Titanium jaw implant self-adaptive drug release system

Abstract

The invention relates to a titanium jaw implant self-adaptive drug release system which comprises a drug storage cavity formed in the surface of a titanium jaw implant; the medicine carrying microspheres are arranged in the inner wall of the medicine storage cavity; the semipermeable membrane covers the medicine release opening of the medicine storage cavity; the carrier protein channel is formed in the semipermeable membrane and is used for allowing drug molecules released by the drug-loading microspheres to pass through; when the PH value of tissue fluid from an inflammation area in the medicine storage cavity reaches a threshold value, the medicine carrying microspheres are infiltrated by the tissue fluid, then are separated from the inner wall of the medicine storage cavity and are swelled and decomposed to release medicine molecules, and the medicine molecules enter cells through the carrier protein channel through the semipermeable membrane to kill pathogenic bacteria. When the PH value of the tissue fluid in the medicine storage cavity does not reach a threshold value, the medicine carrying microspheres do not swell, decompose and release the medicine, and the medicine carrying microspheres are limited by the size and cannot penetrate through the semi-permeable membrane. The invention constructs an effective titanium jaw implant self-adaptive drug release system.

Description

Technical Field

[0001] This invention relates to the field of medical device design technology, and in particular to an adaptive drug delivery system for a titanium jawbone implant. Background Technology

[0002] Titanium and titanium alloys have become mainstream implant materials in the field of jawbone defect repair due to their excellent biocompatibility, high specific strength, and corrosion resistance. However, clinical data show that the infection rate after jawbone implantation is as high as 8%-15% (mainly Gram-positive bacteria such as Staphylococcus aureus and Staphylococcus epidermidis). Among these, about 30% of infection cases lead to treatment failure due to bacterial biofilm formation, ultimately requiring a second surgery to remove the implant. Traditional systemic antibiotic administration has the risks of insufficient local drug concentration, systemic toxicity, and the proliferation of drug-resistant bacteria. While surface drug-loaded coatings (such as hydroxyapatite and polylactic acid drug-loaded layers) can inhibit bacterial proliferation in the short term, they face the drawbacks of drug burst release or failure due to the dynamic complexity of the jawbone microenvironment (such as the decrease in pH value during inflammation) and limited functionality. Therefore, there is a need to develop a titanium implant drug delivery system that can dynamically respond to the infection microenvironment (such as pH value and osmotic pressure) and synergistically regulate the dual functions of antibacterial and osteogenic (good biocompatibility, which is conducive to osteoblast adhesion) to solve the contradiction between "antibacterial and osteogenic" in the field of jawbone repair and reduce the postoperative infection rate.

[0003] In summary, the design and fabrication of titanium jawbone adaptive systems is essentially an integrated design and manufacturing problem involving bone implant structure design, material composition, and functional realization. However, current related technologies or methods neglect this aspect, failing to deeply couple drug storage space, drug release mechanism, and functional realization. This results in complex fabrication processes, untimely responses, excessive reliance on external stimuli, and low drug loading rates. Specifically, this manifests as: firstly, the contradiction between complex fabrication processes and large-scale production; secondly, the disconnect between passive release systems and dynamic treatment needs; thirdly, dependence on external stimuli, which can increase clinical risks; and fourthly, the dilemma of balancing drug loading efficiency and structural stability. Summary of the Invention

[0004] Therefore, the technical problem to be solved by the present invention is to overcome the problem that the existing titanium jawbone implant drug delivery system fails to achieve deep coupling of drug storage space, drug release mechanism and function.

[0005] To address the aforementioned technical problems, this invention provides an adaptive drug delivery system for titanium jaw implants, comprising:

[0006] The drug storage cavity is located on the surface of the titanium jawbone implant;

[0007] Drug-loaded microspheres are embedded in the inner wall of the drug storage cavity;

[0008] A semi-permeable membrane covers the drug release port of the drug storage cavity;

[0009] Carrier protein channels, located on a semipermeable membrane, allow drug molecules released from drug-loaded microspheres to pass through.

[0010] Specifically, when the pH value of the tissue fluid from the inflammatory area in the drug storage cavity reaches the threshold, the drug-loaded microspheres are infiltrated by the tissue fluid, detach from the inner wall of the drug storage cavity, swell and decompose to release drug molecules, and the drug molecules enter the cells through the carrier protein channel via the semipermeable membrane to disinfect pathogens; when the pH value of the tissue fluid in the drug storage cavity does not reach the threshold, the drug-loaded microspheres will not swell and decompose to release drugs, and the drug-loaded microspheres are limited by size and cannot pass through the semipermeable membrane.

[0011] In one embodiment of the present invention, the drug-loaded microspheres are pH-sensitive drug-loaded microspheres. Based on the pH value of the lesion area, pH-sensitive drug-loaded microspheres are divided into pH-low sensitive drug-loaded microspheres and pH-high sensitive drug-loaded microspheres. The pH-low sensitive drug-loaded microspheres are drug-loaded microspheres used to respond to pH changes in tissue fluid with mild inflammation, and the pH-high sensitive drug-loaded microspheres are drug-loaded microspheres used to respond to pH changes in tissue fluid with severe inflammation.

[0012] In one embodiment of the present invention, the drug storage cavity includes a pH-low sensitivity drug-loaded microsphere covering area near the drug release port and a pH-high sensitivity drug-loaded microsphere covering area away from the drug release port, wherein the pH-high sensitivity drug-loaded microsphere covering area is used to house the pH-high sensitivity drug-loaded microspheres, and the pH-low sensitivity drug-loaded microsphere covering area is used to house the pH-low sensitivity drug-loaded microspheres.

[0013] In one embodiment of the present invention, when the pH value of the tissue fluid in the drug storage cavity reaches a threshold, the drug-loaded microspheres, after being wetted by the tissue fluid, detach from the inner wall of the drug storage cavity and swell and decompose to release drug molecules. The drug molecules enter the cells through the carrier protein channel and the semipermeable membrane to disinfect pathogens. Specifically:

[0014] When inflammation first occurs, the pH of the lesion area decreases, cells dehydrate, and an osmotic pressure difference is created inside and outside the cells to form tissue fluid. The tissue fluid passes through the semipermeable membrane into the drug storage cavity. The pH-sensitive drug-loaded microspheres in the area covered by the drug release port detach from the inner wall of the drug storage cavity under the infiltration of tissue fluid, forming a suspension of pH-sensitive drug-loaded microspheres with the tissue fluid. When the pH value of the suspension reaches the drug release threshold of the pH-sensitive drug-loaded microspheres, the pH-sensitive drug-loaded microspheres swell and decompose to release drug molecules. The drug molecules pass through the semipermeable membrane into the cells under the action of the concentration gradient through the carrier protein channels, disinfecting pathogens.

[0015] In one embodiment of the present invention, when the pH value of the tissue fluid in the drug storage cavity reaches a threshold, the drug-loaded microspheres, after being wetted by the tissue fluid, detach from the inner wall of the drug storage cavity and swell and decompose to release drug molecules. The drug molecules enter the cells through the carrier protein channel and the semipermeable membrane to disinfect pathogens. Specifically:

[0016] When inflammation recurs or worsens, the pH of the lesion area decreases again, cells dehydrate again, and the osmotic pressure difference between the inside and outside of the cells increases, forming tissue fluid. The tissue fluid passes through the semipermeable membrane and re-enters the drug storage cavity, further raising the fluid level in the drug storage cavity. The pH-sensitive drug-loaded microspheres in the area covered by the pH-sensitive drug-loaded microspheres, far from the drug release port, detach from the inner wall of the drug storage cavity under the infiltration of tissue fluid, forming a suspension of pH-sensitive drug-loaded microspheres with the tissue fluid. When the pH value of the suspension reaches the drug release threshold of the pH-sensitive drug-loaded microspheres, the pH-sensitive drug-loaded microspheres swell and decompose, releasing drug molecules. Under the action of the concentration gradient, the drug molecules pass through the semipermeable membrane through the carrier protein channel and enter the cell to disinfect pathogens.

[0017] In one embodiment of the present invention, the drug storage cavity satisfies:

[0018] Obtain the concentration C of intracellular osmotic active particles in the inflammatory lesion area. cell Concentration of extracellular osmotic active particles C in a healthy environment cavity Establish the liquid level-osmotic pressure balance equation:

[0019] ΔП=П cell -П cavity =(C cell -C cavity )RT

[0020] Then, calculate the liquid level height h in the drug storage chamber according to the liquid level-osmotic pressure balance equation ΔП:

[0021] h=βL p ΔПt response

[0022] The depth H of the drug storage chamber is determined based on the liquid level height h in the storage chamber:

[0023] H≥max{h}

[0024] Among them, П cell Intracellular osmotic pressure, П cavity Where R is the extracellular osmotic pressure, T is the gas constant, and t is the absolute temperature. response L is the response time of the drug release system, β is the liquid level response adjustment factor, and L p The hydraulic permeability of the semipermeable membrane.

[0025] In one embodiment of the present invention, the drug storage cavity satisfies:

[0026] By Q single =Q total / n yields the required mass of drug-loaded microspheres to be attached to a single drug reservoir, Q single Q represents the required mass of microspheres to be attached to a single drug reservoir. total The total mass of the drug-loaded microspheres carried by the titanium jaw implant is n, which is the number of drug storage cavities.

[0027] The height of the coverage area of ​​pH-sensitive drug-loaded microspheres and pH-sensitive drug-loaded microspheres in the drug storage cavity is designed, wherein...

[0028] Height of the pH-low sensitivity drug-loaded microsphere coverage area: h1=(Q1 / Q single H, Q1 = 0.3Q single ;

[0029] Height of the pH-sensitive drug-loaded microsphere coverage area: h2 = H - h1;

[0030] Where Q1 is the mass of the pH-low-sensitivity drug-loaded microspheres, and H is the depth of the drug storage cavity.

[0031] In one embodiment of the present invention, the drug storage cavity satisfies:

[0032] A ring-radial texture is designed on the inner wall of the drug storage cavity. The ring-radial texture is obtained by laser etching and includes a ring texture and a radial texture. The ring texture consists of several rings obtained by laser etching on the inner wall of the drug storage cavity, and the texture spacing SI1 between adjacent rings is 100±7.5μm. The radial texture consists of several straight lines obtained by laser etching on the inner wall of the drug storage cavity, and the texture spacing SI2 between adjacent straight lines is 100±6μm.

[0033] The intersection of the annular-radial texture with the drug release port of the storage cavity forms a hydrophilic texture modification region and a hydrophobic texture modification region. The hydrophilic texture modification region is a laser-etched area, and the hydrophobic texture modification region is an un-laser-etched area. The hydrophilic texture modification region has a hydrophilic contact angle of 50-70°, and the hydrophobic texture modification region has a hydrophobic contact angle of 120-140°.

[0034] In one embodiment of the present invention, the semipermeable membrane is composed of a regenerated cellulose membrane with a thickness of 50-80 μm and a molecular weight cutoff of 1500-2500 Da.

[0035] In one embodiment of the present invention, the pH-sensitive drug-loaded microspheres have a particle size of 20-40 μm, and the pH-insensitive drug-loaded microspheres have a particle size of 40-50 μm.

[0036] The technical solution of the present invention has the following advantages compared with the prior art:

[0037] This invention utilizes a synergistic design of laser etching and surface modification to construct hydrophilic / hydrophobic gradient wettability zones on the surface of titanium implants. The superhydrophobic properties of the hydrophobic zones inhibit bacterial adhesion, while the hydrophilic zones enable efficient drug loading and targeted adhesion of osteoblasts. Combined with a smart responsive drug release mechanism, the drug release rate can be dynamically adjusted according to the local microenvironment, significantly prolonging the drug's action period and improving targeting. Its fabrication process employs an integrated molding technology, simplifying the traditional multi-step coating process. While ensuring structural stability and biocompatibility, it achieves synergistic optimization of antibacterial and osteointegration functions, making it particularly suitable for long-term treatment needs in complex biological microenvironments, effectively inhibiting bacterial growth and promoting osteointegration.

[0038] The adaptive drug release system for titanium jaw implants designed in this invention extends the antibacterial time from 36 hours to 60 hours compared to the direct release group. This system exhibits excellent sustained-release performance and environmental responsiveness, and can sense environmental changes and adjust the drug release rate. Attached Figure Description

[0039] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings.

[0040] Figure 1 This is a schematic diagram of the overall adaptive drug delivery system for the titanium jawbone implant in an embodiment of the present invention;

[0041] Figure 2 This is a diagram illustrating the working mechanism of the adaptive drug delivery system for the titanium jaw implant in this embodiment of the invention.

[0042] Figure 3 This is a schematic diagram of the drug storage cavity structure in an embodiment of the present invention;

[0043] Figure 4 This is a schematic diagram of the ring-radial texture in the drug storage cavity in an embodiment of the present invention;

[0044] Figure 5 This is a schematic diagram of the longitudinal section of the drug storage cavity in an embodiment of the present invention;

[0045] Figure 6 This is a schematic diagram of the distribution of pH-sensitive / pH-sensitive drug-loaded microspheres in an embodiment of the present invention;

[0046] Figure 7 This is a comparison chart of the cumulative release rates of different pH-sensitive drug-loaded microspheres in the embodiments of the present invention;

[0047] Figure 8 This is a comparative statistical chart of antibacterial experiments in the embodiments of the present invention;

[0048] Figure 9This is a schematic diagram of the contact angles of the hydrophilic texture modification region and the hydrophobic texture modification region in an embodiment of the present invention.

[0049] Figure labeling: 1. Pathogen; 2. Semipermeable membrane; 3. Drug-loaded microsphere; 4. Carrier protein channel; 5. Microsphere drug release; 6. Drug molecule; 7. Longitudinal section of the matrix; 8. Lesion adhesion surface; 9. Drug release port; 10. Drug reservoir; 11. Ring-radial texture; 12. Matrix; 13. Center of drug release port; 14. Hydrophilic texture modification region; 15. Hydrophobic texture modification region. Detailed Implementation

[0050] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0051] Example 1

[0052] Reference Figure 1 , Figure 2 , Figure 3 As shown, this invention relates to an adaptive drug delivery system for titanium jaw implants, comprising:

[0053] Several drug storage cavities 10 are formed on the surface of the titanium jawbone implant (i.e., the base 12);

[0054] Drug-loaded microspheres 3 are embedded in the inner wall of the drug storage cavity 10;

[0055] A semi-permeable membrane 2 covers the drug release port 9 of the drug storage cavity 10;

[0056] Carrier protein channel 4, located on the semipermeable membrane 2, is used to allow drug molecules 6 released from drug-loaded microspheres 3 to pass through;

[0057] Specifically, when the pH value of the tissue fluid from the inflammatory area in the drug storage cavity 10 reaches the threshold, the drug-loaded microspheres 3, after being infiltrated by the tissue fluid, detach from the inner wall of the drug storage cavity 10 and swell and decompose to release drug molecules 6. The drug molecules 6 enter the cells through the semipermeable membrane 2 via the carrier protein channel 4 to disinfect pathogens 1. When the pH value of the tissue fluid in the drug storage cavity 10 does not reach the threshold (divided into the pH threshold of tissue fluid in mild inflammation and the pH threshold of tissue fluid in severe inflammation), the drug-loaded microspheres 3 cannot pass through the semipermeable membrane 2 due to size limitations. (It should be noted here that the drug-loaded microspheres 3 will detach from the inner wall of the drug storage cavity 10. Even though they detach from the inner wall, if the pH does not drop to the threshold, the drug-loaded microspheres 3 will not decompose and release drug molecules 6.)

[0058] In this embodiment, the drug-loaded microsphere 3 is a pH-sensitive drug-loaded microsphere. Based on the pH value of the lesion area, the pH-sensitive drug-loaded microspheres are divided into pH-low sensitive drug-loaded microspheres and pH-high sensitive drug-loaded microspheres. The pH-low sensitive drug-loaded microspheres are attached to the proximal end of the drug release port 9 and are used to respond to pH changes in mild inflammatory tissue fluid (tissue fluid pH is lower than the pH threshold of mild inflammatory tissue fluid, for example, 6.5). The pH-high sensitive drug-loaded microspheres are attached to the distal end of the drug release port 9 and are used to respond to pH changes in severe inflammatory tissue fluid (tissue fluid pH is lower than the pH threshold of highly inflammatory tissue fluid, for example, 5.5).

[0059] In this embodiment, the drug storage cavity 10 includes a pH-low-sensitivity drug-loaded microsphere-covered area near the drug release port 9 (e.g., Figure 6 The area within the drug storage cavity 10 at height h1 is the location of the drug storage cavity 10, and the area covered by the pH-sensitive drug-loaded microspheres far from the drug release port 9 (e.g., Figure 6 The height h2 inside the central drug storage cavity 10 is the area where it is located. The area covered by the pH-sensitive drug-loaded microspheres is used to set the pH-sensitive drug-loaded microspheres, and the area covered by the pH-insensitive drug-loaded microspheres is used to set the pH-insensitive drug-loaded microspheres.

[0060] Please see Figure 1 and Figure 2 When inflammation first occurs, the pH of the lesion area decreases, cells dehydrate, and an osmotic pressure difference is created inside and outside the cells, forming a low-pH tissue fluid. This tissue fluid permeates through the semipermeable membrane 2 into the drug storage chamber 10. The low-pH drug-loaded microspheres near the drug release port 9 detach from the inner wall of the drug storage chamber 10 under the influence of the tissue fluid, forming a suspension containing the low-pH drug-loaded microspheres. When the pH of the suspension reaches the release threshold of the low-pH drug-loaded microspheres, the microspheres swell and decompose, releasing drug molecules 6. Drug molecules 6, under the influence of the concentration gradient, pass through the semipermeable membrane 2 via the carrier protein channel 4 and enter the cells, disinfecting pathogens 1. Because drug molecules 6 disinfect pathogens 1, the human cells spontaneously restore their pH to approximately normal 7.4 through mechanisms such as proton exchange. In short, the pH of the originally low-pH tissue fluid becomes normal. In practical applications, the normal-pH tissue fluid permeates through the semipermeable membrane 2 and is absorbed by the human body. This pH regulation process is known as osmotic pressure self-regulation.

[0061] Please see Figure 1 and Figure 2When inflammation recurs or worsens, the pH of the lesion area decreases again, and the cells dehydrate again (the more severe the inflammation, the more dehydration). The osmotic pressure difference between the inside and outside of the cells increases, forming tissue fluid with an even lower pH. The tissue fluid passes through the semipermeable membrane 2 and re-enters the drug storage cavity 10. The fluid level in the drug storage cavity 10 further increases (higher than the fluid level when the inflammation first occurred). The pH-sensitive drug-loaded microspheres in the area covered by the pH-sensitive drug-loaded microspheres, which are far from the drug release port 9, detach from the inner wall of the drug storage cavity 10 under the infiltration of the tissue fluid, forming a suspension of pH-sensitive drug-loaded microspheres with the tissue fluid. When the pH value of the suspension reaches the drug release threshold of the pH-sensitive drug-loaded microspheres, the pH-sensitive drug-loaded microspheres swell and decompose, releasing drug molecules 6. Drug molecules 6 pass through the semipermeable membrane 2 and enter the cells under the action of the concentration gradient through the carrier protein channel 4, disinfecting pathogens 1. As drug molecule 6 kills pathogens 1, human cells spontaneously restore their pH to approximately normal pH 7.4 through mechanisms such as proton exchange. In short, the pH of the tissue fluid, which was originally lower, becomes normal. In practical applications, the normal pH tissue fluid passes through the semipermeable membrane 2 and is absorbed by the human body. This pH regulation process is called osmotic pressure self-regulation.

[0062] The process of eliminating pathogen 1 described above can be repeated multiple times.

[0063] The drug storage chamber 10 in this embodiment satisfies the following:

[0064] Obtain the concentration C of intracellular osmotic active particles in the inflammatory lesion area. cell Concentration of extracellular osmotic active particles C in a healthy environment cavity Establish the liquid level-osmotic pressure balance equation:

[0065] ΔП=П cell -П cavity =(C cell -C cavity )RT

[0066] Then, calculate the liquid level height h in the drug storage chamber 10 according to the liquid level-osmotic pressure balance equation ΔП:

[0067] h=βL p ΔПt response

[0068] The depth H of the drug storage chamber 10 is determined based on the liquid level height h in the storage chamber:

[0069] H≥max{h}

[0070] Among them, П cell Intracellular osmotic pressure, П cavity Where R is the extracellular osmotic pressure, T is the gas constant, and t is the absolute temperature. response L is the response time of the drug delivery system. pβ represents the hydraulic permeability of the semipermeable membrane, and β is the level response adjustment factor, which is used to compensate for fluid resistance in actual biological environments.

[0071] (In practice, h is affected by factors such as changes in tissue fluid viscosity and protein adsorption on the surface of the semipermeable membrane.) β can correct the difference between the theoretical and actual liquid level heights within the drug storage cavity 10. The calculated result h serves as the central basis for the spatial structure design of the drug storage cavity 10, determining the stratification start and end points of drug release. It also provides quantitative support for the subsequent allocation of the height h1 of the pH-low-sensitivity drug-loaded microsphere coverage area and the height h2 of the pH-high-sensitivity drug-loaded microsphere coverage area, ensuring that the drug storage cavity 10 can accurately activate the corresponding drug release areas at different stages of inflammation.

[0072] The drug storage chamber 10 in this embodiment satisfies the following:

[0073] By Q single =Q total / n yields the required mass of drug-loaded microspheres 3 to be attached to a single drug storage cavity 10, Q single Q represents the required mass of microspheres to be attached to a single drug reservoir. total The total mass of the drug-loaded microspheres carried by the titanium jaw implant is n, which is the number of drug storage cavities.

[0074] The height of the coverage area of ​​pH-low sensitive drug-loaded microspheres and pH-high sensitive drug-loaded microspheres is designed in the drug storage cavity 10, wherein...

[0075] Height of the pH-low sensitivity drug-loaded microsphere coverage area: h1=(Q1 / Q single H, Q1 = 0.3Q single ;

[0076] Height of the pH-sensitive drug-loaded microsphere coverage area: h2 = H - h1;

[0077] Where Q1 is the mass of the pH-low-sensitivity drug-loaded microspheres, and H is the depth of the drug storage cavity.

[0078] The drug storage chamber 10 in this embodiment satisfies the following:

[0079] Please see Figure 3 and Figure 4 A ring-radial texture 11 is designed on the inner wall of the drug storage cavity 10. The ring-radial texture 11 is obtained by laser etching and includes a ring texture and a radial texture. The ring texture is a number of rings obtained by oblique laser etching on the inner wall of the drug storage cavity 10, and the texture spacing SI1 between adjacent rings is 100±7.5μm. The radial texture is a number of straight lines obtained by vertical laser etching on the inner wall of the drug storage cavity 10, and the texture spacing SI2 between adjacent straight lines is 100±6μm.

[0080] In this embodiment, the intersection of the annular-radial texture 11 and the drug release port 9 of the drug storage cavity 10 forms a texture modification zone. Please refer to [link to relevant documentation]. Figure 4 The texture modification region includes a hydrophilic texture modification region 14 and a hydrophobic texture modification region 15. It should be noted that the hydrophilic texture modification region 14 is the area laser-etched (because the drug reservoir 10 is treated with silicone oil and laser-etched, it facilitates the adhesion of drug-loaded microspheres 3), while the hydrophobic texture modification region 15 is the area not laser-etched (because it is not laser-etched, it facilitates the release of drug-loaded microspheres 3). In this embodiment, the hydrophilic texture modification region 14 has a 50-70° hydrophilic contact angle (easier to adhere to drug-loaded microspheres 3), and the hydrophobic texture modification region 15 has a 120-140° hydrophobic contact angle (not easy to adhere to drug-loaded microspheres 3). Please refer to... Figure 9 , Figure 9 In (a), the hydrophilic texture modified region 14 has a measured contact angle CA (the angle between the solid-liquid interface line and the tangent of the gas-liquid interface when the droplet reaches mechanical equilibrium on the inner wall of the drug storage cavity 10) of 57°. In (b), the hydrophobic texture modified region 15 has a measured contact angle CA (the angle between the solid-liquid interface line and the tangent of the gas-liquid interface when the droplet reaches mechanical equilibrium on the inner wall of the drug storage cavity 10) of 134°.

[0081] The semipermeable membrane 2 in this embodiment is composed of a regenerated cellulose membrane with a thickness of 50-80 μm and a molecular weight cutoff of 1500-2000 Da.

[0082] In this embodiment, the particle size of the pH-sensitive drug-loaded microspheres is 20-40 μm, and the particle size of the pH-insensitive drug-loaded microspheres is 40-50 μm. The drug loading rate of the drug-loaded microspheres 3 is 3.8%-4.5%.

[0083] In this embodiment, the diameter of the drug release port 9 in the drug storage chamber 10 ranges from 9 to 9.6 mm, and the volume of a single chamber in the drug storage chamber 10 is 91.9 to 111.5 mm. 3 The cavity depth-to-diameter ratio is 1:3.

[0084] In this embodiment, the drug storage chamber 10 is a funnel-shaped drug storage chamber. The function of the space (cylindrical space) in the funnel-shaped drug storage chamber without the attached drug-loaded microspheres 3 is to provide cavity volume and buffer level rise rate. For details, please refer to [reference needed]. Figure 5 and Figure 6 .

[0085] The invention will be described in detail below through a specific case:

[0086] This embodiment takes the Ti / HA biomimetic titanium implant (composed of 85% pure titanium and 15% hydroxyapatite by mass), which is commonly used in oral and maxillofacial transplantation and repair surgery, as an example. The design and preparation of the adaptive drug delivery system of the titanium jaw implant and the osteogenic (good biocompatibility, which is conducive to osteoblast adhesion) antibacterial application test were carried out at room temperature.

[0087] S1. Structural Design of Adaptive Drug Delivery System for Titanium Jawbone Implants

[0088] S11. Based on the patient's pathological characteristics, ciprofloxacin hydrochloride (CIP, molecular weight 331.34 g / mol) was selected as a small molecule drug with a UV characteristic peak at 277 nm. Combined with the drug loading rate formula α = m... drug / m microsphere ×100%=4.13%, where m drug For the mass of drug molecule 6, m microsphere This represents the total amount of pH-sensitive drug-loaded microspheres. Total amount of drug-loaded microspheres (Q) total =(Q daily ×T therapy Let Q be the daily drug requirement. daily =20mg, treatment cycle is T therapy =7 days, determine the total amount Q of drug-loaded microspheres required to be loaded onto the substrate 12 (i.e., titanium jaw implant). total =3.4g. Based on the pH fluctuation range of the lesion area, the pH trigger threshold for low-sensitivity drug-loaded microspheres was defined as 6.5, and the pH trigger threshold for high-sensitivity drug-loaded microspheres as 5.5.

[0089] S12. Based on the depth distribution of the longitudinal section of the jawbone lesion area, the drug storage cavity 10 is configured using geometric parameters; the concentration of intracellular permeable active particles C in the inflammatory lesion area is obtained through clinical testing. cell Concentration of extracellular osmotic active particles C in a healthy environment cavity Establish the liquid level-osmotic pressure balance equation:

[0090] ΔП=П cell -П cavity =(C cell -C cavity )RT

[0091] Then, calculate the liquid level height h in the drug storage chamber 10 according to the liquid level-osmotic pressure balance equation ΔП:

[0092] h=βL p ΔПt response

[0093] The depth H of the drug storage chamber is determined based on the liquid level height h in the drug storage chamber 10:

[0094] H≥max{h}

[0095] Among them, П cell Intracellular osmotic pressure, П cavity Where R is the extracellular osmotic pressure, T is the gas constant, and t is the absolute temperature. response L is the response time of the drug delivery system. pβ represents the hydraulic permeability of the semipermeable membrane, and β is the level response adjustment factor.

[0096] S13, please refer to Figure 5 The drug storage chamber 10 is designed with a release port 9 diameter D1 = 9 mm, a storage chamber depth H = 3 mm, an inner orifice diameter D2 = 3 mm, and a storage chamber quantity n = 1. This is based on... Figure 3 The longitudinal section 7 of the substrate (longitudinal section of the titanium jawbone implant) shows that the drug storage cavity 10 is a funnel-shaped drug storage cavity, formed by Q. single =Q total / n This yields the required mass of pH-sensitive drug-loaded microspheres for a single drug reservoir 10. Each reservoir 10 is loaded with 3.4 g of drug-loaded microspheres 3. The mass of pH-insensitive drug-loaded microspheres is Q1 = 0.3Q. single =1.02g, the height of the pH-low-sensitivity drug-loaded microsphere coverage area is h1 = (Q1 / Q single H = 0.9 mm, the height of the pH-sensitive drug-loaded microsphere coverage area is h2 = H - h1 = 2.1 mm, and the mass of the pH-sensitive drug-loaded microsphere is...

[0097] Q2 = 0.7Q singl =2.38g.

[0098] S14. A ring-radial texture 11 is designed on the inner wall of the drug release port 9 of the drug storage cavity 10. The ring-radial texture 11 is obtained by laser etching and includes a ring texture and a radial texture. The ring texture consists of several rings obtained by laser etching on the inner wall of the drug storage cavity 10, and the texture spacing SI1 between adjacent rings is 100±7.5μm. The radial texture consists of several straight lines obtained by laser etching on the inner wall of the drug storage cavity 10, and the texture spacing SI2 between adjacent straight lines is 100±6μm. At the intersection of the annular-radial texture 11 and the drug release port 9, a hydrophilic texture modification region 14 and a hydrophobic texture modification region 15 are formed. The hydrophilic texture modification region 14 is a laser-etched region, and the hydrophobic texture modification region 15 is an un-laser-etched region. The hydrophilic texture modification region 14 has a hydrophilic contact angle of 50-70°, and the hydrophobic texture modification region 15 has a hydrophobic contact angle of 120-140°.

[0099] S2, Laser Additive / Subtractive Material Preparation and Surface Modification of Drug Storage Chamber 10

[0100] S21. First, perform a CT scan on the patient's transplant site. Import the obtained 557 image packages into DICOM software to reconstruct the model and output the original STL file. Then, import it into the 3D modeling software Geomagic Studio for small plane-to-solid conversion, mandibular model extraction, surface smoothing (mandibular model surface roughness Ra≤0.8μm), local manual repair, and then open the drug storage cavity 10 on the lesion-adhering surface 8 of the titanium mandibular implant according to the design requirements of step S1. Generate an STL printing model file, denoted as X. Then, import the model file X into the SLM printer, set the laser power to 200W, scanning speed to 800mm / s, overlap rate to 50%, and layer thickness t=30μm, and start printing. After printing, remove the implant and perform heat treatment, support removal, grinding and polishing in sequence to complete the preparation of the geometric structure of the drug storage cavity 10.

[0101] S22. Use Sky Scan 1176 Micro-CT in conjunction with a Hexagon coordinate measuring machine to check the dimensional accuracy of the printed parts. If the deviation from the design model is less than 0.5mm, it is considered qualified; otherwise, readjust the printing parameters and repeat step S21 until it is qualified.

[0102] S23. Immerse the qualified parts in a glass beaker containing silicone oil and place them in a constant temperature drying oven for heat treatment. The treatment conditions are 200℃ constant temperature for 2 hours.

[0103] S24. Extract the coordinate point set Set X of the drug release port center 13 of the drug storage cavity 10 in the model file X. Draw the dwg file of the center point set to be etched in AutoCAD. Import it into the TANGOR femtosecond laser from Amplitude, France. Set the laser wavelength λ to 355nm, laser power P to 5W, laser frequency f to 30kHz, pulse width to 35ns, and scanning speed to 50mm / s. Turn on the laser to perform annular etching according to the preset path. Then change the pulse width to 25ns to perform radial etching according to the preset path.

[0104] S25. Immerse the etched printed part in anhydrous ethanol solution for ultrasonic cleaning to remove residual silicone oil on the surface. Then transfer the sample to a constant temperature drying oven for drying to complete the surface preparation of the drug storage cavity 10.

[0105] S26. Use an OCA20 contact angle meter to measure whether the water contact angle of the texture modification zone of the drug storage cavity 10 meets the design requirements in step S13. If it does not meet the requirements, fine-tune the laser parameters in step S24 and repeat steps S24-S25 until it meets the design requirements.

[0106] S3, pH-sensitive drug-loaded microsphere release testing and assembly of adaptive drug release system for titanium jaw implants

[0107] S31. Dissolve CIP powder in hydrochloric acid solution to prepare CIP solutions (simulating drug molecule 6) with different concentration gradients from 0-300 μg / mL. Measure the absorbance (A) of the CIP solutions at 277 nm using a UV spectrophotometer. Through linear fitting analysis, the regression equation is obtained: A = 0.0678C + 0.0445, where C is the CIP solution concentration. Calculate the R² of the regression equation. 2 Value, R 2 The closer the value is to 1, the better the regression equation A fits. In this example, R... 2 A value of 0.9958 indicates a good fit.

[0108] S32. Weigh out three groups of samples, each with a mass of m. drug =10mg drug-loaded microspheres 3 (see also) Figure 7 CIP-gelatin drug-loaded microspheres, CIP-PLGA drug-loaded microspheres, and CIP-chitosan drug-loaded microspheres were placed in centrifuge tubes, and PBS buffers with different pH values ​​(5.5, 6.5, and 7.4) with a volume of V0 = 2 mL were added to simulate oral inflammation, mild inflammation, and normal environments. The tubes were then sealed, and all centrifuge tubes were placed in a water bath constant temperature shaker. The temperature was set to 37°C to simulate the physiological temperature of the human body, and the shaker speed was set to 80 rpm to ensure that the drug-loaded microspheres 3 were released under slow and uniform conditions.

[0109] S33. At time t0 = 1 h, a 0.45 μm aqueous syringe was used to extract volume V. e =1.5mL of release solution, measure the absorbance of the release solution with a UV spectrophotometer, substitute it into the regression equation in step S31 to calculate the drug CIP concentration, and add an equal volume of buffer solution;

[0110] S34. Repeat step S33 every 1 hour to obtain the concentration of drug CIP (0.02065, 0.14455, ..., 0.18585, 0.18585 μg / mL) at (1 h, 2 h, ..., 23 h, 24 h) for the CIP-gelatin microsphere group under inflammatory conditions.

[0111] S35, At this time C 24 =C 25 If the drug CIP concentration no longer increases at 24h and 25h, then the drug release is considered to have stabilized, according to E. r =(V e Σ n n-1 C n-1 +V0C n ) / m drug The cumulative drug release rate was calculated to be 99% (×100%), with a release time of 24 hours. The results are as follows: Figure 7 As shown;

[0112] S36. The CIP-gelatin microspheres with the highest drug loading rate and best drug release performance are attached to the above-mentioned drug storage cavity 10 in sections using a vacuum drying method. Details are as follows: Figure 6 As shown, a regenerated cellulose membrane with a molecular weight cutoff of 2000 Da is coated onto the drug release port 9 of the drug storage cavity 10 to complete the assembly of the adaptive drug release system for the titanium jaw implant.

[0113] It should be noted that in the experiment, this embodiment uses a regenerated cellulose membrane as a semipermeable membrane 2 to simulate the cell membrane of the human body. When the titanium jawbone implant is put into actual use, there is no need to set up an additional regenerated cellulose membrane. The cell membrane of the human body (phospholipid bilayer structure) is directly used as the semipermeable membrane 2 to directly contact the titanium jawbone implant.

[0114] S4. Evaluation of the antibacterial performance of the adaptive drug delivery system for titanium jaw implants.

[0115] S41. After diluting Staphylococcus aureus, spread it evenly on an agar plate, and then place the assembled drug storage chamber 10 (covered with a semi-permeable membrane 2) into the corresponding container. Figure 8 The experimental group in, and Figure 8 The direct release group (without semipermeable membrane 2) was dynamically cultured in close contact with the agar surface, and the diameter of the inhibition zone was measured every 12 hours. Staphylococcus aureus was then spread on the agar culture dish again to simulate the situation of inflammation recurrence or aggravation.

[0116] S42. For the experimental group, the titanium jawbone implant was constructed as a cylinder with a diameter D0 = 10 mm. The diameters of the transparent inhibition zone (a circular area free of pathogens) were measured at different times (0, 12, 24, 36, 48, 60, 72 h) at 10, 36.5, 43.8, 40.2, 32.1, 10.2, and 10 mm, respectively. According to D = (D0 = 10 mm),... n The width of the antibacterial band (the strip from the cylindrical titanium jawbone implant to the edge of the antibacterial ring) is calculated as 0, 13.2, 16.9, 15.1, 11.05, 0.1, 0 mm, where D... n This refers to the diameter of the inhibition zone. Starting from 60 hours, the diameter D of the inhibition zone... n The inhibition time remained unchanged at 60 hours; however, in the direct release group, the diameter of the inhibition zone D remained unchanged within 0-12 hours. n Rapidly expands to 44.5mm, with the inhibition zone diameter D increasing over 12-24 hours. n The diameter remained around 43.4 mm; however, starting from 36 hours, sporadic colonies began to appear within the inhibition zone, as shown in the following results. Figure 8 As shown.

[0117] This embodiment demonstrates through an antibacterial zone experiment that the adaptive drug release system for the titanium jaw implant designed in this invention extends the antibacterial time from 36 hours to 60 hours compared to the direct release group. This system exhibits excellent sustained-release performance and environmental responsiveness, capable of sensing environmental changes and adjusting the drug release rate accordingly.

[0118] Although preferred embodiments of this application have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of this application.

[0119] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. An adaptive drug delivery system for titanium jaw implants, characterized in that: include The drug storage cavity is located on the surface of the titanium jawbone implant; Drug-loaded microspheres are embedded in the inner wall of the drug storage cavity; A semi-permeable membrane covers the drug release port of the drug storage cavity; Carrier protein channels, located on a semipermeable membrane, allow drug molecules released from drug-loaded microspheres to pass through. Specifically, when the pH value of the tissue fluid from the inflammatory area in the drug storage cavity reaches the threshold, the drug-loaded microspheres are infiltrated by the tissue fluid, detach from the inner wall of the drug storage cavity, swell and decompose to release drug molecules, and the drug molecules enter the cells through the carrier protein channel via the semipermeable membrane to disinfect pathogens; when the pH value of the tissue fluid in the drug storage cavity does not reach the threshold, the drug-loaded microspheres will not swell and decompose to release drugs, and the drug-loaded microspheres are limited by size and cannot pass through the semipermeable membrane.

2. The adaptive drug delivery system for titanium jaw implants according to claim 1, characterized in that: The drug-loaded microspheres are pH-sensitive drug-loaded microspheres. Based on the pH value of the lesion area, pH-sensitive drug-loaded microspheres are divided into pH-low sensitive drug-loaded microspheres and pH-high sensitive drug-loaded microspheres. The pH-low sensitive drug-loaded microspheres are used to respond to pH changes in tissue fluid during mild inflammation, while the pH-high sensitive drug-loaded microspheres are used to respond to pH changes in tissue fluid during severe inflammation.

3. The adaptive drug delivery system for titanium jaw implants according to claim 2, characterized in that: The drug storage cavity includes a pH-low sensitivity drug-loaded microsphere covering area near the drug release port and a pH-high sensitivity drug-loaded microsphere covering area away from the drug release port. The pH-high sensitivity drug-loaded microsphere covering area is used to house the pH-high sensitivity drug-loaded microspheres, and the pH-low sensitivity drug-loaded microsphere covering area is used to house the pH-low sensitivity drug-loaded microspheres.

4. The adaptive drug delivery system for titanium jaw implants according to claim 3, characterized in that: When the pH value of the tissue fluid in the drug storage cavity reaches the threshold, the drug-loaded microspheres, after being infiltrated by the tissue fluid, detach from the inner wall of the drug storage cavity, swell, decompose, and release drug molecules. The drug molecules enter the cells through the carrier protein channels and semipermeable membrane to disinfect pathogens. Specifically: When inflammation first occurs, the pH of the lesion area decreases, cells dehydrate, and an osmotic pressure difference is created inside and outside the cells to form tissue fluid. The tissue fluid passes through the semipermeable membrane into the drug storage cavity. The pH-sensitive drug-loaded microspheres in the area covered by the drug release port detach from the inner wall of the drug storage cavity under the infiltration of tissue fluid, forming a suspension of pH-sensitive drug-loaded microspheres with the tissue fluid. When the pH value of the suspension reaches the drug release threshold of the pH-sensitive drug-loaded microspheres, the pH-sensitive drug-loaded microspheres swell and decompose to release drug molecules. The drug molecules pass through the semipermeable membrane into the cells under the action of the concentration gradient through the carrier protein channels, disinfecting pathogens.

5. The adaptive drug delivery system for titanium jaw implants according to claim 3, characterized in that: When the pH value of the tissue fluid in the drug storage cavity reaches the threshold, the drug-loaded microspheres, after being infiltrated by the tissue fluid, detach from the inner wall of the drug storage cavity, swell, decompose, and release drug molecules. The drug molecules enter the cells through the carrier protein channels and semipermeable membrane to disinfect pathogens. Specifically: When inflammation recurs or worsens, the pH of the lesion area decreases again, the cells dehydrate again, the osmotic pressure difference between the inside and outside of the cells increases, forming tissue fluid. The tissue fluid passes through the semipermeable membrane and re-enters the drug storage cavity. The liquid level in the drug storage cavity rises further. The pH-sensitive drug-loaded microspheres in the area covered by the pH-sensitive drug-loaded microspheres far from the drug release port detach from the inner wall of the drug storage cavity under the infiltration of tissue fluid, forming a suspension with the tissue fluid containing pH-sensitive drug-loaded microspheres. When the pH value of the suspension reaches the drug release threshold of the pH-sensitive drug-loaded microspheres, the microspheres swell and decompose, releasing drug molecules. The drug molecules, under the action of the concentration gradient, pass through the semipermeable membrane through the carrier protein channel and enter the cell to disinfect pathogens.

6. The adaptive drug delivery system for titanium jaw implants according to claim 1, characterized in that: The drug storage chamber satisfies: Obtain the concentration C of intracellular osmotic active particles in the inflammatory lesion area. cell Concentration of extracellular osmotic active particles C in a healthy environment cavity Establish the liquid level-osmotic pressure balance equation: ΔP=P cell -P cavity =(C cell -C cavity )RT Then, calculate the liquid level height h in the drug storage chamber according to the liquid level-osmotic pressure balance equation ΔП: h=βL p ΔПt response The depth H of the drug storage chamber is determined based on the liquid level height h in the storage chamber: H≥max{h} Among them, П cell Intracellular osmotic pressure, П cavity Where R is the extracellular osmotic pressure, T is the gas constant, and t is the absolute temperature. response L is the response time of the drug release system, β is the liquid level response adjustment factor, and L p The hydraulic permeability of the semipermeable membrane.

7. The adaptive drug delivery system for titanium jaw implants according to claim 1, characterized in that: The drug storage chamber satisfies: By Q single =Q total / n yields the required mass of drug-loaded microspheres to be attached to a single drug reservoir, Q single Q represents the required mass of microspheres to be attached to a single drug reservoir. total The total mass of the drug-loaded microspheres carried by the titanium jaw implant is n, which is the number of drug storage cavities. The height of the coverage area of ​​pH-sensitive drug-loaded microspheres and pH-sensitive drug-loaded microspheres in the drug storage cavity is designed, wherein... Height of the pH-low sensitivity drug-loaded microsphere coverage area: h1=(Q1 / Q single H, Q1 = 0.3Q single ; Height of the pH-sensitive drug-loaded microsphere coverage area: h2 = H - h1; Where Q1 is the mass of the pH-low-sensitivity drug-loaded microspheres, and H is the depth of the drug storage cavity.

8. The adaptive drug delivery system for titanium jaw implants according to claim 1, characterized in that: The drug storage chamber satisfies: A ring-radial texture is designed on the inner wall of the drug storage cavity. The ring-radial texture is obtained by laser etching and includes a ring texture and a radial texture. The ring texture consists of several rings obtained by laser etching on the inner wall of the drug storage cavity, and the texture spacing SI1 between adjacent rings is 100±7.5μm. The radial texture consists of several straight lines obtained by laser etching on the inner wall of the drug storage cavity, and the texture spacing SI2 between adjacent straight lines is 100±6μm. The intersection of the annular-radial texture with the drug release port of the storage cavity forms a hydrophilic texture modification region and a hydrophobic texture modification region. The hydrophilic texture modification region is a laser-etched area, and the hydrophobic texture modification region is an un-laser-etched area. The hydrophilic texture modification region has a hydrophilic contact angle of 50-70°, and the hydrophobic texture modification region has a hydrophobic contact angle of 120-140°.

9. The adaptive drug delivery system for titanium jaw implants according to claim 1, characterized in that: The semi-permeable membrane is composed of regenerated cellulose membrane with a thickness of 50-80 μm and a molecular weight cutoff of 1500-2500 Da.

10. The adaptive drug delivery system for titanium jaw implants according to claim 2, characterized in that: The pH-sensitive drug-loaded microspheres have a particle size of 20-40 μm, and the pH-insensitive drug-loaded microspheres have a particle size of 40-50 μm.

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