Resorbable implants for bone defect reconstruction

Abstract

A device (200) for repairing bone defects prevents the formation of pits and easily noticeable tissue at the bone repair site. The device can be used to repair burr holes in the skull, improving cosmetic results and reducing or eliminating functional handicaps that can result from combing and hairdressing. The device is secured to the bone defect by expanding the device within the bone defect using a filament element (210) or by adhesive. Tissue ingrowth into the device regenerates bone at the defect site and prevents the formation of pits or easily noticeable tissue. The device preferably comprises a ceramic and poly-4-hydroxybutyrate or its copolymer, or a ceramic and poly(butylene succinate) or its copolymer.

Description

[Technical field]

[0001] FIELD OF THEINVENTION

[0001] The present invention relates generally to the field of surgery, and more particularly to implantable medical devices for bone reconstruction, repair of bone defects, and cranial reconstruction. [Background technology]

[0002] 2. Background of the Invention

[0002] Head trauma that results in damage to blood vessels in the meninges, the thin layers of tissue that cover the brain, can cause acute or chronic subdural hematomas (CSDH). CSDH occurs when one of the blood vessels in the meninges ruptures, causing blood to pool and form a bulge just below the dura, the outermost tissue of the meninges. CSDH is a dangerous condition that requires immediate medical intervention because the increased blood has nowhere to go and can press against the brain, potentially resulting in death.

[0003]

[0003] Neurosurgeons treat CSDH by creating small holes in the skull, called burr holes. These holes relieve pressure on the brain caused by blood pooling. The process of creating small holes in the skull is known as trepanation.

[0004]

[0004] Treatment of CSDH is rapidly becoming one of the most common neurosurgical procedures, especially as the population ages and the use of antithrombotic drugs increases.

[0005]

[0005] Neurosurgeons may also sometimes use the same method to treat epidural hematomas, which are caused by blood pooling under the skull and just above the dura layer. Epidural hematomas tend to be more common in younger patients. Neurosurgeons may also perform burr holes to treat other conditions, such as certain brain tumors, hydrocephalus, bleeding from the brain, and collections of pus around the meninges.

[0006]

[0006] Although patients with conditions such as CSDH often make full neurological recoveries after surgery, the skull defects caused by burr hole trephinations often result in undesirable depressions in the scalp that are not only often cosmetically unacceptable to the patient, but can also cause hassle during combing and hairdressing.

[0007]

[0007] Attempts to overcome the problems associated with bone defects or depressions have included the use of various covers and plugs to obtain more acceptable cosmetic and functional results. The covers and plugs also serve to seal the burr hole and protect the underlying tissue and brain from infection or other potential trauma.

[0008]

[0008] A common option for burr hole repair has been the use of a cover that fits over the top of the burr hole. These covers are typically screwed into the skull. The covers are often made of a metal such as titanium and are typically in the form of a plate with holes for fixation. However, covers are not ideal as they leave a permanent foreign body inside the patient.

[0009]

[0009] As an alternative to permanent titanium covers, burr holes have been packed with absorbent gelatin sponges, such as GELFOAM, marketed by Pfizer. Im et al. (The efficacy of titanium burr hole cover for reconstruction of skull defect after burr hole trephination of chronic subdural hematoma, Korean J Neurotrauma, 2014, 10(2):76-81) compared the efficacy of packing the burr hole with GELFOAM to the use of titanium burr hole covers. In a follow-up study, 40% of patients treated with titanium burr hole covers were dissatisfied with the cosmetic result, and 40% of patients complained of functional handicaps. In comparison, 76.6% of GELFOAM patients interviewed were dissatisfied with the cosmetic result, and 64.1% of patients complained of functional handicaps. Patients treated with GELFOAM were reported to have an average scalp depression of 2.45 mm after treatment.

[0010]

[0010] Other approaches to filling burr holes have included the use of autologous tissues, such as bone, bone powder, muscle, and fat tissue (all of which require harvesting), as well as synthetic substitutes, such as polymethylmethacrylate or polypropylene (which are permanent materials), and polycaprolactone. Kubota et al. (Long-term follow-up for ossification of autologous bone plug and skin sinking after periosteum-preserved burr hole surgery, Surgical Neurology International, 2017, 8:204.) disclose the use of bone plugs made from bone powder. The extent of skin sinking at 12 months in patients who received bone plugs was reported to be an average of 1.2 mm, ranging up to 2.35 mm.

[0011]

[0011] Teoh et al., U.S. Patent Application Publication No. 20070083268, discloses a polycaprolactone plug for repairing a burr hole. Schantz et al. 2006 (Cranioplasty after trephination using a novel biodegradable burr hole cover: technical case report, Neurosurgery, 2006, 58(1 Suppl): ONS-E176) also discloses the use of bone plugs containing polycaprolactone.

[0012]

[0012] U.S. Patent No. 6,350,284 to Toermaelae et al. discloses a bioabsorbable cranial implant comprising a hard plate layer and a fibrous web layer for attachment to a patient's outer skull to repair a cranial defect. Summary of the Invention [Problem to be solved by the invention]

[0013]

[0013] Despite the above, there is still a need for devices as described herein that can be used to repair burr holes. In particular, there is a need for the development of devices for repairing burr holes that prevent the formation of dents after cranial surgery. Such devices would improve the cosmetic outcome for the patient and also eliminate the functional handicaps that may occur during, for example, combing and hairdressing. These devices would also be easy to implant and would not interfere with any subsequent imaging techniques, such as CT and magnetic resonance imaging. There is also a need for devices for repairing burr holes that do not leave a permanent foreign body in the skull, but rather promote the regeneration of calvarial bone so that the properties of the regenerated bone mimic those of the hard tissue surrounding the burr hole. Ideally, the device would allow for early and stable integration into the skull and, over time, be replaced by autogenous bone to be resorbed. Additionally, there is a need to develop an instrument for sealing a burr hole that allows the surgeon to re-access the burr hole for subsequent procedures so that the surgeon does not have to drill another burr hole in the patient's skull. [Means for solving the problem]

[0014] Summary of the Invention

[0014] Described herein are medical devices that can be used in the reconstruction of the skull, particularly following a surgical procedure in which a neurosurgeon creates a burr hole in a patient's skull, and the device is used to repair the burr hole. In some embodiments, the device is located substantially within the burr hole, or components of the device are located within the burr hole, and components of the device are located outside the burr hole on the exterior surface of the skull. Components on the exterior surface of the skull prevent the implanted device from becoming dislodged from the burr hole and terminating inside the skull, for example, between the skull and the meninges. In some embodiments, the device does not extend below the thickness of the skull (i.e., does not extend into the space between the skull and the meninges).

[0015]

[0015] In some embodiments, the device has a stem component and a cap component, and the cap is connected to the stem. In a sense, the stem is a ridge that protrudes from the cap. The stem component is inserted into the burr hole with the cap component located on the outer surface of the skull when the device is implanted. The cap component has a flange to ensure that the stem of the device cannot slip out of the burr hole or protrude directly below the skull.

[0016]

[0016] In some embodiments, the medical device includes a filament element that extends beyond the circumference of the stem. The filament element provides the device with a self-locking feature. The filament element can engage cancellous bone of the skull to secure the device within the burr hole. In some embodiments, the filament element is a flexible bristle.

[0017]

[0017] In some embodiments, barbs, hooks or tines extend from the stem body to engage the walls of the bone hole and inhibit removal of the medical device.

[0018]

[0018] In some embodiments, the cap has a convex shape that is designed to reduce the formation of a depression in the skull at the burr hole site.

[0019]

[0019] In some embodiments, the instrument has a stem that exerts pressure on the sidewall of the burr hole when the stem is inserted into the burr hole. In some embodiments, the stem is designed to expand within the burr hole. In some embodiments, the stem is designed to be compressed within the burr hole.

[0020]

[0020] In some embodiments, the device includes a stem component connected to a cap component, and the stem of the device is sized to at least partially fill the burr hole, more preferably to fill the burr hole. The cap of the device has a flange, which is sized to prevent the device from dislodging and to prevent the stem of the device from being pushed too far through the burr hole toward the meninges. In some embodiments, the device is sized such that the difference between the diameter of the stem of the device inserted into the burr hole and the diameter of the burr hole is 2mm or 1mm or less, preferably the stem diameter is less than the diameter of the burr hole. In some embodiments, the diameter of the stem of the device increases after implantation to form a tight fit and seal of the device within the burr hole.

[0021]

[0021] In another embodiment, the device is a rivet that includes two separate components, a pin component and a cylindrical hollow core component with a flange. The cylindrical hollow core component is inserted into the burr hole until the flange abuts the outer surface of the skull. The pin component is then inserted into the cylindrical hollow core component, expanding the cylindrical hollow core component and pressing the cylindrical hollow core component against the side wall of the burr hole. In some embodiments, the pin component is a rivet push pin, the length of the pin is short and its diameter is large when inserted into the cylindrical hollow core component. In another embodiment, the device includes a pin component and a cylindrical hollow core component with a flange, and the pin is threaded so that it can be threaded into the cylindrical hollow core component. Threading the pin into the cylindrical hollow core component expands the cylindrical hollow core component and applies pressure to the side wall of the burr hole, holding the device in place and sealing the burr hole. In some embodiments, the pins are made of a permanent material, such as a permanent polymer, so that they can be removed for subsequent procedures.

[0022]

[0022] In several embodiments, the device includes a cylindrical stem component connected to a cap having a flange.

[0023]

[0023] In several embodiments, the stem and cap have an open pore structure.

[0024] In some embodiments, the device includes a triangular open pore structure, and the triangular open pore structure includes layers of crossed filaments. In some embodiments, the triangular open pore structure is formed with layers of filaments positioned at angles of 0, 60, and 120 degrees to each other. In some embodiments, the elastic modulus of the device with the triangular open pore structure is 0.5 MPa to 20 GPa.

[0025]

[0025] In several embodiments, the cylindrical stem component is sized to be inserted into the bone defect and the diameter of the flange is larger than the diameter of the cylindrical stem.

[0026] In some embodiments, the triangular open pore structure device includes a resorbable polymer, hi some embodiments, the resorbable polymer is poly-4-hydroxybutyrate or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof.

[0027]

[0027] In some embodiments, the burr hole is sealed by physical expansion of the medical device within the burr hole. The device preferably further includes a flange to orient the device within the burr hole. In other embodiments, the device is secured in place using fibrin glue.

[0028]

[0028] The device reduces or prevents the formation of a dent in the skull after surgery in which a burr hole is created. The device improves the cosmetic outcome by leaving no dent or only a slightly sunken dent in the postoperative skull after implantation of the device. The device reduces or eliminates functional handicaps that may result, for example, from combing and hairdressing.

[0029]

[0029] In some embodiments, the device creates hard tissue on the exterior of the skull at the entry point to the burr hole after implantation. The hard tissue prevents the repair site from being palpable and from forming a depression at this location. In some embodiments, the device creates hard tissue on the exterior of the skull at the entry point to the burr hole and softer tissue within the burr hole.

[0030]

[0030] The device is preferably resorbable and degrades after implantation unless it contains permanent pins. In some embodiments, the device is sized to at least partially fill the burr hole, and more preferably to incorporate the physical shape of the burr hole.

[0031] In some embodiments, the device is implanted without fastening the device to the exterior surface of the skull. The device is implanted without the use of additional fixation devices such as screws, studs, staples, and sutures.

[0032]

[0032] The device preferably degrades over time, leaving no trace of the device. The device is rapidly and stably integrated into the skull. The device is designed to allow tissue in-growth, specifically bone in-growth, within the burr hole. The device preferably induces osteogenesis and new bone formation within the burr hole as the device degrades, and more preferably the burr hole is filled with calvarial bone. The nature of the new bone formed in the burr hole is preferably similar to the nature of the bone surrounding the burr hole. The device produces a stable skull formation. The device preferably does not leave any permanent foreign material within the skull, unless it contains a permanent pin that can be removed in a subsequent procedure. The device allows the burr hole to be filled without forming a depression in the outer surface of the skull. The repaired burr hole is stable to palpation. Follow-up palpation at 3, 6 and 12 months post-operatively preferably shows no dimpling at the burr hole site.

[0033] In some embodiments, the device is porous, more preferably having a porosity of 50-75%, or a packing density of 0.4-0.7. In some embodiments, the device has different porosities in different components of the device. In some embodiments, the device has high porosity in the region of the interlaminar layer of the skull and lower porosity in the region located at the entry point to the burr hole. In some embodiments, the density of the device is 0.2-0.6 g / cm. 3 It is.

[0034]

[0034] In some embodiments, in devices having a stem component and a cap component, the porosity of the stem component is different from the porosity in the cap component. In some embodiments, the pore size in the stem component may be different when measured longitudinally (along the axis of the stem) versus transversely (along the cross section of the stem). In some embodiments, the pore size in the cap component may be different when measured longitudinally (in the direction of the axis of the device) versus transversely (along the cross section of the cap). In some embodiments, the pore size in the stem component is 0.05-2 mm in the longitudinal direction. In some embodiments, the pore size in the stem component is 0.05-1 mm in the transverse direction. In some embodiments, the pore size in the stem component is 0.05-2 mm in the longitudinal direction and 0.05-1 mm in the transverse direction, with the longitudinal dimension being selected to be greater than the transverse dimension. In some embodiments, the dimensions of the pores in the cap component are 0.01-0.5 mm in the longitudinal direction. In some embodiments, the dimensions of the pores in the cap component are 0.01-0.2 mm in the transverse direction. In some embodiments, the dimensions of the pores in the cap component are 0.01-0.5 mm in the longitudinal direction and 0.01-0.2 mm in the transverse direction, the longitudinal dimension being selected to be greater than the transverse dimension.

[0035]

[0035] In several embodiments, the device includes a filament, such as a 3D printed filament, and the filament has a thickness of 0.05 to 0.8 mm.

[0036]

[0036] In embodiments, the elastic modulus of the device is from 0.5 MPa to 20 GPa, more preferably from 1 MPa to 4 GPa, and even more preferably from 10 MPa to 1 GPa.

[0037]

[0037] In some embodiments, the device further comprises a ceramic. The ceramic helps promote bone formation within the implant. In some embodiments, the ceramic comprises hydroxyapatite, alpha-tricalcium phosphate, beta-tricalcium phosphate (β-TCP), sintered hydroxyapatite, and precipitated hydroxyapatite, monocalcium phosphate monohydrate, dicalcium phosphate dihydrate, dicalcium phosphate anhydrate, amorphous calcium phosphate, tetracalcium phosphate, and octacalcium phosphate. In some embodiments, the device has different amounts of ceramic in different components or locations of the device. In some embodiments, in a device that includes a stem component and a cap component, the amount of ceramic in the stem component of the device is different from the amount of ceramic in the cap component of the device. In some embodiments, the amount of ceramic in the stem component is less than the amount of ceramic in the cap component. In some embodiments, the amount of ceramic in the stem component is 0.5-50 wt.%. In some embodiments, the amount of ceramic in the cap component is 0.5-80 wt.%, more preferably 5-50 wt.%. In some embodiments, the amount of ceramic in the stem component is 0.5-50 wt.%, and the amount of ceramic in the cap component is 1-70 wt.%, with the amount of ceramic in the stem being less than the amount of ceramic in the cap. In some embodiments, the amount of ceramic in the implanted device exceeds the amount of ceramic in the interlaminar region (cancellous bone located between the outer and inner layers of compact bone in the skull) at the entry point to the burr hole. Increasing the amount of ceramic in the implanted device near the entry point to the burr hole encourages the formation of hard tissue at the entry point that cannot be depressed. Using a high percentage of ceramic at this burr hole entry point helps prevent the formation of soft tissue in this vicinity and helps prevent the formation of easily noticeable tissue and depressions in the skull. The low percentage of ceramic in the implanted device in the interlaminar region helps create a slightly softer and more porous cancellous bone structure.

[0038]

[0038] In several embodiments, the device includes a filament, such as a 3D printed filament, and the filament has a thickness of 0.05 to 0.8 mm.

[0039]

[0039] A method for preparing the device is also described. The device can be preferably made using 3D printing or molding, such as injection molding, but can also be prepared by other methods including particle leaching, phase separation, foaming, and fiber processing. The device is preferably made by 3D printing or molding a composition including ceramic and P4HB or its copolymer, or PBS or its copolymer, to produce a device including a stem with an attached cap for insertion into a burr hole, or a cylindrical hollow core component with a flange and a separate pin that is inserted into the cylindrical hollow core component.

[0040] In some embodiments, the ceramic-containing device is prepared such that when the device is implanted, the amount of ceramic near the entry point into the burr hole exceeds the amount of ceramic located in the center of the burr hole. Preferably, the ceramic is β-TCP.

[0041]

[0041] In some embodiments, the device is 3D printed and has a structure that includes a filament. Preferably, the 3D printed device is printed using melt extrusion deposition. In some embodiments, the device is 3D printed with a filament, where the filament has a thickness of 0.05-0.8 mm. The distance between the filaments in the 3D printed device can vary. In a device that includes a cap and a stem, the distance between the filaments in the stem component of the device can be different than the distance between the filaments in the cap of the device. In some embodiments, the distance between the filaments in the stem component of the device is 0.05-2 mm. In some embodiments, the distance between the filaments in the cap component of the device is 0.01-0.5 mm. In some embodiments, the distance between the filaments in the stem component of the device is between 0.05 and 2 mm, and the distance between the filaments in the cap component of the device is between 0.01 and 0.5 mm, the distance between the filaments in the stem component of the device exceeds the distance between the filaments in the cap component of the device, and optionally, the thickness of the filaments is between 0.05 and 0.8 mm.

[0042]

[0042] In some embodiments, the pores in the stem component of the device including the cap component and the stem component have a longitudinal dimension of 0.05 to 2 mm. In some embodiments, the pores in the stem component of the device including the cap component and the stem component have a transverse dimension of 0.05 to 1 mm. In some embodiments, the pores in the stem component of the device including the cap component and the stem component have a longitudinal dimension of 0.05 to 2 mm and a transverse dimension of 0.05 to 1 mm, the longitudinal dimension being selected to be greater than the transverse dimension. In some embodiments, the pores in the cap component of the device including the cap component and the stem component have a longitudinal dimension of 0.01 to 0.5 mm. In some embodiments, the pores in the cap component of the device including the cap component and the stem component have a transverse dimension of 0.01 to 0.2 mm. In some embodiments, the dimensions of the pores in the cap component of a device including a cap component and a stem component are 0.01-0.5 mm in the longitudinal direction and 0.01-0.2 mm in the transverse direction, with the longitudinal dimension selected to be greater than the transverse dimension.

[0043] In some embodiments, the device includes a cap component and a stem component, with a filament element extending from the outer periphery of the stem component, the protruding filament element having a length measured from the outer periphery of the stem component to the tip of the element of between 0.1 and 5 mm, and a diameter of between 0.15 and 0.8 mm.

[0044]

[0044] The device is preferably formed from a resorbable polymer, including poly-4-hydroxybutyrate (P4HB) and its copolymers, and poly(butylene succinate) (PBS) and its copolymers. In some embodiments, the device is formed from poly-4-hydroxybutyrate and its copolymers with one or more ceramics, or poly(butylene succinate) or its copolymers with one or more ceramics.

[0045] In some embodiments, the device further comprises a bioactive agent. In some embodiments, the device comprises an antimicrobial or antibiotic agent.

[0046]

[0046] The device comprises materials that do not interfere with imaging techniques, including CT and magnetic resonance imaging.

[0047]

[0047] In some embodiments, the device can be used to repair bone defects in the metaphyseal region, for example, due to removal of cysts, tumors, and orthopedic devices, and harvesting of autografts. In other embodiments, the device can be used in repairing traumatic fractures, including fractures of the distal radius, proximal humerus, pelvis, proximal femur, distal femur, tibial plateau, tibial pilon, and calcaneus. The device can be used to repair bone defects resulting from revision of total joints, or osteotomy procedures, for example, of the distal radius or tibial plateau. The device can also be used in the treatment of tuberosity defects, or to fill defects in the iliac crest, for example, due to removal of autografts. In some embodiments, the device may be implanted into bone defects, such as fracture voids, by impaction to allow natural bone remodeling or healing. In other embodiments, the device may be combined with bone marrow aspirate or blood prior to implantation. Such devices may be used to deliver mesenchymal stem cells to the implantation site, where these stem cells may differentiate into bone-forming cells to promote healing and repair.

[0048]

[0048] A method for implanting the device is also described. The device, including a stem connected to a cap, is preferably inserted into the burr hole such that the stem hooks within the burr hole, a flange on the cap is positioned in contact with the outer surface of the skull, and a filament element present on the stem engages the cancellous bone of the skull. The device preferably includes a ceramic, and is preferably positioned such that there is a higher concentration of ceramic in the device near the entrance to the burr hole than near the interlaminar layer of the skull. In another embodiment, a device including a cylindrical hollow core with a flange and a separate pin is implanted by inserting the cylindrical hollow core into the burr hole until the flange is flush with the outer surface of the skull, and then inserting the pin into the cylindrical hollow core component.

[0049]

[0049] In view of the above, it is therefore an object of the present invention to provide a medical device for filling a burr hole.

[0050]

[0050] It is yet another object of the present invention to provide a medical device for filling a bone hole, defect, or wound.

[0051]

[0051] Yet another object of the present invention is to provide a medical device that not only fills the burr hole but also prevents the formation of a depression in the skull following burr surgery.

[0052]

[0052] It is yet another object of the present invention to provide a method for manufacturing a medical device for filling a burr hole that prevents the formation of a cavity in the skull after the burr hole procedure.

[0053]

[0053] Yet another object of the present invention is to provide a method for implanting a medical device into a burr hole.

[0054]

[0054] These and other objects, aspects, and advantages of the subject invention will become apparent from consideration of the following description when taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0055] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1]

[0055] A diagram of a medical device (100) according to an embodiment of the present invention being inserted into a burr hole (130) in the skull (140), showing the stem (110) and cap (120) of the device, the inner skull surface (160), the outer skull surface (150), the interdiscal layer (170), and the meninges (180). [Figure 2A]

[0056] FIG. 2 is a front view of a medical device (200) according to an embodiment of the present invention for insertion into a burr hole, showing a stem (240) with filament elements or bristles (210) and a cap (220) with a flange (230). [Figure 2B]

[0057] FIG. 2B is an isometric view of the bottom side of the medical device (200) shown in FIG. 2A. [Figure 2C]

[0058] FIG. 2B is a top view of the medical device (200) shown in FIG. 2A, showing the triangular porous structure. [Diagram 3]

[0059] FIG. 1 shows a bottom view of a medical device (300) for filling a burr hole, according to an embodiment of the invention, prepared by 3D printing P4HB with a packing density of 70%, a drop ratio of 1.3, an average filament (310) diameter (φF) of 285 μm, and an average distance between the printed filaments DAVE of 200 μm. [Figure 4]

[0060] FIG. 1 shows a bottom view of a medical device (400) for filling a burr hole, according to an embodiment of the invention, prepared by 3D printing P4HB with a packing density of 65%, an average distance between the printed filaments (410) of 250 μm, and a drop ratio of 1.3. [Diagram 5]

[0061] FIG. 1 shows a bottom view of a medical device (500) for filling a burr hole, according to an embodiment of the invention, prepared by 3D printing P4HB with a packing density of 55%, an average distance between filaments (510) of 350 μm, and a drop ratio of 1.3. [Figure 6]

[0062] FIG. 1 shows a bottom view of a medical device (600) for filling a burr hole, according to an embodiment of the invention, prepared by 3D printing P4HB with a packing density of 45%, an average distance between filaments (610) of 500 μm, and a drop ratio of 1.3. [Figure 7]

[0063] FIG. 1 shows a bottom view of a medical device (700) for filling a burr hole, according to an embodiment of the invention, prepared by 3D printing P4HB with a packing density of 40%, an average distance between filaments (710) of 575 μm, and a drop ratio of 1.3. [Figure 8A]

[0064] FIG. 8 is an isometric view of an apparatus (800) for filling a burr hole according to an embodiment of the present invention, showing a rivet push pin (810) inserted into a cylindrical hollow core (820) with a flange (830). [Figure 8B]

[0065] FIG. 8B is an exploded isometric view of the rivet push pin (810) and cylindrical hollow core (820) shown in FIG. 8A. [Figure 8C]

[0066] FIG. 8B is an exploded front view of the rivet push pin (810) and cylindrical hollow core (820) shown in FIG. 8A. [Figure 9A]

[0067] FIG. 1 is an isometric view of an instrument (900) for filling a burr hole, according to an embodiment of the invention, showing a threaded pin (910) inserted into a cylindrical hollow core (920). [Figure 9B]

[0068] FIG. 9B is a front view of the device (900) shown in FIG. 9A showing the threaded pin (910) inserted into the cylindrical hollow core (920). [Figure 9C]

[0069] 9C is a cross-sectional view of the device (900) shown in FIG. 9B taken along line 9C-9C. [Figure 9D]

[0070] FIG. 9B is a top view of the device (900) shown in FIG. 9A showing the flange (930) of the cylindrical hollow core (920) and the head (940) of the threaded pin with a hexagonal socket (960). [Figure 9E]

[0071] FIG. 9B is a bottom view of the device (900) shown in FIG. 9A showing the textured flange (950) of the cylindrical hollow core (920). [Figure 10A]

[0072] FIG. 1 is a bottom isometric view of a medical device (1000) for filling a burr hole according to an embodiment of the present invention, comprising a rectangular open pore structure with an average distance between filaments of 250 μm. [Figure 10B]

[0073] FIG. 10 is a bottom isometric view of another medical device (1020) for filling a burr hole in accordance with an embodiment of the present invention, comprising a parallelogram-shaped open pore structure and an average distance between filaments of 760 μm. [Figure 11]

[0075] A magnified portion of a medical device from above, according to an embodiment of the present invention, showing a triangular open pore structure due to layers of crossed filaments. [Figure 12] FIG. 13 is a side view of a cylindrical stem (1040) of a medical device for filling a burr hole according to an embodiment of the present invention, prepared by repeating each filament layer before changing the printing angle of the filament layer, which serves to increase the lateral porosity (L). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] Detailed Description of the Invention

[0076] Before describing the invention in detail, it should be understood that the invention is not limited to the specific variations described herein, since various changes or modifications may be made to the described invention without departing from the spirit and scope of the invention, and equivalents may be substituted. As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has separate components and features that may be easily separated or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Furthermore, many modifications may be made to adapt a particular situation, material, composition of matter, process, act(s) or step(s) of a process to one or more objectives, spirit or scope of the invention. All such modifications are intended to be within the scope of the claims appended hereto.

[0057]

[0077] The methods described herein may be carried out in any order of the described events that is logically possible, as well as in the order of the described events. Moreover, when a range of values ​​is provided, it is understood that every intervening value between the upper and lower limit of that range, and any other stated or intermediate value within that stated range, is also included within the invention. It is also contemplated that any optional features of the described variations of the invention may be set forth and claimed independently, or in combination with any one or more of the features described herein.

[0058]

[0078] All existing subject matter discussed herein (e.g., publications, patents, patent applications, and hardware) is incorporated by reference in its entirety into this specification, unless the subject matter may conflict with the subject matter of the present invention, in which case it is effective to present it herein.

[0059]

[0079] Reference to a singular item includes the possibility of a plurality of the same items. More specifically, in this specification and the appended claims, the singular forms "a," "an," "said," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement shall serve the function of the preceding description with respect to the recitation of the claimed elements or the use of exclusive terms such as "solely," "only," as in connection with the use of a "negative" limitation. Finally, unless otherwise defined, all technical and scientific terms used herein shall be recognized to have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0060]

[0080] In embodiments of the invention, the implantable medical device seals the burr hole after the burr procedure, reduces or eliminates the formation of a dent on the exterior surface of the skull, improves cosmetic results, reduces or eliminates palpability at the burr hole site, and reduces or eliminates the functional handicap the patient faces while barbering or combing hair. The medical device can be sized for use in different sized burr holes. The medical device can also be used in the repair of other bone defects. The medical device is preferably resorbable, porous, and allows for tissue ingrowth.

[0061]

[0081] In some embodiments, the device has a stem component connected to a cap component. The device is used by inserting the stem component into the burr hole until the flange of the cap component abuts the exterior surface of the skull. The device is preferably sized to prevent backing out of the burr hole. In some embodiments, the device has a filament element extending from the periphery of the stem, which engages the cancellous bone tissue surrounding the burr hole when the device is inserted into the burr hole. The filament element locks the device in place. In some embodiments, the device expands after implantation to prevent its backing out of the burr hole. In other embodiments, the stem is glued in place. Preferably, the flange of the cap component prevents the stem component from protruding into the space between the interior surface of the skull and the meninges. After implantation, tissue ingrowth into the device begins and bone regenerates within the burr hole. Over time, the device degrades and is replaced with autogenous bone. 1 illustrates the placement of instrument (100) within a burr hole (130) with the burr hole stem (110) positioned through the interlaminar layer (170) of the skull and the instrument cap positioned on the exterior surface of the skull. The flange (190) of the cap (120) extends beyond the periphery of the burr hole, ensuring that the instrument cannot be extended beyond the interior surface (160) of the skull and damage the underlying meninges (180) or become dislodged from the burr hole.

[0062]

[0082] In some embodiments, the device has a cylindrical hollow core component with an attached flange and a separate pin component. The device is used by embedding the cylindrical hollow core component in a burr hole and inserting the pin component into the cylindrical hollow core component. Insertion of the pin component into the cylindrical hollow core component expands the cylindrical hollow core component and causes it to apply pressure to the side wall of the burr hole, thereby securing the device within the burr hole. The pin may be a push pin rivet. The length of the pin may be shorter as its diameter increases. The flange of the cylindrical hollow core component prevents the cylindrical hollow core component from protruding into the space between the inner surface of the skull and the meninges. After implantation, tissue ingrowth into the device begins and bone regenerates within the burr hole. Over time, unless the pin component is made of a permanent material, the device will completely degrade and be replaced with autogenous bone.

[0063]

[0083] In other embodiments, the pin of the instrument is threaded and screws into the cylindrical hollow core. In other embodiments, the pin is tapered and presses into the cylindrical hollow core, expanding the diameter of the cylindrical hollow core. In some embodiments, the cylindrical hollow core further includes a flange to prevent the cylindrical hollow core from being pressed too far through the burr hole and into the space between the inner skull surface and the meninges.

[0064]

[0084] In some embodiments, the implanted device is more ceramic, less porous, or both more ceramic and less porous at the entry point to the burr hole than in the bipolar region of the burr hole (i.e., the cancellous region of the skull). After implantation, the ceramic-rich and / or less porous nature of the device aids in the regeneration of hard tissue at the entry point to the burr hole. The regenerated hard tissue reduces or eliminates the easy perception in the area of ​​the burr hole and reduces or eliminates the formation of a dent in the skull at the entry point to the burr hole.

[0065]

[0085] I. Definition

[0086] "Absorbable," as generally used herein, means that a material is broken down within the body and the breakdown products are eliminated or excreted from the body. The terms "absorbable," "resorbable," "degradable," and "erodible," with or without the prefix "bio," may be used interchangeably herein to describe materials that are broken down and gradually absorbed, excreted, or eliminated by the body.

[0066]

[0087] As used herein, "bioactive agent" is used to refer to a therapeutic, prophylactic or diagnostic agent, preferably an agent that promotes healing and regeneration of host tissue, and also an agent that prevents, inhibits or eliminates infection. "Drug, agent" is intended to include the single such entity, as well as the plural such entity.

[0067]

[0088] "Biocompatibility" as generally used herein means a biological response to a material or device that is appropriate for the device's intended use in the body. Any metabolic products of these materials should also be biocompatible.

[0068]

[0089] A "blend," as generally used herein, means a physical combination of different polymers, as opposed to a copolymer formed from two or more different monomers.

[0069]

[0090] "Burst hole" as generally used herein means a small hole made in the skull.

[0070]

[0091] As used herein, "calvarium" means a skull cap.

[0071]

[0092] "Copolymer of poly(butylene succinate)" as generally used herein means any polymer containing one or more different diol, diacid or hydroxycarboxylic acid units, e.g., 1,4-butanediol units and succinic acid units, with hydroxycarboxylic acid groups with one or more carboxylic acid or hydroxy acid groups. The copolymer may also contain chain extenders, coupling agents, crosslinking agents or branching agents.

[0072]

[0093] "Copolymer of poly-4-hydroxybutyrate" as generally used herein means any polymer containing 4-hydroxybutyrate with one or more different hydroxy acid units.

[0073]

[0094] The "interdiscal zone" is an area within the skull that is located between the two outer cortical layers of bone. The interdiscal zone contains cancellous bone.

[0074]

[0095] As used herein, "drop ratio" refers to the ratio of drop width to drop height during 3D printing.

[0075]

[0096] As used herein, "Elongation to break" means the increase in length of a material that occurs when a tension force is applied to break the material, expressed as a percentage of the original length of the material.

[0076]

[0097] As used herein, "Endotoxin unit" is determined using the Limulus amebocyte lysate (LAL) assay as further described by Gorbet et al. Biomaterials, 26:6811-6817 (2005).

[0077]

[0098] As used herein, "fill density" is the ratio of the volume occupied by 3D printed material, expressed as percent infill, divided by the total volume of the 3D printed object.

[0078]

[0099] As used herein, "dispense rate" defines droplet output.

[0079]

[0100] As used herein, a "macroporous" material or structure has an average pore size diameter of at least 25 microns, more preferably at least 50 microns, and even more preferably at least 75 microns.

[0080]

[0101] As used herein, "molecular weight" refers to weight average molecular weight (Mw) rather than number average molecular weight (Mn), unless otherwise specified, and is measured by GPC using polystyrene as a standard.

[0081]

[0102] "Oriented," as generally used herein, refers to the molecular alignment of polymer chains within a material. A drawn polymer can be partially oriented to highly oriented, with the tensile strength increasing with increasing degree of orientation. For example, a non-oriented polymer fiber can be drawn to orient the fiber, thereby resulting in a polymer fiber with higher tensile strength.

[0082]

[0103] "Poly-4-hydroxybutyrate" as generally used herein means a homopolymer containing 4-hydroxybutyrate units, also referred to herein as Tepha's P4HB™ polymer or TephaFLEX® biomaterial (manufactured by Tepha, Inc., Lexington, Mass.).

[0083]

[0104] "Poly(butylene succinate)" as generally used herein means a polymer containing 1,4-butanediol units and succinic acid units.

[0084]

[0105] As used herein, "trepanation" refers to the process of creating a burr hole in the skull.

[0085]

[0106] II. Materials for preparing the equipment for skull reconstruction

[0107] According to the embodiments of the invention described herein, an implantable medical device is disclosed, namely, a device for filling burr holes, reducing or preventing the formation of indentations in the skull after burr surgery, and reducing or eliminating physical handicaps during combing or hairdressing. In some embodiments, the device is porous and is inserted into the burr hole to repair the burr hole without forming indentations on the outer surface of the skull. The sealing of the burr hole protects the underlying tissue and brain from infection or other possible trauma. The device preferably includes a resorbable material, and more preferably a resorbable polymer, which provides a scaffolding structure for tissue ingrowth and gradually degrades as it is replaced by autologous tissue, unless a subsequent procedure is planned.

[0086]

[0108] Referring again to FIG. 1, an embodiment of an instrument (100) for insertion into a burr hole (130) in a skull (140) is shown in accordance with the subject matter of the present invention. As described further herein, the instrument (100) is preferably porous and has a stem component (110) for placement in the burr hole (130) and a connecting cap component (120) with a flange (190) that abuts the outer surface (150) of the skull when the instrument (100) is inserted into the burr hole. The instrument may further include a filament element emanating from the periphery of the stem that allows the stem to be retained within the burr hole. In embodiments, the diameter of the stem component (110) of the instrument (100) is sized to fit into the burr hole. In embodiments, the filament element emanating from the stem (110) is sized to penetrate the cancellous bone of the skull when the instrument is implanted. The device remodels in vivo to seal the burr hole without forming a dimple in the outer surface of the skull. In embodiments, the cap has a convex shape to prevent the formation of a dimple at the burr hole site. The device has a composition and porosity that prevents or reduces the formation of a dimple at the entry point to the burr hole. The device reduces or eliminates the easy perception due to the formation of a dimple in the skull at the site of the burr hole or due to the formation of soft tissue (instead of hard tissue) at this site.

[0087]

[0109] In other embodiments, the device has a cylindrical hollow core component with a flange that is inserted into the burr hole, and a separate pin that is inserted into the cylindrical hollow core component to secure the device within the burr hole. The device remodels in vivo to seal the burr hole without forming a dent in the outer surface of the skull. In embodiments, the pin has a convex head to prevent or reduce the formation of a dent at the entry point to the burr hole. The device has a composition and porosity that prevents or reduces the formation of a dent at the entry point to the burr hole. The device reduces or eliminates the easy perception due to the formation of a dent in the skull at the site of the burr hole, or due to the formation of soft tissue (instead of hard tissue) at this site. In embodiments, the pin can be made of a permanent polymer to allow its removal and eliminate the need to drill a new burr hole for a subsequent procedure using the same burr hole.

[0088]

[0110] The medical device is preferably made from absorbable polymers if no subsequent treatment is considered. Additionally, the device may be molded or made from a single component such as a filament. The filament may be unoriented, partially or fully oriented, and the filament may be 3D printed. The medical device may optionally include bioactive agents, as well as cells, such as stem cells. The medical device so formed may preferably have a pyrogen level of less than 20 endotoxin units per device, and may be sterilized.

[0089]

[0111] A. Material

[0112] The medical device may comprise permanent and / or degradable materials, and more preferably is made entirely from degradable materials unless subsequent procedures are anticipated. In a preferred embodiment, the device for sealing the burr hole is made from one or more absorbable polymers, preferably absorbable thermoplastic polymers and copolymers.Implantable devices may be made of, for example, polymers, including but not limited to, polymers of glycolic acid, lactic acid, 1,4-dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, 4-hydroxybutyric acid, ε-caprolactone, 1,4-butanediol, and succinic acid, such as polyglycolic acid, polylactic acid, polydioxanone, polycaprolactone, copolymers of glycolic acid and lactic acid, such as VICRYL® polymers, MAXON® polymers, and MONOCRYL® polymers, such as poly(lactide-co-caprolactone); poly(orthoesters); polyanhydrides; poly(phosphazenes); polyhydroxyalkanoates (PHAs); synthetic or biologically based polymers. Chemically prepared polyesters; polycarbonates; tyrosine polycarbonates; polyamides (e.g., synthetic and natural polyamides, polypeptides, and poly(amino acids)); polyesteramides; poly(alkylene alkylates); polyethers (e.g., polyethylene glycol, PEG, and polyethylene oxide, PEO); polyvinylpyrrolidone or PVP; polyurethanes; polyetheresters; polyacetals; polycyanoacrylates; poly(oxyethylene) / poly(oxypropylene) copolymers; polyacetals, polyketals; polyphosphoric acids; (phosphorous acid-containing) polymers; polyphosphoesters; polyalkylene oxalates oxalates; polyalkylene succinates; poly(maleic acid); silk (including recombinant silk and silk derivatives and analogs); chitin; chitosan; modified chitosan; biocompatible polysaccharides; hydrophilic or water-soluble polymers such as polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP) with blocks of other biocompatible or biodegradable polymers, such as poly(lactide), poly(lactide-co-glycolide), or polycaprolactone and its copolymers, such as random and block copolymers thereof. Preferably, the absorbable polymer or copolymer is substantially or completely resorbed two years after implantation.

[0090]

[0113] Blends of polymers, preferably absorbable polymers, may also be used to prepare the medical device. Particularly preferred blends of absorbable polymers include, but are not limited to, polymers of glycolic acid, lactic acid, 1,4-dioxanone, trimethylene carbonate, 3-hydroxybutyric acid, 4-hydroxybutyric acid, ε-caprolactone, 1,4-butanediol, succinic acid, or copolymers thereof.

[0091]

[0114] In a particularly preferred embodiment, the medical device comprises poly-4-hydroxybutyrate (Tepha's P4HB™ polymer, Lexington, Mass.) or copolymers thereof, and in one embodiment is made entirely of P4HB or copolymers thereof. Copolymers include P4HB with another hydroxy acid, such as 3-hydroxybutyrate, and P4HB with glycolic or lactic acid monomers. P4HB is a strong, flexible thermoplastic polyester that is biocompatible and resorbable (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 to 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 using polystyrene standards), more preferably 100 kDa to 600 kDa. Polymer weight average molecular weights of 50 kDa and above are preferred for processing and mechanical properties.

[0092]

[0115] In another preferred embodiment, the medical device comprises a polymer comprising at least a diol and a diacid. In a particularly preferred embodiment, the polymer used to prepare the device is poly(butylene succinate) (PBS), where the diol is 1,4-butanediol and the diacid is succinic acid. The poly(butylene succinate) polymer may be a copolymer comprising other diols, other diacids, or combinations thereof. For example, the polymer may be a poly(butylene succinate) copolymer further comprising one or more of the following: 1,3-propanediol, 2,3-butanediol, ethylene glycol, 1,5-pentanediol, glutaric acid, adipic acid, terephthalic acid, malonic acid, methylsuccinic acid, dimethylsuccinic acid, and oxalic acid. Examples of preferred copolymers are: poly(butylene succinate-co-adipate), poly(butylene succinate-co-terephthalate), poly(butylene succinate-co-butylene methyl succinate), poly(butylene succinate-co-butylene dimethyl succinate), poly(butylene succinate-co-ethylene succinate), and poly(butylene succinate-co-propylene succinate). The poly(butylene succinate) polymer or copolymer may also further 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, trimesic acid, citric acid, glycerol propoxylate, and tartaric acid. A particularly preferred agent or agent for branching, chain extending, or crosslinking poly(butylene succinate) polymers or its copolymers is a hydroxycarboxylic acid unit. Preferably, the hydroxycarboxylic acid unit has two carboxylic acid groups and one hydroxyl group, two hydroxyl groups and one carboxyl group, three carboxyl groups and one hydroxyl group, or two hydroxyl groups and two carboxyl groups.In one preferred embodiment, the device comprises poly(butylene succinate) with malic acid as a branching, chain extender, or crosslinker. The polymer is 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-butylene glycol-co-succinic acid) crosslinked or chain extended with malic acid. It should be understood that references to malic acid and other crosslinking, coupling, branching, and chain extenders include polymers prepared with these agents or agents, where the agents or agents have undergone further reactions during processing. For example, the agents or agents may be dehydrated during polymerization. Thus, poly(butylene succinate)-malic acid copolymer refers to a copolymer prepared from succinic acid, 1,4-butanediol, and malic acid. In another preferred embodiment, malic acid may be used as a branching, chain extender, or crosslinking agent to prepare 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 with one or more of the following: chain extenders, coupling agents, crosslinkers, and branching agents. In a particularly preferred embodiment, the poly(butylene succinate) and copolymers thereof contain at least 70%, more preferably 80%, and even more preferably 90% by weight of succinic acid and 1,4-butanediol units. Polymers comprising a diacid and a diol, such as poly(butylene succinate) and its copolymers, and others described herein, preferably have a weight average molecular weight (Mw) based on gel permeation chromatography (GPC) against polystyrene standards of 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 particularly preferred embodiments, the weight average molecular weight of the polymers and copolymers is from 50,000 Da to 300,000 Da, and more preferably from 75,000 Da to 300,000 Da.In one preferred embodiment, the poly(butylene succinate) or copolymers thereof used to fabricate the device, or components of the device, have the following properties: density 1.23-1.26 g / cm. 3 , a glass transition temperature of -31°C to -35°C, a melting point of 113°C to 117°C, a melt flow rate (MFR) of 2 to 10g / 10 minutes at 190°C / 2.16Kgf, and a tensile strength of 30 to 60MPa.

[0093]

[0116] When the burr hole can be accessed in a subsequent procedure, the device can include components made of permanent materials. For example, the device can include a permanent pin as further disclosed herein. Permanent materials that can be used to prepare the components of the device, such as the pin, include: metals, alloys, ceramics, and non-degradable polymers. Examples of suitable metals and alloys include stainless steel, tantalum, titanium, cobalt-chromium, iron, zirconium, manganese, and magnesium alloys, and Nitinol. Examples of suitable non-degradable polymers that can be used to prepare the components of the device, such as the pin, include ethylene and propylene polymers and copolymers, such as ultra-high molecular weight polyethylene, ultra-high molecular weight polypropylene, nylon, polyesters, such as poly(ethylene terephthalate), poly(polytetrafluoroethylene), polyurethane, poly(ether-urethane), poly(methyl methacrylate), polyether ether ketone, polyolefins, and poly(ethylene oxide).

[0094]

[0117] B. Additives

[0118] Some additives may be incorporated into the device, preferably into the absorbent polymer, copolymer or blend thereof used to make the device. These additives may be incorporated during the compounding process after fabrication of the device. For example, the additives may be melt compounded with the polymer or mixed using solution-based processing.

[0095]

[0119] In preferred embodiments, the additive is biocompatible, and even more preferably, the additive is both biocompatible and resorbable.

[0096]

[0120] In one embodiment, the additive may be a nucleating agent and / or a plasticizer. These additives may be added in sufficient amounts to produce the desired results. Generally, these additives may be added in amounts of 1% to 20% by weight. Nucleating agents may be incorporated to increase the crystallization rate of the polymer, copolymer, or blend. Such additives may be used, for example, to facilitate device fabrication and to improve the mechanical properties of the device. 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, ammonium chloride, and aromatic amino acids such as tyrosine and phenylalanine.

[0097]

[0121] Plasticizers that may be incorporated into the composition to prepare the device include, but are not limited to, di-n-butyl maleate, methyl laurate, dibutyl fumarate, di(2-ethylhexyl)(dioctyl) maleate, paraffin, dodecanol, olive oil, soybean oil, polytetramethylene glycol, methyl oleate, n-propyl oleate, tetrahydrofurfuryl oleate, epoxidized linseed oil, 2-ethyl hexyl epoxytallate, glycerol triacetate, methyl linoleate, dibutyl fumarate, methyl acetyl ricinoleate, acetyl tri(n-butyl) citrate ... Examples of suitable plasticizers include acetyl triethyl citrate, tri(n-butyl)citrate, triethyl citrate, bis(2-hydroxyethyl)dimerate, butyl ricinoleate, glyceryl tri-(acetyl ricinoleate), methyl ricinoleate, n-butyl acetyl rincinoleate, propylene glycol ricinoleate, diethyl succinate, diisobutyl adipate, dimethyl azelate, di(n-hexyl)azelate, tri-butyl phosphate, and mixtures thereof. Particularly preferred plasticizers are the citrate esters.

[0098]

[0122] C. Bioactive Agents

[0123] Medical devices can be loaded or coated with bioactive agents. Bioactive agents can be included in the device for a variety of reasons. For example, bioactive agents can be included to improve tissue ingrowth into the device, to improve tissue maturation, e.g., bone formation, to effect delivery of active agents, to improve wettability of the implant, to prevent infection, and to improve cell attachment. Bioactive agents can also be incorporated in different concentrations in different regions of the device, e.g., to promote cortical or cancellous bone formation in the skull.

[0099]

[0124] In a preferred embodiment, the bioactive agent is a ceramic. More preferably, the bioactive agent is a bioceramic, more preferably a resorbable bioceramic. The ceramic helps promote bone formation within the burr hole and at the entry point to the burr hole. The ceramic is preferably an osteoinductive ceramic. The osteoinductive ceramic aids in the process of bone formation. In embodiments, the ceramic includes calcium phosphate, calcium orthophosphate, hydroxyapatite, alpha-tricalcium phosphate, beta-tricalcium phosphate (β-TCP), sintered hydroxyapatite, precipitated hydroxyapatite, monocalcium phosphate monohydrate, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, amorphous calcium phosphate, tetracalcium phosphate, and octacalcium phosphate. A particularly preferred ceramic is β-TCP. The amount of ceramic in the device may be 0.1-80 wt.%, or more preferably 5-50 wt.%.

[0100]

[0125] The device may include a cell adhesion factor, such as a cell adhesion polypeptide. As used herein, the term "cell adhesion polypeptide" refers to a compound that has at least two amino acids per molecule and can bind cells by cell surface molecules. Cell adhesion polypeptides include any of the proteins of the extracellular matrix known to play a role in cell adhesion, such as fibronectin, vitronectin, laminin, elastin, fibrinogen, collagen type I, type II, and type V, as well as synthetic peptides with similar cell adhesion properties. Cell adhesion polypeptides also include peptides derived from any of the above proteins, including fragments or sequences that contain binding domains.

[0101]

[0126] The device may incorporate wetting agents designed to improve the wettability of the device surface and porous devices so that fluids can be easily absorbed onto the device surface and to promote cell attachment and / or modify the water contact angle of the device surface. Examples of wetting agents include polymers of ethylene oxide and propylene oxide, such as polyethylene oxide, polypropylene oxide, or copolymers thereof, such as PLURONICS®. Other suitable wetting agents include surfactants or emulsifiers.

[0102]

[0127] The device may include gels, hydrogels, or living hydrogel hybrids to further improve wettability throughout the thickness or diameter of the device and to encourage cell growth. Hydrogel hybrids consist of living cells encapsulated within biocompatible hydrogels such as gelatin, silk gel, and hyaluronic acid (HA) gel.

[0103]

[0128] The device may contain active agents designed to stimulate cellular ingrowth, including growth factors, cell differentiation factors, cellular recruiting 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 factors (FGFs), transforming growth factors (TGFs), platelet-derived growth factors (PDGFs), epidermal growth factors (EGFs), granulocyte-macrophage colony-stimulating factors (GMCSFs), vascular endothelial growth factors (VEGFs), insulin-like growth factors (IGFs), hepatocyte growth factors (HGFs), interleukin-1-B (IL-1 B), interleukin-8 (IL-8), and nerve growth factors (NGFs), and combinations thereof.

[0104]

[0129] Other bioactive agents that may be incorporated into the device include antimicrobial agents, especially antibiotics, bactericides, oncological agents, anti-scarring agents, anti-inflammatory agents, anesthetics, small molecule drugs, anti-angiogenic and pro-angiogenic factors, immunomodulatory agents, and blood coagulants. Bioactive agents may be proteins, such as collagen and antibodies, peptides, polysaccharides, such as chitosan, alginic acid, hyaluronic acid and their derivatives, nucleic acid molecules, small molecular weight compounds, such as steroids, inorganic materials, such as hydroxyapatite, or complex mixtures, such as platelet-rich plasma. Suitable antimicrobial agents include: bacitracin, biguanides, triclosan, gentamicin, minocycline, rifampin, vancomycin, cephalosporins, copper, zinc, silver, and gold. Nucleic acid molecules may include DNA, RNA, siRNA, miRNA, antisense, or aptamers.

[0105]

[0130] In yet another preferred embodiment, the device may incorporate a system for controlled release of the therapeutic or prophylactic agent.

[0106]

[0131] D. Filament

[0132] The device may include a filament. The filament may preferably be made from a degradable thermoplastic polymer, even more preferably a degradable thermoplastic polyester. The filament is preferably made from a degradable material listed in section II.A above. In a preferred embodiment, the filament is made from P4HB or a copolymer thereof. In another preferred embodiment, the filament is made from poly(butylene succinate) or a copolymer thereof. The filament may be 3D printed, a monofilament fiber, a multifilament fiber, or a combination thereof. The filament may be twisted, untwisted, or substantially parallel strands. The filament may be unoriented, partially oriented, highly oriented, or a combination thereof. Preferably, the filament is unoriented. The diameter of the filament may range from 0.05 to 0.8 mm, more preferably 0.1 to 0.4 mm, and even more preferably 0.15 to 0.3 mm. The weight average molecular weight of the filament polymer may be between 10 kDa and 1,200 kDa, more preferably between 50 kDa and 600 kDa. Preferably, the tensile modulus of the filament is between 10 and 1,000 MPa, more preferably between 30 and 300 MPa, even more preferably between 30 and 60 MPa. The filament may have a short-term degradation profile, a long-term degradation profile, or a combination thereof. In one embodiment, the short-term degradation profile is between 1 and 12 weeks, and the long-term degradation profile is between 12 weeks and 5 years, more preferably between 4 months and 2 years. The filaments of the device may have different degradation rates in vivo. Some filaments may degrade quickly, while others may degrade slowly. In another embodiment, the filament comprises an additive or bioactive agent. In a preferred embodiment, the filament comprises a ceramic, more preferably a resorbable bioceramic, and even more preferably, the filament comprises β-TCP.

[0107]

[0133] The filaments may be produced by any suitable method, such as 3D printing, melt extrusion, and solvent spinning, although 3D printing is preferred. In a particularly preferred embodiment, the filaments are produced by melt extrusion deposition.

[0108]

[0134] In embodiments, the filaments are produced by melt extrusion deposition of P4HB or a copolymer thereof, or of poly(butylene succinate) or a copolymer thereof. More preferably, the filaments are produced by melt extrusion deposition of a blend of P4HB and β-TCP, or of a blend of poly(butylene succinate) or a copolymer thereof and β-TCP.

[0109]

[0135] Devices capable of filling burr holes can be prepared from the filaments described above. Such devices can be produced from slowly degrading and rapidly degrading filaments, degradable filaments of different molecular weights, non-oriented, partially oriented, and fully oriented filaments, filaments of different elongation to break, tensile strength, and tensile modulus values, or combinations thereof.

[0110]

[0136] E. Foams and Porous Components

[0137] The device may include foams or other porous compositions. These compositions are preferably made from degradable thermoplastic polymers, even more preferably from degradable thermoplastic polyesters. The compositions are preferably made from the degradable materials listed in Section II.A above. The compositions may be made by any suitable method, such as melt and solution foaming, particulate leaching and phase separation techniques. In a preferred embodiment, the porous compositions are made by 3D printing. In a preferred embodiment, the compositions are made from P4HB or copolymers thereof or poly(butylene succinate) or copolymers thereof. The compositions may optionally be crosslinked. Preferably, the weight average molecular weight of the polymer of the composition is between 10 kDa and 1,200 kDa, but more preferably between 50 kDa and 600 kDa. The compositions may have an open or closed cell structure. In one embodiment, the construct has an open cell content of at least 10%, preferably at least 25%, more preferably at least 50%. The cell size may be up to 5 mm. The construct has a density of preferably 1 g / cm. 3 less than 0.75 g / cm 3 The foam may have a short term degradation profile of 1 to 12 weeks, or a long term degradation profile of 12 weeks to 5 years, or 12 weeks to 2 years. The composition may include additives or bioactive agents. Preferably, the composition further comprises a ceramic, more preferably a resorbable bioceramic. Even more preferably, the composition comprises P4HB and β-TCP, or poly(butylene succinate) or a copolymer thereof and β-TCP.

[0111]

[0138] Devices for filling burr holes can be prepared from the compositions described above. Such devices can be produced from foams and porous compositions with open or closed cell structures, with different cell sizes and densities, with different molecular weights, and with different degradation profiles.

[0112]

[0139] III. Method for manufacturing an instrument for reconstructing a bone defect including a burr hole

[0140] Various methods can be used to manufacture medical devices for repairing bone defects, specifically for reconstructing burr holes, and several different examples are described herein. The device reduces or eliminates the formation of a dent on the outer surface of the skull at the entry point to the burr hole. The device preferably replaces hard tissue instead of soft tissue at the entry point to the burr hole, thereby reducing or eliminating the easy perception at the burr hole site. In some embodiments, the device repairs the burr hole without forming a dent in the skull of more than 1 mm against the outer surface of the skull at the burr hole entry point. Preventing dents is important in improving cosmetic results and preventing handicaps to combing and hairdressing.

[0113]

[0141] The device is implanted into the burr hole to seal it. The device prevents infection or possible trauma to the tissue and brain underneath the burr hole. The device minimizes or eliminates the formation of pits in the skull. The device improves cosmetic results and reduces or eliminates functional handicaps, including combing and hairdressing. The device allows for tissue ingrowth. The device may provide a scaffolding structure to allow for tissue ingrowth. The device is preferably partially or fully resorbable, but in embodiments may include permanent components that can be removed to facilitate a second neurosurgical procedure using the same burr hole. The device degrades preferably in less than 5 years, more preferably in less than 2 years, and even more preferably in less than 1 year. The device preferably includes a resorbable polymer. The device is preferably fully resorbed after implantation and replaced with autogenous bone, preferably calvarial bone. The resorption of the device prevents any interference with imaging techniques such as CT and magnetic resonance imaging. The device creates hard tissue at the entry point to the burr hole, which is not easily felt. The device allows for early and stable integration into the skull, and over time is replaced as it is resorbed and replaced by new hard tissue.

[0114]

[0142] The device has a three-dimensional shape and may be unitary or may include two or more components. For example, the device may be unitary with a stem connected to a cap. Or, the device may include two components, such as a cylindrical hollow core and a pin, which may be inserted into the hollow core. Both the cylindrical hollow core and the pin may be made of a resorbable material. Alternatively, the pin may be made of a permanent material so that it can be removed for subsequent procedures so that the surgeon does not have to drill another burr hole in the patient's skull.

[0115]

[0143] The device is preferably dimensioned such that it can be inserted and secured in the burr hole. Preferably, the diameter of the device is similar in size to the diameter of the burr hole. In some embodiments, the difference between the outside diameter of the stem of the device or the core of the cylindrical hole and the diameter of the burr hole is ±2 mm, more preferably ±1 mm. The device is preferably dimensioned such that after implantation, the device fits tightly into the burr hole. In some embodiments, the device can be glued in place, for example, by fibrin glue. The device preferably has a shape that prevents the device from protruding into the space between the inner surface of the skull and the meninges. The device preferably has a flange that prevents it from emerging from the burr hole in close proximity to the meninges.

[0116]

[0144] In particularly preferred embodiments, the device comprises poly-4-hydroxybutyrate or copolymers thereof, or poly(butylene succinate) or copolymers thereof, even more preferably in the form of a porous composition.

[0117]

[0145] The device may include additives listed in Section II.B, and bioactive agents listed in Section II.C. The device may be coated with one or more of the following: bioactive agents, antibiotics, and antimicrobial agents.

[0118]

[0146] The manufactured device preferably has an endotoxin content of less than 20 endotoxin activity units, making it suitable for implantation into a patient's body. The manufactured device is preferably sterile. In embodiments, the device is sterilized by gamma irradiation, electron beam irradiation, or with ethylene oxide gas, preferably cold ethylene oxide gas.

[0119]

[0147] A. Examples of devices for burr hole reconstruction

[0148] In one preferred embodiment, the instrument is designed to repair a burr hole using a stem component connected to a cap component with a flange section. A diagram showing an instrument (200) with a stem component (240), a cap component (220) and a flange (230) is shown in Figures 2A, 2B and 2C. The instrument may include a stem component (240) suitable for placement in a burr hole and a cap component (220) suitable for placement at an entry point to the burr hole. The flange (230) is sized to abut the outer surface of the skull when the instrument is inserted into the burr hole and to prevent the instrument from being pushed too far into the burr hole. In particular, the flange prevents the stem of the instrument from extending into the space between the inner skull surface and the meninges.

[0120]

[0149] The device (200) shown in Figures 2A-2C has a filament element (210) that is designed to secure the device in place once inserted into the burr hole. The filament element is designed to be flexible so that it bends during insertion of the device into the burr hole, but then penetrates the cancellous bone of the skull to hold the device in place. In some embodiments, the filament element (240) has a brush-like or bristle-like shape and stiffness.

[0121]

[0150] The orientation and arrangement of the filament elements may vary. In some embodiments, and as shown in FIG. 2A, the array of bristles is aligned along the stem axis (A S ) laterally (approximately 90 degrees).

[0122]

[0151] In other embodiments, the array of bristles extends at an angle from the stem axis. The angle of the bristles from the stem axis can range from 0 to 90 degrees, or 30 to 60 degrees, and in some embodiments, 40 to 50 degrees. Placing the bristles at an acute angle from the stem axis does not impede insertion of the stem, and in contrast inhibits retraction of the stem from the burr hole. In particular, as the stem is retracted from the burr hole, the bristles are biased to further hook into the bone mass. In some embodiments, the instrument (200) is self-locking.

[0123]

[0152] In some embodiments, the cap component (220) has a convex shape. The convex shape is designed to minimize the formation of a dimple at the entry point to the burr hole. The diameter of the stem (240) is sized to fit into the burr hole. Preferably, the diameter of the stem is within ±2 mm, more preferably ±1 mm, of the diameter of the burr hole. The diameter of the flange (230) is larger than the diameter of the burr hole.

[0124]

[0153] The filament element (240) preferably has a length less than half the length of the stem (240) of the device. E ) is measured from the circumference of the stem (240) to the outermost tip of the filament element (210). In some embodiments, the length (L E ) is 0.1-5 mm, more preferably 1-2 mm. In some embodiments, the diameter of the elements is 0.15-0.8 mm. In some embodiments, the device is solid, but in more preferred embodiments, the device (200) is porous, and even more preferably, comprises a resorbable polymer, which is replaced over time by in-grown hard tissue. In some embodiments, the device (200) comprises a filament. The filament is preferably 3D printed. The entire device, including the filament elements, may be 3D printed.

[0125]

[0154] In another preferred embodiment, the device is designed to repair a burr hole using a cylindrical hollow core component and a separate pin that is inserted into the hollow core. A diagram showing the device (800) with a pin (810) inserted into the cylindrical hollow core component (820) is shown in FIG. 8A. The cylindrical hollow core component (820) preferably includes a flange (830). The device is implanted into the burr hole by forcing the cylindrical hollow core component into the burr hole until the flange of the cylindrical hollow core component presses against the outer surface of the skull surrounding the burr hole. The pin (810) shown in FIG. 8B is then forced into the cylindrical hollow core component (820) shown in FIG. 8B to secure the device (800) within the burr hole and close the burr hole. The pin (810) may be a rivet push pin (see FIG. 8C) designed to apply pressure to the cylindrical hollow core when inserted into it and force the core (820) into firm contact with the inside of the burr hole. The pin (810) may be designed such that at least a portion of its diameter is larger than the diameter of the cylindrical hollow core. The pin (810) may also be designed such that its diameter increases as the pin is inserted into the cylindrical hollow core. In some embodiments, the cylindrical hollow core has a pin stop (840) as shown in FIG. 8B, which prevents the pin from advancing completely through the core. The pin stop (840) may be used in conjunction with a rivet push pin (810) of the type shown in FIG. 8B, which is designed to press into the cylindrical hollow core (820), latch it in place as shown in the assembled device (800), and apply a lateral force to the cylindrical hollow core to secure the device in place within the burr hole. In some embodiments, the head of the pin (810) may have a convex shape that is designed to reduce the formation of a dent at the entry point into the burr hole.

[0126]

[0155] The dimensions of the device may vary, except as limited by any of the appended claims. Referring to FIG. 8C, in some embodiments of the invention, the outer diameter (DEXT ) can range from 6 to 25 mm ± 2 mm or from 8 to 15 mm ± 1 mm; flange diameter (D F ) preferably extends at least 2 mm beyond the outer periphery of the cylindrical hollow core; F ) is preferably less than 5 mm; the length (L CORE ) is preferably less than 11 mm; and the wall thickness of the cylindrical hollow core excluding the flanges (T W ) may be about 3 mm.

[0127]

[0156] In a further preferred embodiment, the cylindrical hollow core component may be used in conjunction with a threaded pin to repair and seal a burr hole. A view of the instrument (900) with a threaded pin (910) partially inserted into the cylindrical hollow core component (920) is shown in Figures 9A and 9B. The cylindrical hollow core component (920) includes a flange (930) as shown in Figure 9D, which properly positions the instrument within the burr hole and prevents the instrument from protruding into the space between the inner skull surface and the meninges. Once the cylindrical hollow core component is inserted into the burr hole with the flange (930) abutting the outer skull surface, the threaded pin (910) is threaded into the cylindrical hollow core. A cross section (section AA) of the instrument showing the threaded pin (910) threaded into the cylindrical hollow core (920) is shown in Figure 9C. The threaded pin (910) has a hexagonal socket (960) in its head (940), as shown in FIG. 9D, to allow the pin to rotate. The underside of the flange is preferably textured (950), as shown in FIG. 9E, to prevent rotation of the cylindrical hollow core. The textured surface abuts the external skull surface and prevents rotation of the cylindrical bore core (920). Preferably, the threaded pin (910) is tapered so that once tightened within the cylindrical hollow core (920), it exerts pressure on the cylindrical hollow core so that it is secured to the side wall of the burr hole. In one embodiment, the head (940) of the pin may have a convex shape. The convex shape is designed to reduce the formation of a dent at the entry point to the burr hole.

[0128]

[0157] In some embodiments, pins 810 and 910 are designed to be removable for subsequent procedures. Removable pins allow the surgeon to later access the burr hole without having to drill a new burr hole into the skull. Removable pins 810 and 910 can be formed from permanent materials, including permanent polymers, ceramics, and metals, including those listed in Section II.A.

[0129]

[0158] B. Dimensions of the device for burr hole reconstruction

[0159] Burr holes are generally drilled with a diameter of 6-25 mm, usually 8-19 mm, although smaller and larger holes can be made in the skull. The devices disclosed herein are designed such that the diameter of the stem component (e.g., outer diameter of (240)) or the cylindrical hollow core outer diameter (e.g., outer diameter of (820) and (920)) is within ±2 mm, or more preferably ±1 mm, of the burr hole diameter. This design allows for a tight fit of the device within the burr hole. In one embodiment, the diameter of the stem of the device (200) or the outer diameter of the cylindrical hollow core of the device, e.g., (820) or (920), is 6-25 mm ±2 mm, more preferably 8-19 mm ±1 mm.

[0130]

[0160] The diameter of the pin (910) inserted into the cylindrical hollow core to secure the device in the burr hole is preferably 0.5 to 2 mm, more preferably 0.5 to 1 mm, larger than the inner diameter of the cylindrical hollow core (920). For example, if the inner diameter of the cylindrical hollow core (920) is 6 mm, the diameter of the pin (910) is preferably 6.5 mm or 7 mm. The larger diameter pin presses the cylindrical hollow core against the cancellous bone of the skull and secures the device at the implantation site. In one embodiment, the desired diameter of the pin (910) is d pin and d pin is the expression:

[0161] d pin +2×d thickness =d hole +0.5~2mm

[0162] (where the diameter of the burr hole is d hole and the wall thickness of the cylindrical hollow core (920) is d thickness is) It can be calculated using

[0131]

[0163] The rivet push pin (810) is designed to have a first outer diameter that allows for insertion into the cylindrical hollow core and a second expanded outer diameter that secures the device (800) in the burr hole. Preferably, the second expanded outer diameter is 0.5-2 mm, more preferably 0.5-1 mm, larger than the inner diameter of the cylindrical hollow core (820). Expansion of the rivet push pin (810) within the cylindrical hollow core (820) presses (compresses) the core against the cancellous bone of the skull to secure the device (800) at the implantation site.

[0132]

[0164] In some embodiments, insertion of the pin expands the hollow core, creating an interference fit between the medical device and the bone hole, securely securing the medical device within the hole.

[0133]

[0165] The size of the flange of the device (e.g., 230, 830, or 930) should be sufficient to prevent the device from passing through the burr hole and into the space between the inner skull surface and the meninges. Preferably, the flange extends beyond the circumference of the burr hole on the outer surface of the skull by at least 2 mm, more preferably at least 3 mm, but no more than 20 mm, more preferably no more than 10 mm. For example, the outer diameter of the stem component (e.g., 240) or cylindrical hollow core component (e.g., 820 or 920) is 14 mm, and the diameter of the flange is preferably at least 18 mm, more preferably at least 20 mm. The preferred diameter of the flange is between 10 mm and 29 mm, but can be smaller or larger depending on the size of the burr hole and the amount of desired overlap of the flange with the skull. Preferably, the diameter of the flange is between 12 mm and 19 mm.

[0134]

[0166] The average thickness of the skull is 6.5 mm in men and 7.1 mm in women. The devices disclosed herein are designed such that the burr hole is at least partially filled with the device and can be completely filled with the device. However, the devices are designed such that the stem component (e.g., 240) of the device (e.g., 200) or the cylindrical hollow core component (e.g., 820 and 920) of the device is less than the thickness of the skull. This prevents the device from protruding into the space between the inner skull surface (160) and the meninges (180), where it could potentially cause tissue damage. In some embodiments, the length of the stem of the device (e.g., 200) or the cylindrical hollow core component (e.g., 820 or 920) of the device is less than 6 mm, more preferably less than 5 mm, and more preferably less than 4 mm.

[0135]

[0167] The profile of the device protruding from the skull at the outer surface (150) of the skull is preferably relatively small after insertion of the device into the burr hole. Preferably, the cap component (220) should not protrude above the surface of the skull, for example by more than 5 mm, more preferably by more than 3 mm, and even more preferably by more than 1 mm. Similarly, the profile of the device including the pin component and the cylindrical hollow core component, for example (800) and (900), should not protrude above the surface of the skull, for example by more than 5 mm, more preferably by more than 3 mm, and even more preferably by more than 1 mm, after implantation of the device into the burr hole. In some embodiments, the heads of the cap component (220) and the pin components (810) and (910) preferably have a convex shape. In some embodiments, the length of the device inserted into the burr hole, measured longitudinally, is between 2 and 7 mm, more preferably between 3 and 5 mm, and the length of the device not inserted into the burr hole, measured longitudinally, is between 0.5 and 5 mm, and even more preferably between 1 and 2 mm.

[0136]

[0168] C. Device Porosity

[0169] Devices for sealing burr holes, including those shown in Figures 2-9, are preferably porous or become porous after implantation. The devices may be macroporous. Preferably, the porosity of the device is 50-70%. In some embodiments, the device is 3D printed and has a packing density of 0.4-0.7. In some embodiments, the device comprises P4HB or PBS, or copolymers thereof, and has a packing density of 0.2-0.6 g / cm. 3 In one embodiment, the device has an average pore size diameter, pore size dimension, or interfilament distance of 0.01 mm to 2 mm, more preferably 0.05 mm to 1 mm, and even more preferably 0.075 mm to 0.5 mm. The pore size of the device may be different in different regions of the device. The region of the device located within the burr hole may have larger pores or pore size than the region of the device located at the entry point to the burr hole. An device (200) for insertion into a burr hole, including a stem component (240) and a cap component (220) with a flange (230), designed to abut the exterior surface of the skull, may have larger pores or larger pore size in the stem component (240) than in the cap component (220) or the flange component (230). For example, the average pore size may be 0.05-2 mm in the stem component (240) and 0.01-0.5 mm in the cap component (220) or flange component (230), with the average pore size in the stem component being larger than the average pore size in the flange component.

[0137]

[0170] Devices including cylindrical hollow cores and pins, such as those shown in Figures 8 and 9, can be porous. Devices (800) or (900) for insertion into a burr hole, including a pin component (810) or (910) and a cylindrical hollow core component (820) or (920), can also have a larger average pore size or larger average pore size in the stem region located in the burr hole than in the flange regions (830) and (930). The cylindrical hollow cores of this device design, such as (820) and (920), can be porous and have an average pore size dimension of 0.05 to 2 mm, more preferably 0.075 to 1 mm. The pins of this device design, such as (810) and (910), can be solid, but also porous with an average pore size dimension of 0.075 mm to 1 mm. The pore size of the flange regions of the cylindrical hollow core, such as (830) and (930), may be porous and may have an average pore size dimension of 0.01 to 1 mm, or 0.025 to 0.5 mm.

[0138]

[0171] D. Equipment containing ceramics

[0172] The device may include ceramic in an amount of 0.1 wt.% to 80 wt.%, more preferably 5 wt.% to 60 wt.%, and even more preferably 10 wt.% to 40 wt.%. Preferably, the ceramic is blended with a resorbable polymer, more preferably P4HB or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof. The amount of ceramic in the device may be different in different locations or regions of the device. For example, a device that includes a flange component, such as (230), (830), or (930), may have a higher wt.% ceramic in the flange component than in the region of the device that is inserted into the burr hole. Thus, the flange component (230) may have a higher wt.% ceramic than the stem component (240), and the flange components (830) and (930) may have a higher wt.% ceramic than the section of the cylindrical hollow core (820) or (920) that is inserted into the burr hole. In some embodiments, the amount of ceramic present in the region of the device that is inserted into the burr hole is between 0.5 and 50 wt.%. In some embodiments, the amount of ceramic in the implanted device is greater at the burr hole entry point than the amount of ceramic present in the portion of the device that is located within the burr hole and surrounded by the interlaminar layer. The increased amount of ceramic in the implanted device near the burr hole entry point encourages the formation of hard tissue at the entry point that cannot be depressed. The placement of a device with a high percentage of ceramic near the burr hole entry point helps prevent the formation of soft tissue in this vicinity and helps prevent the formation of tissue and depressions that are easily felt in the skull. The low percentage of ceramic in the implanted device, surrounded by the interlaminar layer, helps create a slightly softer and more porous cancellous bone structure.

[0139]

[0173] E. Fabrication of equipment for burr hole reconstruction

[0174] In one embodiment, the device is prepared by 3D printing. Suitable methods for 3D printing the device include fused filament fabrication, fused pellet deposition, melt extrusion deposition, selective laser melting, printing of slurries and solutions using a coagulation bath, and printing using a binder solution and powder granules. Preferably, the device is prepared by melt extrusion deposition. The devices shown in Figures 3-7 were manufactured by melt extrusion deposition.

[0140]

[0175] In a typical procedure, the device is prepared by melt extrusion deposition of a resorbable polymer, and preferably a blend of ceramic and resorbable polymer. The device can be formed, for example, from a blend of P4HB and ceramic, preferably β-TCP, using the following procedure: Pellets of P4HB (e.g., Mw 100-600 kDa) are blended with β-TCP and compounded prior to 3D printing. Preferably, the amount of β-TCP in the device is 0.5-80 wt.%, more preferably 5-50 wt.%. Pellets containing P4HB and β-TCP can be 3D printed to form a burr hole repair device (e.g., as shown in Figures 2A-C), for example, using an Arburg Freeformer 3D printer and using the printing parameters shown in Table 1, and a 3D CAM (Computer Aided Design Model) for a burr hole implant. The average diameter of the printed 3D filaments is selected based on the properties of the desired device, including porosity or packing density (i.e., the number of 3D printed filaments per mm between the contours of the 3D printed device). Preferably, the average filament diameter is between 50 and 800 μm, more preferably between 100 and 600 μm, and even more preferably between 150 and 550 μm.

[0141]

[0176] The printing pattern is also selected based on the properties of the desired device. For example, the filaments can be printed layers at angles of 0, 60, and 120 degrees to each other, forming a triangular open pore structure. Or, the filaments can be placed at other angles to each other, resulting in other geometric open pore structures, including, for example, squares, quadrilaterals, parallelograms, and other shapes, whether polygonal or not. 3D printing of devices is highly desirable because it allows for precise control of the shape of the device. In one embodiment, the 3D printed device is printed in the shape shown in device (200), where the device has a round cap (220) connected to a round stem (240) with a small diameter, creating a flange (230). Device (200) also has filament elements (210) protruding from the periphery of the stem. The dimensions of the cap, stem, and flange are selected according to the dimensions of the burr hole that needs to be filled. The flange is printed to extend beyond the edge of the burr hole by at least 2 mm, such that the diameter of the printed flange is at least 4 mm greater than the diameter of the burr hole. S ) is printed so that its length is less than the thickness of the burr hole. Typically, a stem (240) is printed that is 2-7 mm in length.

[0142]

[0177] The cap (220) is preferably printed such that its thickness in the longitudinal direction (in the direction of the stem) is between 1 mm and 5 mm. The filament elements are preferably printed such that they extend 0.1 to 5 mm, more preferably 1 to 2 mm, outward from the circumference of the stem. The filament elements are preferably printed with a diameter of 0.15 to 0.8 mm. The cap preferably has a convex shape. The filament size and printing pattern are tailored to select the desired porosity of the device. The device may be printed such that the porosity or packing density of the device may be the same throughout the device or may be different in different regions of the device. For example, the cap (220) of the device may be printed with a different packing density than the stem (240) of the device.

[0143]

[0178] Figures 3-7 show devices for filling burr holes, 3D printed with different packing densities. The packing density of the device shown in Figure 3 is, for example, 70%. The packing density of the device shown in Figure 4 is 65%. The packing density of the device shown in Figure 5 is 55%. The packing density of the device shown in Figure 6 is 45% and the packing density of the device shown in Figure 7 is 40%. As is evident from Figures 3-7, the porosity of the device increases as the packing density decreases. The packing density may also be increased to eliminate porosity or to create a device with reduced porosity. As described in Example 8, herein, the packing density may be varied during the manufacture of the device, for example, to create a solid cap (220) connected to a porous stem (240), or to create a device with porosity in both the cap (220) and stem (240), but with different levels of porosity in the cap (220) and stem (240), as described in Example 8. Devices may be 3D printed with porosity between 0.5 and 80%, but more preferably between 30 and 75%. Devices may be printed such that the size of the pores or the distance between the filaments in the stem (240) and cap (220) are different. For example, the device may be printed such that the distance between the filaments in the stem is 0.05 to 2 mm, more preferably 0.075 to 1 mm, even more preferably 0.1 to 0.6 mm in the longitudinal direction of the stem and 0.05 to 1 mm, more preferably 0.075 to 0.5 mm, even more preferably 0.1 to 0.25 mm in the transverse direction of the stem. The device may be printed such that the distance between the filaments in the cap is 0.01 to 0.5 mm, more preferably 0.025 to 0.2 mm, even more preferably 0.025 to 0.1 mm in the longitudinal direction of the cap and 0.01 to 0.2 mm, more preferably 0.01 to 0.1 mm, even more preferably 0.01 to 0.05 mm in the transverse direction.

[0144]

[0179] Referring to FIG. 3, the device preferably has a filament-to-filament distance (D AVE) is at least 50 μm, more preferably at least 100 μm, and even more preferably at least 200 μm, but less than 1 mm.

[0145]

[0180] In some embodiments, the filaments are applied in separate or individual layers (e.g., one layer at a time, overlapping or stacked). Within a single layer, each filament may have the same orientation or direction. For example, as shown in FIG. 3, the filaments within each layer extend in the same direction across the stem axis and are generally parallel to one another. Furthermore, the distance between the filaments 310 is equal. However, in other embodiments (not shown), the distance between the filaments within a single layer may vary.

[0146]

[0181] As described herein, in embodiments, layers of filaments are applied, printed, or stacked (one on top of the other) to form a device. A second layer of filaments, with the filaments oriented in a second direction or angle, is applied over a first layer of filaments, with the filaments oriented in a first direction or angle. Applying layers of filaments with different orientations creates a cross, triangle, or other polygon-like open pore structure when viewed from the top or bottom of the device, as shown, for example, in Figures 2B, 2C.

[0147]

[0182] The device may also be printed such that the wt.% of ceramic (e.g., β-TCP) in the filaments located in the stem (240) is different than the wt.% of ceramic in the filaments located in the cap (220). For example, the device may be printed such that the filaments in the stem (240) have 0.5-50 wt.%, more preferably 5-40 wt.%, and even more preferably 10-35 wt.% ceramic, and the filaments in the cap (220) have 0.5-80 wt.%, and more preferably 5-50 wt.%, ceramic, where the amount of ceramic in the filaments in the cap is higher than the filaments in the stem.

[0148] [Table 1]

[0149]

[0183] The parameters shown in Table 1 may be used to 3D print a device using P4HB or a blend of P4HB and a ceramic, such as β-TCP. The parameters shown in Table 2 may be used to 3D print a device using poly(butylene succinate) or a copolymer thereof, or a blend of poly(butylene succinate) or a copolymer thereof and a ceramic, such as β-TCP.

[0150] [Table 2]

[0151]

[0184] Examples of 3D printed devices for repairing bone defects with various open pore structures are shown in Figures 10A and 10B. The device shown in Figure 10A was printed with P4HB containing 20% ​​(w / w) β-TCP, has adjacent layers of filaments oriented at a 90 degree angle to each other, and has an average pore diameter size of 250 μm. The device shown in Figure 10B was printed with P4HB, has adjacent layers of fibers oriented at a 60 degree angle to each other, and has an average pore diameter size of 760 μm. The figure shows a bottom isometric view of a device with a cylindrical stem connected to a cap with a flange, where the stem and cap have an open pore structure.

[0152]

[0185] In the examples shown in Figures 10A and 10B, the print or filament orientation angles are 90 degrees and 60 degrees, respectively. However, these angles can be varied to create open pore structures of different shapes. Individual layers can be printed at various angles ranging from 45 to 90 degrees, for example.

[0153]

[0186] The number of layers having different orientation angles or print angles can also vary. In some embodiments, 2-3 different types of layer orientations are used. However, in other embodiments, 3-5 or more different types or print angles or layer orientations are provided.

[0154]

[0187] Examples of pore shapes resulting from the stacked layer arrangements described herein may also vary and include, but are not limited to: triangle, square, trapezoid, parallelogram, diamond, rhomboid, pentagon, or another polygon. In a preferred embodiment, the device for repairing bone defects has a triangular open pore structure and is made from P4HB or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof.

[0155]

[0188] A close-up of an exemplary triangular pore structure is shown in FIG. 11. The triangular open pore structure (1052) is generally defined by stacking layers of filaments such that the filaments (e.g., l1, l2, l3) cross. In FIG. 11, there are three types of layers, including a first layer having filaments oriented at 0 degrees from the horizontal, corresponding to one or more filaments l1; a second type of layer having filaments oriented at 60 degrees from the horizontal, corresponding to filament l3, and a third type of layer having filaments oriented at 120 degrees from the horizontal, corresponding to filament l2. Collectively, the arrangement of layers having filaments oriented at different angles creates the triangular open pore structure shown in FIG. 11 and serves to encourage tissue ingrowth.

[0156]

[0189] In embodiments, the elastic modulus of the device is between 0.5 MPa and 20 GPa. The cylindrical stem is sized to be inserted into the bone defect, and the diameter of the flange is greater than the diameter of the cylindrical stem.

[0157]

[0190] 12 shows a side view of a 3D printed structure of a cylindrical stem (1040) of a medical device with an open pore structure (e.g., as shown in FIGS. 2-7, 10A and 10B, 11), where the lateral porosity (L) has been increased by repeating the printing of each filament layer once (e.g., l1, l1) before changing the filament orientation or printing angle. Repeating layers of filaments in the same orientation creates an "effective layer" that is twice as tall (e.g., the effective first layer includes l1 and l1) and increases the lateral porosity (L) of the device.

[0158]

[0191] In some embodiments, the transverse porosity (L) is different from the vertical porosity (V). The transverse porosity is smaller or larger than the vertical porosity (V). In some embodiments, the transverse porosity is adjusted relative to the vertical porosity by increasing or decreasing the number of layers of repeated filaments.

[0159]

[0192] Repeated printing of layers before changing the printing angle can also be used to increase the strength of the device. In the example shown in FIG. 12, two filament layers are printed at a 0 degree angle, then the printing angle is changed to print two filament layers at a 60 degree angle, then two filament layers are printed at another angle, such as a 120 degree angle. The process is then repeated to build up the porous structure to the desired dimensions. To create even larger pore sizes, multiple layers (e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more layers) can be printed (i.e., repeated) at the same angle before the printing angle is changed. It should be understood that, according to the present invention, these angles can be changed to form open pore structures of different shapes, with two or more filament layers printed at the same angle before the printing angle is changed.

[0160]

[0193] The various shapes of open pore structures described can be used to prepare any part of the device or all of the device, such as the cylindrical stem and flanges. Larger pore sizes, especially those located in the lateral regions and cylindrical stem of the device, are favorable for supporting cell proliferation and tissue ingrowth, controlling key cellular processes and pathways, providing nutrition and nutrient transport to, for example, pre-osteoblasts, and facilitating the excretion of metabolic products, allowing the inflow of fluids, and facilitating the invasion of the 3D structure by fibrovascular tissue and the development of mature osteons.

[0161]

[0194] In another embodiment, the device is prepared by molding, preferably by injection molding. The devices (800) and (900) shown in Figures 8 and 9, respectively, can be prepared by molding, more specifically by injection molding. The device (800) can be prepared by injection molding the components (810) and (820) using a suitable mold and assembled by inserting the pin (810) into the cylindrical hollow core (820). The device (900) can also be prepared by injection molding the components (910) and (920) using a suitable mold and assembled by screwing the pin (910) into the cylindrical hollow core (920). Preferably, the devices (800) and (900) are injection molded from P4HB or its copolymers, poly(butylene succinate) or its copolymers, or blends of these polymers with ceramic, preferably β-TCP.

[0162]

[0195] Devices can be injection molded from blends of P4HB and its copolymers, or P4HB and copolymers with ceramics, such as β-TCP, using the following procedure.

[0163]

[0196] The polymer or blend is dried before molding to avoid significant loss of intrinsic viscosity. Preferably, the polymer or blend is dried so that the moisture content of the molding composition is 0.5 wt.% or less, more preferably 0.05 wt.% or less, as measured gravimetrically. The polymer or blend may be dried in vacuum. In a particularly preferred method, the polymer or blend is dried in a vacuum chamber under a vacuum of at least 10 mbar, more preferably at least 0.8 mbar, to a moisture content of 0.03 wt.%. High temperatures below the melting point of the polymer pellets may also be used in the drying step. Alternatively, the polymer may be dried by extraction into a solvent and reprecipitation or by the use of a desiccant. The moisture content of the polymer or blend may be determined using a VaporPro Moisture Analyzer from Arizona Instruments, or a similar instrument. Injection molding of the polymer or blend uses controlled processing conditions of temperature, time, speed, and pressure, where the dried pellets are melt processed, injected into a mold, cooled, and then molded. A suitable injection molding machine for preparing the device is a hydraulic injection molding machine with an 18 mm screw with four heating zones to melt the polymer or blend. Suitable conditions for injection molding the device are given in Table 3. As shown in Table 3, the heating zones can be set at: Zone 1 150-180°C, Zone 2 170-190°C, Zone 3 180-220°C, and Nozzle 180-220°C. The mold temperature can be set at 3-40°C. The extruder screw speed can be set at 20-400 rpm, more preferably 300 rpm. Preferably, the injection pressure is set at 750 psi (5.17 MPa) to 1250 psi (8.62 MPa), more preferably 850 psi (5.86 MPa) to 1000 psi (6.89 MPa). In one embodiment, the injection speed is set in the range of 5 cm / sec to 20 cm / sec, more preferably about 10 cm / sec. The injection fill cycle depends on the inherent viscosity of the polymer or blend, and can be adjusted as desired by selection of the injection speed, polymer or blend melt temperature, and mold temperature.In one embodiment, the holding pressure is set at 750 psi (5.17 MPa) to 1250 psi (8.62 MPa), more preferably 850 psi (5.86 MPa) to 1000 psi (6.89 MPa), and the holding time is preferably set at 2 to 8 seconds, more preferably 3 to 5 seconds. Preferably, the cooling time of the molded device or component is 60 to 150 seconds, more preferably 90 to 120 seconds. Those skilled in the art will recognize that the process is not limited to the conditions in Table 3 or to hydraulic injection molding machines, and that molding of the present invention may also be performed using electric, mechanical, and hybrid injection molding machines.

[0164] [Table 3]

[0165]

[0197] In embodiments, the injection molding equipment containing P4HB or copolymers thereof is annealed. Annealing the equipment increases the crystallinity of the polymer or blend. Preferably, the P4HB injection molding equipment is annealed at a temperature of preferably 45-55°C, but not exceeding 60°C. In a preferred embodiment, the injection molding equipment may be heated in a water bath. One skilled in the art will recognize that the crystalline content ratio of the injection molding equipment may also be adjusted by varying the retention time in the mold, the cooling rate of the mold, and by annealing the molded parts in a post-molding heating cycle.

[0166]

[0198] Devices for sealing burr holes, such as (800) and (900), can be injection molded from poly(butylene succinate) and its copolymers, and blends of poly(butylene succinate) and its copolymers with ceramics, such as β-TCP, using the conditions shown in Table 3.

[0167]

[0199] IV. Methods for Implanting a Device to Close a Burr Hole

[0200] In certain embodiments, the device is implanted within the body to repair a bone defect, and more specifically, the device is implanted in the skull to fill a burr hole.

[0168]

[0201] Prior to implantation, the device is sterilized. The device can be sterilized, for example, by the use of ethylene oxide gas or exposure to gamma irradiation or an electron beam.

[0169]

[0202] An appropriate size instrument for plugging the burr hole is preferably selected based on the size of the drill bit used to form the burr hole. Or, alternatively, an appropriate size instrument is selected by a measurement of the diameter of the burr hole. The diameter of the stem (240) or cylindrical hollow core (820) or (920) inserted into the burr hole is preferably the diameter of the burr hole ±2 mm, or more preferably ±1 mm of the burr hole diameter. For example, if the diameter of the burr hole is 10 mm, an instrument is selected that has a stem or cylindrical hollow core with a diameter of 10 mm ±2 mm, or more preferably 10 mm ±1 mm.

[0170]

[0203] In some embodiments, the diameter of the stem preferably exceeds the diameter of the burr hole by 0.5-2 mm to provide an interference fit when the stem is positioned within the burr hole.

[0171]

[0204] The method of implantation of the device will depend on the particular design of the device.

[0172]

[0205] An instrument including a cap (220) with a filament element (240) and a stem (240), such as (200) as shown in Figures 2A-C, may be implanted in a burr hole by inserting the stem (240) into the burr hole until the flange (230) rests on the outer surface of the skull. As the instrument is inserted into the burr hole, the filament element engages the cancellous bone of the skull to secure the self-locking instrument in place. In a preferred embodiment, the instrument (e.g., 200) is coated with autologous blood from the calvarium marrow space prior to insertion into the burr hole. Optionally, the instrument (200) may also be secured in place using fibrin glue.

[0173]

[0206] A device including a pin and a cylindrical hollow core, such as (800) and (900) shown in Figures 8 and 9, respectively, may be implanted into a burr hole by first inserting the cylindrical hollow core (820) or (920) into the burr hole. The cylindrical hollow core is inserted into the burr hole until the flanges (830) and (930) abut the outer surface of the skull. The cylindrical hollow cores (820) and (920) may be coated with autologous blood from the marrow cavity of the calvaria prior to implantation. Optionally, the cylindrical hollow cores (820) and (920) may be secured in place using fibrin glue.

[0174]

[0207] After insertion of a cylindrical hollow core, such as (820) or (920), pins (810) and (910), respectively, can be inserted into the cylindrical hollow core. Pin (810) can simply be pushed into cylindrical hollow core (820) until it is seated in place, and pin (810) expands the cylindrical hollow core, thereby securing the device within the burr hole. In some embodiments, an interference fit is created.

[0175]

[0208] The pin stop (840) prevents the pin (810) from traveling through the burr hole and out into the space between the inner skull surface and the meninges, and provides resistance to the rivet push pin (810) being pressed into engagement within the cylindrical hollow core (820). The pin (910) may be threaded into the cylindrical hollow core (920) by inserting a suitable tool into the hexagonal socket and rotating the pin until it is fully inserted into the cylindrical hollow core (920), as shown in FIG. 9A.

[0176]

[0209] In an alternative embodiment, the device (800) may be implanted in one step, where the pin (810) is preloaded into the cylindrical hollow core (820), but not fully inserted into the hollow core, and the pin and cylindrical hollow core assembly is implanted. The assembly is pushed into the burr hole until the flange (830) of the cylindrical hollow core contacts the outer surface of the skull. The pin (810) is then pushed downward into the cylindrical hollow core (820) to expand the cylindrical hollow core and secure the device within the burr hole. The device (800) may be coated with autologous blood from the marrow cavity of the calvarium prior to implantation. Optionally, fibrin glue may be used to help secure the device (800) within the burr hole.

[0177]

[0210] After insertion of the device (e.g. (200), (800) or (900)) into the burr hole, the scalp is preferably closed with resorbable sutures, e.g. Vicryl size 3 / 0, and the skin is closed with permanent sutures, e.g. Prolene size 3 / 0.

[0178]

[0211] In one embodiment, the device is used to seal burr holes created during chronic subdural hematomas, epidural hematomas, as well as other types of neurosurgical treatments.

[0179]

[0212] The invention will be further understood with reference to the following non-limiting examples. EXAMPLES

[0180]

[0213] Working Example

[0214] Example 1: Porous implants for burr hole closure made by 3D printing of P4HB containing β-TCP

[0215] Porous implants for burr hole bone defect occlusion were made from compounded pellets of P4HB (Mw 380 kDa) containing 5, 20, and 40 wt.% beta-tricalcium phosphate (β-TCP). The implants were prepared by 3D printing with melt extrusion deposition using an Arburg Freeformer 3D printer with the printing parameters shown in Table 1. The design of the implant (200) is shown in FIG. 2. The average diameter of the printed filament of the implant was 250 μm. The layers of the filament were crossed at angles of 0, 60, and 120 degrees. A triangular open pore structure was formed using a lay down pattern with layers oriented at 0 / 60 / 120 degrees to each other. As shown in FIGS. 2A-2C, the implant (200) had a shape including two parts. The first part was a cap (220) with a flange (230) and the second part was a stem (240) (or ridge). The cap was sized so that the flange (230) extended beyond the contours of the defect outside the bone defect to ensure that the stem remained within the bone defect. The stem (240) was sized to remain within the burr hole upon implantation. The flange diameter was 10-25 mm and the stem diameter was 7-19 mm. The porosity of the implant was 30-75% and the average distance between the filaments was 200 μm to allow for tissue ingrowth.

[0181]

[0216] Example 2: Porous implant for burr hole closure made by 3D printing of P4HB with 70% packing density

[0217] The method described in Example 1 was repeated, except that the implants were made from P4HB alone, rather than from P4HB compounded with β-TCP. The implants were produced using the same printing parameters listed in Table 1. The implants were produced with P4HB filaments of average diameter 285 μm, which were deposited layer by layer using melt extrusion deposition. The average distance between the filaments (D AVE ) was 200 μm. The implant produced according to this method and shown in Figure 3 had a packing density of 70% and a drop ratio of 1.3.

[0182]

[0218] Example 3: Porous implant for burr hole closure made by 3D printing of P4HB with 65% packing density

[0219] The method described in Example 2 was repeated, except that the packing density shown in Table 1 was changed from 70% to 65%. The average distance between the filaments in the implant was 250 μm. An implant produced according to this method is shown in FIG. 4.

[0183]

[0220] Example 4: Porous implant for burr hole closure made by 3D printing of P4HB with 55% packing density

[0221] The method described in Example 2 was repeated, except that the packing density shown in Table 1 was changed from 70% to 55%. The average distance between the filaments in the implant was 350 μm. An implant produced according to this method is shown in FIG. 5.

[0184]

[0222] Example 5: Porous implant for burr hole closure made by 3D printing of P4HB with 45% packing density

[0223] The method described in Example 2 was repeated, except that the packing density shown in Table 1 was changed from 70% to 45%. The average distance between the filaments in the implant was 500 μm. An implant produced according to this method is shown in FIG. 6.

[0185]

[0224] Example 6: Porous implant for burr hole closure made by 3D printing of P4HB with 40% packing density

[0225] The method described in Example 2 was repeated, except that the packing density shown in Table 1 was changed from 70% to 40%, and the average distance between the filaments in the implant was 575 μm. An implant produced according to this method is shown in FIG.

[0186]

[0226] Example 7: Porous implants for burr hole closure made by 3D printing of poly(butylene succinate) at packing densities of 35%, 40% and 45%

[0227] The method described in Example 1 was repeated, except that the implants were made from poly(butylene succinate) (Mw 177 kDa) instead of P4HB, and the packing densities were 35%, 40% and 45%. The devices were printed using the parameters shown in Table 1, with an average filament diameter of 245 μm. The filaments were deposited layer by layer using 3D printing by melt extrusion deposition. The filament layers were crossed at angles of 0, 60 and 120 degrees. A laydown pattern of layers oriented at 0 / 60 / 120° to each other was used to form a triangular open pore structure.

[0187]

[0228] Example 8: Porous implant for burr hole closure made by 3D printing of P4HB and β-TCP with a hard cap

[0229] The method described in Example 1 was repeated, except that the printing density of the cap component of the implant was increased to produce a solid cap without interconnected pores.

Claims

1. 1. An instrument for repairing a bone defect, the instrument comprising: a stem connected to a cap having a flange, the instrument further comprising bristles extending from an outer periphery of the stem, the instrument being porous, the bristles being configured to engage cancellous bone of the bone defect to secure the instrument within the bone defect.

2. The device of claim 1 , wherein the device has pores in the cap and stem, and the average pore diameter of the pores in the stem is greater than the average pore diameter of the pores in the cap.

3. The device of claim 1 , wherein the device comprises a ceramic and a concentration of the ceramic in the stem is less than a concentration of the ceramic in the flange.

4. The device of claim 2, wherein the average pore diameter in the stem is between 0.05 and 2 mm, and the average pore diameter in the cap is between 0.01 and 0.5 mm.

5. The device of claim 1 or 4, wherein the device comprises a resorbable polymer.

6. An instrument for repairing a bone defect, the instrument comprising a stem connected to a cap having a flange, the instrument further comprising bristles extending from the outer periphery of the stem, the instrument being porous and comprising a resorbable polymer, the resorbable polymer being poly-4-hydroxybutyrate or a copolymer thereof, or poly(butylene succinate) or a copolymer thereof.

7. 10. The device of claim 1, wherein the bone defect is a burr hole in the skull and the diameter of the stem of the device is sized 2 mm or less less than the diameter of the burr hole.

8. The device of claim 1 , wherein the bristles extend at least 1 mm from the circumference of the stem.

9. The device of any one of claims 1 to 8, wherein the stem and cap are formed by stacking multiple layers of filaments.

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