Medical implant for marking a surgical site

Abstract

An implantable fiducial marker device having a predetermined shape can deform when stress is applied in vivo and return to its shape when the stress is removed, which reduces patient discomfort and palpability. The device can be used to reshape irregular tumor resection cavities into more ideal shapes for radiation therapy, allowing more accurate treatment. After treatment, the device is absorbed, eliminating unnecessary testing when clinicians are unaware of implanted fiducial marker devices. When the device is implanted in the breast after lumpectomy, tissue ingrowth into the device can also result in improved cosmetic outcomes. The device preferably comprises poly-4-hydroxybutyrate or poly(succinoglycolate) or copolymers thereof.

Description

Technical Field

[0001] This invention generally relates to the field of surgery, and more particularly, to medical implants that can be used to delineate the edges of a surgical site during radiotherapy. Background Technology

[0002] Radiation therapy is typically performed after tumor removal to destroy remaining cancer cells and reduce the risk of cancer recurrence. However, delineating the tissue margins of a post-radiotherapy tumor cavity can be challenging. Traditionally, clinicians rely on the presence of surgical scars or seromas to identify the site and target volume for radiation therapy. However, these methods are not the most accurate and not only reduce the effectiveness of radiation therapy but also increase the chance of damage to surrounding healthy tissue. Accurately locating the margins of a tumor resection cavity can also be extremely difficult because cavities can have irregular shapes, and in some tissues, their shape can change over time. For example, a tumor cavity can grow or shrink during respiration, or even change size and shape due to continuous radiation therapy treatment.

[0003] To address these issues, clinicians frequently use fiducial marker devices to better define the location of cavities and provide clearer targets for external radiation beam therapy. A fiducial marker device is a marker or set of markers placed in the imaging field as a reference point. It can be used for the planning target volume (PTV) of radiotherapy, as well as for specific locations and shapes within the target body. PTV is determined by: measuring the gross tumor volume (GTV), adding margins to the disease spread that cannot be fully imaged to reach the clinical target volume (CTV), and further adding additional margins around the CTV to ensure that the radiotherapy is actually delivered to the CTV.

[0004] The primary reference markers used in the treatment of breast cancer, abdominal cancer, liver cancer, lung cancer, and prostate cancer are typically small metallic objects, such as metal clips or metal pellets. While these small metallic objects can be beneficial as reference markers, their migration is known to result in a target volume larger than necessary for radiotherapy. Their ability to accurately define the volume of tumor resection cavities, which may have irregular shapes, is also limited.

[0005] To more accurately locate the volume of the radiation target after tumor resection and prevent the migration of the metal clip, a three-dimensional reference marker has been disclosed.

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

[0007] Stubbs’ U.S. Patent Nos. 9,014,787 and 9,199,092 disclose a rigid bioresorbable three-dimensional reference marker comprising a metallic element having an arm originating 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 Application Nos. 20130289389 and 20130289390 to Hermann disclose a three-dimensional reference marker device that includes absorbable material and radiovisible elements to make the device visible when placed in a surgical resection cavity.

[0009] Wiens, N. et al. Effect of Surgical marker placement on post-operative radiation boost target volume, J Radiat Oncol, 7:175-179, (2018) discloses a three-dimensional spiral reference marker with six metal clips. The marker is a rigid device made of 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 several years after placement. They reported the presence of the marker in the body 2.8 years after implantation, and that the marker remained palpable. The palpability of this device is particularly problematic in breast cancer treatment for several reasons. First, the presence of a marker device in the breast can be painful and can cause discomfort, especially if any stress or tension is applied to the breast. The BioZorb device is made of polylactic acid, a polymer with an elastic modulus greater than 3 GPa, which gives the device rigidity so that it does not deform under stress and returns to its original shape. Srour and Chung 2019 disclosed that the presence of the BioZorb device is painful enough for a patient to require surgical removal. Second, the long-term presence of a foreign mass in a patient's breast can cause anxiety, especially in breast cancer patients. Third, clinicians unaware that the device has been implanted in the breast may perform unnecessary tests to investigate the foreign mass, thus increasing patient anxiety. Srour and Chung 2019 reported that clinicians performed additional imaging on 8.8% of patients examined because they were unaware of the labeled device. Fourth, the slow absorption and long-term tactile presence of the device can limit clinicians' ability to detect breast cancer recurrence. See also Hermann's U.S. Patent No. 10,500,014 and Stubbs' U.S. Patent No. 9,014,787.

[0010] Despite the foregoing, there remains a need for three-dimensional reference markers, as described herein, which can be used to shape the surgical margins of irregularly shaped tumor cavities into a more defined volumetric shape to provide clear targets for radiotherapy. In particular, there is a need to develop three-dimensional reference markers that degrade rapidly in vivo. Such markers are ideally imperceptible when implanted in the breast, have a lower elastic modulus than existing reference markers so that they can deform under stress or tension, and do not cause pain after implantation. There is also a need to develop reference markers that allow tissue to grow inward to fill the voids in the tumor cavity. These markers are particularly desirable in breast treatment, as tissue growth into the voids in the tumor resection cavity will provide improved cosmetic outcomes. There is also a further need to develop three-dimensional reference markers comprising one or more bioactive agents, such as chemotherapeutic agents, antitumor agents, immunomodulators, hormones, antiangiogenic agents, antibiotics, radiation sensitizers, and immunotherapeutic agents. Reference markers can be used for the treatment of soft tissue cancers, including breast cancer, abdominal cancer, liver cancer, muscle cancer, kidney cancer, lung cancer, and prostate cancer. Summary of the Invention

[0011] This document describes absorbable three-dimensional reference markers that can be used to provide more precise delivery of radiotherapy to the tissue margins of a tumor resection cavity by conforming the irregular shape of the cavity to the shape of the marker. In some embodiments, the reference marker is formed in a predetermined shape desired for radiotherapy and implanted into the tumor resection cavity to shape the cavity into a more ideal shape for radiotherapy, such as a spherical or ellipsoidal shape. The reference marker allows the volume of the tumor resection cavity to be more accurately defined and targeted during radiotherapy. The reference marker reduces the radiation dose received by the normal tissue surrounding the tissue resection cavity and reduces the size of the periphery of the cavity that needs to be treated with radiation.

[0012] In some embodiments, the reference marker is untouchable at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after implantation, particularly when it is in the patient's breast. In some embodiments, the reference marker is immediately untouchable after implantation, particularly when it is in the patient's breast. In some embodiments, the predetermined shape of the reference marker deforms under stress or tension. In some embodiments, the predetermined shape of the reference marker is flexible or compressible, and the shape is not rigid. In some embodiments, the predetermined shape of the reference marker deforms under stress or tension and returns to its predetermined shape when the stress or tension is removed. The return of the predetermined shape when the stress or tension is removed allows the marker to be used to accurately define the target volume for radiotherapy. The ability of the reference marker to deform under stress or tension reduces or eliminates the tactileness of the marker, particularly in the breast. The ability of the reference marker to deform in the breast under stress or tension also reduces or eliminates the likelihood of the device causing pain in the breast. In some embodiments, the elastic modulus of the reference marking device is less than 50 MPa, and more preferably less than 10 MPa, but greater than 0.5 kPa.

[0013] The reference marker has a predetermined shape, wherein an outer region defines the outer perimeter of the device. In some embodiments, the outer region of the three-dimensional marker is defined by a convex surface. In some embodiments, the outer perimeter of the marker is defined by a spherical, spiral, ellipsoidal, isosceles ellipsoid, cylindrical, elongated spherical, or oblate shape. In other embodiments, the outer perimeter of the marker is defined by a parallelepiped or elliptical shape. In some embodiments, the marking device includes a three-dimensional frame, skeleton, or support defining its predetermined shape and the outer region of the device. In some embodiments, the three-dimensional frame, skeleton, or support may be an ellipsoidal spiral, spherical spiral, cylindrical spiral, or other spiral defining the outer region. In other embodiments, the three-dimensional frame, skeleton, or support defining the outer region of the reference marker may be a skeleton polyhedron, skeleton sphere, skeleton ellipsoid, skeleton cylinder, or skeleton parallelepiped.

[0014] In some embodiments, the outer region of the reference mark defining the device boundary may have a first end and a second end, a longitudinal axis of 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 mark is 1 to 6 cm, and the diameter (d) or width (w) is 1 to 5 cm. In these embodiments, the size of the mark, for example (l) × (d), may be 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 the reference mark defining the device boundary may have a first end and a second end, a longitudinal axis of 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 length (l) of the mark is 1 to 4 cm, the width (w) of the mark is 1 to 3 cm, and the height (h) of the mark is 1 to 2 cm. In some of these other embodiments, the size of the marker, for example (l)×(w)×(h), can be 3×2×1cm, 3×3×1cm, 1×1×2cm, 2×1×2cm and 1×2×2cm.

[0015] In some embodiments, the reference marker is porous or has an open framework, skeleton, or scaffold to allow tissue inward growth. In some embodiments, the reference marker has a porous structure to allow tissue inward growth. Tissue inward growth can help secure the device in place and fix the position of the visual marker on the device. In some embodiments, the reference marker maintains its predetermined shape or can recover its predetermined shape in the absence of stress or tension until tissue grows inward into the device that has secured the visual marker in place. Tissue inward growth can also fill voids in tumor resection cavities and cause improved cosmetic outcomes in some treatments (e.g., breast cancer). In some embodiments, the reference marker can be used as a void filler.

[0016] In some embodiments, reference markers are used as oncoplastic devices. In some embodiments, reference markers are used to reliably mark surgical sites. In some embodiments, reference markers are used to define the planned target volume (PTV) for radiotherapy. Reference markers can also be used for radiographic disease monitoring.

[0017] In some embodiments, the reference marker comprises multiple visualization markers. The visualization markers are used to determine the planned target volume (PTV) for radiotherapy and to focus 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 some embodiments, the visualization markers are made of titanium, stainless steel, gold, or composite polymer materials (e.g., a polymer mixed with barium sulfate). In some embodiments, the visualization markers are encapsulated with hydrogel. In some embodiments, the visualization markers are radiopaque clasps attached to the outer region of the reference marker to provide an imageable three-dimensional target. In some embodiments, the visualization markers are attached to the outer region of the reference marker to prevent clasp migration and irradiation of a volume larger than desired. In some embodiments, the visualization markers are positioned at a first and a second end of the longitudinal axis of the device such that their length (l) is imageable in vivo, and the visualization markers are also positioned around the periphery at the midpoint of the longitudinal axis between the first and second ends such that their diameter or width is imageable.

[0018] In some embodiments, the predetermined shape of the reference mark or the frame of the reference mark is formed of a radiolucent material. In other embodiments, the predetermined shape of the reference mark or the frame of the reference mark is formed of a non-radiolucent material or a combination of radiolucent and non-radiolucent materials.

[0019] In some implementations, the reference markers have full radiographic visualization capabilities.

[0020] The predetermined shape of the reference mark is absorbable. In some embodiments, the visual mark attached to or incorporated into the predetermined shape is permanent or absorbable.

[0021] In some embodiments, the predetermined shape of the reference marker is absorbable. In some embodiments, the absorbable reference marker maintains its predetermined shape in vivo for a sufficient period of time to complete the radiotherapy treatment in the absence of stress or tension. In some embodiments, the reference marker maintains its predetermined shape or recovers its predetermined shape in the absence of stress or tension for 1, 2, 3, 4, 5, 6, 7, 8, or 9 months after implantation. In some embodiments, the predetermined shape of the reference marker is absorbed 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. Absorption of the predetermined shape eliminates the need for a secondary surgical intervention to remove the marker. Absorption also eliminates the possibility that the device may cause any pain or discomfort, eliminates the possibility that clinicians unaware of the device will perform unnecessary testing to investigate its presence, and eliminates any patient anxiety caused by the presence of the marker, particularly in the breast of a cancer patient.

[0022] In some implementations, the three-dimensional frame, skeleton, or support of the reference marker may be formed from one or more filaments and may optionally incorporate one or more struts.

[0023] In some embodiments, the reference marker comprises a polymer strut, fiber, coil, or spring having one or more of the following properties: (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 value of 22% to 1,000%, and 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. In some embodiments, the reference marker comprises a unit cell formed from a polymer strut, fiber, coil, or spring having these properties. In some embodiments, the unit cell is part of the frame, skeleton, or support of the reference marker. In some embodiments, the unit cell may have the same or different properties. In some embodiments, the polymer strut, fiber, coil, or spring is absorbable. In some embodiments, the elastic modulus of the reference mark is less than 50 MPa, more preferably less than 10 MPa, but greater than 0.5 kPa, and the reference mark is formed of 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%, and 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.

[0024] In some embodiments, the reference tissue marking device includes an absorbable porous scaffold having a predetermined 3D shape defining the periphery of the device, wherein the predetermined shape is deformable under stress and recovers its shape upon removal of stress, and wherein the scaffold includes visual markings at discrete locations on the periphery of the device. In some embodiments, the reference marking device has a predetermined 3D shape and shape memory.

[0025] In some embodiments, the predetermined shape of the reference marker is formed from an absorbable polymer. The absorbable polymer can be used to form a three-dimensional framework, skeleton, or scaffold defining the outer region of the reference marker and its predetermined shape. In some embodiments, the predetermined shape or framework of the reference marker is formed from poly-4-hydroxybutyrate (P4HB) or a copolymer thereof, or from poly(butylene succinate) (PBS) or a copolymer thereof.

[0026] In some embodiments, the reference markers are prepared by 3D printing, including fused extrusion deposition, filament fabrication, fused pellet deposition, selective laser melting, printing with a coagulation bath on slurries and solutions, and printing with binder solutions and powders or particles. In some embodiments, the reference markers are prepared by injection molding and by injection molding with a multi-part mold.

[0027] In some embodiments, the reference marker can be secured to the tumor bed or surgical resection cavity using permanent sutures, absorbable sutures, U-shaped staples, or other fixation methods. Fixation helps prevent any subsequent migration of the device. In some embodiments, the reference marker includes one or more suture holes to secure the device in place. Sutures can pass through the holes and be secured to the tissue to prevent device migration after implantation.

[0028] In some implementations, a baseline marker is implanted after mass resection for targeting the planned target volume (PTV) of radiotherapy and for delivering postoperative enhanced irradiation to the breast.

[0029] In some implementations, the reference label includes one or more of the following: chemotherapeutic agents, antitumor agents, antiangiogenic agents, immunomodulators, hormones, immunotherapeutic agents, antibiotics, and radiation sensitizers.

[0030] In some embodiments, the polymer used to prepare the reference 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 some embodiments, the endotoxin content of the benchmark implant is less than 20 endotoxin units per implant. In some embodiments, the benchmark is sterilized by ethylene oxide, electron beam, or gamma irradiation.

[0032] In some implementations, benchmark markers can be used to treat soft tissue cancers, including breast cancer, abdominal cancer, liver cancer, muscle cancer, kidney cancer, lung cancer, and prostate cancer.

[0033] In some embodiments, a method of implanting a reference marker device includes: creating a cavity in a patient by removing soft tissue from a location within the body through an open surgical incision; inserting a reference marker device having an absorbable porous stent having a predetermined shape defining the periphery of the device, wherein the predetermined shape has shape memory; and closing the surgical site. The method may also include suturing the device into the cavity. Optionally, the creation step is performed in the patient's breast, and the device is implanted into the cavity within the patient's breast. In a preferred embodiment, the method includes creating the cavity during a mass resection procedure.

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

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

[0036] In some embodiments, the method forms a reference marker device based on a 3D model and optionally includes a step of generating a 3D model based on image data from the patient. Some examples of image data include 3D image data generated from CT or MRI scans. In practice, some embodiments include generating 3D image data of a tumor or lesion or tissue volume and generating (optionally 3D printing) a reference marker device based on the 3D image data.

[0037] In some implementations, a physician-customizable reference marker kit includes: at least one reference marker device comprising a 3D body and a plurality of fixed, spaced-apart visual marker engagement features; and a plurality of visual markers, each visual marker comprising a mating feature for connection with the visual marker engagement features, such that one or more visual markers can be fixed to the 3D body of the reference marker device as desired by the physician.

[0038] In some implementations, the visual marker engagement feature is a hole, and the visual marker mating feature is a post.

[0039] In view of the above, one object of the present invention is to provide an absorbable reference mark.

[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 preparing a flexible reference marker that does not cause pain after implantation.

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

[0043] These and other objects, aspects and advantages of the present invention will become apparent from the following description with reference to the accompanying drawings. Brief description of the attached diagram

[0045] Figures 1A to 1B A front view and an isometric view of a porous reference marking device (100) according to an embodiment of the present invention are shown, the device having an open porous honeycomb support structure. The device (100) has an ellipsoidal or spherical shape with a base diameter or length (l) and height (h), as shown in... Figure 1A middle.

[0046] Figures 2A to 2B A front view and an isometric view of a porous reference marking device (200) according to an embodiment of the present invention are shown, respectively. The device has an open porous honeycomb support structure and six titanium clips (210a to f) disposed on an outer region of the structure's periphery to allow imaging of the device's dimensions. The device (200) has a base diameter or length (l) and a height (h), shown in… Figure 2A middle.

[0047] Figure 3A This is an exploded view of a porous absorbable reference mark (300) according to an embodiment of the present invention, showing a post or pin holder (310) designed to receive a visual mark, the visual mark being a non-transparent post or pin (320).

[0048] Figure 3B yes Figure 3A The cross-sectional view of the porous absorbable reference mark (300) along the line “3B-3B” is shown in the figure.

[0049] Figure 3C yes Figure 3A The diagram shows a perspective view of a porous absorbable reference device (300), which shows a plurality of post or pin retainers (310) located on the surface of the device, and a non-transparent post or pin (320) above the post or pin retainers. Invention Details

[0051] Before describing the invention in detail, it should be understood that the invention is not limited to the specific variations set forth herein, as various changes or modifications and equivalent alternatives can be made to the described invention without departing from the spirit and scope of the invention. It will be apparent to those skilled in the art, upon reading this disclosure, that each embodiment of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated from or combined with features of any of the other several embodiments without departing from the scope or spirit of the invention. Furthermore, numerous modifications can be made to adapt particular circumstances, materials, composition, processes, process behavior, or steps to the purpose, spirit, or scope of the invention. All such modifications are intended to fall within the scope of the claims set forth herein.

[0052] The methods described herein can be performed in any logically possible order of the events described, as well as in the order in which the events are described. Furthermore, where a range of values ​​is provided, it should be understood that every intermediate value between the upper and lower limits of the range, and any other specified value or intermediate value within that specified range, is covered within the scope of this invention. Additionally, any optional features of the inventive variations contemplated herein may be described and claimed independently or in combination with any one or more of the features described herein.

[0053] All existing subjects mentioned herein (e.g., publications, patents, patent applications, and physical objects) are incorporated herein by reference in their entirety, unless such subject matter may conflict with the subject matter of this invention (in which case the subject matter presented herein shall prevail).

[0054] References to singular items include the possibility of multiple identical items. More specifically, unless the context clearly indicates otherwise, nouns without quantifiers used herein and in the appended claims mean one / agent or more / agents. It should also be noted that the claims may be drafted to exclude any optional elements. Similarly, this statement is intended to serve as a prior basis for the use of such exclusive terms, such as “merely,” “only,” etc., or the use of “negative” limiting terms, associated with the recitation of elements of the claims. Finally, it is to be understood that, unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0055] In some embodiments of the invention, an absorbable three-dimensional reference marker is implanted into a tumor resection cavity to shape the cavity into a target volume for radiotherapy with more precisely defined tissue margins, reduce the size of the tissue margins around the cavity to be irradiated, minimize exposure of healthy tissue to irradiation, deform in vivo under stress or tension so that it is not palpable or a source of pain, and restore its original shape in vivo when the stress or tension is removed during radiotherapy. The reference marker is sized for use in tumor resection cavities of varying sizes. The reference marker is porous and allows tissue inward growth. In some embodiments, the reference marker has an internal scaffold structure that promotes tissue inward growth. Tissue inward growth allows the device to be secured in place and can also provide improved cosmetic results by filling tissue voids. After radiotherapy, the three-dimensional structure of the reference marker is absorbed.

[0056] In some implementations, the implant includes an outer surface or peripheral structure (e.g., a shell) and an internal, organized structure that supports the peripheral structure and provides interconnected porous structures.

[0057] In some embodiments, the reference marker has a predetermined three-dimensional shape that is intangible after implantation, particularly in the patient's breast. When stress or tension is applied to the reference marker in the body, the marker deforms and returns to its predetermined shape when the stress or tension is removed, for example, during imaging. In some embodiments, the reference marker has shape memory to allow it to deform from its predetermined shape when stress is applied and to return to its predetermined shape when the stress is removed. In some preferred embodiments, the marker is flexible, unlike existing reference marker devices which are rigid, and can be compressed. After the compressive force is removed, the marker returns to its predetermined shape. In some embodiments, the elastic modulus of the reference marker is 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.

[0058] In some 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 and second ends. The reference marker has a three-dimensional outer region defining the periphery of the device. When implanted into a tumor resection cavity, the outer region shapes the cavity such that the tissue edges of that shape can be easily irradiated. In some embodiments, the outer region is shaped such that the periphery of the device has a spherical, ellipsoidal, isosceles ellipsoidal, cylindrical, elongated spherical, oblate, elliptical, or parallelepiped shape. In some embodiments, the outer region of the reference marker is formed by a frame, skeleton, or scaffold. In some embodiments, the frame, skeleton, or scaffold is formed by one or more filaments and may optionally incorporate one or more struts. In some embodiments, the frame, skeleton, or scaffold may be a helix or spiral defining the periphery of the marker, including an ellipsoidal helix, a spherical helix, a cylindrical helix, or a skeleton polyhedron, skeleton sphere, skeleton ellipsoid, skeleton cylinder, or skeleton parallelepiped.

[0059] In some embodiments, the reference marker is porous, or an open framework, skeleton, or scaffold that allows tissue to grow inward into the reference marker. Tissue inward growth anchors the device to the tumor bed, preventing migration, and secures the visualization marker at the edge of the resection cavity. In some embodiments, the three-dimensional structure of the reference marker degrades after tissue inward growth has secured the visualization marker in place.

[0060] In some implementations, the reference markers are also used as gap fillers. Tissue growing inward into the gaps of the tumor resection cavity can provide improved cosmetic results in the treatment of certain cancers (such as breast cancer) by eliminating visible defects.

[0061] In some embodiments, the reference marker includes multiple visualization markers placed on the marker, such that the marker volume can be imaged post-implantation, used for planning the irradiation target volume, and for focusing irradiation on the target site. The visualization markers are radiopaque and, in some embodiments, are fixed to an outer region of the reference marker to allow visualization of the outer region. Connecting the visualization markers to the outer region of the marker prevents visualization marker migration. In some embodiments, the visualization markers can be imaged using one or more of the following methods: ultrasound, X-ray, MRI, CT, mammography, positron emission tomography (PET), and single-photon emission computed tomography (SPECT).

[0062] In some implementations, the visual markers are made of titanium, stainless steel, gold, or composite polymer materials (e.g., polymers mixed with barium sulfate).

[0063] In some embodiments, hydrogel is used to package visual markers or devices. The hydrogel can be used to improve the visibility of the device. Preferably, the hydrogel is absorbable.

[0064] In some embodiments, the reference marker also includes one or more suture holes. The suture holes can be used to secure the marker within the tumor resection cavity by suturing the device in place. The holes also make it easier to shape the tumor resection cavity into the form of the marker.

[0065] In some implementations, the integrity of the three-dimensional structure of the reference marker remains intact during radiotherapy but degrades thereafter. After the three-dimensional structure degrades, only a non-degradable, visual marker remains in the body. In some implementations, the three-dimensional structure of the reference marker is absorbed in the body in less than 6 to 24 months. A second procedure to remove the reference marker after radiotherapy is not required.

[0066] In some embodiments, the three-dimensional shape of the reference marker comprises an absorbable polymer. In some embodiments, the three-dimensional shape comprises P4HB or a copolymer thereof, or PBS or a copolymer thereof.

[0067] In some implementations, the reference label may include one or more of the following: chemotherapeutic agents, antitumor agents, antiangiogenic agents, immunomodulators, hormones, immunotherapeutic agents, antibiotics, and radiation sensitizers.

[0068] In some embodiments, the three-dimensional shape of the reference marker is 3D printed. In some embodiments, the marker is 3D printed from a composition comprising an absorbable polymer. In some embodiments, the three-dimensional shape of the reference marker is prepared by injection molding, including injection molding using a multi-part mold.

[0069] In some implementations, the benchmark marker is used for radiation therapy in patients with soft tissue cancers, including breast cancer, abdominal cancer, liver cancer, muscle cancer, kidney cancer, lung cancer, and prostate cancer. In a preferred implementation, the benchmark marker is used for breast cancer treatment and is implanted after mass resection to facilitate radiation-enhanced treatment of the breast.

[0070] In some implementations, the implanted reference marker is sutured to the appropriate location within the body to prevent its migration. The marker can be sutured in place using absorbable or permanent sutures. These sutures can be monofilament or multifilament.

[0071] I. Definition

[0072] As used in this article, "bioactive agent" refers to a therapeutic agent, preventive agent, or diagnostic agent, preferably an agent that promotes the healing and regeneration of host tissues, as well as a therapeutic agent that prevents, inhibits, or eliminates infection. "Reagent" without a quantifier indicates one or more "reagents".

[0073] As is commonly used in this article, "biocompatibility" means that the biological response of a material or device is suitable for its intended in vivo application. Any metabolites of these materials should also be biocompatible.

[0074] As is commonly used in this article, “blend” refers to a physical combination of different polymers, as opposed to a copolymer formed from two or more different monomers.

[0075] As used in this article, “clinical target volume” or “CTV” means that the total tumor volume (GTV) plus the volume of disease spread around the edge of the GTV that cannot be fully imaged.

[0076] As is commonly used herein, “polymer of poly(butylene succinate)” means any polymer comprising 1,4-butanediol units and succinic acid units, and one or more different diol, diacid, or hydroxycarboxylic acid units, wherein the hydroxycarboxylic acid units comprise hydroxycarboxylic acid groups having one or more carboxylic acid or hydroxy acid groups. The copolymer may also contain chain extenders, coupling agents, crosslinking agents, or branching agents.

[0077] As is commonly used in this article, “polymer of poly-4-hydroxybutyrate” means any polymer containing 4-hydroxybutyrate having one or more different hydroxy acid units.

[0078] As used in this article, “droplet ratio” refers to the ratio of droplet width to droplet height during 3D printing.

[0079] As used in this article, "elongation at break" refers to the increase in the length of a material when tension is applied to cause it to break. Elongation at break is expressed as a percentage of the original length of the material.

[0080] The term “endotoxin unit” used in this article was determined using the limulus amebocyte lysate (LAL) assay, as described in Gorbet et al. Biomaterials, 26:6811-6817 (2005).

[0081] As used in this article, “total tumor volume” or “GTV” refers to the extent of a tumor that is image-, palpable, or visible.

[0082] The “macropore” materials or structures used herein have an average pore diameter of at least 25 micrometers, more preferably at least 50 micrometers, and even more preferably at least 75 micrometers.

[0083] Unless otherwise stated, “molecular weight” as used herein refers to weight-average molecular weight (Mw), not number-average molecular weight (Mn), and is measured by GPC relative to polystyrene.

[0084] As used in this article, "orientation" generally refers to the molecular arrangement of polymer chains in a material. A stretched polymer becomes partially oriented, and then highly oriented, and its tensile strength increases with increasing orientation. For example, unoriented polymer fibers can be stretched to become oriented, resulting in polymer fibers with higher tensile strength.

[0085] As used in this article, “planned target volume” or “PTV” refers to the volume to be treated, for example, by radiotherapy. PTV can be determined by: measuring the total tumor volume (GTV), adding margins to the disease spread that cannot be fully imaged to reach the clinical target volume (CTV), and further adding additional margins to the CTV to ensure that the radiotherapy is actually delivered to the CTV.

[0086] In this article, "poly-4-hydroxybutyrate" generally refers to homopolymers containing 4-hydroxybutyrate units. In this context, it may refer to Tepha's P4HB. TM polymer or Biomaterials (manufactured by Tepha, Inc., Lexington, MA).

[0087] In this article, "poly(butylene succinate)" generally refers to a polymer containing 1,4-butanediol units and succinic acid units. It can be abbreviated as "PBS".

[0088] In this article, “radiotherapy” is generally used to refer to cancer treatment that uses external high-energy beams (such as X-rays or protons) to kill cancer cells.

[0089] In this article, "non-transmissive" refers to structures or materials that resist the passage of X-rays.

[0090] As used herein, “absorbable” generally means that a material degrades in the body and that the degradation products are eliminated or excreted from the body. The terms “absorbable,” “biodegradable,” and “biodegradable,” whether or not they are prefixed with “bio,” are used interchangeably in this document to describe materials that decompose and are gradually absorbed, excreted, or eliminated by the body.

[0091] The term “tissue edge” as used in this article typically refers to, for example, the edge of tissue surrounding a tumor.

[0092] II. Materials used for preparing reference markers

[0093] According to some embodiments of the invention described herein, an implantable medical device, i.e., a reference marker comprising a three-dimensional absorbable structure, has a predetermined shape that is deformable in the body when stress or tension is applied and returns to its predetermined shape when the stress or tension is removed. The deformability of the marker device eliminates the pain and tactile limitations associated with more rigid reference marker devices. In some embodiments, the elastic modulus of the reference marker device is 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 characteristics are designed to allow the reference marker to elastically deform under compression or tension.

[0094] The three-dimensional shape of the marker degrades more rapidly in the body, which helps reduce the likelihood that the marker may cause pain or discomfort in patients, and also eliminates the possibility that clinicians who are unaware of the marker will perform unnecessary tests to characterize the foreign object, which can increase patient anxiety.

[0095] In some implementations, the reference marker allows tissue to grow inward into the marking device after implantation. This inward growth fixes the position of the visualized marker on the device but can also fill gaps left by the tumor. For patients, particularly in breast cancer treatment, filling these gaps can result in improved cosmetic outcomes.

[0096] In some embodiments, the reference marker has an outer region defining the outer periphery of the device. In some embodiments, the outer periphery of the device is spherical, spherical, ellipsoidal, cylindrical, parallelepiped, or convex. In some embodiments, the outer region is formed by an absorbable three-dimensional structure. In some embodiments, the three-dimensional structure is a frame, skeleton, or scaffold. In some embodiments, the frame, skeleton, or scaffold comprises one or more filaments. The frame, skeleton, or scaffold may also include struts. In some embodiments, the frame, skeleton, or scaffold is a helix or polyhedron defining the outer region. In some embodiments, the reference marker has a scaffold structure. The scaffold structure has an open, porous structure designed to promote inward tissue growth.

[0097] In some implementations, a reference marker is implanted into the tumor resection cavity, and the cavity is shaped to resemble the peripheral boundary of the marker device defined by the outer region of the device. The shaped tumor cavity formed by the reference marker has a more clearly defined tissue edge that is easier to irradiate than the irregular shape of the tumor resection cavity, which reduces the tissue edges that need to be irradiated and reduces unnecessary exposure of healthy tissue to irradiation.

[0098] In some implementations, the reference marker comprises multiple visualization markers. The visualization markers are anchored to or incorporated into the three-dimensional structure of the device in a manner that allows clinicians to determine the planned target volume, the irradiation planned target volume, and (if necessary) to continue radiographic disease monitoring. The visualization markers are preferably radiopaque and provide high contrast when the reference marker is imaged. In some implementations, the visualization markers are concentrically attached to an outer region of the reference marker to provide an imageable three-dimensional view of the tissue resection cavity and to prevent the visualization markers from migrating from their implantation site. The latter can result in an irradiated tissue volume that is larger than desired.

[0099] In some embodiments, the three-dimensional structure of the reference marker comprises an absorbable polymer. In some embodiments, the absorbable polymer degrades in vivo in less than 6 to 24 months. In some embodiments, the absorbable polymer is a thermoplastic polymer. In some embodiments, the absorbable polymer degrades after radiotherapy is completed. In some embodiments, the absorbable polymer degrades after tissue inward growth, and the visual marker of the reference marker is already fixed in place. In some embodiments, the absorbable polymer allows the predetermined shape of the reference marker to deform in the presence of stress or tension and to return to its predetermined shape when the stress or tension is removed. In some embodiments, the absorbable polymer is flexible, compressible, or elastomer. In some embodiments, the outer region of the reference marker is a three-dimensional structure, wherein the three-dimensional structure is a frame, skeleton, or scaffold, and the frame, skeleton, or scaffold is formed of the absorbable polymer. In some embodiments, the frame, skeleton, or scaffold is formed of one or more absorbable filaments or struts.

[0100] In some implementations, the reference marker may also contain a bioactive agent.

[0101] In some embodiments, the three-dimensional structure of the reference marker is formed by 3D printing. In some embodiments, the framework, skeleton, or scaffold of the three-dimensional structure is formed by 3D printing absorbable polymers. In other embodiments, the reference marker is molded.

[0102] The baseline marker preferably has a pyrogen level of less than 20 endotoxin units / devices and may be sterilized.

[0103] A. Materials

[0104] The reference marker may contain permanent and / or degradable materials, and more preferably be made entirely of degradable materials, in addition to being a permanent or absorbable visual marker. In some embodiments, the outer region of the reference marker or the scaffold structure of the reference marker is made of a degradable material. In a preferred embodiment, the reference marker contains one or more absorbable polymers, preferably absorbable thermoplastic polymers and copolymers.

[0105] Reference marks can be prepared, for example, from polymers including but not limited to: glycolic acid, lactic acid, 1,4-dihydroxyethyl glycolic acid, and hydroxyethyl glycolic acid. Polymers of ketones, trimethylene carbonates, 3-hydroxybutyric acid, 4-hydroxybutyric acid, ε-caprolactone, 1,4-butanediol, and succinic acid, as well as polymers of polyglycolic acid, polylactic acid, and polydidimethylformamide. Copolymers of ketones, polycaprolactone, glycolic acid, and lactic acid, for example polymer, and Polymers, including poly(lactide-co-caprolactone); poly(orthoester); polyanhydride; poly(phosphazene); polyhydroxyalkanoates (PHA); synthetic or bio-based polyesters; polycarbonates; tyrosine polycarbonates; polyamides (including synthetic and natural polyamides, peptides, and poly(amino acids)); polyesteramides; poly(alkylene alkylates); polyethers (e.g., polyethylene glycol PEG and polyethylene oxide PEO); polyvinylpyrrolidone or PVP; polyurethanes; polyether esters; polyacetals; polycyanoacrylates; poly(ethylene oxide) / poly(propylene oxide) copolymers; polyacetals, polyketides; polyphosphates (polyphosphates). Phosphate; (phosphorus-containing) polymers; polyphosphoesters; polyalkylene oxalates; polyalkylene succinates; poly(maleic acid); filaments (including recombinant filaments and filament derivatives and analogs); chitin; chitosan; modified chitosan; biocompatible polysaccharides; hydrophilic or water-soluble polymers, such as polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP), and blocks of other biocompatible or biodegradable polymers, such as poly(lactide), poly(lactide-co-glycolic acid), or polycaprolactone and their copolymers, including random copolymers and block copolymers thereof. Preferably, the absorbable polymer or copolymer will be substantially or completely absorbed in less than 6 to 24 months after implantation.

[0106] Polymers, preferably blends of absorbable polymers, can also be used to prepare reference markers. Particularly preferred blends of absorbable polymers include, but are not limited to, blends containing glycolic acid, lactic acid, and 1,4-dihydroxybenzene. Blends formed from polymers of ketones, trimethylene carbonates, 3-hydroxybutyric acid, 4-hydroxybutyric acid, ε-caprolactone, 1,4-butanediol, succinic acid, or copolymers thereof.

[0107] In a particularly preferred embodiment, the reference label comprises poly-4-hydroxybutyrate (Tepha P4HB). TMPolymers (Lexington, MA) or copolymers thereof, and in one embodiment may be made entirely of P4HB or copolymers thereof, except for visual markings. Copolymers include P4HB having other hydroxy acids (e.g., 3-hydroxybutyrate), and P4HB having glycolic acid or lactic acid monomers. P4HB is a biocompatible and absorbable strong, flexible thermoplastic polyester (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 hydrolyzes to its monomers, and the monomers are metabolized into carbon dioxide and water via the Krebs cycle. In a preferred embodiment, the weight-average molecular weight (Mw) of the P4HB homopolymer and its copolymers is in the range of 50 kDa to 1,200 kDa (by GPC relative to polystyrene), and 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 higher is preferred for processing and mechanical properties.

[0108] 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 device is poly(butylene succinate) (PBS), wherein the diol is 1,4-butanediol and the diacid is succinic acid. The poly(butylene succinate) polymer can be a copolymer of other diols, other diacids, or combinations thereof. For example, the polymer can be a poly(butylene succinate) copolymer that also contains 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. Examples of some preferred copolymers are: poly(butylene succinate-co-adipate), poly(butylene succinate-co-terephthalate), poly(butylene succinate-co-methylbutylene succinate), poly(butylene succinate-co-dimethylbutylene succinate), poly(butylene succinate-co-ethylene glycol succinate), and poly(butylene succinate-co-propylene glycol succinate). The poly(butylene succinate) polymer or copolymer may further comprise one or more of the following: chain extenders, coupling agents, crosslinking agents, and branching agents. For example, poly(butylene succinate) or its copolymers may be branched, chain-extended, or crosslinked by adding one or more of the following agents: malic acid, trimethylolpropane, trimesolic acid, citric acid, glycerol propoxylate, and tartaric acid. Particularly preferred reagents for branching, chain extending, or crosslinking poly(butylene succinate) polymers or copolymers thereof are hydroxycarboxylic acid units. Preferably, the hydroxycarboxylic acid unit has two carboxyl 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 a preferred embodiment, the reference designation includes poly(butylene succinate) containing malic acid as a branching agent, chain extender, or crosslinking agent. The polymer may be referred to as poly(butylene succinate) crosslinked or chain extended with malic acid, succinic acid-1,4-butanediol-malic acid copolyester, or poly(1,4-butanediol-co-succinic acid) crosslinked or chain extended with malic acid. It should be understood that references to malic acid and other crosslinking agents, coupling agents, branching agents, and chain extenders include polymers prepared with these reagents, wherein the reagents have undergone further reactions during processing. For example, the reagents may undergo dehydration during polymerization. Therefore, poly(butylene succinate)-malic acid copolymers refer to copolymers prepared from succinic acid, 1,4-butanediol, and malic acid. In another preferred embodiment, malic acid can be used as a branching agent, chain extender, or crosslinking agent for preparing copolymers of poly(butylene succinate) and adipate, which may be referred to as poly[(butylene succinate)-co-adipate] crosslinked or chain-extended with malic acid. 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 a particularly preferred embodiment, poly(butylene succinate) and its copolymers comprise 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. Based on gel permeation chromatography (GPC) relative to the polystyrene standard, the weight-average molecular weight (Mw) of polymers comprising diacids and diols, including poly(butylene succinate) and its copolymers and other polymers comprising diacids and diols described herein, is preferably from 10,000 Da to 400,000 Da, more preferably from 50,000 Da to 300,000 Da, and even more preferably from 100,000 Da to 200,000 Da. In a particularly preferred embodiment, the weight-average molecular weight of the polymers and copolymers is from 50,000 Da to 300,000 Da, more preferably from 75,000 Da to 300,000 Da. In a preferred embodiment, the poly(butylene succinate) or its copolymer used to manufacture the device or device components has one or more, or all, of the following properties: 1.23 g / cm. 3 Up to 1.26 g / cm 3 The density, glass transition temperature from -31°C to -35°C, melting point from 113°C to 117°C, melt flow rate (MFR) at 190°C / 2.16 kgf at 2 g / 10 min to 10 g / 10 min, and tensile strength from 30 to 60 MPa.

[0109] B. Additives

[0110] Certain additives may be incorporated into the device, preferably into the absorbable polymer, copolymer, or blend thereof used in the manufacture of the device. These additives may be incorporated during the compounding process before the device is manufactured. For example, the additives may be melt-blended with the polymer or compounded using a solution-based method.

[0111] In a preferred embodiment, the additive is biocompatible, and even more preferably, the additive is biocompatible and absorbable.

[0112] In one embodiment, the additive may be a nucleating agent and / or a plasticizer. These additives may be added in an amount sufficient to produce the desired results. Typically, these additives may be added in amounts from 1% to 20% by weight. Nucleating agents may be incorporated to increase the crystallization rate of the polymer, copolymer, or blend. Such agents can be used, for example, to facilitate the manufacture of devices and improve the mechanical properties of the devices. 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.

[0113] Plasticizers that may be incorporated into compositions used in the preparation apparatus include, but are not limited to, dibutyl maleate, methyl laurate, dibutyl fumarate, di(2-ethylhexyl)(dioctyl)maleate, paraffin wax, dodecyl alcohol, olive oil, soybean oil, polytetramethylene glycol, methyl oleate, n-propyl oleate, tetrahydrofurfuryl oleate, epoxidized linseed oil, 2-ethylhexyl epoxy tall oil, glyceryl triacetate, methyl linoleate, dibutyl fumarate, methyl acetyl ricinoleate, and acetyl tri(n-butyl) limonene. Citrate esters, acetylacetyl triethyl citrate, tri(n-butyl) citrate, triethyl citrate, bis(2-hydroxyethyl) dimerate, butyl ricinoleate, glyceryl tri(acetylacetyl) ricinoleate, methyl ricinoleate, n-butylacetylacetyl 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.

[0114] C. Visual Markings

[0115] The reference marker may comprise one or more visual markers. The visual markers may comprise permanent materials, biodegradable materials, or a combination thereof. Preferably, the visual markers are fully biodegradable. The visual markers may be incorporated into one or more portions or all of the material used to form the outer region of the reference marker, or the support structure of the reference marker. In a preferred embodiment, the visual markers are incorporated into an absorbable polymer. In some embodiments, the visual markers are incorporated into an absorbable polymer and also incorporated into the reference markers at one or more locations.

[0116] Suitable visual markers that can be incorporated into the reference markers include visual 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.

[0117] In some implementations, the visual markers are made of radiopaque material.

[0118] In some embodiments, the visual marker comprises one or more of the following: titanium, stainless steel, tungsten, barium, zinc, zirconium, strontium, ytterbium, gold, and bismuth. In some embodiments, the visual marker is one or more of the following: barium sulfate, iodide compounds, bismuth compounds, zinc oxide, zirconium dioxide, titanium dioxide, iodoform, iodide compounds, bismuth oxide, basic bismuth carbonate, bismuth oxychloride, ytterbium trifluoride, and strontium carbonate.

[0119] In some implementations, the visual markers are wires, clips, metals, alloys, ceramics, or powders. Powders that may be incorporated into the reference markers include: titanium, strontium carbonate, zirconium dioxide, barium sulfate, and bismuth(III) oxide.

[0120] In some embodiments, the visual marker is a composite material. In some embodiments, the visual marker may be a composite of poly-4-hydroxybutyrate or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof, with a radiopaque material. In some embodiments, the visual marker is a composite of poly-4-hydroxybutyrate 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, iodide compounds, bismuth compounds, zinc oxide, zirconium dioxide, titanium dioxide, iodoform, bismuth oxide, basic bismuth carbonate, bismuth oxychloride, ytterbium trifluoride, and strontium carbonate. In a preferred embodiment, the visual marker is a composite of poly-4-hydroxybutyrate or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof, with barium sulfate, zirconium dioxide, or both barium sulfate and zirconium dioxide.

[0121] In some implementations, the visualization marker is selected from one or more of the following: sodium fluorescein, cholecystocyanate meglumine, iodophthalate meglumine, diatrizoate meglumine, ioflupane i-123, perfluoropropane, sodium diatrizoate, ferumoxsil, gadopentetate diglumine, indium in-111 penetate disodium, gadodiamine, gadofusamide, gadoxetate disodium, technetium TC-99M glucohepanoate, gadobutrate diglumine, human albumin, technetium TC-99M etidronate, technetium TC-99M mertiatide, technetium TC-99M pyrophosphate, technetium TC-99M depreotide, technetium TC-99M fanolesomab, and technetium TC-99M... Ferpentetate, Technetium TC-99M albumin, Technetium TC-99M glucono-p-glucose, Technetium TC-99M sestamibi, Technetium TC-99M ethamexicam, Technetium TC-99M lidofenin, Technetium TC-99M medronate, Technetium TC-99M pyrophosphate, Technetium TC-99M pentiate, Technetium TC-99M disofenin, Technetium TC-99M sodium pertechnetate, Technetium TC-99M succinate, Technetium TC-99M tetrofosmin, Technetium TC-99M bicisate, Technetium TC-99M pyrophosphate / trimethophosphate, Technetium TC-99M Teboroxime, Xenon XE-133, Xenon XE-127, Gadolinium phosphoglycerate trisodium, Iodobenzylguanidine sulfate I-123, Ammonia, N-13, Florbetapir F-18, Technetium TC-99M Pentate, Technetium TC-99M Sulfur Colloid, Technetium TC-99M Sodium Pertechnetate, Technetium TC-99M Stattapy, Rubidium Chloride RB-82, Arcitumomab, Choline-11, Sodium Chromate Cr-51, Ethiodized Oil, Ferum Oxide, Fluoride Deoxyglucose F-18, Sodium Fluorescein, Gadobutrol, Gadoteridol, Gallium Citrate GA-67, Sodium Iodophthalate I-125, Ioxaglate Meglumine, Sodium IodophthalateSodium iodide (I-131), Indocyanine Green, Indium Chloride (I-111), Indium Hydroxyquinoline (I-111), Indium I-111 Penetreotide, Indocyanine Green, Iopamidol, I-125 Serum Albumin, Iohexol, Ioversol, Ioxilan, Iopromide, Capromab Pendetide, Thallium Chloride TL-201, Nofetumomab, Iodixanol, Sodium Iodophthalate, Krypton, Kr-81M, Iodohippurate Sodium I-123, Rose Bengal Sodium I-131, Mangafodipir Trisodium, Xenon XE-133, Tyropanoate sodium, Cyanocobalamin, Cyanocobalamin CO-57, Ferric ammonium citrate, Ferrous citrate, Fluoride-deoxyglucose, Sodium fluoride F-18, Gallium citrate GA-67, Sodium iodohippurate I-131, Dimyristic lecithin, Perfluorohexane, Perfluorobromoane, Iodobenzylguanidine sulfate I-131, Sodium iodide I-131, Calcium metrizoate, Calcium metrizoate meglumine, Magnesium metrizoate, Sodium metrizoate, Manganese chloride tetrahydrate, Imciromab pentetate, Iophendylate, Dimethylsiloxane-cellulose, and Trisodium pentetate YB-169. Other examples of appropriate visual markers are listed in Savitt et al. 1987, The radiopacity of ingested medications, Ann. Emerg. Med., 16(3): 331-9.

[0122] In some embodiments, the device is coated to improve its visibility, or a visual marker is coated to improve its visibility. In some embodiments, the device comprises a hydrogel to improve its visibility. The hydrogel may be coated on the device or on a visual marker of the device. Suitable hydrogels may be physically or chemically cross-linked. Preferably, the hydrogel is absorbable. In some embodiments, the hydrogel comprises polysaccharides. In some embodiments, the hydrogel comprises hyaluronic acid, alginate (e.g., sodium alginate or calcium alginate), collagen, gelatin, fibroin, pectin, matrix gum, and chitosan, or derivatives thereof. In some embodiments, the hydrogel is derived from one or more of the following: poly(ethylene oxide), poly(vinyl alcohol), poly(lactic acid), and poly(acrylate fumarate). Other examples of hydrogels include poly(ethylene glycol) diacrylate and poly(acrylamide).

[0123] In some embodiments, the hydrogel coating contains visual markers of the following: titanium, stainless steel, tungsten, barium, zinc, zirconium, strontium, ytterbium, gold, bismuth, barium sulfate, iodide compounds, bismuth compounds, zinc oxide, zirconium dioxide, titanium dioxide, iodoform, bismuth oxide, basic bismuth carbonate, bismuth oxychloride, ytterbium trifluoride, and strontium carbonate, and the visual markers may further contain absorbable polymers, such as poly-4-hydroxybutyrate or copolymers thereof, or poly(butylene succinate) or copolymers thereof.

[0124] C. Bioactive agents

[0125] The reference marking device may be loaded or coated with a bioactive agent. The bioactive agent may be included in the device for a variety of reasons. For example, it may be included to improve tissue inward growth into the device, to improve tissue maturation, to provide agent delivery, to improve implant wettability, to prevent infection, and to improve cell adhesion. In some embodiments, the bioactive agent may also be incorporated into different regions of the device at different concentrations.

[0126] In other embodiments, the device may include cell adhesion factors, including cell adhesion peptides. As used herein, the term "cell adhesion peptide" refers to a compound having at least two amino acids per molecule that is capable of binding to cells via cell surface molecules. Cell adhesion peptides include any extracellular matrix proteins known to play a role in cell adhesion, including fibronectin, fibronectin, laminin, elastin, fibrinogen, type I, type II, and type V collagen, as well as synthetic peptides with similar cell adhesion properties. Cell adhesion peptides also include peptides derived from any of the aforementioned proteins, including fragments or sequences containing binding domains.

[0127] The device may incorporate a wetting agent designed to improve the wettability of the device surface, allowing fluids to be readily absorbed onto the device surface and into porous devices, and promoting cell attachment and / or altering the water contact angle of the device surface. Some examples of wetting agents include polymers of ethylene oxide and propylene oxide, such as polyethylene oxide, polypropylene oxide, or copolymers thereof, for example... Other suitable wetting agents include surfactants or emulsifiers.

[0128] The device may contain gels, hydrogels, or mixtures of active hydrogels to further improve wetting properties and promote cell growth across the entire thickness or diameter of the device. The hydrogel mixture consists of live cells encapsulated in biocompatible hydrogels such as gelatin, silk gels, and hyaluronic acid (HA) gels.

[0129] The device may contain active agents designed to stimulate inward cell growth, including growth factors, cell differentiation factors, cell recruitment factors, cell receptors, cell binding factors, cell signaling molecules such as cytokines, and molecules that promote cell migration, cell division, cell proliferation, and extracellular matrix deposition. Such active agents include fibroblast growth factor (FGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), granulocyte-macrophage colony stimulation 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), and combinations thereof.

[0130] Other bioactive agents that can be incorporated into the device include antimicrobial agents, particularly antibiotics, disinfectants, oncology agents, anti-scarring agents, anti-inflammatory agents, anesthetics, small molecule drugs, anti-angiogenic and pro-angiogenic factors, immunomodulators, and coagulants. Bioactive agents can be proteins such as collagen, as well as antibodies, peptides, polysaccharides such as chitosan, alginate, 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 can include DNA, RNA, siRNA, miRNA, antisense molecules, or aptamers.

[0131] In a preferred embodiment, the bioactive agent is selected from one or more of the following: chemotherapeutic agents, antitumor agents, immunomodulators, hormones, antiangiogenic agents, antibiotics, radiation sensitizers, and immunotherapeutic agents.

[0132] In yet another preferred embodiment, the device may be incorporated into a system for controlled release of a therapeutic or preventative agent.

[0133] III. Method for preparing a reference marker device

[0134] Several methods can be used to prepare reference marker devices, and several different examples are described in this paper.

[0135] When a more rigid reference marker is implanted in the breast, the device can eliminate or reduce pain felt by the patient during their normal daily activities. In contrast to a more rigid reference marker implanted in the breast, the device described herein is intangible when implanted in the breast or other tissues, or becomes intangible after implantation, and is deformable under stress and returns to its shape when the stress is removed.

[0136] This device also reduces or eliminates the possibility that clinicians unaware of the device will perform unnecessary procedures to characterize foreign bodies in patients. Unlike existing partially absorbable or slowly absorbable devices, the device disclosed herein is absorbed more rapidly and can be generated along with visual markers, allowing the entire device to be absorbed.

[0137] Unlike existing devices, the device disclosed herein can also incorporate a scaffold designed to promote inward tissue growth into the entire void space of the tumor resection cavity. This inward tissue growth not only helps to secure the device in place but also acts as a void filler and helps prevent fluid buildup in the cavity post-surgery. Through promoting inward tissue growth and relatively rapid absorption, this device can provide improved cosmetic outcomes for patients, particularly in the treatment of breast cancer. For example, instead of the hard, rigid reference markers made of polylactic acid that have been felt in the breast for years, inward tissue growth into the reference marker scaffold will fill the void space of the tumor resection cavity with naturally tactile tissue, and the reference markers will completely degrade without leaving any palpable foreign matter.

[0138] A. Examples of reference marking devices

[0139] The reference marking device is designed to shape the tumor resection cavity into a defined target volume with precisely defined tissue margins for radiotherapy, and is designed to determine the planned target volume. Shaping the tumor resection cavity into a defined shape reduces the size of the tissue margins around the cavity that need to be irradiated, and reduces the exposure of the patient's healthy tissue to radiation.

[0140] In a preferred embodiment, the reference marker device has an open, porous scaffold structure of a predetermined shape defining the outer periphery of the device. The open, porous scaffold structure facilitates inward tissue growth, which helps to secure the visual marker in place after implantation. Inward tissue growth also prevents fluid accumulation in the tissue resection cavity and results in improved cosmetic outcomes, for example, after mass excision.

[0141] An example of an open porous scaffold structure (100) designed to promote inward tissue growth into a reference marker device within the device. Figure 1AAs shown in Figure C. The porous three-dimensional scaffold structure (100) of the marking device has a honeycomb structure formed in an ellipsoidal or spherical shape and an outer region defining the outer periphery of the device. The scaffold is designed such that the structure of the reference marking device has a fully interconnected porous structure. Preferably, the scaffold of the reference marking device has a unitary structure. The completely open structure of the scaffold provides an environment that allows cells to invade and proliferate in the marking device after implantation. Tissue inward growth into the honeycomb structure helps to hold the device in place so that it does not migrate. Tissue inward growth into the honeycomb structure also allows the device to be used as a void filler. Tissue inward growth helps to reduce or eliminate fluid accumulation in the postoperative tumor resection cavity and provides improved cosmetic results, for example, in mass resection procedures, by reducing or eliminating visible tissue defects. 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 of filaments. The three-dimensional honeycomb frame, skeleton, or scaffold (100) of the marking device is capable of shaping the tissue resection cavity into a defined shape to define the planned target volume for radiotherapy. Shaping an irregularly shaped tissue resection cavity into a predetermined shape for a cellular scaffold (100) reduces the size of the tissue margins surrounding the cavity requiring irradiation and reduces exposure of healthy patient tissue to irradiation. The three-dimensional cellular structure (100) of the tissue marker is not rigid but compressible under stress or tension. Optionally, in some embodiments, the three-dimensional cellular structure (100) has shape memory. The elastic modulus of the reference marker device (100) is less than 50 MPa, more preferably less than 1 MPa, and even more preferably less than 100 kPa. These properties allow the predetermined shape of the reference marker to shape the tissue in the tumor resection cavity into the desired shape for radiotherapy, and also allow the predetermined shape to deform under stress or tension and to recover its predetermined shape when the stress or tension is removed. For example, when the scaffold is implanted in a patient's breast, stress or tension from the patient's bra can temporarily deform the predetermined shape (100), and once the bra is removed, the scaffold will recover its predetermined shape, and any visual markers placed on the periphery of the scaffold can still be used to accurately define the planned target volume for radiotherapy. This property of the cellular structure (100) can eliminate or reduce pain or tactile sensitivity of the device, especially when implanted in a patient's breast. It is noteworthy that the predetermined shape of the stent (100) and its ability to return to its shape after the application and removal of stress or tension need only be maintained during radiation therapy or when any visual markers placed around the stent are fixed in place by inward tissue growth. Once radiation therapy is completed or such visual markers are fixed in place, the stent may lose its ability to return to its predetermined shape, and preferably the stent is absorbed. Preferably, the stent structure is absorbed in less than 6 to 24 months.

[0142] The scaffold (100) of the device may be prepared from one or more of the materials disclosed in Section II.A. Preferably, the scaffold (100) is prepared from poly-4-hydroxybutyrate or a copolymer thereof or poly(butylene succinate) or a copolymer thereof, or contains one or more of these polymers.

[0143] Four constructs with device (100) designs were prepared by 3D printing from poly-4-hydroxybutyrate. The elastic modulus of each of these devices was measured and found to be in the range of 0.35 MPa to 0.01 MPa.

[0144] Visual markers can be incorporated into Figure 1A The marking device is incorporated into the filaments of the honeycomb structure (100) shown in C. Visual markings can also be used with, for example... Figure 2A The external region of the support structure shown in C is connected. Device (200) is an example of a reference marking device, which consists of... Figure 1AThe honeycomb open porous scaffold structure shown in Figure C is formed, but with six visual markers (210a, 210b, 210c, 210d, 210e, 210f, collectively referred to as "visual markers (210)") connecting to the outer region of the scaffold structure. Multiple visual markers may be connected to the device (200), but six visual markers are preferably used. The device (200) has an open porous three-dimensional honeycomb scaffold structure having interconnected porous structures formed in ellipsoidal and spherical shapes, and an outer region defining the outer periphery of the device. The open porous scaffold structure promotes inward cell growth and tissue formation, which anchors the scaffold in place and prevents scaffold migration, and importantly, the visual markers (210) are anchored in positions around the outer periphery of the marking device such that they are located at the edge of the excised tumor cavity. Inward tissue growth into the device (200) can provide improved cosmetic results by filling voids (e.g., voids left after a mass excision procedure). The reference marker (200) has a predetermined shape formed by a three-dimensional frame, skeleton, or scaffold, preferably wherein the frame, skeleton, or scaffold is formed of filament, and the shape is capable of shaping the tumor resection cavity into a suitable shape for the planned target volume for radiotherapy, but is compressible under stress or tension and will return to its predetermined shape when the stress or tension is removed. The scaffold of the reference marker is designed to maintain its predetermined shape, as well as deform under stress and tension, and return to its predetermined shape during the radiotherapy period or the time required for the visualization marker (210) to be fixed in place by tissue ingrowth into the scaffold. The scaffold is preferably absorbed 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 periphery of the marking device. The scaffold of the device (200) can be prepared from one or more of the materials disclosed in Section II.A.

[0145] Another example of a reference marking device (300) is in Figure 3A As shown in the diagram, the reference marking device (300) has an open, porous scaffold structure in a spherical shape, designed to facilitate inward tissue growth with a post or pin retainer (310) into which radiopaque posts or pins (320) can be inserted to form visible markings on the device surface. The implant may comprise an external surface or peripheral structure (e.g., a shell 350) and an internal organized structure that supports the peripheral structure and provides an interconnected network of porous structures or pores.

[0146] The cross section of the device (300) obtained along line 3B-3B is in Figure 3B As shown in the diagram. The locking feature (330) on the non-transparent post / pin (320) is in Figure 3BAs shown in the diagram. The locking feature allows for the securing of radiopaque posts or pins to the outer region of the support. Multiple radiopaque posts or pins (320), preferably six, can be positioned on the outer region of the device (300). Proper placement of these posts or pins allows for imaging of the outer region of the device (300) for planning target volume and radiotherapy.

[0147] In some embodiments, the visualization markers are located around the periphery of the device, such that the markers are positioned at the edge of the resected tumor cavity. In some specific embodiments, the visualization markers are placed at the first and second ends of the device's longitudinal axis, allowing imaging of the device's length (l) in vivo. The markers may also be placed around the periphery at the midpoint of the longitudinal axis, allowing imaging of the device's diameter or width.

[0148] Figure 3CThe locations of three post or pin retainers (310) located in the outer region of the reference marking device (300) are shown, wherein radiopaque posts or pins (320) can be inserted to allow imaging of the device. The device (300) has an integral structure. The device (300) may be formed of a honeycomb structure or other suitable open porous structure, which provides an environment that allows cells to invade and proliferate after implantation. Tissue inward growth into the structure (300) helps to hold the device in place so that it does not migrate and to fix the location of the visualized marker located around the periphery of the marking device at the edge of the resected tumor cavity. Tissue inward growth into the structure (300) also allows the device to be used as a void filler, reducing or eliminating fluid accumulation in the postoperative tumor resection cavity, and providing improved cosmetic results, for example, in mass resection procedures by reducing or eliminating visible tissue defects. 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 of filaments. The three-dimensional frame, skeleton, or scaffold (300) of the marking device is capable of shaping the tissue resection cavity into a defined shape to define the planned target volume for radiotherapy. The three-dimensional structure (300) of the tissue marker is not rigid but compressible under stress or tension. The elastic modulus of the device (300) is less than 50 MPa. These properties allow the predetermined shape to shape the tissue in the tumor resection cavity into the desired shape for radiotherapy, and also allow the predetermined shape to deform under stress or tension and to return to its predetermined shape when the stress or tension is removed. This property of the structure (300) can eliminate or reduce the pain or tactile perceptibility of the device, especially when implanted in a patient's breast. It is noteworthy that the predetermined shape of the scaffold and its ability to return to its shape after the application and removal of stress or tension need only be maintained during radiotherapy or when the visual marker (320) is fixed in place by inward tissue growth. Once radiotherapy is completed or the visual marker is fixed in place, the scaffold may lose its ability to return to its predetermined shape, and the scaffold is preferably absorbed. Preferably, the scaffold structure (300) is absorbed in less than 6 to 24 months. The support of the device (300) may be made of one or more of the materials disclosed in Section II.A. Preferably, the device (300) is made of poly-4-hydroxybutyrate or a copolymer thereof or poly(butylene succinate) or a copolymer thereof, or contains one or more of these polymers.

[0149] The scaffold structure of the reference marking device can also be 3D printed in other shapes suitable for radiotherapy, including spherical, hemispherical, spherical, ellipsoidal, cylindrical, parallelepiped, and convex shapes. These scaffold structures are formed as open porous structures and are preferably fabricated by 3D printing three-dimensional frames, skeletons, or scaffolds. These frames, skeletons, or scaffolds can be formed from one or more filaments and may optionally include struts. The frames, skeletons, or scaffolds may contain one or more polyhedra.

[0150] B. Dimensions of the reference marking device

[0151] The reference marker device is sized for use in tumor resection cavities of varying sizes. The reference marker device is also sized to define the planning target volume (PTV) for radiotherapy. (Refer to again...) Figure 1A , 1B The device can be formed in a shape having a longitudinal axis having a first end, a second end, and a length (l) between the first end and the second end. The length (l) is typically 1 to 6 cm, including 1, 2, 3, 4, 5, and 6 cm.

[0152] A device can be formed having a length (l) or a width (w) at the midpoint of a longitudinal axis between a first end and a 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 dimensions for reference marks are (l) × (w) of 2 × 2 cm, 2 × 3 cm, 3 × 3 cm, 3 × 4 cm, 4 × 4 cm, and 4 × 5 cm. In some embodiments, the base region is circular, and the length and width are equal to each other.

[0153] It is also possible to form a device having a first end and a second end, a longitudinal axis of length (l) between the first end and the second end, and a width (w) and a 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 (l) of 1 to 4 cm, (w) of 1 to 3 cm, and (h) of 1 to 2 cm. Particularly common dimensions for reference marks are length (l) × width (w) × height (h) of 3 × 2 × 1 cm, 3 × 3 × 1 cm, 1 × 1 × 2 cm, 2 × 1 × 2 cm, and 1 × 2 × 2 cm.

[0154] C. Porosity of the reference marking device

[0155] In some embodiments, the open porous scaffold structure of the reference marker device preferably includes macropores to facilitate inward growth of cells and tissues into the interior of the scaffold structure. The macropores preferably have an average pore diameter or size of at least 25 micrometers, more preferably at least 50 micrometers, and even more preferably at least 75 micrometers. The average pore diameter or size can range from 0.075 mm to 10 mm. The pore size can vary in different regions of the scaffold of the device.

[0156] Suitable porous supports for a reference marking device can be formed from hollow or skeletal unit cells. Porous supports with defined dimensions, shapes, and volumes can be formed by connecting hollow or skeletal unit cells together to form a predetermined shape for a three-dimensional reference marking device. These porous reference marks can be produced using unit cells of the same or different sizes and shapes in different shapes and dimensions. In some particularly preferred embodiments, the hollow and skeletal unit cells are compressible, and even more preferably, can recover to their original dimensions after compression. A particularly preferred embodiment is a compressible reference mark comprising hollow or skeletal unit cells that can recover to its original dimensions after compression.

[0157] The labeling device formed from hollow or skeletal unit cells may contain two or more unit cells, but more preferably 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 1,000, 10,000 or more unit cells. The unit cells forming the scaffold structure of the device may be connected to one or more unit cells of the same or different types. The unit cells forming the scaffold structure of the labeling device may have pores with a width or diameter of 500 μm to 2 cm, and more preferably 1 mm to 1 cm. The unit cells of the device may have the same pore size or mixed pore sizes. The reference labeling device formed from unit cells preferably has a low volumetric density, providing a large surface area and void volume. Preferably, the size of the unit cells is selected such that the porous scaffold can be assembled from unit cells with a low volumetric density, which can be easily colonized by cells and invaded by tissues and blood vessels.

[0158] By appropriately selecting the size and shape of the unit cells, different types of reference marker scaffolds with varying volumetric densities can be generated. The properties of scaffolds formed from repeating units are highly predictable and can be predicted based on the size of the unit cells and the materials used to prepare them. Unit cells with different physical properties can be prepared by selecting the size, geometry, and materials used to prepare them. Selecting specific unit cell sizes and materials allows for the generation of scaffolds from the units that are compressible, can be inserted into tumor resection cavities, and conform the tissue edges of the cavity to the predetermined shape of the marker device.

[0159] Hollow or skeletal unit cells of porous reference devices 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 provide devices with specific porosity and specific shapes and volumes. The width of the filaments in the unit cell 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 reference markers is that the filament width and length required to produce porous scaffolds with specific elastic moduli or other mechanical properties can be calculated for a given material. In some embodiments, the mechanical properties of the reference-marked scaffold can be changed by alternatively changing the size of the filaments in the unit cell without changing the shape of the unit cell. In a preferred embodiment, the porosity, size, and material of the unit cells forming the reference-marked scaffold are selected such that the scaffold prepared from the unit cells has properties similar to those of soft tissue. For example, the porosity, size, and material of the unit cells can be selected to provide scaffold structures with mechanical properties similar to those of breast tissue. In another preferred embodiment, the unit cell of the reference marking device can be compressed and optionally returns to its original shape when the compressive force is released.

[0160] The unit cell of the reference marking device can be prepared from one or more of the materials disclosed in Section II.A. Preferably, the unit cell is prepared from a composition comprising poly-4-hydroxybutyrate or a copolymer thereof or poly(butylene succinate) or a copolymer thereof.

[0161] An example of a porous reference marker device formed by hollow honeycomb unit cells is shown in Figure 1A As shown in C. Other examples of porous reference marking devices formed by unit cells include devices formed by skeletal unit cells in which the unit cells have a polyhedral shape.

[0162] D. Visual markings of the benchmark marking device

[0163] A reference marker device with visual markings was fabricated, allowing clinicians to use the device to determine the planned target volume and accurately deliver radiation therapy to patients. The visual markings were located on the external region of the reference marker device in a manner that allowed clinicians to image the device dimensions within the body.

[0164] Visual markers can be incorporated into the structure of the outer region of the marking device. For example, a translucent material can be used as a visual marker and incorporated into the filament of the device present in the outer region of the marking device, such that the translucent material is present at specific discrete locations, rather than throughout the entire outer region of the device. Positioning the translucent material at discrete locations allows for subsequent imaging of the device's interior, which would be impaired or potentially blocked if the translucent material were incorporated into the entire outer region of the device. If the translucent material is absorbable and the three-dimensional porous structure of the marking device is made of absorbable material, the device made in this way can be fully absorbable. In some embodiments, an absorbable marking device can be prepared by incorporating barium sulfate at discrete locations into the outer region of an absorbable porous scaffold structure of a reference marker. Preferably, barium sulfate is incorporated at discrete locations into the filament of the outer region of the marking device made of one or more absorbable polymers. For example, a translucent material (e.g., barium sulfate) can be incorporated into... Figure 1A The marking device (100) shown in Figure C is located at discrete positions of the filaments in the honeycomb structure. Barium sulfate can be coated with hydrogel to improve the visualization of the markings.

[0165] In other embodiments, visual markers can be attached to external areas of the 3D marking device. The visual markers can be, for example, clips, clamps, or lines made of a translucent material, and can be attached to the external areas of the device at discrete locations. Figure 2A Figures C to C show a front view, a side view, and an isometric view of a reference marker (200) formed by a cellular porous support structure, which has six visual markers (210) connected to the outer area of ​​the marked support structure. Any number of visual markers can be connected to the device (200), but six visual markers are preferred.

[0166] In other embodiments, the visual marker may be a non-transparent post or pin connected to an external area of ​​the device. An example of a reference marker device with a non-transparent post or pin is... Figure 3A As shown in C. In this example, the non-transmissive post or pin (320) can be connected to the reference marking device at discrete locations by inserting the post or pin (320) into the post or pin retainer (310) and securing it in place using the locking feature (330).

[0167] Reference Figure 2A and 2BIn one preferred embodiment, the reference marking device has visual markers (210c, 210d) located at a first end and a second end of the longitudinal axis of the device. Positioning the visual markers at the first and second ends of the longitudinal axis of the device allows for imaging of the length (l) of the device within the body. In another preferred embodiment, the reference marking device has visual markers placed around the periphery of the device at the midpoint of the longitudinal axis of the device between the first and second ends of the device's diameter or width. Preferably, four visual markers (210a, 210b, 210e, 210f) are located around the periphery of the device at the midpoint of the device, and two visual markers (210c, 210d) are located at the first and second ends of the marking longitudinal axis. In another embodiment, visual markers are placed at each pole of the 3D scaffold, such as the North and South Poles, and additional visual markers are placed along one or more latitudes of the 3D body.

[0168] In some embodiments, the device may include a hydrogel. The hydrogel can be used to improve the visibility of the visual markers. For example, the hydrogel may be used in combination with barium sulfate or iodixanol to improve the visibility of the device. The hydrogel may be coated on the visual markers or on the device itself.

[0169] The reference marking device may include the visual markings listed in Section II.C above.

[0170] E. Manufacturing of reference marking devices

[0171] In one embodiment, a reference marking device is fabricated by 3D printing. Suitable methods for 3D printing the device include filament fabrication, molten pellet deposition, melt extrusion deposition, selective laser melting, printing slurries and solutions using a coagulation bath, and printing using binder solutions and powder particles. Preferably, the device is fabricated by melt extrusion deposition.

[0172] In one implementation scheme. Figure 1A The porous scaffold structure shown in Figure C can be prepared by melt extrusion deposition of poly-4-hydroxybutyrate (P4HB) using the following procedure. Figure 1AThe ellipsoidal and spherical porous honeycomb scaffold structures of the reference marking devices shown in Figures C and D can be 3D printed from P4HB (Mw 380kDa) pellets using, for example, an Arburg Freeformer 3D printer and 3D CAM (Computer-Aided Design Modeling). The average diameter of the printed 3D filaments is selected based on the desired characteristics of the marking device, including porosity or infill density (i.e., the number of 3D-printed filaments per millimeter between the contours of the 3D-printed device). Preferably, the average filament diameter is 50 to 800 μm, more preferably 100 to 600 μm, and even more preferably 150 to 550 μm. 3D printing of devices is highly desirable because it allows for precise control of the shape of devices with open porous structures, and the 3D-printed structures support inward tissue growth. 3D printing is also highly desirable for fabricating devices with shape memory.

[0173] once Figure 1A If the reference marker bracket shown in C is 3D printed, then visual markers can be added to the bracket to form... Figure 2A The device shown in section C. Any suitable method can be used to attach the visual marker to the external area of ​​the support structure. Preferably, the visual marker can be clipped, pinned, sewn, or glued to the support structure.

[0174] In other embodiments, a reference marking device having radiopaque material incorporated at discrete locations on the periphery of the device can be produced by 3D printing the device from a combination of a polymer and a composition comprising a radiopaque material. An exemplary material combination is, but is not limited to, a polymer comprising barium sulfate.

[0175] In some embodiments, the reference marker implant is formed of a skeletal polyhedron, wherein the breaking load of the edges and vertices of the unit cells forming the skeletal polyhedron is 0.1 to 200 N, more preferably 1 to 100 N, and even more preferably 2 to 50 N. In some embodiments, the breaking elongation of the edges and vertices of these unit cells is 22% to 1,000%, and more preferably 100% to 700%. In some embodiments, the elastic modulus of the edges and vertices of these unit cells is 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, breaking elongation, and elastic modulus of the edges and vertices of the unit cells may be the same throughout the skeletal polyhedron or unit cells, or these values ​​may be different throughout the skeletal polyhedron and unit cells. The polymer struts forming the edges and apex of the unit cell preferably have one or more of the following properties: (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 some embodiments, the elastic modulus of the reference marker implant formed by the skeletal polyhedron is less than 50 MPa, more preferably 0.1 kPa to 10 MPa, and the polymer struts or fibers forming the unit cells of the skeletal polyhedron have one or more of the following properties: (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 value of 22% to 1,000%, and 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.

[0176] In some implementations, a reference marker device with one or more suture holes is fabricated, for example, by 3D printing. These suture holes can be used during device implantation to secure the device and prevent its migration. The one or more suture holes are preferably located on the periphery of the device.

[0177] In some implementations, the reference marker may also contain one or more bioactive agents. These agents can be applied once the porous scaffold structure of the device is formed, or the bioactive agents can be incorporated into the device during the 3D printing process.

[0178] The reference marker device is preferably prepared with an endotoxin content of less than 20 endotoxin units, making the device suitable for implantation in patients.

[0179] IV. Methods for implanting reference marker devices

[0180] The device is sterilized before implantation. For example, it can be sterilized by using ethylene oxide gas, cold ethylene oxide gas, exposure to gamma radiation, or electron beam irradiation.

[0181] Benchmarking devices are particularly well-suited for and can be used to treat breast cancer, where the device can be implanted after tumor resection. Benchmarking devices can also be used to treat other soft tissue cancers, including liver cancer (e.g., treating liver tumors), muscle cancer (e.g., treating the muscle of a sarcoma), abdominal cancer, kidney cancer, lung cancer, and prostate cancer. Specifically, the device can be used in situations where tissue has been removed from a patient, and the patient may require radiation therapy at or near the site of tissue removal. Benchmarking devices can also be used in locations within the body at high risk of cancer development. In these cases, the device can be used to monitor the patient or for radiation therapy if cancer subsequently develops.

[0182] The reference marker device can be used by implantation in the tumor bed or surgical resection cavity and can be imaged prior to irradiation delivery. The device can be imaged using 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 the device provides images of the device that can be used to calculate the planned target volume for radiotherapy and guide irradiation delivery to the tumor resection site.

[0183] In some implementations, the reference marker can be fixed to the tumor bed or surgical resection cavity using permanent sutures, absorbable sutures, U-shaped staples, or other fixation methods. Fixation helps prevent any subsequent migration of the device until tissue grows inward to secure the device.

[0184] In some implementations, the reference marker may include one or more suture holes to secure the device in place. Sutures may pass through these holes and be secured to the tissue to prevent the device from migrating after implantation.

[0185] In some cancer treatments, multiple radiation doses are required over days, weeks, or months. In these cases, reference marking devices can be used to repeatedly identify tumor resection cavities and guide further radiotherapy.

[0186] The reference marker device can also be used to deliver one or more bioactive agents in vivo. For example, the reference marker may contain one or more of the following that can be delivered near the implantation site: chemotherapeutic agents, antitumor agents, antiangiogenic agents, immunomodulators, hormones, immunotherapeutic agents, antibiotics, and radiation sensitizers.

[0187] Reference marker devices can also be implanted in tissue to fill cavities. In this application, the device serves as a cavity filler. 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 provide improved cosmetic results, especially after mass resection procedures.

[0188] The invention will be further understood by referring to the following non-limiting embodiments. Example

[0189] Example 1: Fabrication of a reference scaffold marker from poly-4-hydroxybutyrate (P4HB) by 3D printing

[0190] The porous reference marker device was fabricated from P4HB (Mw 380kDa) granules via 3D printing. P4HB filaments were deposited layer-by-layer using melt extrusion deposition under the conditions shown in Table 1. The device's open porous scaffold structure is constructed as follows: Figure 1A The honeycomb structure shown in Figure B is formed. The structure has an ellipsoidal or spherical shape, wherein the length (l) of the structure is 2 to 6 cm and the height (h) is 2 to 8 cm. The device is formed from a fully interconnected porous structure with open porosity to provide a morphology that allows cells to invade the scaffold and proliferate after implantation. The elastic modulus of the reference marker device prepared according to Example 1 is 0.01 MPa to 0.35 MPa.

[0191] In some implementations, the length (l) is equal to the width (w) to form a substantially circular base region, in which case the length or width may also be referred to as the base diameter.

[0192] Example 2: Clips for reference marks prepared from poly-4-hydroxybutyrate and barium sulfate or poly-4-hydroxybutyrate and zirconium dioxide

[0193] Visualized marker clips suitable for attachment to reference marker supports (e.g., the support prepared in Example 1) can be prepared by injection molding of a composition comprising poly(4-hydroxybutyrate) and barium sulfate or poly(4-hydroxybutyrate) and zirconium dioxide microparticles. Alternatively, the clips can be formed from an acetone solution of poly(4-hydroxybutyrate) and barium sulfate or an acetone solution of poly(4-hydroxybutyrate) and zirconium dioxide.

[0194] Example 3: Preparation of reference markers from poly-4-hydroxybutyrate (P4HB) by 3D printing together with barium sulfate clips for visualization.

[0195] Six barium sulfate-containing poly-4-hydroxybutyrates prepared in Example 2 were sandwiched on the outer periphery of the cellular scaffold structure prepared in Example 1. Figure 2A To the position shown in C, to allow imaging of the dimensions of the reference marker device.

[0196] Example 4: A reference mark was prepared by 3D printing of poly-4-hydroxybutyrate (P4HB) together with a titanium clip visualization mark.

[0197] Porous reference marker devices were fabricated from P4HB (Mw 380kDa) using melt extrusion deposition. P4HB filaments were deposited layer-by-layer to form an open porous scaffold with a honeycomb structure. Six titanium clips were then placed on the outer periphery of the honeycomb scaffold structure to allow for the fabrication of reference markers such as… Figure 2A The dimensions of the device shown in C are imaged.

Claims

1. An implantable reference tissue marker device comprising: An absorbable porous support having a predetermined 3D shape and defining the outer periphery of the device, wherein the absorbable porous support has shape memory to form the predetermined 3D shape when the absorbable porous support is unconstrained, and Multiple visual markers are arranged at discrete locations on the outer periphery of the device, wherein the scaffold comprises connected unit cells, and wherein the unit cells are skeletal polyhedra, wherein the porous scaffold has an elastic modulus greater than 0.5 kPa and less than 50 MPa.

2. The device of claim 1, wherein the porous support comprises a polymer strut, fiber, coil, or spring 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) an elongation at break of 22% to 1,000% or 100% to 700%; and (iv) an elastic modulus of 0.05 to 3 GPa or 0.2 to 0.8 GPa.

3. The apparatus of claim 1, wherein the visual marker is absorbable.

4. The device of claim 1, wherein the device is implanted in the patient’s breast and the device is intangible immediately after implantation, or intangible for 1, 2, 3, 4, 5 or 6 months after implantation.

5. The device of claim 1, wherein the edges and vertices of the skeletal polyhedron are formed of polymer struts or fibers.

6. The device of claim 5, wherein the edge is the apex of the unit cell, the unit cell having one or more of the following properties: 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 of 0.05 to 3 GPa, 0.1 to 3 GPa, or 0.2 to 0.8 GPa.

7. The device of claim 1, wherein the device has a longitudinal axis having a first end, a second end, and a midpoint between the first end and the second end, and wherein the visual marker is located at the first end and the second end of the longitudinal axis and surrounds the outer periphery of the device at the midpoint of the device, and optionally, the support includes a marker holder for securing the visual marker at the discrete positions.

8. The device of claim 1, wherein the device maintains its predetermined shape without stress for at least 1, 2, 3, 4, 5 or 6 months after implantation.

9. The device of claim 1, wherein the absorbable porous stent is absorbed in less than 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8 or 7 months after implantation.

10. The device of claim 1, wherein the device further comprises one or more suture holes.

11. The device of claim 1, wherein the device further comprises one or more of the following: a bioactive agent, a hydrogel, hyaluronic acid or a derivative thereof, or an alginate.

12. The apparatus of claim 11, wherein the bioactive agent is selected from one or more of the following: chemotherapeutic agents, antitumor agents, immunomodulators, hormones, antiangiogenic agents, antibiotics, radiation sensitizers, and immunotherapeutic agents.

13. The device of claim 1, wherein the outer periphery of the device defined by the predetermined shape is spherical, ellipsoidal, cylindrical, quasi-spherical, or parallelepiped.

14. The apparatus of claim 1, wherein the visual 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.

15. The apparatus of claim 1, wherein the apparatus comprises an absorbable polymer.

16. The apparatus of claim 15, wherein the apparatus comprises an oriented absorbable polymer.

17. The apparatus of claim 15, wherein the absorbable polymer is poly-4-hydroxybutyrate or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof.

18. The device of claim 1, wherein the device comprises one or more portions of a translucent fiber or a translucent strut or a clip.

19. The device of claim 5, wherein the device is formed by a method comprising forming a unit cell of the scaffold by 3D printing fibers or struts.

20. The apparatus of claim 19, wherein the apparatus is formed by one of the following methods: melt extrusion deposition, filament fabrication, melt pellet deposition, selective laser melting, printing polymer slurry or solution using a coagulation bath, and printing using a binder solution and polymer powder particles.

21. The device of claim 20, wherein the device is formed of poly-4-hydroxybutyrate or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof.

22. The implantable reference tissue marker device of claim 1, comprising: The outer peripheral surface or shell; Suitable for supporting an organized structure within the shell; and Multiple visual markers are arranged at discrete locations on the outer peripheral surface, wherein the internal organized structure is an absorbable porous scaffold with a predetermined 3D shape.

23. The device of claim 22, wherein the internal organized structure is a network of interconnected holes.

24. The device of claim 23, wherein the hole is formed between at least one of the fiber, beam, and support.

25. The device of claim 22, wherein the housing comprises a radiopaque material.

26. The apparatus of claim 22, further comprising a plurality of visual mark engagement features along the outer periphery, such that the plurality of visual marks can be removably attached to the reference tissue marking apparatus in a variety of different arrangements.

27. A physician-customizable baseline marker kit, which includes: At least one reference tissue marking device as claimed in claim 1, the device comprising a 3D body and a plurality of fixed, spaced-apart visual marking engagement features; and A plurality of visual markers, each visual marker including a mating feature for connecting with the visual marker engagement feature, such that one or more of the visual markers can be fixed to the 3D body of the reference tissue marking device as desired by a physician, wherein the visual marker engagement feature is a hole, and the mating feature of the visual marker is a post, the post including a mating feature for fixing the post in the hole.

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