An alendronate-modified alginate injectable hydrogel, and a preparation method and application thereof

Abstract

The application discloses an alendronate modified alginate injectable hydrogel as well as a preparation method and application thereof. Specifically provided is an Alg-ALN injectable active hydrogel which can be used as a 'local administration and microenvironment regulation medium' cooperating with an injection instrument or a porous hollow bone nail and the like implant fixation device, and provides a new technical approach for improving long-term stability and bone reconstruction quality in osteoporosis related bone internal fixation and bone defect repair.

Description

Technical Field

[0001] This invention belongs to the field of biomaterials technology, specifically relating to an alendronic acid-modified alginate injectable hydrogel, its preparation method, and its application. Background Technology

[0002] To improve fixation strength in osteoporotic bone, polymethyl methacrylate (PMMA) bone cement is widely used clinically to reinforce pedicle screws or vertebral bodies. However, numerous clinical reports also indicate that PMMA bone cement is a non-degradable inert material that releases significant heat during curing. Furthermore, its polymerization shrinkage and viscosity changes are difficult to control precisely, making it prone to leakage into the venous system or spinal canal, potentially leading to serious complications such as pulmonary embolism and nerve compression. Related literature reports a high incidence of bone cement leakage in PMMA-enhanced techniques, with some cases resulting in symptomatic pulmonary embolism and even death. In addition, PMMA lacks biological integration with the host bone, and long-term residue may interfere with bone remodeling, making subsequent revision or removal of internal fixation procedures more difficult.

[0003] To overcome the inertness and non-degradability of PMMA, researchers have developed various injectable calcium phosphate cement (CPC) and its composites. However, most of these are based on inorganic bone cement, resulting in relative brittleness and limited plasticity. Existing technologies have incorporated the anti-bone resorption drug alendronate (ALN) into hydrogel systems to improve plasticity. However, current ALN-functionalized hydrogels are mainly used for intra-articular injection or targeted bone therapy for tumors. In weight-bearing areas such as osteoporotic long bones or vertebrae, soft hydrogels alone cannot provide effective mechanical support. Even with the addition of inorganic phases in some studies, the content, distribution, and interfacial bonding of inorganic phases with the hydrogel network are mostly based on simple physical mixing, offering limited improvement to the overall compressive modulus, durable support capacity, and osteoconductivity of the material.

[0004] In clinical practice, there is a lack of injectable hydrogels that rapidly gel in vivo. Such materials require a certain cross-linking density and rate; however, excessively rapid or over-cross-linking can lead to overly rigid materials with pores that hinder cell infiltration. Conversely, insufficient cross-linking density results in weak gel mechanical properties and susceptibility to collapse. Achieving a balance between injectability, gelation rate, mechanical properties, and cell adhesion / infiltration remains a common challenge for existing hydrogel systems. Current technologies generally employ a "physical mixing" strategy, physically dispersing ALN as a free drug within the hydrogel matrix or loading it onto the surface of inorganic particles through physical adsorption. While this physical mixing system achieves localized ALN delivery to some extent, it suffers from inherent drawbacks such as drug burst release, difficulty in precisely controlling release behavior, and a lack of stable binding between the drug and the carrier. Especially in weight-bearing bone sites, physical mixing systems struggle to achieve long-term retention and sustained action of ALN at bone lesions. Furthermore, these physical mixing systems often require the introduction of additional thickeners or inorganic phases to regulate release behavior or enhance mechanical properties, further increasing system complexity and compromising batch-to-batch stability. Summary of the Invention

[0005] In the prior art, in order to achieve local administration of bisphosphonate drugs and improve their tissue compatibility, a physical mixing strategy is generally adopted, that is, dissolving bisphosphonates in a hydrogel containing a high molecular weight thickener (such as sodium carboxymethyl cellulose, alginate, etc.), thereby increasing the viscosity of the formulation (usually ≥220 mPa·s) to delay the diffusion of the drug in the tissue, thereby reducing the peak local drug concentration and thus alleviating adverse reactions such as inflammation and tissue necrosis (see CN1427727A).

[0006] In view of this, the present invention provides a hydrogel system covalently conjugated with a bisphosphonate and a polymer matrix, which completely breaks through the above-mentioned technical formula, specifically providing an alendronate-modified alginate injectable hydrogel and its preparation method and application.

[0007] The present invention achieves the above objectives using the following technical solution: In this invention, unlike existing materials that simply physically mix or adsorb ALN, the inventors use condensing agents such as carbodiimide (EDC / NHS) to condense the amino group of ALN with the carboxyl group of the alginate molecule, forming an Alg-ALN covalent conjugate. By controlling the concentration, molecular weight, and ionic crosslinking conditions of the Alg-ALN solution, the material exhibits a highly fluid solution state at room temperature, allowing it to be smoothly injected into osteoporotic bone through narrow injection channels, porous hollow bone nails, or other implantable carriers; after injection, it passes through Ca²⁺... +Isovalent cations trigger in-situ cross-linking to form a continuous three-dimensional hydrogel network that tightly surrounds the trabecular bone region around the device, providing a more favorable habitat and remodeling environment for local osteoblasts and bone marrow stromal cells.

[0008] A first aspect of the present invention provides an injectable hydrogel comprising a bisphosphate-polysaccharide matrix covalently conjugated and an inorganic phase, wherein the inorganic phase is selected from at least one of hydroxyapatite and β-tricalcium phosphate.

[0009] In an optional embodiment, the mother liquor concentration of the bisphosphate-polysaccharide matrix covalent conjugate is 1.8-3 w / v.

[0010] In an optional embodiment, the inorganic phase is hydroxyapatite, and the mother liquor concentration of the hydroxyapatite is 50-500 mM.

[0011] In an optional embodiment, the inorganic phase is β-tricalcium phosphate, and the concentration of the mother liquor of β-tricalcium phosphate is 100-1000 mM.

[0012] In an optional embodiment, the injectable hydrogel is gelled via crosslinking ions, including but not limited to Ca²⁺. + or its salts, Sr² + or its salts, Ba² + or its salts, Ca² + / Sr² + Complex salts.

[0013] In some embodiments, the bisphosphate includes pharmaceutically acceptable salts of alendronate, risedronate, zoledronic acid, etidronic acid, clodronate, pamidronate, ibandronic acid, incardronate, opadronic acid, and minodronate.

[0014] In a specific embodiment of the present invention, the bisphosphate is alendronate.

[0015] In optional embodiments, the polysaccharide matrix includes alginate, hyaluronic acid and its derivatives, carboxymethyl cellulose, and carboxymethyl chitosan.

[0016] In a specific embodiment of the present invention, the polysaccharide matrix is ​​alginate.

[0017] In some embodiments, the bisphosphate-polysaccharide matrix covalent conjugate is conjugated via an EDC / NHS coupling chemical reaction.

[0018] In some embodiments, the inorganic phase and the bisphosphate-polysaccharide matrix covalently conjugate in the injectable hydrogel provided by the present invention can be packaged, stored, and used in various forms. For example, they can be loaded separately or together. For example, they can be stored in liquid or solid powder form.

[0019] A second aspect of the present invention provides a method for preparing an injectable hydrogel, the method comprising the steps of: Algate was dissolved in the aqueous phase, and a carbodiimide condensing agent and N-hydroxysuccinimide were added to activate some of the carboxyl groups. Sodium alendronate was added, and the condensation yielded the Alg-ALN covalent conjugate. The purified Alg-ALN covalent conjugate was dissolved in physiological buffer solution, and an inorganic phase was added to disperse it uniformly, triggering ionic cross-linking to obtain the injectable hydrogel.

[0020] In an optional embodiment, the inorganic phase is selected from at least one of hydroxyapatite and β-tricalcium phosphate.

[0021] In an optional embodiment, the concentration of the Alg-ALN covalent conjugate in the physiological buffer is 1.8-3 w / v.

[0022] In optional embodiments, the purification method includes dialysis, ultrafiltration, and precipitation.

[0023] In an optional embodiment, the uniform dispersion is achieved by stirring or ultrasonic homogenization.

[0024] In some embodiments, the inorganic phase is pre-prepared into a suspension mother liquor before addition. When the inorganic phase is hydroxyapatite, the concentration of the suspension mother liquor is 50-500 mM; when the inorganic phase is β-tricalcium phosphate, the concentration of the suspension mother liquor is 100-1000 mM.

[0025] In some embodiments, the feed ratio of the Alg-ALN covalent conjugate to the inorganic phase is (92~99):(1~8).

[0026] The third aspect of this invention provides the application of the hydrogel described in the first aspect and the injectable hydrogel obtained by the preparation method described in the second aspect in the preparation of bone repair materials.

[0027] The terms "bone repair material," "bone filling material," "filling material," or "repair material" used in this invention are used interchangeably to refer to any material used to fill or repair bone defects, including materials that can be hardened in situ, such as flowable media. Bone repair materials may also include other types of "fillers," such as filaments, microspheres, powders, granular elements, sheets, strips, tubular materials, etc., as well as autologous or allogeneic graft materials. Filler materials may also include other chemicals, pharmacological preparations, or other bioactive agents. The term "flowable media" generally refers to absorbable or non-absorbable biocompatible preparations, such as polymers, including thermosetting or thermoplastic polymers, such as PMMA (polymethyl methacrylate), bone void fillers, cement, or pharmaceutical preparations.

[0028] In an optional embodiment, the bone repair material is a repair material for osteoporotic bone.

[0029] In this invention, the term "osteoporotic bone" refers to the state of bone tissue affected by osteoporosis. It encompasses all bone sites throughout the body that have undergone pathological changes due to osteoporosis. This includes, but is not limited to, areas of bone loss, microstructural damage, and fragility fractures caused by osteoporosis in weight-bearing or non-weight-bearing areas such as the vertebral bodies of the spine and the proximal femur (hip).

[0030] The osteoporotic bone repair material refers to a material that can cope with the following special bone tissue conditions: reduced bone mass, significantly reduced bone mineral density (BMD) per unit volume, microstructural damage (such as thinning, breakage, and reduction in the number of trabeculae, loss of connectivity; thinning of the bone cortex, and increased porosity), decreased mechanical properties (such as increased bone fragility, reduced strength, inability to withstand normal physiological loads, and fragility fractures caused by slight external forces), and imbalance in bone remodeling.

[0031] In optional embodiments, the bone repair material is used in conjunction with porous hollow bone screws, other internal fixation devices with side holes or pore structures, vertebral body reinforcement catheters, hollow screws, controllable injection systems, dual-lumen syringes, and guidewire guiding catheters.

[0032] In an optional embodiment, the bone repair material is used in conjunction with porous hollow bone screws.

[0033] The fourth aspect of the present invention provides an osteoporosis bone repair product, the product comprising the hydrogel described in the first aspect and / or an injectable hydrogel obtained by the preparation method described in the second aspect.

[0034] In optional embodiments, the product further includes one or more of the following: porous hollow bone screws, other internal fixation devices with side holes or pore structures, vertebral body reinforcement catheters, hollow screws, controllable injection systems, dual-lumen syringes, and guidewire guiding catheters.

[0035] In an optional embodiment, the product further includes an instruction manual, which includes instructions for the following usage: The Alg-ALN composite solution is loaded into a syringe or pre-filled channel and injected into osteoporotic bone under image guidance via a porous hollow bone screw, vertebral enhancement device, or other implantable device with side holes / porous structures; after injection, the Alg-ALN solution in Ca²⁺… + In a plasma environment, the material is gelled in situ, filling the gaps between the trabecular bone around the device to form an active hydrogel layer that surrounds the implant, thereby achieving local release of ALN and regulation of the bone microenvironment.

[0036] The ionic environment includes Ca²⁺. + Its salts (such as CaCl2) can be used as the main ionic crosslinking agents, either alone or in combination with Sr²⁺. + Mg² + Multiple cations are used in combination. Ca² + The cross-linking method of its salts includes partially removing Ca²⁺ before injection. + Premixed in Alg-ALN solution, and further cross-linked after injection into local body fluids; or, Alg-ALN composite solution and Ca²⁺ + The solutions are loaded separately and then mixed in narrow channels or porous hollow bone nails before being injected into osteoporotic bone to complete in-situ gelation.

[0037] Advantages and benefits of the present invention: The Alg-ALN injectable active hydrogel of the present invention achieves fundamental optimization of pharmacokinetic behavior by crossing the technical path of "physical mixing → chemical conjugation", and achieves unexpected technical effects.

[0038] The hydrogel of this invention simplifies the formulation components, resulting in a simpler system composition compared to existing technologies. It avoids the risks of foreign body reactions or long-term toxicity that thickeners may pose, thus improving biocompatibility. Furthermore, this hydrogel offers advantages such as more stable and controllable local bone administration, achieving long-lasting sustained release, suitability for use with injection devices such as porous hollow bone screws, and the ability to regulate the active microenvironment and support bone tissue ingrowth. It also facilitates optimization for different sites and devices. The gelation time, injectability, and in vivo stability can be individually optimized based on different bone sites, types of porous hollow bone screws, or injection routes, demonstrating significant potential for widespread application. Attached Figure Description

[0039] Figure 1 This is a demonstration image showing the effect of hydrogel being extruded and shaped arbitrarily using a syringe.

[0040] Figure 2The graph shows the bioactivity assays at the cellular level using hydrogels. In graph A, the bioactivity assays of huBMSCs with different inorganic phases are shown, and in graph B, the bioactivity assays of ALPs with different inorganic phases are shown.

[0041] Figure 3 Figure showing the results of HA-crosslinked Alg-ALN / CaP hydrogel promoting osteogenic differentiation of BMSCs in vitro.

[0042] Figure 4 The image shows the results of Alg-ALN / CaP active hydrogel inhibiting osteoclastosis.

[0043] Figure 5 This is a statistical chart showing the results of in vivo animal experiments on osteoporosis using OVX.

[0044] Figure 6 The hydrogel preparation route provided by this invention. Detailed Implementation

[0045] The reagents, raw materials, and experimental consumables used in this invention are readily available to those skilled in the art and, unless otherwise specified, can be obtained commercially. Experimental methods not specifying particular conditions in this invention are typically performed under conventional conditions or according to the manufacturer's recommendations. In particular, the following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. It should be noted that the experimental conditions and results described in the following examples are for illustrative purposes only and should not, and will not, limit the invention as described in the claims.

[0046] The present invention will be further illustrated below with reference to specific embodiments. These specific embodiments are for illustrative purposes only and should not be construed as limiting the invention. Those skilled in the art will understand that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the invention. The scope of the invention is defined by the claims and their equivalents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0047] Example I. Materials and Reagents β-Tricalcium phosphate (C139913-25g). Stock solution 100 mM, 31.018 mg / mL. Weigh 31.018 mg and sterilize under UV light.

[0048] Hydroxyapatite (HAP), CAS No.: 1306-06-5, specifications or purity: ≥97%, <100 nm particles. Stock solution 100 mM, 100.462 mg / mL. Weigh 100.462 mg and sterilize under UV light.

[0049] Anhydrous calcium chloride (CaCl2, specification or purity: AR, 96.0%), CAS No.: 10043-52-4. Stock solution 100mM, 11.1 mg / mL. Dissolve 10 mL, filter sterilize.

[0050] II. Experimental Methods 1. Using an EDC / NHS coupling chemical reaction, sodium alendronate (ALN) is modified onto sodium alginate molecules to obtain Alg-ALN with anti-osteoclast function and bone-targeting potential; then, it is compounded with inorganic components such as hydroxyapatite (HA) or β-tricalcium phosphate (β-TCP) to rapidly form an injectable hydrogel of Alg-ALN / HA (or Alg-ALN / β-TCP) through ionic cross-linking.

[0051] 1) Construction of Alg-ALN covalent conjugate: Alg (Alg) with a certain viscosity (Aladdin, catalog number: S434499, low viscosity) was selected as the hydrogel matrix, dissolved in the aqueous phase and the pH was adjusted to a suitable range; a carbodiimide condensing agent (such as EDC) and N-hydroxysuccinimide (NHS) were added to the alginate solution to activate some carboxyl groups; sodium alendronate (ALN) was added and reacted at room temperature for 24 hours to allow the amino group of ALN to condense with the activated carboxyl group of alginate, thus obtaining the Alg-ALN covalent conjugate; unreacted small molecules were removed by dialysis and lyophilization to obtain the purified Alg-ALN product.

[0052] 2) Preparation of Alg-ALN / CaP composite injectable hydrogel precursor solution: The purified Alg-ALN was dissolved in physiological buffer solution, and the solid content and solution viscosity were adjusted to make it dissolve into a transparent viscous solution at room temperature; hydroxyapatite powder (HA), β-tricalcium phosphate (β-TCP) and / or its calcium-containing particles were dispersed or dissolved in deionized water as needed, and homogenized in the solution by stirring or ultrasonication to make it uniformly dispersed.

[0053] 3) Ion-crosslinked triggered in-situ gelation: The Alg-ALn solution is rapidly and uniformly mixed with hydroxyapatite powder (HA), β-tricalcium phosphate (β-TCP), and / or its calcium-containing particle solution under vortexing or shaking, as needed. The mass ratio of Alg-ALN to the inorganic phase and the overall solid content are optimized according to the actual application site and instrument channel diameter to ensure good injectability of the composite solution within the acceptable injection pressure range. Ca²⁺ can be used.+ Its salts (such as CaCl2) can be used as the main ionic crosslinking agents, or they can be used alone or with Sr²⁺. + Mg² + Multiple cations are used in combination.

[0054] Crosslinking methods can be: Before injection, part of Ca² + Premixed in Alg-ALN solution; or, the Alg-ALN composite solution and Ca²⁺ + The solutions are loaded separately and then injected into the osteoporotic bone after being mixed in narrow channels or porous hollow bone screws.

[0055] By adjusting Ca² + The concentration, Alg-ALN concentration, and injection / mixing method are all optimized to ensure that the injectability is within an appropriate range, allowing doctors to form a stable three-dimensional hydrogel network in a short period of time after injection.

[0056] 4) Application method when used in conjunction with injection devices or porous hollow bone screws: The prepared Alg-ALN composite solution is loaded into a syringe or pre-filled channel and injected into osteoporotic bone under image guidance through a porous hollow bone screw, vertebral enhancement device or other implantation device with side holes / porous structure; after injection, Alg-ALN / CaP hydrogel fills the gaps between the trabeculae around the device, forming an active hydrogel layer surrounding the implant, realizing the local release of ALN and regulation of the bone microenvironment.

[0057] 2. To investigate the osteogenic differentiation regulation capacity of Alg-ALN / HA active hydrogel in the context of osteoporosis / bone aging, human bone marrow mesenchymal stem cells (huBMSC) were used as a cell model to systematically evaluate the biocompatibility and osteogenic effects of Alg-ALN / HA and its inorganic components.

[0058] 3. To verify the in vivo application potential of Alg-ALN / HA active hydrogel in the context of osteoporosis / bone aging, an osteoporosis model was established using ovariectomized (OVX) rats. Different materials were implanted in bone defects or related bone areas, and changes in bone mass and bone microstructure were compared among the groups. The experimental setup included a blank control group, a sodium alginate (Alg) group alone, an Alg-ALN group alone, and a HA or TCP crosslinking group with Alg-ALN. Follow-up was conducted at 4 and 8 weeks.

[0059] III. Experimental Results 1. Material gelation performance testing: In terms of material characterization, the focus is on evaluating the material's gelation performance and injectability. By observing the gelation time, gel morphology, and injection propulsion, it was confirmed that the Alg-ALN / CaP system can rapidly gel under physiological conditions and meet the requirements of clinical injection operations (Tables 1-2).

[0060] Table 1. Results of gelation time for different composite components

[0061] Table 1 evaluates the gelling properties and injectability of the composite system under room temperature conditions. The gelling criterion was as follows: after mixing the mother liquors of each component in an EP tube, the gelation endpoint was reached when the system showed no flowability after the tube was inverted, and the gelation time was recorded. Simultaneously, the macroscopic morphology and color changes of the mixture before and after crosslinking were observed. Experimental results show that the Alg-ALN and HA or β-TCP composite system described in this invention is uniformly milky white after mixing, crosslinks to form a non-flowing hydrogel when inverted, and shows no significant color change before and after gelation, exhibiting good gelling stability and injectability.

[0062] This invention evaluates the injectability of Alg-ALN / CaP composite hydrogel precursor solutions by simulating actual clinical injection pathways. The specific procedure is as follows: the needle of a 1 mL standard screw-type syringe is removed, the prepared hydrogel (after gelation) is drawn into the syringe, and the needle is reattached. At room temperature (25±1)℃, the syringe plunger is pushed at a constant speed (approximately 5-10 mm / s) with the operator's thumb, and the entire process of the solution being extruded through a narrow channel is observed and recorded. Experimental results show that the Alg-ALN / CaP composite solutions prepared according to the various embodiments of this invention can be smoothly and continuously extruded under the above conditions, with no obvious solid-liquid separation or blockage observed during extrusion; the extruded hydrogel filaments are malleable and can be bent and shaped arbitrarily as needed (e.g., Figure 1 (As shown in the figure). This result indicates that the hydrogel described in this invention has good injectability and can meet the operational requirements of being injected into osteoporotic bone defect areas in the body through implantation devices such as narrow-diameter injection channels, porous hollow bone nails, or vertebral body enhancement catheters.

[0063] It should be noted that in the comparative experiments, when gelatin-alendronic acid conjugate (Gel-ALN) was used instead of Alg-ALN and compounded with MgB2, although it initially exhibited faster gelation behavior, the resulting gel rapidly dissociated upon contact with water or PBS, failing to maintain the integrity of the three-dimensional network structure and thus failing to meet the basic requirements for material stability in the in vivo physiological environment. Therefore, this formulation was not adopted. The above comparative results demonstrate that the gelation stability of hydrogels depends not only on the crosslinking rate but also on the compatibility between the polymer matrix and the inorganic phase. The system of this invention, using alginate as the matrix and compounded with a specific inorganic phase, has significant advantages in both rapid gelation and long-term structural stability.

[0064] Table 2. Results of gelling properties and gelling morphology of different composite components

[0065] Table 2 shows that the hydrogel of the present invention is a semi-solid with good plasticity after gelation, and can be continuously extruded and maintain its shape under injection pressure.

[0066] 2. Evaluation of in vitro osteogenic function and cell compatibility: Both HA and β-TCP-induced cross-linking hydrogels promoted the proliferation of huBMSCs within 72 h, and the cell viability was significantly higher than that of the control group, indicating that Alg-ALN / CaP hydrogels have good cell compatibility and can enhance cell viability. Figure 2 ).

[0067] Figure 3 The results showed that the Alg-ALN / CaP active hydrogel could inhibit osteoclast formation. TRAP (tartrate-resistant acid phosphatase) is a specific marker of osteoclasts. A decrease in cell number indicates that osteoclast formation or survival was inhibited. The fluorescence signal intensity of CTSK (cathepsin K) was significantly reduced in the Alg-ALN / CaP hydrogel group, further confirming the decreased osteolytic activity. The hydrogel effectively inhibited osteoclast formation and its mediated bone resorption, demonstrating that the Alg-ALN / CaP active hydrogel has a significant inhibitory effect on osteoclast formation, especially since the Alg-ALN conjugate itself has a significant osteoclast-inhibiting effect.

[0068] Figure 4 This study demonstrates the in vitro promotion of bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation using HA-crosslinked Alg-ALN / CaP hydrogel as an example. The relative expression levels of key osteogenic differentiation markers—the osteoblast-specific transcription factor Runx2, the late osteogenic marker osteocalcin (OCN), and type I collagen (Col1)—all showed a significant upward trend. This indicates that the Alg-ALN / CaP active hydrogel has a certain osteogenic effect.

[0069] The above results indicate that the hydrogel not only has advantages in terms of structure and gelation, but also exhibits good biological effects in promoting BMSC proliferation and early osteogenic differentiation, providing important in vitro experimental evidence for its use as a local delivery carrier for anti-bone aging.

[0070] 3. Validation of the bone-improving effect in the OVX rat osteoporosis model Analysis of relevant bone morphological parameters using microCT yielded the following results: Figure 5 As shown: Under normal control conditions, osteoconductive materials such as HA and TCP can improve local bone microstructure indices to a certain extent; in the context of OVX osteoporosis, the unmodified carrier alone has limited effect on improving trabecular morphology; the ALN-modified hydrogel group showed a trend of improved bone quality at both 4 and 8 weeks, and some bone morphological indices (such as Tb.N and Tb.Th) were better than those in the unmodified group and the blank control group, suggesting that Alg-ALN / CaP active hydrogels that deliver ALN locally help improve the bone microstructure damaged by OVX.

[0071] The above description of the embodiments is only for understanding the method and core ideas of the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principles of the invention, and these improvements and modifications will also fall within the protection scope of the claims of the present invention.

Claims

1. An injectable hydrogel, characterized in that, The hydrogel comprises a bisphosphate-polysaccharide matrix covalently conjugated with an inorganic phase, wherein the inorganic phase is selected from at least one of hydroxyapatite and β-tricalcium phosphate.

2. The hydrogel according to claim 1, characterized in that, The mother liquor concentration of the bisphosphate-polysaccharide matrix covalent conjugate is 1.8-3 w / v % %. Preferably, the inorganic phase is hydroxyapatite, and the concentration of the mother liquor of the hydroxyapatite is 50-500 mM; Preferably, the inorganic phase is β-tricalcium phosphate, and the concentration of the mother liquor of β-tricalcium phosphate is 100-1000 mM.

3. The hydrogel according to claim 1, characterized in that, The bisphosphates include pharmaceutically acceptable salts of alendronate, risedronate, zoledronic acid, etidronic acid, clodronate, pamidronate, ibandronic acid, incardronate, opadronic acid, and minodronate. Preferably, the bisphosphate is alenphosphate.

4. The hydrogel according to claim 1, characterized in that, The polysaccharide matrix includes alginate, hyaluronic acid and its derivatives, carboxymethyl cellulose, and carboxymethyl chitosan; Preferably, the polysaccharide matrix is ​​alginate.

5. The hydrogel according to claim 1, characterized in that, The bisphosphate-polysaccharide matrix covalent conjugate achieves conjugation through an EDC / NHS coupling chemical reaction.

6. A method for preparing injectable hydrogels, characterized in that, The preparation method includes the following steps: Algate was dissolved in the aqueous phase, and a carbodiimide condensing agent and N-hydroxysuccinimide were added to activate some of the carboxyl groups. Sodium alendronate was added, and the condensation yielded the Alg-ALN covalent conjugate. The purified Alg-ALN covalent conjugate was dissolved in physiological buffer, and an inorganic phase was added to disperse it evenly, triggering ionic cross-linking to obtain the injectable hydrogel. Preferably, the inorganic phase is selected from at least one of hydroxyapatite and β-tricalcium phosphate; Preferably, the concentration of the Alg-ALN covalent conjugate in the physiological buffer solution is 1.8-3 w / v.

7. The preparation method according to claim 6, characterized in that, The purification methods include dialysis, ultrafiltration, and precipitation; Preferably, the uniform dispersion is achieved by stirring or ultrasonic homogenization; Preferably, the inorganic phase is pre-prepared into a suspension mother liquor before being added. When the inorganic phase is hydroxyapatite, the concentration of the suspension mother liquor is 50-500 mM; when the inorganic phase is β-tricalcium phosphate, the concentration of the suspension mother liquor is 100-1000 mM. Preferably, the feed ratio of the Alg-ALN covalent conjugate to the inorganic phase is (92~99):(1~8).

8. The application of the hydrogel according to any one of claims 1-5, and the injectable hydrogel obtained by the preparation method according to any one of claims 6-7, in the preparation of bone repair materials; Preferably, the bone repair material is a repair material for osteoporotic bone.

9. The application according to claim 8, characterized in that, The bone repair material is used in conjunction with porous hollow bone screws, other internal fixation devices with side holes or pore structures, vertebral body enhancement catheters, hollow screws, controllable injection systems, dual-lumen syringes, and guidewire-guided catheters. Preferably, the bone repair material is used in conjunction with porous hollow bone screws.

10. An osteoporosis bone repair product, characterized in that, The product includes the hydrogel according to any one of claims 1-5 and / or the injectable hydrogel obtained by the preparation method according to any one of claims 6-7; Preferably, the product further includes one or more of the following: porous hollow bone screws, other internal fixation devices with side holes or pore structures, vertebral body reinforcement catheters, hollow screws, controllable injection systems, dual-lumen syringes, and guidewire guiding catheters.

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