A three-dimensional multi-level porous bone repair scaffold and its preparation method and application

Abstract

The present invention provides a three-dimensional multi-level porous bone repair scaffold for near-infrared light responsive PTHrP-2 pulse release and its preparation method and application, the method comprising the steps of: 1) preparing a large mesoporous bioactive nanosphere loaded with carbon quantum dots as a photothermal material; 2) polymerizing the photothermal material, NIPAM and NMA to obtain a composite thermosensitive hydrogel; 3) preparing a mesoporous bioactive glass powder, pre-compressing it with a pore-forming agent and a binder, and obtaining a three-dimensional multi-level mesoporous bioactive glass scaffold after calcination; 4) using a negative pressure adsorption method to load PTHrP-2 into the scaffold mesopores; 5) placing the three-dimensional scaffold after drug loading in the composite thermosensitive hydrogel, initiating polymerization on the scaffold surface, and obtaining. The scaffold prepared according to the present invention can realize the controllable pulse release of PTHrP-2 in vivo under near-infrared light in vitro, reach the optimal drug concentration in vivo, facilitate the rapid repair of bone defects, and achieve the best therapeutic effect.

Description

Technical Field

[0001] The present invention relates to the field of inorganic nanomaterials and biomaterials, and in particular to a three-dimensional multi-level porous bone repair scaffold capable of responsive to near-infrared light pulse release of PTHrP-2, and a preparation method and application thereof. Background Art

[0002] Parathyroid hormone (PTH) is an important endocrine hormone that plays a vital role in maintaining calcium balance and bone metabolism. In some cases, such as in diseases such as chronic kidney disease and osteoporosis, excessive or low PTH levels can lead to serious physiological and pathological consequences. Studies have shown that continuous PTH treatment can increase osteoclast activity, resulting in greater bone resorption than bone formation, while indirect PTH release can significantly promote bone formation by stimulating osteoblast activity, thereby enhancing fracture healing and bone regeneration. Parathyroid hormone (PTH) is currently the only FDA-approved anabolic drug for the treatment of osteoporosis, and is administered systemically via daily injection. However, daily administration can cause pain and discomfort to patients, and may have significant side effects or risks. Compared with pure PTH, a new type of PTH-related peptide PTHrP-2 (S[PO4]VSEI-QLMHN-LGKHL-NSMER-VEWLR-KKLQD-VHNF-EEE) is easier to synthesize in large quantities at a lower price. The N-terminal phosphorylation and C-terminal triple amino acid (Glu) motif of PTHrP-2 are the main differences between PTHrP-2 and PTH. Studies have shown that several proteins with acidic amino acid sequences as calcium binding sites in their structures can firmly bind to calcium-based materials, thereby increasing their long-term buffered release and increasing osteogenic differentiation ability. However, how to simulate the release law of drug molecules in a normal physiological environment in a timely and appropriate manner to achieve their optimal therapeutic effect based on the specific release kinetics of drug molecules has not been solved.

[0003] Pulse drug release is one of the important means of smart drug delivery. It can achieve a certain amount of drug molecules to be quickly released at a specific location in the body within a certain time range according to external chemical, physical and biological stimuli and achieve the best therapeutic effect. PNIPAM (poly N-isopropylacrylamide) is a thermosensitive hydrogel material. It is widely used in the biomedical field because of its excellent properties, such as low toxicity, high adjustability, biodegradability and responsiveness. Its phase transition temperature (LCST) is about 32°C, which belongs to the heat-shrinkable hydrogel. When the ambient temperature is lower than the lowest LCST, the polymer chain will dissolve in water. When the ambient temperature is higher than the LCST, the polymer chain will dehydrate and precipitate, and the volume will shrink. Introducing a small amount of hydrophilic monomers into the PNIPAM polymer chain can increase the LCST, thereby increasing the scope of application in the human body.

[0004] For bone tissue repair materials, it is not only necessary to release the required growth factors or drugs at specific locations in the body on demand, but also to have interconnected pore structures and appropriate pore sizes to facilitate cell adhesion, tissue growth, oxygen and nutrient transport, and new blood vessel ingrowth. Therefore, it is of great significance to prepare new drug delivery systems to achieve a certain amount of PTHrP-2 pulse release, achieve rapid and high-quality bone defect repair, and minimize the side effects of systemic drug treatment. Summary of the invention

[0005] The purpose of the present invention is to provide a three-dimensional multi-level porous bone repair scaffold capable of near-infrared light responsive PTHrP-2 pulse release and a preparation method and application thereof, so as to solve the problem in the prior art of lacking a bone repair scaffold capable of achieving near-infrared light responsive PTHrP-2 pulse release.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] According to the first aspect of the present invention, there is provided a method for preparing a three-dimensional multi-level porous bone repair scaffold capable of infrared light responsive PTHrP-2 pulse release, comprising the following steps: 1) constructing carbon quantum dot-loaded macroporous bioactive glass nanospheres as photothermal materials CDBGn: the macroporous bioactive glass nanospheres BGn are obtained by self-assembly of amphiphilic copolymer polystyrene-b-polyacrylic acid (PS-b-PAA), cationic surfactant hexadecyltrimethylammonium bromide (CTAB) and Si, Ca-containing precursors under the electrostatic force between interfaces, and a certain amount of macroporous bioactive glass nanospheres are dispersed in anhydrous toluene containing a silane coupling agent APTMS, and refluxed under the protection of a nitrogen atmosphere. After cooling to room temperature, centrifugal washing, vacuum drying, and calcining in a muffle furnace, large mesoporous bioactive glass nanoparticles CDBGn loaded with carbon quantum dots (CD) are obtained; 2) CDBGn and monomers N-isopropylacrylamide (NIPAM) and N-hydroxymethylacrylamide (NMA) in step 1) are weighed according to a certain mass ratio, and after adding an appropriate amount of deionized water to dissolve, a certain amount of crosslinking agent N,N-methyleneacrylamide (MBA) is added, and after stirring for a certain period of time, an initiator ammonium persulfate (APS) and a promoter N,N,N,N-tetramethylethylenediamine (AEMED) are added to form a redox polymerization system, and finally N2 is passed to replace the air in the reaction device to obtain CDBGn / P (NIPAM-co-NMA) composite hydrogel; 3) P123 is used as a template to prepare large mesoporous bioactive glass powder (Mesoporous bioactive The ground and screened MBG, binder and pore-forming agent were mixed evenly in a mass ratio of (0.3-0.6): (0.05-0.15): (0.3-0.6) and poured into a cylindrical mold, preformed under a certain pressure, and calcined in a muffle furnace for 5-7 hours to obtain a three-dimensional multi-level mesoporous bioactive glass scaffold (MBG scaffold, MBGS); 4) PTHrP-2 is immobilized by negative pressure adsorption-lyophilization method, firstly, the prepared 0.05-0.1 mg / mL PTHrP-2 solution is added dropwise to the MBGS prepared in step 3), and then lyophilized after negative pressure adsorption to obtain the drug-loaded scaffold MBGS / PTHrP-2; 5) the drug-loaded scaffold MBGS / PTHrP-2 prepared in step 4) is placed in the composite hydrogel prepared in step 2), so that the composite hydrogel can be completely filled into the macropores of the drug-loaded scaffold MBGS / PTHrP-2, and then an initiator and a promoter are added to form a composite hydrogel on the surface of MBGS, and finally CDBGn / P(NIPAm-co-NMA) / MBGS / PTH is obtained, which is freeze-dried.

[0008] It should be understood that according to the present invention, the prepared composite hydrogel is immersed in a buffer solution. Due to the spatial limitation of the solid particles, the volume expansion of the hydrogel inside the scaffold is less than that of the external hydrogel, resulting in a gap between the scaffold and the hydrogel. Therefore, the final CDBGn / P(NIPAm-co-NMA) / MBGS / PTH scaffold can be peeled off from the hydrogel and freeze-dried for subsequent testing.

[0009] Preferably, the mass ratio of BGn to APTES in step 1) is (0.6-1): (0.2-0.4). The bioglass nanospheres attached with carbon quantum dots not only have biological activity, but also have excellent photothermal properties.

[0010] Preferably, in step 1), the temperature of the first calcination is 400-600°C, the heating rate is 1°C / min, and the calcination time is 4-6 hours; the temperature of the second calcination is 200-700°C, and the calcination time is 1-4 hours. The first calcination is to obtain mesoporous bioactive glass nanospheres, and the second calcination is to obtain carbon quantum dots.

[0011] Preferably, in the step 2), the mass ratio of CDBGn, monomer N-isopropylacrylamide, and N-hydroxymethylacrylamide is (0.01-0.05):(0.4-0.5):(0-0.1).

[0012] Preferably, in the step 2), in order to avoid the appearance of a small amount of flocs inside the hydrogel when adding, the accelerator tetramethylethylenediamine AEMED needs to be diluted 15-30 times with water and adjusted to neutrality with acetic acid before use.

[0013] Preferably, in step 3), the mesoporous bioactive glass powder MBG is prepared by evaporation-induced self-assembly. Preferably, the molar ratio of SiO2:CaO:P2O5 in the prepared mesoporous bioactive glass powder MBG is 80:15:5.

[0014] Preferably, in step 3), the binder is polyvinylpyrrolidone (PVP), and the pore-forming agent is polyethylene glycol particles (PEG) with a size of 100-400 μm. There are many types of binders and pore-forming agents, but considering safety, PVP and PEG have the best biocompatibility and effect.

[0015] According to a second aspect of the present invention, there is provided a three-dimensional multi-level porous bone repair scaffold prepared according to the above preparation method and responsive to near-infrared light PTHrP-2 pulse release.

[0016] According to a third aspect of the present invention, there is provided a three-dimensional multi-level porous bone repair scaffold capable of responsive to near-infrared light pulse release of PTHrP-2 and its application in the field of bone repair.

[0017] According to a fourth aspect of the present invention, there is provided a three-dimensional multi-level porous bone repair scaffold capable of responsive to near-infrared light pulsed release of PTHrP-2 for use in the preparation of an implantable medical device.

[0018] The creativity of the present invention mainly lies in that a large mesoporous bioactive glass nanosphere loaded with carbon quantum dots is prepared for the first time. More importantly, by preparing such a three-dimensional multi-level porous bone repair scaffold, the pulse delivery of PTHrP-2 by near-infrared light response is realized for the first time. Although there have been literature reports on the delivery of PTH drugs in other pulsed ways, compared with other stimulus responses (such as pH, enzymes, etc.), near-infrared light response can be controlled in vivo and is less affected by unknown factors in the body. The wavelength and intensity of light can be accurately and simply controlled, and the time and location can be controlled with high precision, thereby achieving the effect of precise drug enrichment and realizing the repair of local bone defects. In addition, compared with other systems, CDBGn also gives the hydrogel higher biological activity.

[0019] The three-dimensional multi-level porous bone repair scaffold with near-infrared light responsive PTHrP-2 pulse release prepared according to the present invention includes a main matrix and a thermosensitive hydrogel as a "gate" control system. The main matrix is ​​a mesoporous bioactive glass scaffold for drug loading, and the thermosensitive hydrogel part includes a heat-shrinkable PNIPAM-based composite hydrogel and a near-infrared responsive photothermal material, which is used to expand the daily injection of PTHrP-2 treatment method to in situ delivery of PTHrP-2, realize the pulsed release of drugs at specific locations and times, so as to simulate the functions of life systems and maximize the repair of bone defects.

[0020] In summary, the three-dimensional multi-level porous bone repair scaffold with near-infrared light responsive PTHrP-2 pulse release and its preparation method and application provided by the present invention have the following beneficial effects compared with the prior art:

[0021] 1) The carbon quantum-loaded bioactive glass nanospheres can not only serve as photothermal conversion materials, but also endow the thermosensitive hydrogel P(NIPAm-co-NMA) with near-infrared light response characteristics and good bioactivity. Under the near-infrared light on / off cycle, the thermosensitive hydrogel shell CDBGn / P(NIPAm-co-NMA) acts as a gating system to undergo a reversible phase change to precisely control the release of PTHrP-2 from the MBGS scaffold, achieving rapid and effective bone defect repair;

[0022] 2) Under controllable near-infrared light stimulation in vitro, the pulsed release of PTHrP-2 at specific locations and times in vivo was achieved. The pulsed drug release can simulate the release pattern of some growth factors in vivo to achieve the best therapeutic effect and maximize the repair of bone defects;

[0023] 3) Expanding the treatment method of daily injection of PTHrP-2 to in situ delivery of PTHrP-2 avoids the pain and discomfort caused by daily dosing to patients, while also minimizing the side effects of systemic drug treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The design flow chart of the three-dimensional multi-level bone defect repair scaffold for near-infrared light responsive parathyroid hormone-related peptide pulse release of the present invention;

[0025] Figure 2 and Figure 3 The scanning electron microscope image of CDBGn in Example 1 and its photothermal stability spectrum under 808nm near-infrared light irradiation;

[0026] Figure 4 and Figure 5 The differential thermal scanning result diagram of the CD / BGn / P(NIPAm-co-NMA) thermosensitive hydrogel in Example 1 and the volume phase change diagram of the hydrogel under near-infrared light irradiation;

[0027] Figure 6 is a transmission electron microscopy image of the MBGS powder in Example 1;

[0028] Figure 7 and Figure 8 The scanning electron microscope images of the three-dimensional multi-level porous bone defect repair scaffold released by near-infrared light PTHrP-2 pulse in Example 1 at different magnifications;

[0029] Fig. 9 These are the test results of the near-infrared light response release performance of the three-dimensional multi-level porous bone repair scaffold in Example 1. DETAILED DESCRIPTION

[0030] The present invention is further described below in conjunction with specific examples. It should be understood that the following examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0031] According to the present invention, a method for preparing a three-dimensional multi-level porous bone repair scaffold capable of releasing PTHrP-2 in response to infrared light is provided. Figure 1As shown, the method comprises the following steps: 1) preparing large mesoporous bioactive glass nanospheres by a dual template method, and obtaining large mesoporous bioactive nanospheres loaded with carbon quantum dots as photothermal materials after surface modification and calcination; 2) obtaining a composite hydrogel network structure CDBGn / P (NIPAM-co-NMA) by free radical addition polymerization of the photothermal material, monomers N-isopropylacrylamide and N-hydroxymethylacrylamide; 3) preparing mesoporous bioactive glass powder by using P123 block copolymer, and mixing the powder with a pore-forming agent and a binder by grinding and placing the powder in a mold for pre-compression. , after calcination, a three-dimensional multi-level mesoporous bioactive glass scaffold MBGS is obtained; 4) the parathyroid hormone-related peptide is loaded into the scaffold mesopores by a negative pressure adsorption method to obtain a three-dimensional multi-level scaffold MBGS / PTHrP-2 containing PTH; 5) the drug-loaded three-dimensional multi-level scaffold MBGS / PTHrP-2 is placed in the composite hydrogel network structure CDBGn / P (NIPAM-co-NMA) prepared in step 2), and polymerization is initiated on the surface of the scaffold to prepare a near-infrared light-responsive pulse-release three-dimensional multi-level porous bone repair scaffold.

[0032] Example 1

[0033] (1) Add 25 mg of PS-b-PAA powder to 5 mL of tetrahydrofuran solution, stir and dissolve at room temperature, then quickly pour it into an alkaline solution containing CTAB (add 50 mg of CTAB and 0.5 mL of ammonia water to 20 mL of ultrapure water), then stir the mixed solution in a 35°C water bath for 30 min, add tetraethyl orthosilicate and calcium nitrate tetrahydrate (Si:Ca=75:25) in sequence and stir overnight, collect the obtained sample by centrifugation (10000 rpm, 10 min), wash three times with ethanol and ultrapure water respectively. After vacuum drying, place it in a muffle furnace and calcine at 550°C for 6 h (heating rate of 1°C / min). Obtain large mesoporous bioactive glass nanospheres BGn. Place BGn in a toluene solution containing APTES and reflux at 80°C for 12 h. After washing and drying, place it in a muffle furnace and calcine at 500°C for 1 h to obtain CDBGn. Figure 2 As shown, CDBGn has a surface-exposed large mesoporous structure. Figure 3 The results showed that the temperature of the CDBGn aqueous solution could be increased to 44°C after 5 minutes of 808nm near-infrared light irradiation, and the temperature did not drop significantly after 5 near-infrared light switching cycles, indicating good photothermal stability.

[0034] (2) Weigh 0.4444g NIPAM monomer and 0.0556g NMA monomer and dissolve them in 10mL deionized water. Ultrasonic disperse 0.02g CDBGn in the mixed solution. Add 0.015g MBA and stir for 10min. Then add 0.010g initiator APS and 200μL diluted accelerator. After stirring for 5min, replace the air in the reaction bottle with N2 to obtain CDBGn / P(NIPAm-co-NMA) composite thermosensitive hydrogel. Take about 10mg of P(NIPAm-co-NMA) hydrogel and analyze the LCST of the hydrogel in a differential thermal scanner. Figure 4 It was shown in the study that the hydrogel can undergo volume phase change at around 41°C, which is close to human body temperature. The volume phase change of the composite hydrogel under 808nm near-infrared light was then analyzed. Figure 5 It can be observed that when the temperature rises above LCST under near-infrared light irradiation, the volume of the hydrogel shrinks, while when the near-infrared light is turned off, the temperature drops and the hydrogel swells.

[0035] (3) 8.0 g P123 was dissolved in 120 ml of anhydrous ethanol. After the solution was completely dissolved into a clear solution, 1.0 g 0.5 M hydrochloric acid, 13.4 g tetraethyl orthosilicate, 2.8 g calcium nitrate tetrahydrate and 1.46 g triethyl phosphate were added in sequence. The mixed solution was stirred at room temperature overnight. The uniformly mixed sol was poured into a watch glass for solvent evaporation for 7 days to form a transparent thin layer of dry gel. The dry gel was placed in a muffle furnace and calcined at 700 °C for 6 h at a heating rate of 1.5 °C / min to form mesoporous bioactive glass (MBG). A three-dimensional multi-level mesoporous bioactive glass scaffold (MBG scaffold; MBGS) was prepared by powder pressing. PEG and PVP were used as scaffold pore formers and adhesives, respectively. First, the pore former PEG particles were ground and sieved to obtain particles with a size of about 100-400 μm. Then, MBG powder, PVP and PEG were mixed and stirred at a mass ratio of 0.3:0.05:0.3 for 24 hours, poured into a cylindrical mold with a certain diameter, and pre-pressed under a pressure of 5 MPa. Finally, the pore-forming agent was fully volatilized to form MBGS with predetermined pore sizes by calcining at 600 °C in a muffle furnace for 5 hours. Figure 6 As shown in Figure 2, MBG materials have two-dimensional small mesoporous channels with regular shapes, which can be used for drug loading. Figure 7 and Figure 8 It can be observed that CDBGn / P(NIPAm-co-NMA) with interconnected macroporous structure, MBGS three-dimensional scaffold and surface CDBGn / P(NIPAm-co-NMA) composite hydrogel have irregular network structure.

[0036] (4) PTHrP-2 was immobilized by negative pressure adsorption-lyophilization. First, the prepared 0.1 mg / mL PTHrP-2 solution was added dropwise to the prepared three-dimensional multi-level mesoporous bioactive glass scaffold. The scaffold was placed in a negative pressure vacuum for 6 h to ensure that PTHrP-2 fully entered the mesoporous channels in MNGS. Finally, it was freeze-dried to obtain MBGS / PTHrP-2.

[0037] (5) The prepared drug-loaded scaffold MBGS / PTHrP-2 was placed in a pregel solution containing CDBGn, NIPAM and NMA, so that the pregel solution could completely fill the macropores in the scaffold, and then the same amount of initiator and promoter in step (2) was added to form a composite hydrogel on the surface of MBGS. The prepared composite hydrogel was immersed in a buffer solution. Due to the spatial limitation of the solid particles, the volume expansion of the hydrogel inside the scaffold was less than that of the external hydrogel, resulting in a gap between the scaffold and the hydrogel. Therefore, the final CDBGn / P(NIPAm-co-NMA) / MBGS / PTHrP-2 scaffold can be peeled off from the hydrogel and freeze-dried for subsequent testing. In order to study the release of PTHrP-2 in the three-dimensional multi-level porous scaffold under near-infrared light irradiation, the drug-loaded composite scaffold was placed in 10mL PBS (pH=7.4) buffer and irradiated with 808nm laser (1W / cm 2 ) irradiated for 20 min, and then turned off the near infrared light for 20 min. The mixed solution was centrifuged at different preset time points, the supernatant was taken, and the same volume of PBS was added and redispersed, and the supernatant was collected and analyzed by UV-vis. The results are shown in Fig. 9 As shown, near-infrared light can precisely control the release rate of drugs.

[0038] The above is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. The above embodiments of the present invention can also be modified in various ways. All simple, equivalent changes and modifications made according to the claims and the description of the present invention fall within the scope of protection of the claims of the present invention. The contents not described in detail in the present invention are all conventional technical contents.

Claims

1. A method for preparing a three-dimensional multi-level porous bone repair scaffold capable of responsive to near-infrared light pulse release of PTHrP-2, characterized in that: The following steps are involved: 1) Using amphiphilic copolymer polystyrene- b - Polyacrylic acid and cationic surfactant hexadecyltrimethylammonium bromide and precursors containing Si and Ca are self-assembled under the promotion of electrostatic forces between interfaces, and then placed in a muffle furnace for the first calcination to prepare large mesoporous bioactive glass nanospheres BGn, and then surface modified with silane coupling agent APTES and placed in a muffle furnace for the second calcination to obtain large mesoporous bioactive glass nanospheres CDBGn loaded with carbon quantum dots; 2) The CDBGn prepared in step 1) is dispersed in an aqueous solution containing monomers N-isopropylacrylamide and N-hydroxymethylacrylamide, a certain amount of crosslinking agent N,N-methyleneacrylamide is added and stirred, and then an initiator ammonium persulfate and a promoter N,N,N,N-tetramethylethylenediamine are added to form a redox polymerization system, and finally N2 is passed to replace the air in the reaction device to obtain CDBGn / P(NIPAM- co -NMA) composite hydrogel; 3) P123 was used as a template to prepare large mesoporous bioactive glass powder MBG. The ground and screened MBG, binder and pore-forming agent were mixed evenly in a mass ratio of (0.3-0.6): (0.05-0.15): (0.3-0.6) and poured into a cylindrical mold. The mold was preformed under a certain pressure and calcined in a muffle furnace at 500-700 °C for 5-7 h to obtain a three-dimensional multi-level mesoporous bioactive glass scaffold MBGS. 4) PTHrP-2 was immobilized by negative pressure adsorption-lyophilization method. First, the prepared 0.05-0.1 mg / mL PTHrP-2 solution was added dropwise to the three-dimensional multi-level mesoporous bioactive glass scaffold MBGS prepared in step 3), and then lyophilized after negative pressure adsorption to obtain the drug-loaded scaffold MBGS / PTHrP-2; 5) The MBGS / PTHrP-2 drug-loaded scaffold prepared in step 4) was placed on the CDBGn / P(NIPAM) -co -NMA) composite hydrogel, so that the composite hydrogel can be completely filled into the macropores of the drug-loaded stent MBGS / PTHrP-2, thereby initiating polymerization on the surface of MBGS, and finally obtaining CDBGn / P(NIPAm- co -NMA) / MBGS / PTH, freeze-dried.

2. The preparation method according to claim 1, characterized in that: In the step 1), the mass ratio of BGn to APTES is (0.6-1): (0.2-0.4).

3. The preparation method according to claim 1, characterized in that In the step 1), the temperature of the first calcination is 400-600°C, the heating rate is 1°C / min, and the calcination time is 4-6 h; the temperature of the second calcination is 200-700°C, and the calcination time is 1-4 h.

4. The preparation method according to claim 1, characterized in that: In the step 2), the mass ratio of CDBGn, monomer N-isopropyl acrylamide, and N-hydroxymethyl acrylamide is (0.01-0.05): (0.4-0.5): (0-0.1).

5. The preparation method according to claim 1, characterized in that: In the step 2), the accelerator tetramethylethylenediamine AEMED needs to be diluted 15-30 times with water and adjusted to neutrality with acetic acid before use.

6. The preparation method according to claim 1, characterized in that: In the step 3), the mesoporous bioactive glass powder MBG is prepared by an evaporation-induced self-assembly method.

7. The preparation method according to claim 1, characterized in that In the step 3), the binder is polyvinyl pyrrolidone (PVP), and the pore-forming agent is polyethylene glycol particles (PEG) with a size of 100-400 μm.

8. A three-dimensional multi-level porous bone repair scaffold prepared according to the preparation method according to any one of claims 1 to 7 that responds to near-infrared light and releases PTHrP-2 pulses.

9. Use of the three-dimensional multi-level porous bone repair scaffold capable of near-infrared light responsive PTHrP-2 pulse release according to claim 8 in the field of bone repair.

10. Use of the three-dimensional multi-level porous bone repair scaffold capable of near-infrared light responsive PTHrP-2 pulse release according to claim 8 in the preparation of implantable medical devices.

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