Intelligent preparation system and method of bone repair biological material

Abstract

The invention discloses an intelligent preparation system and method of a bone repair biological material, and relates to the technical field of biomedical materials.The system comprises a raw material pretreatment and conveying unit used for metering, pretreating and independently conveying a calcium phosphate precursor, a decalcified bone matrix, a hydrogel prepolymer, a bone growth promoting factor and PLGA; the nano-microsphere preparation and packaging unit is in communication connection with the raw material pretreatment and conveying unit and used for receiving PLGA and bone growth promoting factors and preparing PLGA nano-microspheres encapsulated with the bone growth promoting factors under the controllable condition, and the particle size of the PLGA nano-microspheres ranges from 80 nm to 500 nm; by means of accurate metering and pretreatment of the intelligent control center on multi-component raw materials, active regulation and control on the particle size of the nano-microspheres and online monitoring and feedback on the mixing reaction process, repeatable and standardized preparation of the bone repair material with the complex formula is achieved.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, specifically to an intelligent preparation system and method for bone repair biomaterials. Background Technology

[0002] Bone repair biomaterials refer to a class of functional materials that can be implanted in the human body to fill, support, or guide bone tissue regeneration. Ideal bone repair materials typically require good biocompatibility, suitable mechanical properties, controllable degradation rates, and the ability to promote osteogenic formation. Therefore, modern bone repair materials are often designed as composite materials, combining the flexibility and injectability of hydrogels, the osteoconductivity of calcium phosphate ceramics, the bioactivity of growth factors, and the protective effect of sustained-release carriers to mimic the complex structure and function of natural bone tissue.

[0003] Traditional solid-state reaction methods struggle to reliably obtain high-purity products. Furthermore, the homogeneous and controllable compounding of components with different physicochemical properties (such as easily hydrated inorganic powders, heat-sensitive protein factors, and organic polymer carriers) while ensuring the active ingredients remain inactive during processing places extremely high demands on traditional batch-based, experience-dependent mixing processes. This can easily lead to problems such as large batch-to-batch performance variations, poor material uniformity, and low efficiency of active factors.

[0004] To address the aforementioned issues, a preparation technique was designed that enables precise process control and ensures consistency in material composition and structure, thereby resolving the technical problems mentioned above. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides an intelligent preparation system and method for bone repair biomaterials, solving the technical problems mentioned in the background section.

[0006] To achieve the above objectives, the present invention provides the following technical solution: an intelligent preparation system for bone repair biomaterials, the system comprising: The system includes: The raw material pretreatment and conveying unit is used for metering, pretreatment and independent conveying of calcium phosphate precursor, decalcified bone matrix, hydrogel prepolymer, bone growth factor and PLGA. The nanosphere preparation and encapsulation unit is communicatively connected to the raw material pretreatment and delivery unit, and is used to receive PLGA and bone growth factor, and to prepare PLGA nanospheres with a particle size of 80-500 nm encapsulated with bone growth factor under controllable conditions. The main mixing and reaction unit is communicatively connected to the raw material pretreatment and conveying unit and the nanosphere preparation and encapsulation unit, and is used to receive and mix calcium phosphate material, decalcified bone matrix, hydrogel material, and PLGA nanospheres or free bone growth factor encapsulated with bone growth factor. The intelligent control center is communicatively connected to all the above-mentioned units. The intelligent control center includes a data storage module, a process model library, and a control execution module. The data storage module stores raw material parameters, target product formulations, and historical process data; the process model library contains at least one phase transition control model for predicting and regulating the purity and phase composition of α-tricalcium phosphate; the control execution module calls the model in the process model library according to the target product formulation to dynamically adjust the operating parameters of each unit in order to prepare bone repair biomaterials that meet the preset requirements.

[0007] Preferably, the raw material pretreatment and conveying unit includes: A dedicated calcination subsystem for preparing high-purity α-tricalcium phosphate is provided. The calcination subsystem is equipped with an ultra-high-speed gas quenching cooling device. The phase change control model of the intelligent control center monitors the calcination temperature in real time and adjusts the cooling rate of the gas quenching cooling device to suppress the phase transition from α-TCP to β-TCP, thereby obtaining α-tricalcium phosphate powder with a purity higher than 95%.

[0008] Preferably, the main mixing and reaction unit includes a first mixing channel and a second mixing channel arranged in parallel; The first mixing channel is used to prepare bone repair biomaterials according to any one of claims 1-6, wherein the calcium phosphate material received therefrom is the high-purity α-tricalcium phosphate, and is mixed with a specific proportion of soluble phosphate, water or aqueous solution to form α-TCP-based bone cement slurry online, and then homogenized with other components; The second mixing channel is used to prepare bone repair materials with other formulations; The intelligent control center selects and activates the corresponding mixing channel and allocates raw materials based on the input target material type.

[0009] Preferably, the nanosphere preparation and packaging unit uses a microfluidic chip device to prepare PLGA nanospheres, and the intelligent control center controls the particle size of the PLGA nanospheres within the range of 373±12nm by adjusting the two-phase flow rate ratio and polymer concentration of the microfluidic chip.

[0010] Preferably, the system further includes an online monitoring and feedback unit, which includes a particle size analyzer, a pH sensor, and a temperature sensor located at the outlet of the main mixing and reaction unit. The online monitoring and feedback unit is connected to the intelligent control center and feeds back the monitoring data to the control execution module in real time. The control execution module dynamically fine-tunes the raw material delivery rate, mixing speed, or reaction temperature based on the deviation between the feedback data and the preset value.

[0011] Preferably, the method includes the following steps: S1: Formula Input and Analysis: Input the final composition formula of the target bone repair biomaterial into the intelligent control center. The formula shall include at least the mass percentage of each component. The control center analyzes the formula and generates the required amount of each raw material and the process route. S2: Raw material preparation and pretreatment: The raw material pretreatment and conveying unit prepares raw materials of corresponding quality and specifications according to the instructions of S1; wherein, in the preparation of α-tricalcium phosphate, the phase change control model controls the calcination and ultra-high speed gas quenching cooling process to obtain high-purity α-TCP powder. S3: Controllable preparation of nanospheres: The nanosphere preparation and encapsulation unit prepares PLGA nanospheres with specified particle size and encapsulation rate according to the formula requirements and if an encapsulation factor is required; S4: Intelligent Mixing and Molding: The main mixing and reaction unit mixes the pretreated calcium phosphate material, decalcified bone matrix, hydrogel material, bone growth factor and / or nanospheres prepared in step S3 according to the formula and selected process route in a precise sequence and proportion; if α-TCP bone cement is to be prepared, high-purity α-TCP powder is mixed with liquid phase and other solid phase components in the first mixing channel; S5: Process monitoring and adaptive adjustment: The online monitoring and feedback unit monitors the key parameters of the mixed product in real time and feeds the data back to the intelligent control center. The control execution module makes real-time parameter fine-tuning based on the feedback to ensure that the product performance meets the standards.

[0012] Preferably, when the calcium phosphate material is selected from hydroxyapatite, β-tricalcium phosphate, or fluorapatite, the system automatically calls the second mixing channel or adjusts the mixing strategy of the first mixing channel to avoid a mixing process that involves a violent hydration reaction with water.

[0013] Preferably, in step S4, when the bone growth factor contains two or three types, the intelligent control center precisely controls the feeding amount of different factor hoppers in the raw material pretreatment and conveying unit, or controls the pumping ratio of different factor solutions in the nanosphere preparation and encapsulation unit, according to the preset factor ratio, so as to achieve factor compounding. Beneficial effects

[0014] This invention provides an intelligent preparation system and method for bone repair biomaterials. Through an intelligent control center, the system enables precise metering and pretreatment of multi-component raw materials, active control of nanosphere particle size, and online monitoring and feedback of the mixing reaction process. This achieves reproducible and standardized preparation of complex-formulated bone repair materials. The system specifically addresses the challenges of purity and phase control for raw materials such as α-tricalcium phosphate. Furthermore, by employing a channel-based, time-sequential mixing strategy, it avoids adverse physicochemical reactions between components, thereby ensuring the uniformity and design consistency of the final product's composition and structure at the process level. Detailed Implementation

[0015] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0016] This invention provides a technical solution: an intelligent preparation system for bone repair biomaterials, the system comprising: The system includes: The raw material pretreatment and conveying unit is used for metering, pretreatment and independent conveying of calcium phosphate precursor, decalcified bone matrix, hydrogel prepolymer, bone growth factor and PLGA. The nanosphere preparation and encapsulation unit is communicatively connected to the raw material pretreatment and delivery unit, and is used to receive PLGA and bone growth factor, and to prepare PLGA nanospheres with a particle size of 80-500 nm encapsulated with bone growth factor under controllable conditions. The main mixing and reaction unit is communicatively connected to the raw material pretreatment and conveying unit and the nanosphere preparation and encapsulation unit, and is used to receive and mix calcium phosphate material, decalcified bone matrix, hydrogel material, and PLGA nanospheres or free bone growth factor encapsulated with bone growth factor. The intelligent control center is communicatively connected to all the above-mentioned units. The intelligent control center includes a data storage module, a process model library, and a control execution module. The data storage module stores raw material parameters, target product formulations, and historical process data; the process model library contains at least one phase transition control model for predicting and regulating the purity and phase composition of α-tricalcium phosphate; the control execution module calls the model in the process model library according to the target product formulation to dynamically adjust the operating parameters of each unit in order to prepare bone repair biomaterials that meet the preset requirements.

[0017] In this embodiment, the raw material pretreatment and conveying unit is further configured to include: A dedicated calcination subsystem for preparing high-purity α-tricalcium phosphate is provided. The calcination subsystem is equipped with an ultra-high-speed gas quenching cooling device. The phase change control model of the intelligent control center monitors the calcination temperature in real time and adjusts the cooling rate of the gas quenching cooling device to suppress the phase transition from α-TCP to β-TCP, thereby obtaining α-tricalcium phosphate powder with a purity higher than 95%.

[0018] In this embodiment, the main mixing and reaction unit is further configured to include a first mixing channel and a second mixing channel arranged in parallel. The first mixing channel is used to prepare bone repair biomaterials according to any one of claims 1-6, wherein the calcium phosphate material received therefrom is the high-purity α-tricalcium phosphate, and is mixed with a specific proportion of soluble phosphate, water or aqueous solution to form α-TCP-based bone cement slurry online, and then homogenized with other components; The second mixing channel is used to prepare bone repair materials with other formulations; The intelligent control center selects and activates the corresponding mixing channel and allocates raw materials based on the input target material type.

[0019] In this embodiment, the nanosphere preparation and packaging unit uses a microfluidic chip device to prepare PLGA nanospheres, and the intelligent control center controls the particle size of the PLGA nanospheres within the range of 373±12nm by adjusting the two-phase flow rate ratio and polymer concentration of the microfluidic chip.

[0020] In this embodiment, the system is further configured to include an online monitoring and feedback unit, which includes a particle size analyzer, a pH sensor, and a temperature sensor located at the outlet of the main mixing and reaction unit. The online monitoring and feedback unit is connected to the intelligent control center and feeds back the monitoring data to the control execution module in real time. The control execution module dynamically fine-tunes the raw material delivery rate, mixing speed, or reaction temperature based on the deviation between the feedback data and the preset value.

[0021] This embodiment further specifies that the method includes the following steps: S1: Formula Input and Analysis: Input the final composition formula of the target bone repair biomaterial into the intelligent control center. The formula shall include at least the mass percentage of each component. The control center analyzes the formula and generates the required amount of each raw material and the process route. S2: Raw material preparation and pretreatment: The raw material pretreatment and conveying unit prepares raw materials of corresponding quality and specifications according to the instructions of S1; wherein, in the preparation of α-tricalcium phosphate, the phase change control model controls the calcination and ultra-high speed gas quenching cooling process to obtain high-purity α-TCP powder. S3: Controllable preparation of nanospheres: The nanosphere preparation and encapsulation unit prepares PLGA nanospheres with specified particle size and encapsulation rate according to the formula requirements and if an encapsulation factor is required; S4: Intelligent Mixing and Molding: The main mixing and reaction unit mixes the pretreated calcium phosphate material, decalcified bone matrix, hydrogel material, bone growth factor and / or nanospheres prepared in step S3 according to the formula and selected process route in a precise sequence and proportion; if α-TCP bone cement is to be prepared, high-purity α-TCP powder is mixed with liquid phase and other solid phase components in the first mixing channel; S5: Process monitoring and adaptive adjustment: The online monitoring and feedback unit monitors the key parameters of the mixed product in real time and feeds the data back to the intelligent control center. The control execution module makes real-time parameter fine-tuning based on the feedback to ensure that the product performance meets the standards.

[0022] In this embodiment, when the calcium phosphate material is selected from hydroxyapatite, β-tricalcium phosphate, or fluorapatite, the system automatically calls the second mixing channel or adjusts the mixing strategy of the first mixing channel to avoid a violent hydration reaction with water during the mixing process.

[0023] In this embodiment, it is further configured that, in step S4, when the bone growth factor contains two or three types, the intelligent control center precisely controls the feeding amount of different factor hoppers in the raw material pretreatment and conveying unit, or controls the pumping ratio of different factor solutions in the nanosphere preparation and encapsulation unit, according to the preset factor ratio, so as to achieve factor compounding.

[0024] Its detailed connection method is a well-known technology in this field. The following mainly introduces the working principle and process, and the specific work is as follows.

[0025] Example: A composite bone repair material for repairing critical-sized bone defects in the rat skull was prepared. The designed formulation of the target product (by mass percentage) was as follows: 20% high-purity α-tricalcium phosphate powder, 20% decalcified bone matrix particles (particle size 100-300 μm), 15% methacrylamide gelatin hydrogel prepolymer solution (concentration 10%), 5% PLGA nanospheres encapsulated with vascular endothelial growth factor (VEGF) (target particle size approximately 370 nm), 0.008% free bone morphogenetic protein-2 (BMP-2), and the balance being phosphate buffer.

[0026] The specific preparation process is as follows: First, the operator inputs the target formula into the human-machine interface of the intelligent control center. After the control execution module of the intelligent control center parses the formula, it generates specific production instructions and activates the "bone cement-hydrogel composite" process route.

[0027] The raw material pretreatment and conveying unit begins executing commands. Its dedicated calcination subsystem starts, using commercially available dicalcium phosphate and calcium carbonate as raw materials, calcining and holding at 1450℃ for 2 hours. Subsequently, the phase change control model, based on a preset α-TCP purity target (>96%), controls an ultra-high-speed gas quenching cooling device to cool the calcined product at a rate of no less than 500℃ / second, obtaining high-purity α-TCP powder (X-ray diffraction analysis shows an α-phase content of 97.5% and a β-phase impurity content of less than 2.5%). Simultaneously, other silos in this unit accurately weigh and convey specified masses of decalcified bone matrix particles, methacrylamide gelatin lyophilized powder, PLGA raw material, VEGF lyophilized powder, and BMP-2 lyophilized powder.

[0028] The nanosphere preparation and encapsulation unit receives PLGA and dichloromethane solutions from the raw material unit, as well as VEGF dissolved in a specific aqueous phase. Based on the formulation requirement of "particle size approximately 370 nm," the intelligent control center calls upon the corresponding parameter set from the process model library to control the microfluidic chip device to operate at the set oil-to-water flow rate ratio, successfully preparing a PLGA nanosphere suspension encapsulated with VEGF. Random sampling using a dynamic light scattering instrument revealed an average particle size of (375±15) nm and an encapsulation rate of 68%.

[0029] The main mixing and reaction unit, upon receiving instructions, activates the first mixing channel. This channel first premixes the pretreated high-purity α-TCP powder, decalcified bone matrix particles, and a portion of phosphate buffer to form a homogeneous slurry. Subsequently, the system sequentially adds a solution of lyophilized methacrylamide gelatin powder dissolved in the remaining buffer, a PLGA nanosphere suspension containing VEGF, and a dissolved BMP-2 solution to the slurry. Mechanical stirring is then performed under low temperature (10°C) and light-protected conditions to form the final composite precursor material. Throughout the mixing process, pH and temperature sensors installed in the mixing tank provide real-time data feedback to the intelligent control center. The data shows that the pH of the mixing system remains stable at 7.4, and the temperature fluctuation does not exceed ±1°C, meeting the process requirements. Therefore, the control execution module does not initiate the parameter adjustment program.

[0030] Ultimately, the system outputs a composite precursor material with suitable viscosity that can be extruded through a syringe at room temperature.

[0031] It should be noted that in this paper, relational terms such as first and second are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations.

Claims

1. An intelligent preparation system for bone repair biomaterials, characterized in that, The system includes: The system includes: The raw material pretreatment and conveying unit is used for metering, pretreatment and independent conveying of calcium phosphate precursor, decalcified bone matrix, hydrogel prepolymer, bone growth factor and PLGA. The nanosphere preparation and encapsulation unit is communicatively connected to the raw material pretreatment and delivery unit, and is used to receive PLGA and bone growth factor, and to prepare PLGA nanospheres with a particle size of 80-500 nm encapsulated with bone growth factor under controllable conditions. The main mixing and reaction unit is communicatively connected to the raw material pretreatment and conveying unit and the nanosphere preparation and encapsulation unit, and is used to receive and mix calcium phosphate material, decalcified bone matrix, hydrogel material, and PLGA nanospheres or free bone growth factor encapsulated with bone growth factor. The intelligent control center is communicatively connected to all the above-mentioned units. The intelligent control center includes a data storage module, a process model library, and a control execution module. The data storage module stores raw material parameters, target product formulations, and historical process data; the process model library contains at least one phase transition control model for predicting and regulating the purity and phase composition of α-tricalcium phosphate; the control execution module calls the model in the process model library according to the target product formulation to dynamically adjust the operating parameters of each unit in order to prepare bone repair biomaterials that meet the preset requirements.

2. The intelligent preparation system for bone repair biomaterials according to claim 1, characterized in that... The raw material pretreatment and conveying unit includes: A dedicated calcination subsystem for preparing high-purity α-tricalcium phosphate is provided. The calcination subsystem is equipped with an ultra-high-speed gas quenching cooling device. The phase change control model of the intelligent control center monitors the calcination temperature in real time and adjusts the cooling rate of the gas quenching cooling device to suppress the phase transition from α-TCP to β-TCP, thereby obtaining α-tricalcium phosphate powder with a purity higher than 95%.

3. The intelligent preparation system for bone repair biomaterials according to claim 1, characterized in that... The main mixing and reaction unit includes a first mixing channel and a second mixing channel arranged in parallel. The first mixing channel is used to prepare bone repair biomaterials according to any one of claims 1-6, wherein the calcium phosphate material received therefrom is the high-purity α-tricalcium phosphate, and is mixed with a specific proportion of soluble phosphate, water or aqueous solution to form α-TCP-based bone cement slurry online, and then homogenized with other components; The second mixing channel is used to prepare bone repair materials with other formulations; The intelligent control center selects and activates the corresponding mixing channel and allocates raw materials based on the input target material type.

4. The intelligent preparation system and method for bone repair biomaterials according to claim 3, characterized in that... The nanosphere preparation and packaging unit uses a microfluidic chip device to prepare PLGA nanospheres. The intelligent control center controls the particle size of the PLGA nanospheres within the range of 373±12nm by adjusting the two-phase flow rate ratio and polymer concentration of the microfluidic chip.

5. The intelligent preparation system for bone repair biomaterials according to claim 4, characterized in that... The system also includes an online monitoring and feedback unit, which includes a particle size analyzer, a pH sensor, and a temperature sensor located at the outlet of the main mixing and reaction unit. The online monitoring and feedback unit is connected to the intelligent control center and feeds back the monitoring data to the control execution module in real time. The control execution module dynamically fine-tunes the raw material delivery rate, mixing speed, or reaction temperature based on the deviation between the feedback data and the preset value.

6. A method for preparing bone repair biomaterials using an intelligent preparation system as described in any one of claims 1-5, characterized in that, The method includes the following steps: S1: Formula Input and Analysis: Input the final composition formula of the target bone repair biomaterial into the intelligent control center. The formula shall include at least the mass percentage of each component. The control center analyzes the formula and generates the required amount of each raw material and the process route. S2: Raw material preparation and pretreatment: The raw material pretreatment and conveying unit prepares raw materials of corresponding quality and specifications according to the instructions of S1; wherein, in the preparation of α-tricalcium phosphate, the phase change control model controls the calcination and ultra-high speed gas quenching cooling process to obtain high-purity α-TCP powder. S3: Controllable preparation of nanospheres: The nanosphere preparation and encapsulation unit prepares PLGA nanospheres with specified particle size and encapsulation rate according to the formula requirements and if an encapsulation factor is required; S4: Intelligent Mixing and Molding: The main mixing and reaction unit mixes the pretreated calcium phosphate material, decalcified bone matrix, hydrogel material, bone growth factor and / or nanospheres prepared in step S3 according to the formula and selected process route in a precise sequence and proportion; if α-TCP bone cement is to be prepared, high-purity α-TCP powder is mixed with liquid phase and other solid phase components in the first mixing channel; S5: Process monitoring and adaptive adjustment: The online monitoring and feedback unit monitors the key parameters of the mixed product in real time and feeds the data back to the intelligent control center. The control execution module makes real-time parameter fine-tuning based on the feedback to ensure that the product performance meets the standards.

7. The method according to claim 6, characterized in that... In step S2, when the calcium phosphate material is selected from hydroxyapatite, β-tricalcium phosphate or fluorapatite, the system automatically calls the second mixing channel or adjusts the mixing strategy of the first mixing channel to avoid a violent hydration reaction with water during the mixing process.

8. The method according to claim 6, characterized in that... In step S4, when the bone growth factor contains two or three types, the intelligent control center precisely controls the feeding amount of different factor hoppers in the raw material pretreatment and conveying unit, or controls the pumping ratio of different factor solutions in the nanosphere preparation and encapsulation unit, according to the preset factor ratio, so as to achieve factor compounding.