A bioabsorbable implant with internal and external absorption properties, and a method for manufacturing the same, for the purpose of further improving bone growth and tissue integration.

Abstract

To provide a bioabsorbable implant made of a multi-component composite material that further improves tissue integration. [Solution] Disclosed are bioabsorbable implants with improved bone growth and tissue integration through the use of internal and external absorption mechanisms, and methods for manufacturing bioabsorbable implants for use in osteotomy and bone and soft tissue reconstruction. The bioabsorbable implant comprises polymer A (e.g., an aliphatic polymer matrix), carbohydrate B (e.g., a bioabsorbable natural carbohydrate filler), and ceramic C. The implant is a porous scaffold structure having suitable porosity, pore size, pore interconnectivity, and mechanical properties to further improve osteoblast invasion and bone formation, thereby promoting tissue integration with the bioabsorbable implant. The implant may be molded as a soft tissue fixation implant such as a wedge, bone graft, or screw.

Description

Technical Field

[0001] Cross - reference to Related Applications

[0001] This application claims the priority of U.S. Patent Application No. 62 / 968,056, filed on January 30, 2020, and U.S. Patent Application No. 63 / 070,704, filed on August 26, 2020, and incorporates these contents by reference herein in their entirety for all purposes.

[0002]

[0002] The present invention relates to medical devices, and more particularly, to bioabsorbable implants such as wedges, bone fillers, and fracture fixation implants. More specifically, such implants may be used in surgeries such as distal femoral osteotomy, high tibial osteotomy, and pediatric osteotomy. Such implants can also be used for proximal humerus fractures, tibial plateau fractures, bone tumors and cysts, cancellous bone fractures, osteolysis of the entire joint, and osteochondral reconstruction.

Background Art

[0003]

[0003] Metal removal surgery is one of the most commonly performed surgical procedures. The number of orthopedic implant removal surgeries in the United States alone corresponds to 90 cases per 100,000 people annually across the country. Some studies have shown pain and discomfort at the site where the metal was implanted, as well as dysfunction due to the removal of the implant. Some studies have reported that the complications due to the removal of metals used in orthopedics are between 24% and 50%.

[0004]

[0004] Bioresorbable implants were introduced to the market to eliminate the need for reoperation to remove metal implants. Bioresorbable implants play a role in regenerative medicine by promoting the recovery of normal function of damaged tissue when the implant is absorbed. Biodegradable synthetic polymers are considered the most commercially competitive for these applications. This is because these synthetic polymers have broad applicability characteristics and can be manufactured in a cost-effective manner. Biodegradable synthetic polymers are also biocompatible, and their physicochemical properties are suitable for a wide range of medical applications, so they can be used in the manufacture of various medical devices, such as sutures, plates, bone fixation devices, stents, screws, and tissue repair. These implants are intended for osseointegration.

[0005]

[0005] Osseointegration is clinically defined as the integration of bone using a surgical implant that induces the bone healing process, including tissue growth from a fractured end, without the formation of any intermediate fibrous tissue. Orthopedic osseointegrated implants are firmly fixed within bone tissue. A common challenge with bone implants is that vibration of the implant in body tissue can cause stress shielding. This stress shielding leads to gradual bone resorption, followed by loss of mechanical stability, and ultimately complete failure of the implant. Implants made of metals such as stainless steel, titanium alloys, and cobalt-chromium alloys can be particularly problematic because they tend to cause stress shielding, which can lead to mechanical instability over time in bone implants.

[0006]

[0006] In recent years, several bioabsorbable polymer devices have become available for creating cost-effective alternatives for certain indications. As is expected with technological advancements, solving one set of challenges has created another. Despite initial promises, the unexpected degradation profiles and secretion of acidic by-products derived from current bioabsorbable implants have limited their penetration into the rapidly growing market due to clinical complications. Bioabsorbable implants have so far failed to provide an excellent absorption and recovery profile as an ideal substitute, due to the common chemical shortcomings of these implants. Reoperations to remove implants are increasing even more rapidly than primary repairs. Poly(lactic acid) (PLA) and poly(glycolic acid) (PGA), the most common medical polymers used in bioabsorbable implants, cause cystic formation (13.3-25.8%) and local inflammation (14-29%). Nine of the ten types of bioabsorbable implants currently available remain partially / completely intact within three years. Therefore, current bioresorbable implants do not improve health outcomes compared to metal implants, due to the unforeseen absorption process and the resulting impairment of tissue integration. [Overview of the project] [Problems that the invention aims to solve]

[0007]

[0007] This disclosure relates to a bioabsorbable implant made of a multi-component composite material that further improves tissue adhesion.

[0008]

[0008] Some embodiments of the present invention relate to a three-component bioabsorbable implant comprising an aliphatic polymer (for example, for the purpose of providing structural integrity), a bioabsorbable natural carbohydrate filler that leaches to the outside of the implant (for example, for the purpose of promoting osseointegration), and a bone-binding mineral (for example, for the purpose of further promoting osseointegration and thereby providing adhesion sites for osteocytes to further improve bone tissue regeneration), wherein the implant has internal and external absorption and excellent bone and tissue bonding. [Means for solving the problem]

[0009]

[0009] The aliphatic polymer may be poly(dl-lactic acid), poly(ε-caprolactone), poly(3-hydroxybutyrate), poly(butylene succinate), poly(propylene carbonate), or poly(propylene fumalate).

[0010]

[0010] The bioabsorbable carbohydrate filler may be cellulose, gelatin, arginate, polycyclic aromatic lignin, or starch. The starch may be corn. The bioabsorbable carbohydrate filler may take the form of particles, fibers, or whiskers. The bioabsorbable carbohydrate may be in the size range of 5 to 30 μm.

[0011]

[0011] The bone-binding mineral may be a ceramic such as calcium phosphate, hydroxyapatite, bioglass 45s5, or other suitable bone-binding mineral. The bone-binding mineral may take the form of particles, fibers, or whiskers. The bone-binding mineral may be in the size range of 1 to 20 μm.

[0012]

[0012] In some embodiments, the implant may be a four-component bioresorbable implant, the fourth component of which is an active agent such as a bone morphogenetic protein, cytokine, or other suitable enzyme-based bone growth agent.

[0013]

[0013] In some embodiments, a bioabsorbable implant can remain implanted if the bioabsorbable natural carbohydrate filler has leached outside the implant for a period of 2 weeks to 6 months. The ceramic also helps promote a secondary porous structure throughout the implant by providing, for example, an adhesion site for newly formed osteocytes. While implanted, the implant can induce cell proliferation and tissue growth from within.

[0014]

[0014] The implant may take the form of a wedge, bone graft material, bone-soft tissue interface fixation implant, soft tissue fixation implant, or implantable putty. For example, the implant may utilize the thermal properties of an aliphatic polymer; for instance, at temperatures of 40-50°C, the implant may be a softened putty-like composition, but after being implanted in the body, the implant may harden to a hardened state.

[0015]

[0015] In some embodiments, the polymer of the implant may be porous. The pores may be manufactured by means such as 3D printing, gas foaming, electrospinning, or salt leaching. The pores may be in the size range of 50 to 400 μm. The porosity may be in the range of 10 to 90%.

[0016]

[0016] Some embodiments of the present invention relate to a bioabsorbable implant comprising an aliphatic polymer that provides structural integrity, a bioabsorbable natural carbohydrate filler that leaches to the outside of the implant, and bone-integrating minerals, and having intrinsic and extratrinsic absorption and excellent bone and tissue integration. The implant may have a pre-implantation state and a post-implantation state. In this case, the bioabsorbable natural carbohydrate filler leaches to the outside of the implant over a period of 2 weeks to 6 months while the implant is in the post-implantation state. The implant can maintain structural load-bearing properties for supporting bone in the post-implantation state even while being gradually absorbed, and can provide sufficient time for osseointegration to regenerate new bone tissue. In some embodiments, the implant may still have load-bearing capacity for at least 3 months to allow sufficient bone growth and osseointegration. The aliphatic polymer may be porous to promote penetration and intrinsic and extratrinsic degradation and absorption.

[0017]

[0017] In another aspect, the present disclosure relates to a method for manufacturing a bioabsorbable implant for orthopedic use. The implant comprises a synthetic aliphatic polymer matrix (polymer A), a natural carbohydrate (carbohydrate B), and an osteointegrating component (ceramic C). This scaffold utilizes the internal and external absorption mechanisms disclosed herein to further enhance bone growth and tissue integration, enabling the manufacture of bioabsorbable implants for osteotomy and bone and soft tissue reconstruction.

[0018]

[0018] Furthermore, this disclosure relates to optimal porous implants for load-bearing and non-load-bearing orthopedic and soft tissue applications, having optimal pore size, porosity and pore interconnectivity, using manufacturing methods such as gas foaming, 3D printing, electrospinning and salt reaching.

[0019]

[0019] Disclosed is a method for manufacturing bioabsorbable implants for osteotomy and bone and soft tissue reconstruction, independent of the selection of materials. The internal and external absorption mechanisms disclosed herein enable the manufacture of bioabsorbable implants that provide secondary osseointegration. The bioabsorbable implant may be a three-block composite material, in which case each block may perform a specific function. Polymer A functions as a composite material matrix selected from aliphatic polymers. Carbohydrate B functions as a rapidly absorbable filler selected from naturally occurring bioabsorbable carbohydrates. Ceramic C functions as a bone-connecting element selected from minerals such as calcium phosphate, hydroxyapatite, and bioglass 45s5.

[0020]

[0020] It should be understood that this method does not depend on the selection of any of the above components. The specific material selections for polymer A, carbohydrate B, and ceramic C presented in the examples herein should not be considered a limitation of the claims. The claims for the method of this innovation should not be limited to the performance of any selection of materials derived from the presented polymer and / or ceramic family.

[0021]

[0021] This disclosure relates to the formation of bioabsorbable implant composite materials that are fundamentally safe and absorbed in a timely manner, such as wedges for osteotomy, bone grafts and screws, rods and / or anchors, and other soft tissue fixation implants, based on technologies such as 3D printing and / or gas foaming, with the objective of providing secondary osseointegration and tissue bonding.

[0022]

[0022] These embodiments, aspects and features of the present disclosure, as well as other embodiments, aspects and features, will be better understood from the following detailed description of such embodiments when read in conjunction with the accompanying drawings and figures. [Brief explanation of the drawing]

[0023] [Figure 1A]It is a diagram of a bioabsorbable implant according to an embodiment. [Figure 1B] It is a scanning electron microscope (SEM) image of a bioabsorbable implant showing polymers, carbohydrates, and ceramics according to an embodiment. [Figure 2A] Figure 2A is a SEM image of different bioabsorbable implants having different weight percentages according to an embodiment. [Figure 2B] Figure 2B is a SEM image of different bioabsorbable implants having different weight percentages according to an embodiment. [Figure 2C] Figure 2C is a SEM image of different bioabsorbable implants having different weight percentages according to an embodiment. [Figure 3] It is a microscopic photograph of a SEM of the surface of a bioabsorbable implant covered by bone cells. [Figure 4A] Figure 4A is a series of micro-computed tomography (micro-CT) time-lapse images of bioabsorbable implants in rats with femoral head defects arranged in chronological order according to an embodiment. [Figure 4B] Figure 4B is a series of micro-computed tomography (micro-CT) time-lapse images of bioabsorbable implants in rats with femoral head defects arranged in chronological order according to an embodiment. [Figure 4C] Figure 4C is a series of micro-computed tomography (micro-CT) time-lapse images of bioabsorbable implants in rats with femoral head defects arranged in chronological order according to an embodiment. [Figure 5] An example of an implant composite material extruded as a filament used for 3D printing of a bioabsorbable implant according to an embodiment is shown. [Figure 6A] The stepwise formation of a porous bioabsorbable implant using gas foaming technology is shown. <00001​​​This demonstrates the stepwise formation of porous, bioabsorbable implants using gas foaming technology. [Figure 7A] This is a micro-CT image of the pore distribution of a bioabsorbable implant according to an embodiment. [Figure 7B] This is a micro-CT image of the pore distribution of a bioabsorbable implant according to an embodiment. [Figure 8A] Figure 8A shows SEM images of bioabsorbable implants with various porosity levels according to the embodiment. [Figure 8B] Figure 8B shows SEM images of bioabsorbable implants with various porosity levels according to the embodiment. [Figure 8C] Figure 8C shows SEM images of bioabsorbable implants with various porosity levels according to the embodiment. [Figure 8D] Figure 8D shows SEM images of bioabsorbable implants with various porosity levels according to the embodiment. [Figure 9A] These are hematoxylin and eosin (H&E) tissue images of skin treated with porous bioabsorbable implants according to the embodiment. [Figure 9B] These are hematoxylin and eosin (H&E) tissue images of skin treated with porous bioabsorbable implants according to the embodiment. [Figure 10A] A graph showing the degradation profile of a bioabsorbable implant according to the embodiment is shown. [Figure 10B] A graph showing the degradation profile of a bioabsorbable implant according to the embodiment is shown. [Figure 11] This document illustrates a method for implanting a bioabsorbable implant according to an embodiment. [Modes for carrying out the invention]

[0024]

[0035] This specification describes bioabsorbable implants for use in osteotomy, interosseous and soft tissue reconstruction, such as fixed implants, bone grafts, and / or wedges, which are capable of inducing bone growth. The implant comprises three blocks, each playing a different role in bone tissue regeneration.

[0025]

[0036] Figure 1A is a diagram of an exemplary bioabsorbable implant 100. In this embodiment, the bioabsorbable implant 100 may be a three-block composite material. The bioabsorbable implant 100 shown has three components: polymer A110, carbohydrate B120, and ceramic 130. Polymer A provides structure to the bioabsorbable implant 100. It should be understood that the structure shown is for illustrative purposes only, and the implant may take many other structures besides the cube shown, such as a disc, square, amorphous shape, putty composition, or otherwise. In addition, the illustration of the implant as a three-block composite material is intended to be non-limiting, and the implant may be composed of any number of preferred components. In the bioabsorbable implant 100 of Figure 1A, carbohydrate B120 is distributed throughout polymer A110. Ceramic C130 is further distributed throughout polymer A110.

[0026]

[0037] Polymer A110 may form an aliphatic polymer matrix that provides structural integrity and mechanical strength. For example, polymer A may be an aliphatic polyester. In some embodiments, polymer A may be one or more of the following: poly(dl-lactic acid), poly(ε-caprolactone), poly(3-hydroxybutyrate), poly(butylene succinate), poly(propylene carbonate and / or poly(propylene fumarate)) and / or copolymers of these such as poly(lactic acid-glycol) acids including 10LA / 90GA, 20LA / 80GA, 25LA / 75GA, 30LA / 70GA, 40LA / 60GA, 45LA / 55GA, 50LA / 50GA, 30LA / 70GA, and poly(ε-caprolactone and propylene carbonate) block copolymers.

[0027]

[0038] In some embodiments, poly(propylene carbonate: PPC) may be used as a polymer matrix. Compared to other biocompatible, biodegradable polymer materials, PPC can further improve tissue binding and absorption. Typically, other such polymers degrade into acidic byproducts that lower the pH of the environment around the transplant site, leading to inflammation and / or cyst formation. This also generally slows down the rate of osseointegration and bone regeneration processes. For example, poly(lactic acid) (PLA) and poly(glycolic acid) (PGA), the most common medical polymers, cause cyst formation (13.3–25.8%) and local inflammation (14–29%). In contrast, PPC degrades into non-acidic byproducts such as water and CO2, which do not have the same problems.

[0028]

[0039] Carbohydrate B120 may be a naturally occurring bioabsorbable filler in the form of particles, clusters, whiskers, and filaments in the micrometer to nanometer size range. Carbohydrate B120 is one or more bioabsorbable carbohydrates such as cellulose, gelatin, arginate, polycyclic aromatic lignin, and / or starch (corn), or a combination thereof. Carbohydrate B120 may function as a rapidly reabsorbable component that creates pores within the polymer A110 matrix as it is absorbed (relatively rapidly compared to the polymer A110 matrix). The resulting pores allow osteocytes to penetrate and adhere to the implant, thus enabling osseointegration. Furthermore, these pores can provide pathways for water to penetrate within the scaffold for intrinsic and extratrinsic absorption. Intrinsic and extratrinsic absorption refers to absorption that occurs at least partially from the internal region of the implant. Absorption can occur throughout the entire implant. During endosomal and extrasomal absorption, water penetrates into the internal region of the implant, initiating implant decomposition not only from within the implant but also from outside (for example, by decomposition and leaching of carbohydrate B to the outside). When this occurs, further space is created for new tissue, which may further promote tissue growth into the internal region of the implant. This is clearly different from many conventional implants, where absorption is mainly possible only from the outside to the inside. The endosomal and extrasomal absorption mechanism is particularly advantageous because it promotes rapid osseointegration throughout the entire implant.

[0029]

[0040] The cell adhesion properties provided by carbohydrates can be particularly important in embodiments using a polymer A110 matrix made of a hydrophobic polymer (e.g., PPC). This is because such polymers tend to hinder cell adhesion. Introducing carbohydrates as fillers into the polymer A matrix (e.g., when polymer A110 is PPC) can counteract these effects.

[0030]

[0041] In embodiments, ceramic C130 may be fine particles of osteoconjugation mineral compounds that provide bioactivity and bone regeneration capabilities. Ceramic C130 may be at least one or a combination thereof of osteoconjugation compounds such as calcium phosphate, hydroxyapatite, and bioglass 45s5. The presence of at least one or a combination thereof of bioactive minerals as ceramic C130 leads to further improvement of osteoconjugation, for example by providing adhesion sites for newly formed osteocytes, as well as the invasion and growth of osteoblasts after transplantation. The weight percentage of ceramic C130 may range from 1% by weight, 2.5% by weight, 5% by weight, 7.5% by weight, 10% by weight, 12.5% ​​by weight, 15% by weight, 17.5% by weight, 20% by weight, 25% by weight, and 30% by weight.

[0031]

[0042] Any suitable combination of the above polymer A110, the above carbohydrate B120, and the above bone-binding mineral (ceramic C130) may be used to produce a suitable implant according to the embodiment. For example, one embodiment of an implant for superior bone resorption may be made from poly(propylene)carbonate and provide the matrix structure of the implant together with starch filler and bioglass 45s5. If the PPC has starch-occupied regions throughout the PPC matrix and pores made of distributed bioglass, the described PPC-starch-bioglass implant may be in a pre-implantation state. In some embodiments, the implant may be pre-formed into a disc, rod, wedge, screw, wire, or any shape suitable for implantation at the implantation site, as will be described in more detail below (for example, with respect to Figures 6A to 8).

[0032]

[0043] The mechanism of internal and external degradation is partly based on the presence of carbohydrate B fillers within the structure of the polymer A matrix. In such embodiments, the degradation time is regulated by the amount of carbohydrate B. At low abundances of 1% to 10% by weight, the degradation profile is reduced. However, the presence of 50% by weight of carbohydrate B creates a rapidly absorbable implant. The weight percentage of carbohydrate B can range from 1% to 5% by weight, depending on the desired degradation profile, to 1% to 20%, 25%, 30%, 35%, 40%, 45%, and 50% by weight.

[0033]

[0044] In some embodiments, the implant can maintain its structural load-bearing properties for supporting bone even while it is being gradually absorbed, allowing sufficient time for osseointegration to regenerate new bone tissue. In some embodiments, the implant may still be load-bearing for at least three months to allow sufficient bone growth and osseointegration.

[0034]

[0045] Carbohydrate B120 can be broken down through bulk erosion as water flows into the implant. Bulk erosion allows for breakdown throughout the entire implant, enabling deeper and greater bone tissue to bond to the implant.

[0035]

[0046] Figure 1B shows an SEM image of a bioabsorbable implant 100 representing polymer A110, carbohydrate B120, and ceramic C130, fabricated according to one embodiment of the present disclosure. SEM images were captured using a Zeiss EVO 50 SEM operated at an accelerating voltage of 10 kV. The sample cross-section was mounted on an aluminum stub using conductive silver paint and gold sputtered before SEM analysis (Emitech K550X sputter coaster).

[0036]

[0047] In embodiments, the implant may incorporate an activator as a fourth component. The activator may be a bioactive compound that further enhances bone growth. The activator may be distributed throughout the implant. The activator may be a bone morphogenic protein (BMP), a cytokine, or a suitable chemical substance that enzymatically promotes bone growth. Such activators can further promote bone growth by generating in the body a flow of ions necessary for bone growth, such as calcium, sodium, potassium, and phosphate. In embodiments, the activator may be an antibacterial agent such as gentamicin or vancomycin to avoid or minimize inflammation and infection, or an anti-inflammatory agent such as dexamethasone and a galectin-3 inhibitor. The activator may be one or a combination of the above bioactive compounds.

[0037]

[0048] Figures 2A and 2C show SEM comparisons of the in-vitro and out-of-vitro absorption mechanisms for implants with different weight percentages of carbohydrate B. These SEM images show implants after 8 weeks of incubation in a simulated body fluid at 37°C in a dynamic environment. SEM images were captured using a Zeiss EVO 50 SEM operated at an accelerating voltage of 10kV. Sample cross-sections were mounted on aluminum stubs using conductive silver paint and gold sputtered before SEM analysis (Emitech K550X sputter coaster).

[0038]

[0049] Figure 2A shows an exemplary implant that results in slow absorption and contains 0% by weight of carbohydrate B. Observations of the implant during use demonstrate that the time required for cells and tissues to reach the inside of the implant without further void formation by carbohydrate B leaching out of the polymer A structure is unfavorable for promoting intrinsic and extrinsic growth.

[0039]

[0050] Figure 2B shows an exemplary implant containing 25% by weight of carbohydrate B. Such implants have a moderate absorption rate.

[0040]

[0051] Figure 2C shows an exemplary implant containing 50 wt% carbohydrate B. As the percentage of absorbable carbohydrate B increases, the degradation profile of the implant increases as higher wt% implants leach out over time. This SEM image shows the implant after 8 weeks of incubation in a simulated body fluid at 37°C in a dynamic environment. SEM images were captured using a Zeiss EVO 50 SEM operated at an accelerating voltage of 10 kV. The sample cross section was mounted on an aluminum stub using conductive silver paint and gold sputtered before SEM analysis (Emitech K550X sputter coaster).

[0041]

[0052] In Figures 2B and 2C, the dashed lines indicate leachate regions that provide a porous scaffold. When water and bodily fluids penetrate, hydrolysis begins from within the bulk of the sample.

[0042]

[0053] Figure 3 shows a SEM micrograph of the surface of a bioabsorbable rod 300 containing an aliphatic polymer matrix (polymer A), a naturally occurring bioabsorbable carbohydrate filler (carbohydrate B), and a bone mineralizer (ceramic C), seeded with human osteoblasts. The cells were induced to adhere to the matrix, but not to the rapidly absorbable filler; however, the layer of bound cells remained stationary on the scaffold surface. The induced binding and proliferation of osteoblasts and osteocytes is used as a method to open pores for exfiltration into the carbohydrate B. These bindings and proliferations allow cells to penetrate and invade the bioabsorbable implant, inducing internal and external tissue growth from the implant's bulk.

[0043]

[0054] Surface morphology was tested using a Zeiss EVO 50 SEM operated at a 10kV acceleration voltage. Sample cross sections were mounted on aluminum stubs using conductive silver paint and sputtered with gold prior to SEM analysis (Emitech K550X sputter coaster). SEM analysis was used to test the cell morphology of osteoblasts on the scaffold surface within 24 hours of culture. For this analysis, samples were placed in a 24-well plate, and 75 μL of cell suspension was added to each well to contain 2 × 10⁵ cells per well. The bound cells were fixed in 2.5% glutaraldehyde for 1 hour and washed at least three times with PBS. The bioabsorbable discs were incubated at room temperature for a further time in a secondary fixative (1% osmium tetroxide in 0.1M PBS). Dehydration was performed sequentially in various grades of ethanol, including 30%, 50%, 70%, and 90%, and pure ethanol. The ethanol residue was removed from the sample using 0.5 mL of hexamethyldisilazane (HMDS), and the sample was incubated at room temperature for 2 minutes. Subsequently, the sample was dried in an unlidded desiccator, and the HMDS was allowed to evaporate overnight. Gold coating was used for final SEM analysis.

[0044]

[0055] Figures 4A to 4C show time-series micro-CT images of a rat femoral head before, during, and after transplantation, according to an embodiment. The implant in Figures 4A to 4C is a three-block composite material for promoting bone regeneration, fabricated according to an embodiment of this disclosure. Polymer A is selected from aliphatic polymers such as polycaprolactone and / or polypropylene carbonate, and carbohydrate B is selected from natural absorbable carbohydrates such as cellulose and / or arginate. Bioactive mineral agents such as hydroxyapatite and / or calcium phosphate were used to further enhance bioactivity and bone regeneration. To simulate distal femoral head osteotomy, the rod was implanted in 15+ week old male Wistar rats (Animal Resources Centre) lacking a femoral head. The rod remained implanted for 12 weeks. The designed internal and external decomposition mechanism is effective in helping to form new tissue within the implant structure as early as 12 weeks after transplantation.

[0045]

[0056] Figure 4A shows a femoral head defect created in the femoral head of a rat for simulating distal femoral head osteotomy. Subsequently, a bioabsorbable implant, such as bioabsorbable implant 100, was implanted into the femoral head defect. Figure 4B shows the femoral head defect of Figure 4A after implantation of a rod-shaped bioabsorbable implant (e.g., bioabsorbable implant 100). Figure 4C shows the same area 12 weeks after implantation. As can be seen in the figures, bone growth can be observed, with the filled tissue expanding beyond the boundary of the initial defect. In addition, tissue growth can be seen in the internal region, which extends beyond the boundary outside the implant and indicates tissue growth inside the implant.

[0046]

[0057] Using a 0.5 mm aluminum filter, 50 kV X-ray tube voltage, 800 μA tube current, and a scanning exposure time of 4500 ms, bioabsorbable rods and / or wedges for osteotomy and / or soft-tissue interface reconstruction shown in Figures 4A-4C were scanned at an isotropic voxel resolution of 14 μm. 0.3 gcm was used for 3D reconstruction using NRecon software. -3Cutoffs of calcified tissue prepared from minerals were used. Figures 4A–4C illustrate the implantation of bioresorbable implants at specific locations by specific surgical procedures, but this disclosure intends for similar implantation at any preferred location for any surgical procedure that is suitable for obtaining similar results.

[0047]

[0058] The implants disclosed herein represent multi-stage osseointegration. For example, an implant enables a two-stage osseointegration process. In this example, initial osseointegration occurs when cells and bodily fluids enter the pores (which can start as porous structures) within the implant. The porosity of the implant allows for intrinsic and extratrinsic absorption from the very beginning. As the implant degrades while in the body (initially mostly due to the external leaching of carbohydrate B, but also due to the slower degradation of polymer A), further pores are generated. These further pores provide a scaffold for secondary osseointegration, enabling further cell intrusion. The further pores allow for further entry of bodily fluids. As a result, the degradation of the implant increases, and further cell intrusion becomes possible in succession. In this way, intrinsic and extratrinsic absorption becomes increasingly possible as the implant degrades. The ability to regulate the degradation profile allows for control over the rate at which secondary osseointegration begins and progresses. Further pores can also further enhance angiogenesis and connective tissue growth. Therefore, improved bone integration and effective healing are achieved.

[0048]

[0059] In some embodiments, a porous structure within the implant can be used to further promote improved tissue regeneration. In such embodiments, the porous structure inside the bioabsorbable implant, composed of polymer A, carbohydrate B, and ceramic C, can be formed using 3D printing, electrospinning, salt leaching, and / or gas foaming. Aliphatic polymers such as PLA, PLGA, and PCL are soluble in carbon dioxide, which allows for the formation of pores using gas foaming.

[0049]

[0060] Figure 5 shows an exemplary 3D-printed bioabsorbable implant composite material according to an embodiment. Figure 5 shows an overall uniform pattern obtained by 3D printing, including an extruded filament. In this embodiment, a single screw extruder was used with a die temperature in the range of 125°C to 210°C, depending on the type of polymer A. 3D printing can yield pore sizes of 100 μm to 150 μm with a porosity range of 10% to 90%.

[0050]

[0061] Figures 6A to 6C illustrate the process for forming one embodiment of a gas-foamed bioabsorbable implant (e.g., bioabsorbable implant 100) in accordance with this disclosure. The gas foaming method can be an efficient technique for generating uniform pores.

[0051]

[0062] Figure 6A shows a custom mold 600 for forming a bioabsorbable implant. The mold assembly may include one or more molds (e.g., molds 605-1, 605-2, and 605-3). The bioabsorbable implant can be fabricated inside these molds by any preferred method (e.g., injection into a mixture). The custom mold 600 may have any number of molds (e.g., one, two, three, four, or more) for forming a large number of bioabsorbable implants. Each mold may have any shape suitable for producing the desired implant. For example, a mold may be configured to produce a disc-shaped implant, a wedge-shaped implant, a rod-shaped implant, or any other preferred implant.

[0052]

[0063] In some embodiments, the custom mold 600 may be filled with a mixture for forming a composite material for a bioabsorbable implant and then placed in a pressure chamber for gas foaming. The pressure chamber for forming bioabsorbable discs, rods, wedges, screws, and wires may be a high-pressure vessel (e.g., Thar, 100 mL Viewcell). Before pressurizing the vessel, a Thar reaction temperature controller is used to set a desired temperature, such as 25°C, 30°C, and 40°C. Using CO2, a syringe pump (e.g., ISCO, Model 500D) may be used to pressurize the system to a predetermined pressure, such as 50 bar, 75 bar, and 125 bar Ps, and then the pump may be operated in constant pressure mode. After a desired time, such as 1 hour, 2 hours, 4 hours, and 12 hours, the temperature can be gradually reduced to room temperature, and the system can be depressurized at a predetermined depressurization rate, such as 0.2 bar / second, 2.5 bar / second, and 10 bar / second.

[0053]

[0064] Figure 6B shows an exemplary implant 610 (disk-shaped implant) formed from a custom mold 600 by the process described above. Figure 6C shows a close-up photograph of the implant 610. As can be seen in the figure, the implant 610 is a porous structure with pores 620 throughout the entire structure. These pores can be obtained by utilizing a gas foaming process to extrude the structure of the implant.

[0054]

[0065] Figures 7A and 7B show different micro-CT images analyzing the pore distribution and overall porosity in sample slices. When evaluating the pore distribution and porosity, temperature, pressure, decompression rate, and immersion time were optimized for each sample based on the solubility of the aliphatic polymer used in carbon dioxide. Subcritical, critical, and supercritical points were determined from the CO2 pressure-temperature phase diagram. This allows for a porosity range of 20% to 75%, enabling a uniform distribution of pores within the bioabsorbable implant bulk, thus providing excellent osseointegration.

[0055]

[0066] Microcomputed tomography (micro-CT) was used to further analyze porous, bioresorbable osseointegrated implants. A Skyscan1072 (Bruker MicroCT) scanner was used, and the specimen was scanned with a microfocus X-ray source. During scanning, the specimen was rotated gradually at over 360°, and X-ray projection images were captured at each stage. Reconstructed images were acquired using Avizo® 3D software, and the 3D porous structure and pore interconnectivity were analyzed.

[0056]

[0067] Figures 8A to 8D show various embodiments of bioabsorbable implants having different porosities based on different gas foaming parameters. Various porous structures can be obtained by changing the temperature and pressure. In some embodiments, the porous structure can have a size in the range of 50 μm to 400 μm. In some embodiments, the implant (e.g., bioabsorbable implant 100) can have a porosity in the range of 10% to 90%.

[0057]

[0068] The pore size of the gas-foamed sample was measured using scanning electron microscopy energy-dispersive X-ray spectroscopy (SEM-EDS). The sample was mounted on an aluminum stub using conductive silver paint and coated with gold using an Emitech K7550X instrument. SEM analysis was performed using a Zeiss EVO 50 SEM operated at a 10kV acceleration voltage. Images were analyzed using ImageJ software (National Institutes of Health, USA). A LaB6 filament was also attached to the SEM instrument, and EDS measurements were performed using the iXRF Iridium Ultra EDS system.

[0058]

[0069] Figure 9 shows hematoxylin and eosin (H&E) histograms of skin treated with porous bioabsorbable discs. In H&E staining, the cell nucleus and cytoplasm were stained using blue and pink dyes, respectively.

[0059]

[0070] The bioabsorbable disc shown in Figure 9 was transplanted into mice, and tissue regeneration was observed. Tissue regeneration was observed as early as two weeks after transplantation. Using a mouse model with subcutaneous transplantation, tissue exudation into the porous scaffold was evaluated. Porous discs (5 mm in diameter and 3 mm in height) were prepared under sterile conditions and handled in a sterile clean bench before transplantation. Pathogenic-free male BALB / c mice (12-14 weeks old, body weight 27 ± 1.9 g) were purchased from the Australian Animal Resources Centre. All animals were obtained, reared, and studied under protocols approved by the Sydney Local Health District (SLHD) Animal Welfare Committee in Sydney, Australia. Each mouse was individually anesthetized by intraperitoneal injection of a mixture of ketamine (50 mg / mL) and xylazine (50 mg / mL) at a volume of 0.01 mL / g of body weight. The backs were shaved, the skin was cleansed with betadine solution, and washed with sterile saline.

[0060]

[0071] Two incisions, approximately 1 cm long, were made in the dorsal region to create subcutaneous sacs into which porous scaffolds were inserted. All wounds were sutured and covered for 7 days with Atlauman® (Hartmann, Australia) and IV3000 wound dressings (Smith & Nephew). Carprofen (5 mg / kg) was administered for anesthesia during and the day after surgery. For the first two days immediately after surgery, each mouse was placed in a separate cage, after which three mice were placed in each cage to allow free access to water and food.

[0061]

[0072] Next, samples were obtained using recognized scientific protocols. Skin biopsies were collected at two weeks post-transplant for histological analysis. Skin biopsies obtained at each time point were fixed in 10% (w / v) formalin for 24 hours, processed, and embedded in paraffin. 5 μm sections were deparaffinized with xylene and stained with hematoxylin and eosin for histological analysis. Figure 9 shows photographs of these biopsy samples.

[0062]

[0073] In addition to solid implants, implants of other shapes may be used. These implants are particularly suited to different surgeries. For example, in some embodiments, the implant may be a putty material in its pre-implant state. Any preferred composition may be used, such as a three-component composition containing the polymer, carbohydrates, and bone-binding minerals described above (alternatively, a four-component composition that may contain an active agent may also be used). In some embodiments, the implant may use PPC as polymer A to form a polymer matrix. In some embodiments, the implant may consist of PPC, a starch-carbohydrate filler, and a ceramic such as bioglass 45s5.

[0063]

[0074] In these PPC implants, the PPC forms a porous matrix that provides the implant with properties such as structural integrity and load-bearing capacity upon transplantation. Starch fillers are dispersed throughout the matrix, and as a result, during erosion, the PPC implant becomes more open for secondary osseointegration with bone tissue, providing both internal and external resorption of the PPC implant. Ceramics such as Bioglass 45s5 are dispersed throughout the PPC implant to promote cell adhesion.

[0064]

[0075] In some embodiments, the PPC implant composition can be made into a putty-like consistency before implantation, and after the PPC implant has been molded into the desired structure, it can be cured into a post-implantation state. In these embodiments, the PPC implant can be heated to a temperature of 40°C to 50°C while it remains in a pre-implantation state. Due to the thermal properties of PPC, the PPC implant can be made into a putty-like consistency before implantation at a much lower temperature than implants using matrices formed from other polymers. For example, an implant containing a PPC matrix can be made into a putty-like consistency that can be molded at a low temperature of approximately 40°C to 45°C, making it easy for surgeons to handle without the need for large, cumbersome thermal protective equipment, and allowing for implantation without causing thermal damage to the patient around the implantation site.

[0065]

[0076] To achieve a putty-like consistency, the PPC implant can be heated to a softening temperature of approximately 40°C to 50°C. During this state, the heating temperature required to achieve the putty-like consistency is lower, allowing the surgeon to easily handle the PPC implant without heat loss that could lead to inaccuracies and errors during implantation. Furthermore, the low thermal difference between the PPC implant and the patient's body temperature in a resting state allows for easy implantation without causing discomfort to the patient due to excessive heat generated by the PPC implant. Preferably, the softening temperature may be approximately 40°C to 45°C to allow for the most lenient handling of the putty-like implant.

[0066]

[0077] During implantation, the putty-like hardness of the PPC implant allows it to cure and harden at a temperature approximately natural to the body, around 37°C. Upon hardening, the structural integrity of the PPC implant provides load-bearing properties throughout the entire implant, reinforcing and supporting the implantation site throughout the healing process. Furthermore, even if the filler decomposes, the PPC implant maintains its load-bearing properties. Further information regarding the load-bearing capacity of PPC can be found in "Reinforced Poly(Propylene Carbonate) Composite with Enhanced and Tunable Characteristics, an Alternative for Poly(lactic Acid)", Applied Materials & Interfaces (2015), which is incorporated herein by reference for all purposes.

[0067]

[0078] After transplantation, the PPC implant may enter a hardened post-transplant state. In the post-transplant state, the matrix of the PPC implant hardens at a body temperature of approximately 37°C, forming a hardened load-bearing structure. In the post-transplant state, over a period of 2 weeks to 6 months, water enters and flows through the PPC implant, causing the starch to decompose through bulk erosion. While carbohydrates decompose from the PPC implant, the matrix can support and bear loads to promote further bone tissue regeneration throughout the PPC implant. Ceramics can form adhesion sites on the PPC matrix and further enhance bone tissue regeneration. Starch can further promote cell adhesion within the PPC matrix, enabling intrinsic and extrainfusion effects.

[0068]

[0079] The specific temperature profile described above is achievable by using PPC as the polymer matrix when the PPC implant is putty-like at approximately 40°C to 45°C, hardens at body temperature (e.g., around 37°C), and has a load-bearing post-implant state. Such a temperature profile is not possible when using most conventional polymers, such as PLA or PGA. Furthermore, as described in more detail above, PPC promotes further absorption, and the decomposition of PPC over time into non-acidic, harmless byproducts can reduce stress on the body during recovery. This aids in patient recovery and can also reduce the need for reoperation due to pain caused by acidic byproducts. While this disclosure focuses on PPC-based implant putty, it is intended that any preferred polymer can be used as polymer A in the implant putty.

[0069]

[0080] Figures 10A and 10B show graphs comparing the degradation profiles of bioabsorbable implant composites with two different ratios of polymer A to carbohydrate B. To simulate the body fluid environment over 26 weeks, degradation profile tests reflecting these graphs were conducted in simulated body fluids saturated with enzymes such as lipase and α-amylase. Degradation was measured in terms of weight loss percentage over 26 weeks.

[0070]

[0081] Figure 10A shows the degradation profile of a bioabsorbable implant composite material with a polymer A:carbohydrate B ratio of 1:1. Figure 10B shows the degradation profile of a bioabsorbable implant composite material with a polymer A:carbohydrate B ratio of 1:0. That is, the graph in Figure 10B reflects data for a composite material that does not contain any carbohydrate B. Comparing these two graphs, the degradation (indicated by weight loss percentage) of the two composite materials remains similar until approximately 4 weeks. At this point, it is clear that the composite material in Figure 10A (containing carbohydrate B) degrades faster than the composite material in Figure 10B (not containing carbohydrate B). As explained in more detail above, 4 weeks may be around the time when carbohydrate B begins to leach out of the composite material in Figure 10A, creating a secondary porous structure. This leads to further osseointegration and infiltration of bodily fluids, which in turn leads to further degradation. As shown in Figure 10B, the effect doubles over time, and if the composite material decomposes at an increasingly rapid rate, an acceleration of the decomposition profile occurs.

[0071]

[0082] In contrast to implants containing only polymer A, bioabsorbable implants with added carbohydrate B degrade more rapidly, allowing the bone to begin supporting weight earlier. As the implant degrades, the bone can gradually support weight, allowing for a more gradual recovery of bone strength and bone healing compared to polymer A-only implants, as shown in Figure 10B, which degrade much more slowly and consequently hinder the bone from supporting weight, thus promoting faster bone healing and bone strength. As described above, the degradation profile is highly tunable, resulting in the formation of an optimal composite material that can support increasing body weight at an optimal rate without overloading the bone structure. For example, the degradation profile can be tuned by adjusting the ratio of polymer A to carbohydrate B.

[0072]

[0083] Figure 11 shows an exemplary method 1100 for implanting a bioabsorbable putty-like implant into a bone graft site in a patient. The method may include, in step 1102, heating the implant to a first temperature above a threshold temperature to make it putty-like. In step 1104, the method may include shaping the implant into a desired form. In step 1106, the method may include applying the implant to the graft site. In step 1108, the method may include cooling the implant to a second temperature below a threshold temperature to harden it.

[0073]

[0084] In some embodiments, the implant of the exemplary method 1100 may consist of an aliphatic polymer such as a bioabsorbable implant 100, a bioabsorbable carbohydrate filler, and a ceramic.

[0074]

[0085] A particular embodiment may, as necessary, repeat one or more steps of the method in Figure 11. While this disclosure describes and illustrates specific steps of the method in Figure 11 as occurring in a particular order, this disclosure intends any preferred steps of the method in Figure 11 in any preferred order. Furthermore, while this disclosure describes and illustrates exemplary methods for implanting a bioabsorbable putty-like implant into a patient's bone graft site, including specific steps of the method in Figure 11, this disclosure intends any preferred methods for implanting a bioabsorbable putty-like implant into a patient's bone graft site, including, as necessary, all or some of the steps of the method in Figure 11, or any preferred steps that do not include these steps. Furthermore, while this disclosure describes and illustrates specific components, apparatus or systems for performing specific steps of the method in Figure 11, this disclosure intends any preferred combination of any preferred components, apparatus or systems for performing any preferred steps of the method in Figure 11.

[0075]

[0086] While specific embodiments of the present invention are described, various modifications, changes, and alternative structures and equivalents are also included within the scope of the invention. Embodiments of the invention are not limited to operations in a particular environment, but can be freely performed in multiple environments. Furthermore, while embodiments of the method of the present invention are described using a specific sequence and steps, it will be apparent to those skilled in the art that the scope of the invention is not limited to the described sequence and steps.

[0076]

[0087] Furthermore, while embodiments of the present invention are described using specific combinations of metals, it should be understood that other combinations of metals also fall within the scope of the invention. Therefore, the specification and drawings should be considered illustrative rather than restrictive. However, additions, deletions, and other modifications and alterations to such specification and drawings are permitted without departing from the broader intent and scope.

Claims

[Claim 1] A bioabsorbable implant having internal and external absorption properties and excellent bone and tissue bonding, An aliphatic polymer configured to provide structural integrity at the transplant site, A bioabsorbable natural carbohydrate filler configured to leach out of the bioabsorbable implant over a certain period of time, Ceramics and, Bioresorbable implants, including those mentioned above.

Images