-4-hydroxybutyric acid copolymer” means any polymer containing 4-hydroxybutyric acid having one or more different hydroxy acid units.

[0071] As used herein, "drop ratio" refers to the ratio of drop width to drop height during 3D printing.

[0072] As used herein, "elongation at break" refers to the increase in length of a material that occurs when tension is applied to break the material. Elongation at break is expressed as a percentage of the material's original length.

[0073] The “endotoxin units” used herein are determined using a horseshoe crab hemocyte extract (LAL) assay, as further described by Gorbet et al. Biomaterials, 26:6811-6817 (2005).

[0074] As used herein, “gross tumor volume,” or “GTV,” means the extent of a tumor that can be imaged, palpable, or seen.

[0075] The “macroporous” materials or structures used herein have an average pore size of at least 25 microns, more preferably at least 50 microns, and even more preferably at least 75 microns.

[0076] As used herein, "molecular weight" refers to weight-average molecular weight (Mw) and not number-average molecular weight (Mn), unless otherwise specified, and is measured by GPC for polystyrene.

[0077] As used herein in general, "orientation" refers to the molecular alignment of polymer chains in a material. A stretched polymer is partially oriented, then highly oriented, with increasing tensile strength as orientation increases. For example, unoriented polymer fibers can be stretched to orient them, resulting in polymer fibers with higher tensile strength.

[0078] As used herein, “Planned Target Volume,” or “PTV,” refers to the volume to be treated, for example, by radiotherapy. PTV can be determined from a measurement of gross tumor volume (GTV), and a margin is added for the extent of disease that cannot be fully imaged to reach the clinical target volume (CTV), and an additional margin is added to the CTV to ensure that radiotherapy is actually delivered to the CTV.

[0079] As used herein, “poly-4-hydroxybutyrate” generally refers to a homopolymer containing 4-hydroxybutyrate units. This may be referred to herein as Tepha’s P4HB® polymer or TephaFLEX® biomaterial (manufactured by Tepha, Inc., Lexington, MA).

[0080] As used herein, "poly(butylene succinate)" generally refers to a polymer containing 1,4-butanediol units and succinic acid units. This may be abbreviated as "PBS".

[0081] As used herein in general, “radiotherapy” refers to cancer treatment that uses a powerful external beam of energy, such as X-rays or protons, to kill cancer cells.

[0082] As used herein, "radiopaque" refers to a structure or material that resists the passage of X-rays.

[0083] As used herein in general, “reabsorbable” means that a material is broken down within the body, and its breakdown products are eliminated or excreted from the body. The terms “absorbable,” “reabsorbable,” “degradable,” and “erosive” may be used herein synonymously, with or without the prefix “biological,” to describe materials that are broken down and gradually absorbed, excreted, or eliminated by the body.

[0084] As used generally in this specification, "tissue margin" refers, for example, to the edge of the tissue surrounding a tumor.

[0085] II. Materials for preparing the reference marker According to embodiments of the present invention described herein, an implantable medical device, i.e., a reference marker having a three-dimensional reabsorbable structure, has a predetermined shape that can be deformed in vivo when stress or tension is applied and returns to that predetermined shape when the stress or tension is removed. The ability of the marker device to deform eliminates the pain and palpability associated with a stiffer reference marker device. In embodiments, the reference marker device has an elastic modulus of less than 50 MPa, more preferably less than 1 MPa, and even more preferably less than 100 kPa, but greater than 0.5 kPa. These properties are designed so that the reference marker can be elastically deformed under compression or tension.

[0086] Furthermore, the 3D shape of the marker decomposes more rapidly in vivo, helping to reduce the likelihood that the marker could cause pain or discomfort to the patient, and eliminating the possibility that an unaware clinician might order unnecessary tests to characterize the foreign body, which could increase the patient's anxiety.

[0087] In this embodiment, the reference marker allows for internal tissue growth within the marker device after implantation. This internal tissue growth fixes the position of the visualization marker on the device, but can also fill any voids left by the tumor. Filling these voids can lead to improved aesthetic outcomes for the patient, particularly in the treatment of breast cancer.

[0088] In embodiments, the reference marker has an outer region that defines the peripheral boundary of the device. In embodiments, the peripheral boundary of the device has a spherical, spheroidal, elliptical, cylindrical, parallelepiped, or convex shape. In embodiments, the outer region is formed from a reabsorbable three-dimensional structure. In embodiments, the three-dimensional structure is a framework, skeleton, or scaffold. In embodiments, the framework, skeleton, or scaffold includes one or more filaments. The framework, skeleton, or scaffold may also include supports. In embodiments, the framework, skeleton, or scaffold is a helical or polyhedron that defines the outer region. In embodiments, the reference marker has a scaffold structure. The scaffold structure has an open porous structure designed to promote internal tissue growth.

[0089] In the embodiment, the reference marker is embedded in the tumor resection cavity and shapes the cavity to the shape of the peripheral boundary of the marker device defined by its outer region. The shaped tumor cavity formed by the reference marker more clearly defines the boundaries of tissue margins that can be irradiated more easily than the irregular shape of the tumor resection cavity, reducing the tissue margins that need to be irradiated and reducing unnecessary radiation exposure of healthy tissue.

[0090] In embodiments, the reference marker comprises a plurality of visualization markers. The visualization markers are fixed to or incorporated into the three-dimensional structure of the device so that a clinician can determine a planned target volume, irradiate the planned target volume, and continue X-ray disease monitoring as needed. The visualization markers are preferably radiopaque and provide high contrast when the reference marker is imaged. In embodiments, the visualization markers are mounted in an external region of the reference marker to provide an imageable three-dimensional view of the tissue resection cavity and to prevent the visualization markers from moving away from their implantation locations. As a result of the visualization markers moving away from their implantation locations, a larger amount of tissue may be irradiated than necessary.

[0091] In the embodiment, the three-dimensional structure of the reference marker includes a reabsorbable polymer. In the embodiment, the reabsorbable polymer degrades in vivo in less than 6 to 24 months. In the embodiment, the reabsorbable polymer is a thermoplastic polymer. In the embodiment, the reabsorbable polymer degrades after the completion of radiotherapy. In the embodiment, the reabsorbable polymer degrades after internal tissue growth, and the visualization marker of the reference marker is fixed in place. In the embodiment, the reabsorbable polymer allows a predetermined shape of the reference marker to deform in the presence of stress or tension, and to recover its predetermined shape when the stress or tension is removed. In the embodiment, the reabsorbable polymer is flexible, compressible, or elastomer. In the embodiment, the outer region of the reference marker is a three-dimensional structure, the three-dimensional structure being a framework, skeleton, or scaffold, and the framework, skeleton, or scaffold is formed from a reabsorbable polymer. In the embodiment, the framework, skeleton, or scaffold is formed from one or more reabsorbable filaments or supports.

[0092] In this embodiment, the reference marker may further contain a bioactive agent.

[0093] In one embodiment, the three-dimensional structure of the reference marker is formed by 3D printing. In another embodiment, the framework, skeleton, or scaffold of the three-dimensional structure is formed by 3D printing of a reabsorbable polymer. In yet another embodiment, the reference marker is molded.

[0094] The reference markers preferably have a pyrogen level of less than 20 endotoxin units per device and can be sterilized.

[0095] A. Material The reference marker may contain permanent and / or degradable materials, and more preferably, be made entirely from degradable materials, except for the visualization marker which may be permanent or reabsorbable. In embodiments, the outer region of the reference marker, or the scaffold structure of the reference marker, is made from degradable materials. In preferred embodiments, the reference marker contains one or more reabsorbable polymers, preferably reabsorbable thermoplastic polymers and copolymers.

[0096] The reference markers include polymers of glycolic acid, lactic acid, 1,4-dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, 4-hydroxybutyric acid, ε-caprolactone, 1,4-butanediol, and succinic acid, as well as other biocompatible or biodegradable polymers, such as poly(lactide), poly(lactide-co-glycolide), or polycaprolactone, and polymers with blocks of their copolymerization, including random copolymers and block copolymers thereof, such as: polyglycolic acid, polylactic acid, polydioxanone, polycaprolactone, copolymers of glycolic acid and lactic acid such as VICRYL® polymer, MAXON® and MONOCRYL® polymer, as well as poly(lactide-co-caprolactone); poly(orthoester); polyanhydride; poly(phosphazene); polyhydroxyalkanoate (PHA); synthetic or biologically prepared polyesters; polycarbonate; tyrofoam These polymers can be prepared from polymers including, but not limited to, synthetic polycarbonates; polyamides (including synthetic and natural polyamides, polypeptides, and poly(amino acids)); polyesteramides; poly(alkylene alkylates); polyethers (such as polyethylene glycol, PEG, and polyethylene oxide, PEO); polyvinylpyrrolidone (i.e., PVP); polyurethanes; polyether esters; polyacetals; polycyanoacrylates; poly(oxyethylene) / poly(oxypropylene) copolymers; polyacetals, polyketals; polyphosphates; (phosphorus-containing) polymers; polyphosphate esters; polyalkylene oxalates; polyalkylene succinates; poly(maleic acid); silk (including recombinant silk and silk derivatives and analogs); chitin; chitosan; modified chitosan; biocompatible polysaccharides; and hydrophilic or water-soluble polymers such as polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP). Preferably, the reabsorbable polymer or copolymer is substantially or completely reabsorbed within 6 to 24 months after implantation.

[0097] Blends of polymers, preferably reabsorbable polymers, can also be used to prepare reference markers. Particularly preferred blends of reabsorbable polymers include, but are not limited to, blends formed from polymers containing glycolic acid, lactic acid, 1,4-dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, 4-hydroxybutyric acid, ε-caprolactone, 1,4-butanediol, succinic acid, or copolymers thereof.

[0098] In a particularly preferred embodiment, the reference marker comprises poly-4-hydroxybutyrate (Tepha's P4HB® polymer, Lexington, MA) or a copolymer thereof, and in one embodiment, except for the visualization marker, it can be entirely made using P4HB or a copolymer thereof. The copolymers include P4HB having another hydroxy acid such as 3-hydroxybutyrate, and P4HB having glycolic acid or lactic acid monomers. P4HB is a strong, flexible thermoplastic polyester that is biocompatible and reabsorbable (Williams, et al. Poly-4-hydroxybutyrate (P4HB): a new generation of resorbable medical devices for tissue repair and regeneration, Biomed.Tech. 58(5):439-452 (2013)). Upon implantation, P4HB is hydrolyzed to its monomers, which are metabolized to carbon dioxide and water via the Krebs cycle. In preferred embodiments, the P4HB homopolymer and its copolymer have a weight-average molecular weight Mw in the range of 50 kDa to 1,200 kDa (by GPC relative to polystyrene), more preferably 100 kDa to 600 kDa, and even more preferably 200 kDa to 450 kDa. A weight-average molecular weight of 50 kDa or more is preferred for processing and mechanical properties.

[0099] In another preferred embodiment, the reference marker comprises a polymer containing at least a diol and a diacid. In a particularly preferred embodiment, the polymer used to prepare the reference marker apparatus is poly(butylene succinate) (PBS), where the diol is 1,4-butanediol and the diacid is succinic acid. The poly(butylene succinate) polymer may be a copolymer with other diols, other diacids, or combinations thereof. For example, the polymer may be a poly(butylene succinate) copolymer further comprising one or more of the following: 1,3-propanediol, 2,3-butanediol, ethylene glycol, 1,5-pentanediol, glutaric acid, adipic acid, terephthalic acid, malonic acid, methylsuccinic acid, dimethylsuccinic acid, and oxalic acid. Preferred copolymers include poly(butylene succinate-co-adipate), poly(butylene succinate-co-terephthalate), poly(butylene succinate-co-butylene methyl succinate), poly(butylene succinate-co-butylene dimethyl succinate), poly(butylene succinate-co-ethylene succinate), and poly(butylene succinate-co-propylene succinate). The poly(butylene succinate) polymer or copolymer may also further contain one or more of the following: chain extenders, coupling agents, crosslinking agents, and branching agents. For example, poly(butylene succinate) or its copolymer may be branched, chain extended, or crosslinked by adding one or more of the following active ingredients: malic acid, trimethylolpropane, trimesic acid, citric acid, glycerol propoxylate, and tartaric acid. A particularly preferred active agent for branching, chain extending, or crosslinking poly(butylene succinate) polymers or copolymers thereof is a hydroxycarboxylic acid unit. Preferably, the hydroxycarboxylic acid unit has two carboxylic acid groups and one hydroxyl group, two hydroxyl groups and one carboxyl group, three carboxyl groups and one hydroxyl group, or two hydroxyl groups and two carboxyl groups. In one preferred embodiment, the reference marker comprises poly(butylene succinate) containing malic acid as a branching agent, chain extender, or crosslinking agent.This polymer may be called malic acid-crosslinked or chain-extended poly(butylene succinate), succinate-1,4-butanediol-malate copolyester, or malic acid-crosslinked or chain-extended poly(1,4-butylene glycol-cosuccinate). References to malic acid and other crosslinking agents, coupling agents, branching agents, and chain extenders should be understood to include polymers prepared using these active ingredients, which undergo further reactions during processing. For example, active ingredients may undergo dehydration during polymerization. Thus, poly(butylene succinate)-malate copolymer refers to a copolymer prepared from succinic acid, 1,4-butanediol, and malic acid. In another preferred embodiment, malic acid may be used as a branching agent, chain extender, or crosslinking agent to prepare a copolymer of poly(butylene succinate) and adipate, which may be called malic acid-crosslinked or chain-extended poly[(butylene succinate)-co-adipate]. As used herein, “poly(butylene succinate) and copolymers” includes polymers and copolymers prepared using one or more of the following: chain extenders, coupling agents, crosslinking agents, and branching agents. In particularly preferred embodiments, the poly(butylene succinate) and copolymers thereof contain at least 70% by weight, more preferably 80% by weight, and even more preferably 90% by weight of succinic acid and 1,4-butanediol units. Polymers containing diacids and diols, including poly(butylene succinate) and copolymers thereof and others described herein, preferably have a weight-average molecular weight (Mw) of 10,000 Da to 400,000 Da, more preferably 50,000 Da to 300,000 Da, and even more preferably 100,000 Da to 200,000 Da, based on gel permeation chromatography (GPC) against a polystyrene standard. In particularly preferred embodiments, the polymer and copolymer have a weight-average molecular weight of 50,000 Da to 300,000 Da, more preferably 75,000 Da to 300,000 Da.In one preferred embodiment, the poly(butylene succinate) or copolymer thereof used to manufacture the apparatus or components of the apparatus has one or more or all of the following properties: 1.23 to 1.26 g / cm³. 3 Density, glass transition temperature of -31°C to -35°C, melting point of 113°C to 117°C, melt flow rate (MFR) of 2 to 10 g / 10 min at 190°C / 2.16 kgf, and tensile strength of 30 to 60 MPa.

[0100] B. Additives Certain additives can be incorporated into the apparatus, preferably the absorbent polymer, copolymer, or blend thereof used to manufacture the apparatus. These additives can be incorporated during the compounding process that follows the manufacture of the apparatus. For example, the additives can be melt-compounded with the polymer or compounded using a solution-based process.

[0101] In preferred embodiments, the additive is biocompatible, and more preferably, the additive is both biocompatible and reabsorbable.

[0102] In one embodiment, the additives may be nucleating agents and / or plasticizers. These additives can be added in amounts sufficient to obtain the desired results. Generally, these additives can be added in amounts of 1% to 20% by weight. Nucleating agents can be incorporated to increase the crystallization rate of polymers, copolymers, or blends. Such active ingredients can be used, for example, to facilitate the manufacture of apparatus and to improve the mechanical properties of apparatus. Preferred nucleating agents include, but are not limited to, salts of organic acids such as calcium citrate, polymers or oligomers of PHA polymers and copolymers, high-melting-point polymers such as PGA, talc, micronized mica, calcium carbonate, calcium phosphate, ammonium chloride, and aromatic amino acids such as tyrosine and phenylalanine.

[0103] Plasticizers that can be incorporated into compositions for preparing the apparatus include di-n-butyl maleate, methyl laurate, dibutyl fumarate, di(2-ethylhexyl) (dioctyl) maleate, paraffin, dodecanol, olive oil, soybean oil, polytetramethylene glycol, methyl oleate, n-propyl oleate, tetrahydrofurfuryl oleate, epoxidized linseed oil, 2-ethylhexyl epoxytarate, glycerol triacetate, methyl linoleate, dibutyl fumarate, and methyl acetyl ricinoleate. The plasticizers include, but are not limited to, acetyl tri(n-butyl) citrate, acetyl triethyl citrate, tri(n-butyl) citrate, triethyl citrate, bis(2-hydroxyethyl) dimerate, butyl ricinoleate, glyceryl tri(acetylricinoleate), methyl ricinoleate, n-butylacetyl ricinoleate, propylene glycol ricinoleate, diethyl succinate, diisobutyl adipate, dimethyl azelaate, di(n-hexyl) azelaate, tributyl phosphate, and mixtures thereof. Particularly preferred plasticizers are citrate esters.

[0104] C. Visualization Markers The reference marker may comprise one or more visualization markers. The visualization markers may include permanent materials, biodegradable materials, or a combination thereof. Preferably, the visualization markers are completely biodegradable. The visualization markers may be incorporated into the material used to form the outer region of the reference marker, one or more parts of the scaffold structure of the reference marker, or all of them. In a preferred embodiment, the visualization markers are incorporated into a reabsorbable polymer. In an embodiment, the visualization markers are incorporated into a reabsorbable polymer and incorporated into the reference marker at one or more locations.

[0105] Suitable visualization markers that can be incorporated into the reference marker include visibility markers that can be detected by one or more of the following methods: X-ray, magnetic resonance imaging, computed tomography, ultrasound, mammography, positron emission tomography, and single-photon emission computed tomography.

[0106] In this embodiment, the visualization marker is made of a radiopaque material.

[0107] In the embodiment, the visualization marker includes one or more of the following: titanium, stainless steel, tungsten, barium, zinc, zirconium, strontium, ytterbium, gold, and bismuth. In the embodiment, the visualization marker is one or more of the following: barium sulfate, iodine compounds, bismuth compounds, zinc oxide, zirconium dioxide, titanium dioxide, iodoform, iodine compounds, bismuth oxide, bismuth subcarbonate, bismuth oxychloride, ytterbium fluoride, and strontium carbonate.

[0108] In the embodiment, the visualization marker is a wire, clip, metal, alloy, ceramic, or powder. Powders that can be incorporated into the reference marker include titanium, strontium carbonate, zirconium dioxide, barium sulfate, and bismuth(III) oxide.

[0109] In the embodiment, the visualization marker is a composite material. In the embodiment, the visualization marker may be a composite of poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof with a radiopaque material. In the embodiment, the visualization marker may be a composite of poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof with one or more of the following: titanium, stainless steel, tungsten, barium, zinc, zirconium, strontium, ytterbium, gold, bismuth, barium sulfate, iodine compounds, bismuth compounds, zinc oxide, zirconium dioxide, titanium dioxide, iodoform, bismuth oxide, bismuth subcarbonate, bismuth oxychloride, ytterbium fluoride, and strontium carbonate. In preferred embodiments, the visualization marker is a composite of poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof, with barium sulfate, zirconium dioxide, or both barium sulfate and zirconium dioxide.

[0110] In the embodiment, the visualization markers are as follows: sodium fluorescein, iodipamide meglumine, iotalamate meglumine, diatrizoate meglumine, ioflupan i-123, perfluthren, sodium diatrizoate, fermoxyl, gadopentetate dimeglumine, indium in-111 pentetate disodium, gadodiamide, gadovercetamide, gadoxetate disodium, technetium TC-99m glucept, gadobenate dimeglumine, albumin human, etidronate technetium TC-99m, technetium TC-99m meritiate Technetium TC-99M pyrophosphate, Technetium TC-99M depreotide, Technetium TC-99M fanoresomab, Technetium TC-99M ferpentetate, Technetium TC-99M albumin, Technetium TC-99M gluceptate, Technetium TC-99M cesamibi, Technetium TC-99M examethadium, Technetium TC-99M lidphenin, Technetium TC-99M mebrophenin, Technetium TC-99M medronate, Technetium TC-99M pyrophosphate, Technetium TC-99M penteter Technetium TC-99M disophenine, Technetium TC-99M sodium pertechnetate, Technetium TC-99M succimer, tetrophosmin technetium TC-99M, technetium TC-99M bicisete, technetium TC-99M pyrophosphate / trimetaphosphate, technetium TC-99M teboroxime, xenon XE-133, xenon XE-127, gadophosbecet trisodium, iobenguan sulfate I-123, ammonia, N-13, florbetapyr F-18, technetium TC-99M pentetaate, technetium TC-99M sulfur colloid, technetium TC-99M sodium pertechnetate, technetium TC-99M cestamibi, rubidium chloride RB-82, alcitumomab, choline-11, sodium chromate CR-51, ethodized oil, fermoxides, fludeoxyglucose F-18, sodium fluorescein, gadobutrol, gadoteridol, gallium citrate GA-67, sodium iotalamate I-125, ioxagrate meglumine, ioxagrate sodium, sodium iodide I-131, indocyanine green,Indium chloride IN-111, Indium IN-111 oxyquinoline, Indium IN-111 pentetreotide, Indocyanine green, Iopamidol, Serum iodide albumin I-125, Iohexol, Ioversol, Ioxiran, Iopromide, Capromab pendetide, Thallium chloride TL-201, Nofetumomab, Iodixanol, Sodium iotalamate, Krypton, KR-81M, Sodium iodidehiprunate I-123, Rose bengal sodium I-131, Mangahodipel trisodium, Xenon XE-133, Sodium tyropanoate, Cyanocobalamin, Cyanocoba One or more of the following are selected: lamin co-57, ferric ammonium citrate, ferrous citrate, fludeoxyglucose, sodium fluoride f-18, gallium citrate ga-67, sodium iodide i-131, dimyristoyl lecithin, perflexan, perflubron, iobenguan sulfate i-131, sodium iodide i-131, calcium metrizoate, meglumine metrizoate, magnesium metrizoate, sodium metrizoate, manganese chloride tetrahydrate, imusilomab pentetate, iofendilate, simethicone cellulose, and calcium trisodium pentetate yb-169. Examples of adding appropriate visualization markers are listed in Savitt et al. 1987, The radiopacity of ingested medications, Ann. Emerg. Med., 16(3):331-9.

[0111] In embodiments, the apparatus is coated to improve its visibility, or the visualization markers are coated to improve their visibility. In embodiments, the apparatus includes a hydrogel to improve its visibility. The hydrogel may be coated on the apparatus or on the visualization markers of the apparatus. A suitable hydrogel may be physically or chemically crosslinked. Preferably, the hydrogel is absorbent. In embodiments, the hydrogel contains polysaccharides. In embodiments, the hydrogel includes hyaluronic acid, alginates, e.g., sodium alginate or calcium alginate, collagen, gelatin, fibrin, pectin, Matrigel, and chitosan, or derivatives thereof. In embodiments, the hydrogel is derived from one or more of the following: poly(ethylene oxide), poly(vinyl alcohol), poly(lactic acid), and poly(propylene fumarate). Other examples of hydrogels include poly(ethylene glycol) diacrylate and poly(acrylamide).

[0112] In embodiments, visualization markers comprising titanium, stainless steel, tungsten, barium, zinc, zirconium, strontium, ytterbium, gold, bismuth, barium sulfate, iodine compounds, bismuth compounds, zinc oxide, zirconium dioxide, titanium dioxide, iodoform, bismuth oxide, bismuth subcarbonate, bismuth oxychloride, ytterbium fluoride, and strontium carbonate are coated with a hydrogel and may further include an absorbent polymer, such as poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof.

[0113] C. Bioactive Agents A reference marker device may be loaded with or coated with a bioactive agent. The bioactive agent may be included in the device for a variety of reasons. For example, the bioactive agent may be included to improve internal tissue growth within the device, to improve tissue maturation, to provide delivery of the activator, to improve implant wettability, to prevent infection, and to improve cell adhesion. In some embodiments, the bioactive agent may also be incorporated in different areas of the device at different concentrations.

[0114] In other embodiments, the apparatus may include cell adhesion factors comprising cell adhesion polypeptides. As used herein, the term “cell adhesion polypeptide” refers to a compound having at least two amino acids per molecule that can bind cells via cell surface molecules. Cell adhesion polypeptides include any of the extracellular matrix proteins known to act in cell adhesion, including fibronectin, vitronectin, laminin, elastin, fibrinogen, type I, type II, and type V collagen, and synthetic peptides having similar cell adhesion properties. Cell adhesion polypeptides also include peptides derived from any of the aforementioned proteins, comprising fragments or sequences containing binding domains.

[0115] The apparatus may incorporate wetting agents designed to improve the wetting properties of the apparatus surface, allowing fluids to be easily adsorbed onto the apparatus surface and within the porous apparatus, promoting cell adhesion, and / or altering the water contact angle of the apparatus surface. Examples of wetting agents include polymers of ethylene oxide and propylene oxide, such as polyethylene oxide and polypropylene oxide, or copolymers thereof, such as PLURONICS®. Other suitable wetting agents include surfactants or emulsifiers.

[0116] The apparatus may include a gel, hydrogel, or living hydrogel hybrid to further improve wetting properties and promote cell growth across the entire thickness or diameter of the apparatus. The hydrogel hybrid consists of living cells encapsulated in a biocompatible hydrogel such as gelatin, silk gel, and hyaluronic acid (HA) gel.

[0117] The device may include activators designed to stimulate cellular endothelial growth, including cell signaling molecules such as growth factors, cell differentiation factors, cell recruitment factors, cell receptors, cell binding factors, and cytokines, as well as molecules that promote cell migration, cell division, cell proliferation, and extracellular matrix deposition. Such activators include fibroblast growth factor (FGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), granulocyte-macrophage colony-stimulating factor (GMCSF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), interleukin-1-B (IL-1B), interleukin-8 (IL-8), and nerve growth factor (NGF), as well as combinations thereof.

[0118] Other bioactive agents that can be incorporated into the device include antimicrobial agents, particularly antibiotics, disinfectants, anticancer agents, scar treatment agents, anti-inflammatory agents, anesthetics, small molecule drugs, anti-angiogenic and pro-angiogenic factors, immunomodulators, and blood coagulants. Bioactive agents may be proteins such as collagen and antibodies, peptides, polysaccharides such as chitosan, alginates, hyaluronic acid and its derivatives, nucleic acid molecules, low molecular weight compounds such as steroids, inorganic materials such as hydroxyapatite, or complex mixtures such as platelet-rich plasma. Suitable antimicrobial agents include bacitracin, biguanides, triclosan, gentamicin, minocycline, rifampin, vancomycin, cephalosporins, copper, zinc, silver, and gold. Nucleic acid molecules may include DNA, RNA, siRNA, miRNA, antisense, or aptamers.

[0119] In preferred embodiments, the bioactive agent is selected from one or more of the following: chemotherapeutic agents, antitumor agents, immunomodulators, hormones, anti-angiogenic agents, antibiotics, radiosensitizers, and immunotherapeutic agents.

[0120] In another preferred embodiment, the device may incorporate a system for controlled release of therapeutic or prophylactic drugs.

[0121] III. Method for Manufacturing a Reference Marker Device Reference marker devices can be manufactured using various methods, and several different examples are described herein.

[0122] The device can eliminate or reduce pain that a patient experiences during their normal daily activities when a more rigid reference marker device is implanted in the breast. In contrast to a more rigid reference marker implanted in the breast, the device described herein is either not palpable when implanted in the breast or other tissue, or becomes palpable after implantation, deforms when stress is applied, and can recover its shape when the stress is removed.

[0123] The device also reduces or eliminates the possibility that clinicians unaware of the device may order unnecessary procedures to characterize foreign bodies in patients. Unlike existing partially reabsorbable or slowly reabsorbable devices, the device disclosed herein can be manufactured using a visualization marker that reabsorbs much faster and makes the entire device reabsorbable.

[0124] Unlike existing devices, the apparatus disclosed herein may also incorporate a scaffold designed to promote internal tissue growth throughout the entire cavity of the tumor resection cavity. This internal tissue growth not only helps to secure the apparatus in place but also acts as a cavity filler, helping to prevent fluid buildup in the cavity after surgery. By promoting internal tissue growth and relatively rapid reabsorption, the apparatus can improve the patient's aesthetic outcomes, particularly in the treatment of breast cancer. For example, instead of feeling a hard, rigid reference marker made of polylactic acid in the breast for many years, internal tissue growth within the reference marker scaffold fills the cavity of the tumor resection cavity with tissue that has a natural feel, and the reference marker completely disintegrates, leaving no palpable foreign body.

[0125] A. Example of a reference marker device The reference marker device is designed to shape the tumor resection cavity into a defined target volume for radiotherapy with precisely defined tissue margins, thereby identifying the planned target volume. By shaping the tumor resection cavity into a defined form, the size of the tissue margins around the cavity requiring irradiation can be reduced, thereby reducing the radiation exposure of the patient's healthy tissue.

[0126] In one preferred embodiment, the reference marker device has an open porous scaffold structure having a predetermined shape that defines the peripheral boundary of the device. The open porous scaffold structure helps to promote internal tissue growth, which helps to fix the visualization marker in place after implantation. Internal tissue growth can also prevent fluid accumulation in the tissue excision cavity, resulting in improved aesthetic outcomes, for example, after mammary gland tumor excision.

[0127] An example of an open porous scaffold structure for a reference marker device (100) designed to promote internal tissue growth within the device is shown in Figures 1A-C. The porous three-dimensional scaffold structure of the marker device (100) has a honeycomb structure formed in an elliptical sphere with an outer region defining the peripheral boundary of the device. The scaffold is designed to have a porous structure in which the structure of the reference marker is fully interconnected. Preferably, the scaffold of the reference marker device has a one-piece structure. The fully open structure of the scaffold provides an environment that allows cells to enter the marker device and proliferate after implantation. Internal tissue growth within the honeycomb structure helps to fix the device in place so that it does not move. Internal tissue growth within the honeycomb structure also allows the device to be used as a void filler. Internal tissue growth helps to reduce or eliminate fluid accumulation in the tumor resection cavity after surgery, improving aesthetic results by reducing or eliminating visible tissue defects, for example in mammary gland tumor excision procedures. The outer region of the scaffold structure (100) has a predetermined shape formed by a three-dimensional frame, skeleton, or scaffold. The three-dimensional frame, skeleton, or scaffold is formed from filaments. The three-dimensional honeycomb frame, skeleton, or scaffold (100) of the marker device can shape the tissue resection cavity into a predetermined shape to define the boundary of the planned target volume for radiotherapy. By shaping the irregularly shaped tissue resection cavity into a predetermined shape of the honeycomb scaffold (100), the size of the tissue margin around the cavity requiring irradiation can be reduced, thereby reducing the radiation exposure of healthy patient tissue. The three-dimensional honeycomb structure (100) of the tissue marker is not rigid, but rather compressible under stress or tension. Optionally, in embodiments, the three-dimensional honeycomb structure (100) has shape memory. The reference marker device (100) has an elastic modulus of less than 50 MPa, more preferably less than 1 MPa, and more preferably less than 100 kPa. These properties not only allow the predetermined shape of the reference marker to shape the tissue within the tumor resection cavity into a shape desirable for radiotherapy, but also allow the predetermined shape to deform under stress or tension and recover its predetermined shape when the stress or tension is removed.For example, when a scaffold is implanted in a patient's breast, its predetermined shape (100) may be temporarily deformed by stress or tension from the patient's bra, but once the bra is removed, the scaffold will recover its predetermined shape, and any visualization markers placed around the scaffold can still be used to accurately define the boundaries of the planned target volume for radiotherapy. This property of the honeycomb structure (100) can eliminate or reduce pain or palpability of the device, especially when implanted in a patient's breast. In particular, the predetermined shape of the scaffold (100), and its ability to recover its shape after stress or tension is applied and then removed, needs to be maintained only for the duration of radiotherapy or while any visualization markers placed around the scaffold are fixed in place by internal tissue growth. Once radiotherapy is completed or such visualization markers are fixed in place, the scaffold may lose its ability to recover its predetermined shape, and preferably, the scaffold is reabsorbed. Preferably, the scaffold structure is reabsorbed within 6 to 24 months.

[0128] The scaffold of the apparatus (100) can be prepared using one or more of the materials disclosed in Section II.A. Preferably, the scaffold (100) is prepared from poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof, or comprises one or more of these polymers.

[0129] Four structures with the design of apparatus (100) were prepared from poly-4-hydroxybutyric acid by 3D printing. The elastic modulus of each of these apparatuses was measured and found to be in the range of 0.35 MPa to 0.01 MPa.

[0130] Visualization markers can be incorporated into the honeycomb structure filaments of the marker device (100) shown in Figures 1A-C. Visualization markers can also be attached to the outer region of the scaffold structure, as shown in Figures 2A-C. Device (200) is an example of a standard marker device formed of a honeycomb open porous scaffold structure shown in Figures 1A-C, in which six visualization markers (210a, 210b, 210c, 210d, 210e, 210f, collectively called "visualization markers (210)") are attached to the outer region of the scaffold structure. Multiple visualization markers can be attached to device (200), but preferably six visualization markers are used. Device (200) has an open porous three-dimensional honeycomb scaffold structure having interconnected porous structures formed in an elliptical spherical shape with an outer region defining the peripheral boundary of the device. The open porous scaffold structure promotes internal cell growth and tissue formation, thereby fixing the scaffold in place, preventing its movement, and, importantly, fixing the visualization marker (210) located around the marker device, so that the visualization marker is positioned at the margin of the cavity of the excised tumor. Internal tissue growth within the device (200) can improve aesthetic results by filling voids such as cavities left after mammary gland tumor excision. The reference marker (200) has a predetermined shape formed by a three-dimensional framework, skeleton, or scaffold, preferably formed from filaments, and its shape is capable of shaping the tumor excision cavity into a shape suitable for the planned target volume for radiotherapy, but is compressible under stress or tension and regains its predetermined shape when the stress or tension is removed. The scaffold for the reference marker is designed not only to maintain its predetermined shape but also to deform under stress and tension, and to recover its predetermined shape during the duration of radiotherapy or for the period necessary for the visualization marker (210) to be fixed in place by internal tissue growth within the scaffold. The scaffold is preferably reabsorbed in less than 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months after the completion of radiotherapy or once the visualization marker (210) has been fixed in place around the marker device.The scaffolding for the apparatus (200) can be prepared using one or more of the materials disclosed in Section II.A.

[0131] Another example of a reference marker device (300) is shown in Figure 3A. The reference marker device (300) has a spherical open porous scaffold structure designed to promote internal tissue growth, having a column or pin holder (310), and radiopaque columns or pins (320) can be inserted into the column or pin holder (310) to form a visible marker on the surface of the device. The implant may include an outer or peripheral structure (e.g., a shell 350) and an internal organizing structure that can support the peripheral structure and provide an interconnected porous structure or mesh of pores.

[0132] A cross-section of the device (300) along line 3B-3B is shown in Figure 3B. A locking feature (330) on a radiopaque column / pin (320) is shown in Figure 3B. The locking feature allows the radiopaque column or pin to be fixed to the outer region of the scaffold. Multiple, preferably six, radiopaque columns or pins (320) can be positioned in the outer region of the device (300). By appropriately arranging these columns or pins, the outer region of the device (300) can be imaged for planning target volume and radiotherapy.

[0133] In some embodiments, the visualization markers are positioned around the device so that they are located at the margins of the cavity of the excised tumor. In certain embodiments, the visualization markers are positioned at the first and second ends of the longitudinal axis of the device so that the length (l) of the device can be imaged in vivo. Markers can also be positioned around the device at the midpoint of the longitudinal axis so that the diameter or width of the device can be imaged.

[0134] Figure 3C shows the positions of three columns or pin holders (310) located in the outer region of the reference marker device (300), into which radiopaque columns or pins (320) can be inserted to enable imaging of the device. The device (300) has a one-piece structure. The device (300) may be formed of a honeycomb structure or other suitable open porous structure that provides an environment that allows cells to enter the marker device and proliferate after implantation. Internal growth of tissue within the structure (300) helps to fix the device in place so that it does not move and fix the position of the visualization marker located around the marker device at the margin of the cavity of the excised tumor. Internal growth of tissue within the structure (300) also allows the device to be used as a void filler, reducing or eliminating fluid accumulation in the tumor excision cavity after surgery and improving aesthetic results by reducing or eliminating visible tissue defects, for example in mammary gland tumor excision procedures. The outer region of the scaffold structure (300) has a predetermined shape formed by a three-dimensional frame, skeleton, or scaffold. The three-dimensional frame, skeleton, or scaffold is formed from filaments. The three-dimensional frame, skeleton, or scaffold (300) of the marker device can shape the tissue resection cavity into a predetermined shape to define the boundary of the planned target volume for radiotherapy. The three-dimensional structure (300) of the tissue marker is not rigid, but rather compressible under stress or tension. The device (300) has an elastic modulus of less than 50 MPa. These properties not only allow the predetermined shape to shape the tissue in the tumor resection cavity into a shape desirable for radiotherapy, but also allow the predetermined shape to deform under stress or tension and recover its predetermined shape when the stress or tension is removed. This property of the structure (300) can eliminate or reduce pain or palpability of the device, especially when implanted in the patient's breast. In particular, the predetermined shape of the scaffold, and its ability to recover that shape after stress or tension is applied and then removed, must be maintained only during the duration of radiotherapy or while the visualization marker (320) is fixed in place by internal tissue growth. Once radiotherapy is completed or the visualization marker is fixed in place, the scaffold may lose its ability to recover its predetermined shape, and the scaffold is preferably reabsorbed.Preferably, the scaffold structure (300) is reabsorbed in less than 6 to 24 months. The scaffold of the apparatus (300) can be prepared using one or more of the materials disclosed in Section II.A. Preferably, the apparatus (300) is prepared from poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof, or comprises one or more of these polymers.

[0135] The scaffold structure of the reference marker device can also be 3D printed in other shapes suitable for radiotherapy, including spherical, hemispherical, spheroidal, elliptical, cylindrical, parallelepiped, and convex shapes. These scaffold structures are formed as open porous structures and are preferably made by 3D printing of three-dimensional frameworks, skeletons, or scaffolds. These frameworks, skeletons, or scaffolds can be formed from one or more filaments and optionally include supports. The frameworks, skeletons, or scaffolds may include one or more polyhedra.

[0136] B. Dimensions of the reference marker device Reference marker devices are sized for use in tumor resection cavities of different sizes. Reference marker devices are sized to define the planned target volume (PTV) for radiotherapy. Referring again to Figures 1A and 1B, the device can be formed in a shape having a longitudinal axis with a first end, a second end, and a length (l) between the first and second ends. The length (l) is typically between 1 and 6 cm, including 1, 2, 3, 4, 5, and 6 cm.

[0137] The device can be formed having a length (l) or width (w) at the midpoint of the longitudinal axis between the first end and the second end. The width (w) at the midpoint of the longitudinal axis of the device is typically 1 to 5 cm, including 1, 2, 3, 4, and 5 cm. Common sizes of reference markers have (l) x (w) dimensions of 2x2 cm, 2x3 cm, 3x3 cm, 3x4 cm, 4x4 cm, and 4x5 cm. In embodiments, the base area is circular, with equal length and width.

[0138] The device may also be formed having a longitudinal axis with a first end and a second end, a length (l) between the first end and the second end, and a width (w) and height (h) at the midpoint of the longitudinal axis between the first end and the second end of the device. Typical values ​​for these dimensions are 1 to 4 cm (l), 1 to 3 cm (w), and 1 to 2 cm (h). Particularly common sizes for reference markers with dimensions of length (l) × width (w) × height (h) are 3x2x1 cm, 3x3x1 cm, 1x1x2 cm, 2x1x2 cm, and 1x2x2 cm.

[0139] C. Porosity of the reference marker device In the embodiment, the open porous scaffold structure of the reference marker device preferably includes macropores that promote the internal growth of cells and tissues into the interior of the scaffold structure. The macropores preferably have an average pore diameter size or dimension of at least 25 microns, more preferably at least 50 microns, and even more preferably at least 75 microns. The average pore diameter size or dimension may be 0.075 mm to 10 mm. The pore size may differ in different areas of the scaffold of the device.

[0140] A suitable porous scaffold for a reference marker device can be formed from hollow or skeletal unit cells. A porous scaffold having a specified size, shape, and volume can be formed by joining hollow or skeletal unit cells together to form a predetermined shape for a three-dimensional reference marker device. These porous reference markers can be manufactured having different shapes and sizes by using unit cells of the same or different sizes and shapes. In a particularly preferred embodiment, the hollow unit cells and skeletal unit cells are compressible, and more preferably, they can be restored to their original dimensions after compression. A particularly preferred embodiment is a compressible reference marker comprising hollow unit cells or skeletal unit cells that can be restored to their original dimensions after compression.

[0141] A marker device formed from hollow or skeletal unit cells may comprise two or more unit cells, more preferably 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 1,000, 10,000 or more. The unit cells of the scaffold structure of the device may be joined to one or more unit cells, which may be of the same type or different types. The unit cells forming the scaffold structure of the marker device may have pores with a width or diameter of 500 μm to 2 cm, more preferably 1 mm to 1 cm. The unit cells of the device may have the same pore size or a mixture of pore sizes. A reference marker device formed from unit cells preferably has a low volume density that provides a large surface area and void volume. Preferably, the dimensions of the unit cells are selected so that a porous scaffold can be assembled from low volume density unit cells that can be easily colonized by cells and penetrated by tissues and blood vessels.

[0142] By appropriately selecting the size and shape of the unit cells, different types of reference marker scaffolds with different volume densities can be manufactured. The properties of scaffolds formed from repeated unit cells are highly predictable and can be predicted based on the dimensions of the unit cells and the materials used to prepare them. By selecting the dimensions, geometric shape, and materials used to prepare the unit cells, unit cells with different physical properties can be manufactured. By selecting specific unit cell dimensions and materials, it is possible to manufacture scaffolds from unit cells that are compressible yet can be inserted into tumor resection cavities, allowing the tissue margins of the cavities to conform to a predetermined shape of the marker device.

[0143] The hollow or skeletal unit cells of the porous reference apparatus can be formed from filaments. The length of the filaments forming these unit cells is preferably 1 mm to 2 cm, more preferably 2 mm to 1 cm, and even more preferably 3 mm to 9 mm. The length of the filaments can be selected to give the apparatus a specific porosity and a specific shape and volume. The width of the filaments in the unit cells is preferably 500 μm to 2 cm, more preferably 1 mm to 2 cm, and even more preferably 1 mm to 9 mm. One advantage of using unit cells to form a reference marker is that the width and length of the filaments required to produce a porous scaffold with a specific elastic modulus or other mechanical properties can be calculated for a given material. In embodiments, the mechanical properties of the scaffold of the reference marker can be changed by changing the dimensions of the filaments of the unit cells instead of changing the shape of the unit cells. In preferred embodiments, the porosity, dimensions, and material of the unit cells forming the scaffold of the reference marker are selected so that the scaffold prepared from the unit cells has properties similar to those of soft tissue. For example, the porosity, dimensions, and material of the unit cells may be selected to provide a scaffold structure having mechanical properties similar to those of breast tissue. In another preferred embodiment, the unit cells of the reference marker device can be compressed and optionally recover their original shape when the compressive force is released.

[0144] The unit cells of the reference marker device can be prepared using one or more of the materials disclosed in Section II.A. Preferably, the unit cells are prepared from a composition comprising poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof.

[0145] Examples of porous reference marker devices formed from hollow honeycomb unit cells are shown in Figures 1A-C. Other examples of porous reference marker devices formed from unit cells include devices formed from skeletal unit cells, where the unit cells have a polyhedral shape.

[0146] D. Visualization marker for reference marker device The reference marker device is prepared with visualization markers that allow clinicians to use the device to determine the planned target volume and accurately deliver radiotherapy to patients. The visualization markers are located in the outer region of the reference marker device so that clinicians can image the dimensions of the device in vivo.

[0147] Visualization markers can be incorporated into the structure of the outer region of the marker device. For example, a radiopaque material can be used as a visualization marker and incorporated into the filament of the device located in the outer region of the marker device such that the radiopaque material is present at specific, individual locations and not throughout the entire outer region of the device. Positioning the radiopaque material at individual locations allows for subsequent imaging of the interior of the device that would be impaired or possibly obstructed if the radiopaque material were incorporated throughout the entire outer region of the device. If the radiopaque material is reabsorbable and the three-dimensional porous structure of the marker device is prepared from the reabsorbable material, the device thus constructed can be fully reabsorbable. In embodiments, a reabsorbable marker device can be prepared by incorporating barium sulfate at individual locations within the outer region of the reabsorbable porous scaffold structure of a reference marker. Preferably, the barium sulfate is incorporated at individual locations within the filament of the outer region of the marker device, which is made from one or more reabsorbable polymers. For example, radiopaque materials such as barium sulfate can be incorporated into individual positions of the honeycomb-structured filaments of the marker device (100) shown in Figures 1A-C. To improve the visibility of the markers, the barium sulfate can be coated with a hydrogel.

[0148] In other embodiments, visualization markers can be attached to the outer region of the three-dimensional marker device. The visualization markers may be, for example, clasps, clips, or wires made of radiopaque material that can be attached to the outer region of the device at individual positions. Figures 2A-C show front, side, and isometric views of a reference marker (200) formed of a honeycomb porous scaffold structure having six visualization markers (210) attached to the outer region of the marker scaffold structure. Any number of visualization markers can be attached to the device (200), but preferably six visualization markers are used.

[0149] In other embodiments, the visualization marker may be a radiopaque column or pin attached to the outer region of the device. An example of a reference marker device having a radiopaque column or pin is shown in Figures 3A-C. In this example, the radiopaque column or pin (320) can be attached to the reference marker device at individual positions by inserting the column or pin (320) into a column or pin holder (310) and securing it in place using a locking feature (330).

[0150] Referring to Figures 2A and 2B, in a preferred embodiment, the reference marker device has visualization markers (210c, 210d) located at the first and second ends of the longitudinal axis of the device. By positioning the visualization markers at the first and second ends of the longitudinal axis of the device, the length (l) of the device can be imaged in vivo. In another preferred embodiment, the reference marker device has visualization markers positioned around the device at the midpoint of the longitudinal axis of the device between the first and second ends of the diameter or width of the device. Preferably, four visualization markers (210a, 210b, 210e, 210f) are positioned at the midpoint around the device, and two visualization markers (210c, 210d) are positioned at the first and second ends of the longitudinal axis of the markers. In another embodiment, visualization markers are positioned at each pole of the 3D scaffold, e.g., the North and South Poles, and additional visualization markers are positioned along one or more latitudes of the 3D body.

[0151] In embodiments, the apparatus may include a hydrogel. The hydrogel can be used to enhance the visibility of the visualization marker. For example, to improve the visibility of the apparatus, the hydrogel can be used in combination with barium sulfate or iodixanol. The hydrogel may be coated on the visualization marker or on the apparatus.

[0152] The reference marker device may include the visualization markers listed in Section II.C above.

[0153] E. Fabrication of a reference marker device In one embodiment, the reference marker device is prepared by 3D printing. Suitable methods for 3D printing the device include fusion filament manufacturing, fusion pellet deposition, melt extrusion deposition, selective laser melting, slurry and solution printing using a solidification bath, and printing using binding solution and powder granules. Preferably, the device is prepared by melt extrusion deposition.

[0154] In one embodiment, the porous scaffold structure shown in Figures 1A-C can be manufactured by melt extrusion deposition from poly-4-hydroxybutyric acid (P4HB) using the following procedure. Pellets of P4HB (molecular weight 380 kDa) can be 3D printed using an Arburg Freeformer 3D printer and 3D CAM (computer-aided design modeling) for, for example, the elliptical spherical porous honeycomb scaffold structure of the reference marker apparatus shown in Figures 1A-C. The average diameter of the printed 3D filaments is selected based on the characteristics of the desired marker apparatus, including porosity or packing density (i.e., the number of 3D printed filaments per mm between the contours of the apparatus to be 3D printed). Preferably, the average filament diameter is 50-800 μm, more preferably 100-600 μm, and even more preferably 150-550 μm. 3D printing of the apparatus is highly desirable because it allows for precise control of the shape of the apparatus having open porous structures, and the 3D printed structure supports internal growth of the tissue. 3D printing is also highly desirable for preparing apparatus with shape memory.

[0155] Once the reference marker scaffold shown in Figures 1A-C is 3D printed, visualization markers can be added to the scaffold to form the device shown in Figures 2A-C. Any suitable method can be used to attach the visualization markers to the outer region of the scaffold structure. Preferably, the visualization markers can be clipped, stapled, sewn, or glued onto the scaffold structure.

[0156] In other embodiments, a reference marker device in which radiopaque material is incorporated at individual locations around the device may be manufactured by 3D printing the device from a combination of a polymer and a radiopaque material. An exemplary material combination is, but is not limited to, a polymer containing barium sulfate.

[0157] In the embodiment, the reference marker implant is formed from a skeletal polyhedron, and the edges and vertices of the unit cells forming the skeletal polyhedron have a breaking load of 0.1 to 200 N, more preferably 1 to 100 N, and even more preferably 2 to 50 N. In the embodiment, the edges and vertices of these unit cells have an elongation at break of 22% to 1,000%, more preferably 100% to 700%. In the embodiment, the edges and vertices of these unit cells have an elastic modulus value of 0.05 to 3 GPa, more preferably 0.1 to 1 GPa, and even more preferably 0.2 to 0.8 GPa. The diameter, width, breaking load, elongation at break, and elastic modulus value of the edges and vertices of the unit cells may be the same throughout the skeletal polyhedron or unit cells, or these values ​​may differ throughout the skeletal polyhedron or unit cells. The polymer struts forming the edges and vertices of the unit cell preferably have one or more of the following characteristics: (i) a breaking load of 0.1 to 200 N, (ii) an elongation at break of 22 to 1,000%, and (iii) an elastic modulus of 0.05 to 1 GPa. In the embodiment, the reference marker implant formed from the skeletal polyhedron has an elastic modulus of less than 50 MPa, more preferably 0.1 kPa to 10 MPa, and the polymer pillars or fibers of the unit cells forming the skeletal polyhedron have one or more of the following characteristics: (i) a diameter of 0.025 to 3 mm, more preferably 0.1 to 2 mm, and even more preferably 0.15 to 1 mm; (ii) an initial breaking load of 0.1 to 200 N, more preferably 1 to 100 N, and even more preferably 2 to 50 N; (iii) a breaking elongation of 22% to 1,000%, more preferably 100% to 700%; and (iv) an elastic modulus value of 0.05 to 3 GPa, more preferably 0.1 to 1 GPa, and even more preferably 0.2 to 0.8 GPa.

[0158] In the embodiment, the reference marker device is prepared, for example, by 3D printing, and has one or more suture eyelets that can be used to fix the device in place and prevent movement of the device during implantation. The one or more suture eyelets are preferably located around the periphery of the device.

[0159] In some embodiments, the reference marker may further include one or more bioactive agents. These active ingredients can be applied once the porous scaffold structure of the apparatus is formed, or the bioactive agents can be incorporated into the apparatus during the 3D printing process.

[0160] The reference marker device is preferably manufactured with an endotoxin content of less than 20 endotoxin units to make the device suitable for implantation in a patient.

[0161] IV. Method for embedding the reference marker device The device is sterilized before implantation. The device can be sterilized, for example, by exposure to ethylene oxide gas, cold ethylene oxide gas, gamma rays, or electron beam irradiation.

[0162] Reference markers are particularly suitable and useful for treating breast cancer, where the device can be implanted after mastectomy. However, reference marker devices can also be used to treat other soft tissue cancers, including liver cancer (e.g., treatment of liver tumors), muscle cancers (e.g., treatment of sarcomas in the muscle), and cancers of the abdomen, kidneys, lungs, and prostate. In particular, the device can be used when tissue is removed from the patient, and the patient may require radiation therapy at or near the tissue removal site. Reference marker devices can also be used in locations within the body where there is a high risk of cancer development. In these cases, the device can be used to monitor the patient or, if cancer subsequently develops, for radiation therapy.

[0163] Reference marker devices can be used by implanting them in the tumor bed or surgical resection cavity and can be imaged before radiation delivery. These devices can be imaged by one or more of the following techniques: X-ray, magnetic resonance imaging, computed tomography, ultrasound, mammography, positron emission tomography (PET), or single-photon emission computed tomography (SPECT). Imaging of the device provides a photograph of the device that can be used to calculate the planned target volume for radiotherapy and to guide the delivery of radiation to the tumor resection site.

[0164] In embodiments, the reference marker can be fixed to the tumor bed or surgical resection cavity using permanent sutures, reabsorbable sutures, staples, or other fixation means. The fixation helps prevent any subsequent movement of the device until internal tissue growth fixes the device in place.

[0165] In the embodiment, the reference marker may be provided with one or more suture eyelets for securing the device in place. Sutures can be passed through these eyelets and secured to the tissue to prevent the device from moving after implantation.

[0166] Some cancer treatments require multiple radiation doses over a period of several days, weeks, or months. In these cases, a reference marker device can be used to repeatedly identify the tumor resection cavity and guide further radiation therapy.

[0167] Reference marker devices can also be used to deliver one or more bioactive agents in vivo. For example, a reference marker may contain one or more of the following that can be delivered near the implantation site: chemotherapeutic agents, antitumor agents, anti-angiogenic agents, immunomodulators, hormones, immunotherapeutic agents, antibiotics, and radiosensitizers.

[0168] Reference marker devices may also be embedded in tissue to fill gaps. In this application, the devices can be used as gap fillers. Reference marker devices can also be used as markers to assist in radiotherapy and to fill tissue resection cavities with new tissue. The latter can improve aesthetic outcomes, particularly after breast tumor removal procedures.

[0169] The present invention can be further understood by referring to the following non-limiting embodiments. [Examples]

[0170] Example 1: Reference scaffold marker made by 3D printing from poly-4-hydroxybutyrate (P4HB) A porous reference marker device was fabricated by 3D printing from a pellet of P4HB (molecular weight 380 kDa). The P4HB filaments were deposited layer by layer using melt extrusion deposition under the conditions shown in Table 1. The open porous scaffold structure of the device was formed as a honeycomb structure as shown in Figures 1A-B. The structure had an elliptical sphere shape with a length (l) in the range of 2-6 cm and a height (h) in the range of 2-8 cm. The device was formed with a fully interconnected porous structure with open porosity to provide a morphology that allows cells to invade and proliferate on the scaffold after implantation. The reference marker device prepared according to Example 1 had an elastic modulus value of 0.01 MPa to 0.35 MPa.

[0171] In the embodiment, the length (l) is equal to the width (w), forming a substantially circular base region, in which case the length or width may also be called the base diameter.

[0172] Example 2: Reference marker clips prepared from poly-4-hydroxybutyric acid and barium sulfate, or poly-4-hydroxybutyric acid and zirconium dioxide. A visualization marker clip suitable for attachment to a reference marker scaffold, such as the scaffold prepared in Example 1, can be prepared by injection molding a composition containing poly-4-hydroxybutyric acid and barium sulfate, or poly-4-hydroxybutyric acid and zirconium dioxide fine particles. Alternatively, the clip may be formed from an acetone solution of poly-4-hydroxybutyric acid and barium sulfate, or an acetone solution of poly-4-hydroxybutyric acid containing zirconium dioxide.

[0173] Example 3: Reference marker made from poly-4-hydroxybutyrate (P4HB) by 3D printing using barium sulfate clip visualization markers. Six poly-4-hydroxybutyrate clips containing barium sulfate, prepared in Example 2, were placed on the outer region surrounding the honeycomb scaffold structure prepared in Example 1, at the positions shown in Figures 2A-C, to enable imaging of the dimensions of the reference marker device.

[0174] Example 4: Reference marker made from poly-4-hydroxybutyrate (P4HB) by 3D printing using a titanium clip visualization marker. A porous reference marker device was fabricated from P4HB (molecular weight 380 kDa) using molten extrusion deposition. P4HB filaments were deposited layer by layer to form an open porous scaffold with a honeycomb structure. Next, six titanium clips were placed on the outer region surrounding the honeycomb scaffold structure, in positions that allowed for imaging of the device dimensions as shown in Figures 2A-C.

Claims

1. A reabsorbable porous scaffold having a predetermined 3D shape and defining the periphery of the apparatus, wherein the reabsorbable porous scaffold has shape memory to form the predetermined 3D shape when the reabsorbable porous scaffold is not constrained, The device comprises a plurality of visualization markers arranged at individual positions around the device, An implantable reference tissue marker device.

2. The apparatus comprises a reabsorbable porous scaffold having a predetermined 3D shape and defining the periphery of the apparatus, the reabsorbable porous scaffold comprising a plurality of visualization markers arranged at individual positions around the apparatus, and the reabsorbable porous scaffold having an elastic modulus of less than 50 MPa. An implantable reference tissue marker device.

3. The porous scaffold has an elastic modulus greater than 0.5 kPa and less than 50 MPa. The apparatus according to claim 1 or 2.

4. The porous scaffold includes polymer columns, fibers, coils, or springs having one or more of the following characteristics: (i) a diameter of 0.025 to 3 mm, 0.1 to 2 mm, or 0.15 to 1 mm; (ii) a breaking load of 0.1 to 200 N, 1 to 100 N, or 2 to 50 N; (iii) a breaking elongation of 22% to 1,000%, or 100% to 700%; and (iv) an elastic modulus value of 0.05 to 3 GPa, or 0.2 to 0.8 GPa. The apparatus according to any one of claims 1 to 3.

5. The aforementioned visualization marker is reabsorbable. The apparatus according to claim 1 or 2.

6. The device is implanted in the patient's breast, and the device is not palpable immediately after implantation, or within 1, 2, 3, 4, 5, or 6 months after implantation. The apparatus according to any one of claims 1 to 5.

7. The scaffold comprises connected unit cells, each unit cell being a skeletal polyhedron, and the edges and vertices of the skeletal polyhedron being formed from polymer pillars or fibers. The apparatus according to any one of claims 1 to 6.

8. The aforementioned edge is the apex of the unit cell having one or more of the following characteristics: a breaking load of 0.1 to 200 N, 1 to 100 N, or 2 to 50 N; an elongation at break of 22% to 1,000%, or 100% to 700%; and an elastic modulus value of 0.05 to 3 GPa, 0.1 to 3 GPa, or 0.2 to 0.8 GPa. The apparatus according to claim 7.

9. The apparatus has a longitudinal axis having a first end, a second end, and an intermediate point between the first end and the second end, the visualization markers are located at the first and second ends of the longitudinal axis and around the apparatus at the intermediate point of the apparatus, and optionally the scaffolding comprises marker holders for fixing the visualization markers at the individual positions. The apparatus according to claim 1 or 2.

10. The device maintains its predetermined shape in a stress-free state for at least 1, 2, 3, 4, 5, or 6 months after being embedded. The apparatus according to claim 1 or 2.

11. The aforementioned reabsorbable porous scaffold is reabsorbed in less than 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, or 7 months after embedding. The apparatus according to claim 1 or 2.

12. The device further comprises one or more suture eyelets. The apparatus according to any one of claims 1 to 10.

13. The apparatus further comprises one or more of the following: a bioactive agent, a hydrogel, hyaluronic acid or its derivatives, or an alginate. The apparatus according to claim 1 or 2.

14. The aforementioned biologically active agent is selected from one or more of the following: chemotherapeutic agents, antitumor agents, immunomodulators, hormones, anti-angiogenic agents, antibiotics, radiosensitizers, and immunotherapeutic agents. The apparatus according to claim 13.

15. The periphery of the device defined by the predetermined shape is spherical, elliptic, cylindrical, spheroidal, parallelepiped, oval, or convex. The apparatus according to any one of claims 1 to 14.

16. The aforementioned visualization marker can be detected by one or more of the following techniques: X-ray, magnetic resonance imaging, computed tomography, ultrasound, mammography, positron emission tomography, and single-photon emission computed tomography. The apparatus according to claim 1 or 2.

17. The apparatus includes a reabsorbable polymer, The apparatus according to any one of claims 1 to 16.

18. The apparatus comprises an oriented reabsorbable polymer, The apparatus according to claim 17.

19. The aforementioned reabsorbable polymer is poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof. The apparatus according to claim 17 or 18.

20. The device comprises one or more sections or clips of radiopaque fibers or radiopaque supports. The apparatus according to any one of claims 1 to 19.

21. The apparatus is formed by a process that includes forming the unit cells of the scaffolding by 3D printing the fibers or supports. The apparatus according to claim 7 or 8.

22. The apparatus is formed by one of the following methods: melt extrusion deposition, fusion filament manufacturing, fusion pellet deposition, selective laser melting, printing of polymer slurry or solution using a solidification bath, and printing using a binding solution and polymer powder granules. The apparatus according to claim 21.

23. The apparatus is formed from poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof. The apparatus according to claim 22.

24. A method for embedding a reference marker device, Creating a cavity in a patient by removing soft tissue through an incision made during open surgery at a certain location within the body, Inserting a reference marker device having a reabsorbable porous scaffold having a predetermined shape that defines the periphery of the device into the cavity, wherein the predetermined shape has shape memory, and insertion is performed. This includes closing the surgical site. method.

25. The further includes suturing the device within the cavity, The method according to claim 24.

26. The steps described above are performed on the patient's breast, and the device is embedded in the cavity of the patient's breast. The method according to claim 24 or 25.

27. The aforementioned cavity is created during the procedure for removing a mammary gland tumor. The method according to claim 26.

28. The apparatus further includes determining the planned target volume (PTV) for the patient's radiotherapy, The method according to any one of claims 24 to 27.

29. The device is further formed by 3D printing. The method according to claim 24.

30. The further includes forming the device based on a 3D model. The method according to claim 29.

31. The further includes generating the 3D model based on image data from the patient, The method according to claim 30.

32. The apparatus is formed from poly-4-hydroxybutyric acid or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof. The method according to any one of claims 24 to 29.

33. A reference marker device comprising a 3D body and a plurality of fixed, spaced-apart visualization marker engagement feature parts, The present invention comprises a plurality of visualization markers, each having a fitting feature portion for connecting to the visualization marker engagement feature portion, thereby allowing one or more of the visualization markers to be fixed to the 3D body of the reference marker device, as desired by the physician. A standard marker kit that can be customized by physicians.

34. The visualization marker engagement feature portion is a hole, and the visualization marker fitting feature portion is a column. The kit according to claim 33.

35. Outer surface or shell, An internally organized structure adapted to support the aforementioned shell, The system comprises a plurality of visualization markers arranged at individual positions on the circumferential surface, wherein the internal organizing structure of each visualization marker is a reabsorbable porous scaffold having a predetermined 3D shape. An implantable reference tissue marker device.

36. The aforementioned internally organized structure is a network of interconnected pores. The apparatus according to claim 35.

37. The pores are formed between at least one of the fibers, beams, and supports. The apparatus according to claim 36.

38. The aforementioned shell includes a radiopaque material, The apparatus according to claim 35.

39. The device further comprises multiple visualization marker engagement features along its periphery, thereby allowing the multiple visualization markers to be detachably fixed to the reference marker device in multiple different arrangements. The apparatus according to claim 35.

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