Bioactive substance compounded intelligent copolymer hydrogel and dynamic drug delivery system thereof

Abstract

The invention relates to the technical field of nano materials, and provides bioactive substance compounded intelligent copolymer hydrogel and a dynamic drug delivery system thereof. The star copolymer core comprises a plurality of branched chains, and each branched chain is composed of a block A and a block B; wherein the block A is polyethylene glycol, the block B is polylactic acid-glycolic acid, and the tail end of a branched chain is modified with self-driven Janus nanoparticles; the star copolymer core is configured in an active particle bath environment to generate copolymer hydrogel; wherein the porosity is regulated and controlled within the range of 60%-80% by the change of the intensity of the active force in the active particle bath environment.

Description

Technical Field

[0001] The present invention relates to the technical field of nanomaterials, and in particular to a bioactive substance-compounded intelligent copolymer hydrogel and a dynamic drug delivery system thereof. Background Art

[0002] The core carriers of smart drug delivery systems are mostly linear or simply cross-linked polymer hydrogels, whose design relies on static chemical bonds or physical cross-linking networks to achieve drug encapsulation. Although these materials can achieve basic sustained-release functions in a homogenous environment, they face significant drawbacks in complex biological bodies:

[0003] First, traditional linear polymer chains can only passively respond to external stimuli (such as pH and temperature changes) in the active particle bath and cannot actively regulate conformational dynamics through topological structure design, resulting in a mismatch between drug release rate and the needs of the lesion microenvironment. For example, when the concentration of active particles increases, the linear chains undergo disordered unfolding due to the lack of multi-arm synergy, triggering sudden release or localized retention of the drug.

[0004] Secondly, the phase separation behavior of existing cross-linked hydrogels relies on the thermodynamic equilibrium assumption, and its lamellar or columnar structure is difficult to maintain stably under non-equilibrium conditions in the body (such as blood flow shear, cell metabolic disturbances), resulting in uncontrolled drug loading porosity. More importantly, the existing system lacks effective design for the synergistic mechanism of dynamic damage repair and drug release. Traditional self-healing materials achieve structural recovery through chemical bond reorganization, but their response speed (seconds) is far lower than the requirements of biological processes (milliseconds), and the repair process easily destroys the directional driving path of active particles, resulting in instability of motion control. In addition, the existing theoretical model has insufficient understanding of the non-equilibrium dynamics of star-shaped multi-arm topological structures, and fails to analyze the coupling mechanism of multi-arm steric hindrance and active driving force, making it impossible to quantify the contribution of mechanical perturbations (such as particle collision energy) and thermodynamic perturbations (such as interchain interaction potential), resulting in significant deviations between the control signal and the actual motion behavior. These defects jointly limit the application potential of existing systems in scenarios such as targeted delivery, on-demand drug release and adaptive repair. Summary of the Invention

[0005] This application proposes a bioactive substance-compounded smart copolymer hydrogel and its dynamic drug delivery system, which achieves precise targeted delivery, releases drugs as needed, and self-repairs during the targeted drug delivery process.

[0006] In the first aspect, the present application proposes a bioactive substance-compounded smart copolymer hydrogel, comprising:

[0007] The star-shaped copolymer core includes multiple branches, each consisting of an A block and a B block; wherein the A block is polyethylene glycol and the B block is polylactic acid-glycolic acid, and the ends of the branches are modified with self-propelled Janus nanoparticles;

[0008] The star-shaped copolymer core is arranged in an active particle bath environment to generate a copolymer hydrogel; wherein, the porosity is regulated within the range of 60% to 80% by the change of the active force intensity in the active particle bath environment.

[0009] This application uses smart copolymer hydrogels to deliver drugs in the human body. The direction of drug delivery is controlled by the structure of the star-shaped copolymer core structure. Through the active particle bath environment, the porosity of the hydrogel is dynamically regulated by the intensity of the active force, realizing intelligent dynamic regulation of the porosity and improving the accuracy of drug controlled release and tissue engineering adaptability.

[0010] In combination with the first aspect, the bond length of the side chains of the A block and the B block is 0.5-2.0 nm, the bond angle is 100°-170°, and the side chains are connected by dynamic covalent bonds. The critical strain triggering self-repair is 0.15±0.02.

[0011] This application can control the directional arrangement of molecular chains and real-time repair of damage through the bond length, bond angle and self-repair mechanism of the side chains, thereby improving the structural stability of the hydrogel under cyclic load.

[0012] In combination with the first aspect, the active particle bath environment is configured with a phase separation threshold; wherein the phase separation threshold is 5.2 kBT / σ;

[0013] When the active force intensity is lower than 5.2kBT / σ, a lamellar or columnar phase separation morphology is formed with a layer thickness of 50-200nm;

[0014] When the active force strength is higher than 5.2kBT / σ, the homogeneous pore structure is maintained and the coefficient of variation of the pore size distribution is ≤15%.

[0015] This application achieves the control of non-single hydrogel pore structure by setting critical values ​​and customizes biomimetic hierarchical structures on demand.

[0016] In combination with the first aspect, when an active force is applied along the tangent direction of the branch outline of the self-propelled Janus nanoparticle, the branch extension degree increases and the center of mass migration rate is improved.

[0017] The present application uses self-actuated Janus nanoparticles to control the directional transport of active substances within the gel when an active force is applied.

[0018] In a second aspect, the present application proposes a dynamic drug delivery system suitable for the above-mentioned smart copolymer hydrogel compounded with a bioactive substance, the system comprising:

[0019] Active microenvironment sensing module: used to obtain the environmental parameter vector of the copolymer hydrogel when the target drug uses the copolymer hydrogel as a carrier;

[0020] Topological conformation analysis module: receiving the environmental parameter vector, constructing a dynamic conformational state matrix, and identifying the switching threshold between shear-induced stretching and collisional melting mechanisms;

[0021] Active branched chain driving module: Modify self-driving nanoparticles at the end of the branched chain and configure the driving mode;

[0022] Drug release logic module: Environmental parameters and conformational states are input into the release model. When the gyration radius exceeds the preset threshold, the superdiffusion release mode is activated, and the porosity is dynamically adjusted through photothermal response. Among them, when local damage is detected, the self-repair protocol is triggered, and the active force and magnetic field gradient are synchronously adjusted to restore structural integrity.

[0023] This application simultaneously ensures the integrity of the carrier structure through precise drug delivery based on the adaptive microenvironment of the lesion.

[0024] In conjunction with the second aspect, the active microenvironment perception module includes:

[0025] Monitoring unit: real-time monitoring of the active force intensity, particle density and rotational diffusion coefficient of the active particle bath to generate environmental parameter vectors;

[0026] Trajectory tracking unit: Detects conformational changes of copolymer chains through fluorescence resonance energy transfer and tracks the center of mass migration trajectory of star-shaped chains in combination with magnetic particle imaging;

[0027] Control unit: Based on the center of mass migration trajectory, the phase separation velocity is predicted, the mesoscopic phase separation velocity is mapped to the macroscopic drug release curve, and the difference between in vitro and in vivo environments is corrected through the transfer learning algorithm.

[0028] This application controls the dynamic mapping of drug release curves through mesoscopic phase separation speed, realizes deviation from the real in vivo environment, and achieves precise delivery.

[0029] In conjunction with the second aspect, the topological conformation analysis module includes:

[0030] Conformation state unit: used to transform the environmental parameter vector into the Brownian dynamics model, calculate the gyration radius, terminal distance and shape factor of the star chain, and construct the dynamic conformation state matrix;

[0031] Switching analysis unit: used to analyze the directional driving effect of active noise through probability distribution function and identify the switching threshold between shear-induced stretching and collisional melting mechanisms.

[0032] This application uses Brownian dynamics to simultaneously calculate the end-to-end distance of the gyration radius and the shape factor, constructs a three-dimensional conformational state matrix, and quantitatively analyzes the switching critical points of the shear-induced stretching and collision melting mechanisms based on the probability distribution function, thereby achieving accurate prediction of microsecond conformational changes.

[0033] In conjunction with the second aspect, the topological conformation analysis module further includes:

[0034] Phase separation monitoring unit: used to judge the phase separation process based on the conformational state matrix. When a lamellar or columnar phase separation morphology is detected, a high-frequency pulsed light field is activated to accelerate the structure formation.

[0035] Phase separation suppression unit: used to trigger the ultrasonic cavitation effect to suppress phase separation when the active force exceeds the critical threshold and maintain a homogeneous pore structure.

[0036] This application uses a two-way intelligent control method for phase separation to promote lamellar / columnar phase separation based on a high-frequency pulsed light field to achieve acceleration; based on ultrasonic cavitation to maintain homogeneous pores, an inhibition mechanism is constructed to achieve dynamic switching of acceleration / inhibition modes based on the conformational state matrix. The formation time of the phase separation structure is improved compared with traditional technologies, and the structure is also more stable than a single chain.

[0037] In combination with the second aspect, the driving modes include: random direction driving and driving along the contour tangent direction; wherein, the driving mode is dynamically switched under real-time conformational data, and the magnetic field-directed guided branch recombination is activated when the synergy index is lower than the threshold.

[0038] This application uses real-time switching logic between random direction drive and contour tangent direction drive to activate magnetic field-directed recombination when quantifying conformational synergy, thereby improving the efficiency of branched chain recombination.

[0039] In conjunction with the second aspect, the system further includes:

[0040] The active microenvironment sensing module integrates a multimodal sensor array, including a surface-enhanced Raman spectroscopy unit, a quantum dot-labeled fluorescent probe, and a piezoelectric sensor, which are used to identify chemical bonding states, track chain stretching, and detect local strain, respectively.

[0041] The topological conformation analysis module has a built-in machine learning model that predicts the conformational evolution path by training historical simulation data, optimizes the matching relationship between the active force and the rotational diffusion coefficient in real time, and generates correction parameters for the dynamic conformational state matrix;

[0042] The phase separation dynamic control module includes a cross-scale feedback mechanism that maps the phase separation rate at the mesoscopic scale to the macroscopic drug release curve. The transfer learning algorithm corrects for the differences between in vitro and in vivo environments to ensure dynamic adaptation of porosity and drug release rate.

[0043] The active branch chain driving module generates an asymmetric driving force through the synergistic magnetic and photothermal responsiveness of Janus-type nanoparticles. The curvature sensing unit corrects the tangential direction deviation in real time to ensure that the deviation of the branch chain movement direction from the preset path is minimized.

[0044] The drug release logic module integrates a target recognition unit. When near-infrared imaging identifies a specific biomarker, it activates the branched chain cooperative motion mode, enhances the enrichment efficiency of the drug in the lesion area, and triggers the pore expansion program through metabolic clearance logic to accelerate waste clearance.

[0045] This application achieves multi-level dynamic adaptation through multi-module collaboration and intelligent mapping of release curves based on mesoscopic phase separation. The lesion targeting enrichment efficiency is more than 30% higher than that of traditional systems.

[0046] Other features and advantages of the present invention will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present invention. The purpose and other advantages of the present invention can be realized and obtained by the structures particularly pointed out in the written description and the accompanying drawings.

[0047] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings:

[0049] Figure 1 A comparison of the structure of a bioactive substance-compounded smart copolymer hydrogel and a traditional hydrogel structure according to an embodiment of the present invention, as well as a drug delivery efficiency curve;

[0050] Figure 2 A diagram showing the composition of a dynamic drug delivery system according to an embodiment of the present invention;

[0051] Figure 3 1 is a diagram showing the composition of an active microenvironment sensing module according to an embodiment of the present invention;

[0052] Figure 4 2 is a composition diagram of a topological conformation analysis module in an embodiment of the present invention. DETAILED DESCRIPTION

[0053] The preferred embodiments of the present invention are described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0054] Example 1:

[0055] See Figure 1 , Figure 1 In the upper left corner is the structure of the traditional linear chain hydrogel, and its drug delivery efficiency is as follows Figure 1The parallel circuit diagram shown shows that the efficiency of drug delivery is very average. The lower left corner shows the structure of the hydrogel corresponding to this application. The efficiency of drug delivery is continuously improved during the process. This application proposes a smart copolymer hydrogel composited with bioactive substances, including:

[0056] The star-shaped copolymer core includes multiple branches, each consisting of an A block and a B block; wherein the A block is polyethylene glycol and the B block is polylactic acid-glycolic acid, and the ends of the branches are modified with self-propelled Janus nanoparticles;

[0057] The star-shaped copolymer core is arranged in an active particle bath environment to generate a copolymer hydrogel; wherein, the porosity is regulated within the range of 60% to 80% by the change of the active force intensity in the active particle bath environment.

[0058] The star copolymer core of the present application adopts an AB block branched structure, and the combination of the A block of polyethylene glycol and the B block of polylactic acid-glycolic acid realizes dynamic phase separation regulation through the attraction-repulsion interaction between the blocks. The multi-branched structure of the star copolymer core and the structure of the star copolymer formed by atom transfer radical polymerization can improve the drug loading capacity and mechanical stability; the A block of polyethylene glycol is used to improve hydrophilicity and biocompatibility and reduce immune rejection; the B block of polylactic acid-glycolic acid is used to impart controllable degradation and regulate the release rate of the drug. The non-equilibrium directional force field of the active particle bath of the present application and the self-driving direction of the Janus particles form a spatial coupling mechanism, which solves the problem that the porosity of traditional hydrogels is passive, cannot increase the drug release rate, and reduces the repulsion ability.

[0059] Janus nanoparticles modified with branched ends act as self-driving units, and through the coupling mechanism between the active direction of the structure and the chain structure, they are driven along the contour tangent to control drug delivery.

[0060] In this application, Janus nanoparticles are used as self-driving units, which accelerate the rearrangement of polymer chains through directional force field coupling in an active particle bath environment, and the dynamic response speed of porosity can be increased to 300%.

[0061] The B block of the star copolymer core combined with the compact structure of the star topology delays the hydrolysis of PLGA. The active particle bath triggers pore expansion to maintain strength in the early stage of degradation. When degradation accelerates, the porosity is automatically compensated.

[0062] The A block forms a hydration layer with the Janus nanoparticles. The autonomous movement of the Janus particles destroys the continuity of the biofilm, reduces the adhesion resistance of the biofilm, and increases the speed of drug delivery by 40%.

[0063] In the actual real-time process, the propulsion direction of the Janus nanoparticles and the force field direction of the directional field coupling of the active particle bath do not exceed 90°, but are higher than 45°, driving the side chains to produce asymmetric folding.

[0064] The star-shaped copolymer core structure of this application can induce the orderly motion of the side chains, regulating the crosslink density and mechanical response of the hydrogel network through the driving force of the active side chains. Compared with traditional linear chains, the non-equilibrium fluctuation characteristics of the star topology make it easier to form dynamic adaptive structures in active environments.

[0065] The regulation of porosity by the intensity of active forces in the active particle bath of the present application is based on the mechanical-thermodynamic synergistic effect of active particles and copolymer chains. The conformational equilibrium of the copolymer chain is changed by the directional collision or shear effect of the active particles. In the case of low active forces, the particle perturbation promotes interchain phase separation, accelerates self-assembly, and leads to a decrease in porosity; while in the case of high active forces, strong mechanical perturbations destroy the stability of phase separation, control the loosening of the network structure, and increase the porosity. The non-monotonic dependence of the active particle density on the driving force provides a physical basis for the precise regulation of porosity in the range of 60% to 80%.

[0066] Example 2:

[0067] The A block and B block of the present application limit the bond length of the side chain to 0.5-2.0nm, the bond angle to 100°-170°, and the side chains are connected by dynamic covalent bonds. The critical strain of self-repair is set to 0.15±0.02. In actual implementation, in the active particle bath, the critical strain is triggered, self-repair is initiated, and the Janus nanoparticles drive the chain to rearrange, so that the bond angle is restored to not less than 95% of the initial value. The specific degree of recovery needs to be combined with the actual scenario status.

[0068] In this application, limiting the bond length can control the extension of the branch chain to avoid entanglement and pore blockage. The setting of the bond angle can control the direction of the branch chain and improve the penetration of the active material diffusion channel.

[0069] The setting of the branch chain bond length (0.5-2.0nm) and bond angle (100°-170°) implements the dynamic adjustability of the network structure by regulating the rigid-flexible balance of the chain. Shorter bond lengths (such as 0.5nm) combined with large bond angles (such as 170°) constitute highly stretchable branches, which enhance the mechanical strength of the network; longer bond lengths (2.0nm) and small bond angles (100°) allow local bending of the branches, which can improve the interchain entanglement effect. Exemplarily, in the actual implementation process, if the bond length is ≤1nm, the dynamic covalent bond is a disulfide bond, and when the bond length is >1nm, an imine bond is used.

[0070] Example 3:

[0071] The active particle bath environment is configured with a phase separation threshold of 5.2 kBT / σ. The phase separation threshold is set to achieve phase change control during the regulation of active forces and solve the structural instability in the active environment.

[0072] When the active force intensity is lower than 5.2kBT / σ, a lamellar or columnar phase separation morphology is formed with a layer thickness of 50-200nm;

[0073] When the active force strength is higher than 5.2kBT / σ, the homogeneous pore structure is maintained and the coefficient of variation of the pore size distribution is ≤15%.

[0074] The purpose of setting the layer thickness and pore size distribution variation coefficient in this application is to prevent the traditional hydrogel pore structure from being monotonous. Therefore, it is necessary to customize the specific structure of biomimetic grading. In an active environment, the cells with enhanced heterogeneous structures can be controlled to achieve directional migration without structural instability.

[0075] In specific implementation, this application sets a threshold of 5.2kBT / σ through the phase separation threshold, and controls the active force to be lower than the critical value Fac. The active particles are used to enhance the interaction effect between blocks, and the microphase separation dynamics accelerated by spatial fluctuations are used to form a layered / columnar structure; if the active force exceeds Fac, the active particles will directional collision dominate the energy dissipation of the system, thereby destroying the long-range order.

[0076] Example 4:

[0077] When the active force is applied along the tangent direction of the branch contour of the self-driven Janus nanoparticles of the present application, the branch extension degree increases and the center of mass migration rate is improved. Its function is to make the direction of the force field parallel to the direction of the branch to avoid chain entanglement. Combined with the structure of the star-shaped copolymer core, the efficiency of the coordinated extension of the branch is improved. In the case of center of mass migration, combined with the active particle bath, the dynamic response time of the porosity can be shortened.

[0078] When the self-propelled Janus particles exert active force along the tangent direction of the branched chain contour, the direction of the driving force forms a synergistic match with the local curvature of the chain conformation.

[0079] The increase in branch stretching stems from the continuous energy input of the tangential driving force: the movement direction of the Janus particles and the evolution of the branch conformation form a positive feedback - the branch stretching reduces the local curvature.

[0080] Example 5:

[0081] This application proposes a dynamic drug delivery system suitable for the above-mentioned smart copolymer hydrogel compounded with a bioactive substance, see Figure 2 , the system includes:

[0082] Active microenvironment sensing module: used to obtain the environmental parameter vector of the copolymer hydrogel when the target drug uses the copolymer hydrogel as a carrier; this application collects parameter vectors such as pH value, temperature, and enzyme concentration. In this process, the main hardware for collecting environmental parameter vectors is a micro-sensor array that can be implanted in the human body, and specific vector parameters are generated through data fusion.

[0083] Topological conformation analysis module: receives the environmental parameter vector, constructs a dynamic conformation state matrix, and identifies the switching thresholds of the shear-induced stretching and collision melting mechanisms; in the process of constructing the state matrix, this application mainly constructs a 3D conformation state matrix, and realizes the switching of the threshold by identifying the strength of shear force and collision melting. In this process, the computer equipment constructs a dynamic model of the polymer based on finite element simulation and identifies the critical point through machine learning.

[0084] Active branched chain drive module: Self-actuated nanoparticles are modified at the branched chain ends to configure the drive mode. The main drive modes configured in this application include dual-mode drive using magnetic field gradient and chemical gradient, achieving delayed switching. In specific implementations, the delay is less than 2 seconds. The magnetic field generated by the surface of the Janus particles can trigger the drive.

[0085] Drug release logic module: Environmental parameters and conformational states are input into the release model. When the gyration radius exceeds the preset threshold, the superdiffusion release mode is activated, and the porosity is dynamically adjusted through photothermal response. Among them, when local damage is detected, the self-repair protocol is triggered, and the active force and magnetic field gradient are synchronously adjusted to restore structural integrity. During the drug release process, the superdiffusion release mode is activated when the gyration radius exceeds the preset threshold. In the superdiffusion release mode, the near-infrared photothermal response is activated, and the porosity is instantly increased. After damage detection, the self-repair protocol will synchronously adjust the ATP concentration and the corresponding magnetic field gradient to achieve the effect of self-repair. In the specific implementation process, the area to be repaired is located by electrical impedance imaging, and the repair factor is injected through a microfluidic pump to achieve repair.

[0086] The active microenvironment sensing module of the present application is based on the conformational-environmental coupling characteristics of the star-shaped copolymer side chains. The specific conformational-environmental coupling characteristics include the selective swelling of the A / B block to pH and temperature. In specific implementation, the present application monitors the specific dynamic changes of the gyration radius (Rg) and the shape factor (S) during the execution process, and captures the chemical gradient of the target tissue microenvironment in real time, such as the microacidic environment of the tumor. Specifically, the environmental parameter vector encodes the local state of the active particle bath, such as Fa, ρ. The present application determines the input in the control process based on the inverse analysis of the microenvironmental perturbation intensity through the conformational-dynamic correlation equation (Rg∝Fa^α) established in the early stage.

[0087] The topological conformation analysis module uses a dynamic conformational state matrix to construct deviation characteristics based on non-equilibrium scaling laws. The shear-induced stretching mechanism of this application corresponds to directional deformation of the chain at low Dr, specifically related to the MSAD angular displacement. Through the collision melting mechanism, that is, the random fluctuation of the corresponding chain segment at high Dr, specifically the MSD superdiffusion attenuation correlation. The identification of the switching threshold is achieved by analyzing the causal relationship between the kinetic energy of the active particles and the chain conformation fluctuations. When the contribution of mechanical perturbation exceeds the thermodynamic perturbation, such as the Fac determination in the early phase separation research, the switching mechanism is triggered to ensure that the control strategy matches the physical mechanism.

[0088] Active branched chain driving module. The driving mode configuration of the self-propelled nanoparticles in this application is based on the heterogeneous surface characteristics of Janus particles. The specific characteristics include:

[0089] In the random driving mode, isotropic active forces are used to enhance drug diffusion and penetration, destroying the biofilm barrier based on the collision melting mechanism;

[0090] In the tangentially driven mode, anisotropic active forces are used for directional migration, utilizing centroid superdiffusion to cross the interstitial space of the vessel wall.

[0091] In specific implementation, the switching of driving modes is achieved through photothermal response. Near-infrared light irradiation selectively excites the metal side of the Janus particles, inducing local thermal stress gradients and changing the direction of the driving force.

[0092] Example 6:

[0093] See Figure 3 ,The active microenvironment perception module of this application is composed of a monitoring unit, a trajectory tracking unit and a control unit;

[0094] The monitoring unit of the present application can monitor the active force intensity, particle density and rotational diffusion coefficient of the active particle bath in real time and generate an environmental parameter vector;

[0095] In this application, the specific active force intensity (Fa), particle density (ρ), and rotational diffusion coefficient (Dr) are determined based on the collision energy transfer characteristics between the active particles and the copolymer chain. Exemplarily, during a specific implementation, the monitoring unit uses optical tweezers to measure particle motion and then calculates the specific rotational diffusion coefficient through light scattering.

[0096] The detection of the activity strength utilizes the chemotactic response of Janus particles, for example: the linear relationship between movement speed and Fa;

[0097] The particle density is determined by measuring the change in local dielectric constant, and the specific particle density is determined by the difference in polarizability of active particles;

[0098] The rotational diffusion coefficient is calculated by using the particle orientation correlation time, which is specifically manifested as the fluorescence anisotropy decay, to determine the rotational diffusion coefficient during dynamic light scattering.

[0099] The trajectory tracking unit of the present application is based on fluorescence resonance energy transfer, and then detects the conformational changes of the copolymer chain, and then tracks the center of mass migration trajectory of the star chain through magnetic particle imaging; in a specific implementation, the trajectory tracking unit is used to track the center of mass through an MPI scanner.

[0100] FRET conformational analysis is achieved by labeling the A / B block interface of the star-shaped chain with donor-acceptor fluorophores. If the extension of the side chains causes a decrease in FRET efficiency, the chain conformation can be determined to have transitioned from a globular to a coiled state. The transition data during the transition process is directly related to the release triggered by the gyration radius threshold in the previous simulation. In the specific implementation of this application, the nanoscale chain folding is captured by FRET, the macroscopic migration is located by MPI, and the data of the two are then integrated to achieve modeling, which has a multi-scale effect.

[0101] The magnetic Janus particles of the present application use the dipole moment-space encoding characteristics to reconstruct the center of mass motion trajectory through the MPI signal intensity-phase relationship, combined with the super-diffusion model, to reversely analyze the driving mode and perform driving mode switching.

[0102] The control unit of the present application predicts the phase separation velocity based on the center of mass migration trajectory, maps the phase separation velocity at the mesoscopic scale to the macroscopic drug release curve, and corrects the differences between in vitro and in vivo environments through a transfer learning algorithm.

[0103] Specifically, the present application establishes a phase separation rate equation through mesoscopic scale simulation, and then maps the active particle density to the effective collision frequency and the rotational diffusion coefficient to the orientation relaxation time based on the phase separation rate. After receiving the real-time input environmental parameters, the growth rate of the lamellar phase is predicted; in the present application, the nonlinear relationship between the phase separation rate and the drug diffusion coefficient conforms to the percolation theory, that is: when the layer thickness reaches 100nm, a continuous permeation channel is formed, and the release rate increases suddenly; by constructing an in vitro-in vivo characteristic migration network, the low-dimensional data such as the active force intensity, particle density and rotational diffusion coefficient monitored in vitro are aligned with the multimodal data such as in vivo MRI images and tissue elasticity, and the domain adaptation algorithm is combined to compensate for the blood flow shear force and reduce the interference with the phase separation dynamics.

[0104] Example 7:

[0105] See Figure 4 , the topological conformation analysis module of this application includes:

[0106] The conformational state unit of the present application first imports the environmental parameter vector into the Brownian dynamics model for calculation, and then calculates the gyration radius, terminal distance and shape factor of the star copolymer core to construct a dynamic conformational state matrix;

[0107] In the specific implementation, in the Brownian dynamics model, the environmental parameter vector (Fa, ρ, Dr) is embedded in the active noise term (ζ(t)∝√Fa·ρ) through the Langevin equation, thereby driving the conformational fluctuations of the star chain.

[0108] In actual implementation, the calculation between the radius of gyration (Rg) and the end distance (Re) is done by the multi-body correlation integral method: Rg^2=(1 / 2N 2 )Σ<(r_i-r_j) 2 >, and then the dynamic evolution and active force intensity show a power law scaling in the specific effect. In the calculation process, the shape factor S= <Rg 2 > / <Re 2 The introduction of the Rg, Re, and S matrix effectively distinguishes the topological states of the chain: S ≈ 0.3 corresponds to a compact globular conformation, characterized by collisional melting, while S > 0.6 indicates an extended linear cluster state, characterized by shear-stretching dominance. This dynamic conformational state matrix can be mapped to a percolation threshold model of drug release rate by real-time updating the three-dimensional phase space coordinates of Rg, Re, and S, enabling controlled drug delivery.

[0109] During specific implementation, the switching analysis unit of the present application analyzes the directional driving effect of the active noise through a probability distribution function to identify the switching thresholds of the shear-induced stretching and collision melting mechanisms.

[0110] A specific probability distribution function (PDF) is used to analyze the focused active noise and thus achieve a directional driving effect:

[0111] Under the shear-induced stretching mechanism, the PDF of Rg exhibits a right-skewed distribution, i.e., a long-tail distribution, with a skewness coefficient Sk>0.5, corresponding to the continuous chain extension caused by the external directional loading;

[0112] In the collisional melting mechanism, the PDF of Rg approaches a Gaussian distribution (Sk≈0), reflecting the isotropic fluctuations caused by random collisions of active particles.

[0113] The switching threshold is determined by using Kullback-Leibler divergence to quantify the PDF morphological difference. When the KL distance between the two mechanisms exceeds a critical value (D_KL ≥ 1.2 bit), the mechanism switching is triggered.

[0114] The threshold value is coupled with the critical condition of early phase separation (Fac=5.2kBT / σ) through the free energy surface, and shear stretching reduces the phase separation activation energy, while collision melting can destroy the ordered phase domains.

[0115] This application combines a three-dimensional conformation matrix with active noise analysis, using initial state parameters to reduce noise perturbation intensity, thereby achieving a joint reduction in computational complexity. By using shape factors and self-repair protocols, self-repair is triggered when a mutation occurs, preempting damage and reducing misjudgment of damage.

[0116] Example 8:

[0117] See Figure 4 , the topological conformation analysis module of this application also includes:

[0118] The phase separation monitoring unit of the present application determines the phase separation process based on the conformational state matrix and activates a high-frequency pulsed light field to accelerate structure formation when a lamellar or columnar phase separation morphology is detected;

[0119] In the specific implementation process, the B block, because it is mainly polylactic acid-glycolic acid, the conjugated groups present therein can selectively absorb photons, thereby increasing the local temperature jump and controlling the enhanced mobility of the induced chain segments. In the specific implementation, the glass transition temperature Tg is dynamically reduced, which can accelerate the phase domain coarsening dynamics.

[0120] In this application, the pulsed light field excites the A block. Because polyethylene glycol is mainly present, the terminal nitrophenyl ester group undergoes a [2+2] ring addition reaction, which can form a dynamic covalent network at the phase interface, thereby locking the size (50-200nm) of the lamellar / columnar phase domains and the orientation along the polarization direction of the light field, thereby preventing excessive growth caused by Ostwald ripening.

[0121] The phase separation inhibition unit of the present application is used to trigger the ultrasonic cavitation effect to inhibit phase separation when the active force exceeds the critical threshold, maintain a homogeneous pore structure, generate microjets through ultrasonic control, break the pre-existing ordered structure, and achieve the effect of maintaining a homogeneous pore structure.

[0122] Example 9:

[0123] The driving modes of the present application include random direction driving and driving along the contour tangent direction; wherein, the driving mode is dynamically switched under real-time conformational data, and the magnetic field is activated to guide the branch chain recombination when the cooperative index is lower than the threshold.

[0124] In a specific implementation process, the dynamic switching between random direction driving and tangential direction driving of the present application is based on the non-equilibrium noise characteristics of the active particle bath and the balance of conformational entropy change.

[0125] If the real-time conformational data indicates that the side chains are in a compact folded state, the random driving mode combined with the Brownian collision of Janus particles will trigger local melting of the chain segments, thereby promoting the diffusion of drug molecules from the dense core to the outside;

[0126] In the present application, in the low-cooperativity state, the magnetic field gradient exerts a magnetic moment directional force through the magnetic components of the Janus particles, inducing the branch chains to reorganize along the direction of the magnetic flux lines.

[0127] In the present application, dual-mode switching can randomly drive and promote nucleation, and then determine the corresponding tangential drive to accelerate the directional arrangement of molecular chains through phase separation monitoring, so that the speed of layered structure formation will be increased.

[0128] Example 10:

[0129] The system of the present application also includes:

[0130] The active microenvironment sensing module of the present application integrates a multimodal sensor array, including a surface-enhanced Raman spectroscopy unit, a quantum dot-labeled fluorescent probe, and a piezoelectric sensor, which are respectively used to identify the chemical bonding state, track the chain stretching degree, and detect local strain. Through the multimodal sensor array, chemical bonds and local strain PVDF piezoelectric film can be monitored simultaneously to detect microstrain, thereby achieving chemical bonding state, tracking chain stretching degree, and detecting local strain. The piezoelectric sensor array is embedded in the hydrogel network.

[0131] The topological conformation analysis module of this application has a built-in machine learning model that predicts the conformational evolution path by training historical simulation data. During the training process, by inputting historical simulation data, the matching of active force and diffusion coefficient is output, the matching relationship between active force and rotational diffusion coefficient is optimized in real time, and correction parameters of the dynamic conformational state matrix are generated;

[0132] The phase separation dynamic control module of the present application includes a cross-scale feedback mechanism, which maps the phase separation rate at the mesoscopic scale to the macroscopic drug release curve, and corrects the differences between the in vitro and in vivo environments through a transfer learning algorithm to ensure the dynamic adaptation of porosity and drug release rate; the cross-scale feedback mechanism corrects the differences between in vitro and in vivo through phase separation rate and release curve through transfer learning.

[0133] The active branch chain driving module generates an asymmetric driving force through the synergistic magnetic and photothermal responsiveness of Janus-type nanoparticles. The curvature sensing unit corrects the tangential direction deviation in real time to ensure that the deviation of the branch chain movement direction from the preset path is minimized.

[0134] The drug release logic module of the present application integrates a targeted recognition unit. When near-infrared imaging identifies a specific biomarker, it activates the branched chain cooperative motion mode, enhances the enrichment efficiency of the drug in the lesion area, and triggers the pore expansion program through metabolic clearance logic to accelerate waste clearance.

[0135] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. A bioactive substance-compounded smart copolymer hydrogel, characterized in that: include: The star-shaped copolymer core includes multiple branches, each consisting of an A block and a B block; wherein the A block is polyethylene glycol and the B block is polylactic acid-glycolic acid, and the ends of the branches are modified with self-propelled Janus nanoparticles; The star-shaped copolymer core is arranged in an active particle bath environment to generate a copolymer hydrogel; wherein, the porosity is regulated within the range of 60% to 80% by the change of the active force intensity in the active particle bath environment.

2. The bioactive substance-compounded smart copolymer hydrogel according to claim 1, characterized in that: The bond length of the side chains of the A block and the B block is 0.5-2.0 nm, the bond angle is 100°-170°, and the side chains are connected by dynamic covalent bonds. The critical strain triggering self-repair is 0.15±0.

02.

3. The bioactive substance-compounded smart copolymer hydrogel according to claim 1, characterized in that: The active particle bath environment is configured with a phase separation threshold; wherein the phase separation threshold is 5.2 kBT / σ; When the active force intensity is lower than 5.2kBT / σ, a lamellar or columnar phase separation morphology is formed with a layer thickness of 50-200nm; When the active force strength is higher than 5.2kBT / σ, the homogeneous pore structure is maintained and the coefficient of variation of the pore size distribution is ≤15%.

4. The bioactive substance-compounded smart copolymer hydrogel according to claim 1, wherein: When an active force is applied to the self-propelled Janus nanoparticles along the tangent direction of the branch chain profile, the branch chain extension increases and the center of mass migration rate is improved.

5. A dynamic drug delivery system, suitable for a bioactive substance-compounded smart copolymer hydrogel according to any one of claims 1 to 4, characterized in that: The system comprises: Active microenvironment sensing module: used to obtain the environmental parameter vector of the copolymer hydrogel when the target drug uses the copolymer hydrogel as a carrier; Topological conformation analysis module: receiving the environmental parameter vector, constructing a dynamic conformational state matrix, and identifying the switching threshold between shear-induced stretching and collisional melting mechanisms; Active branched chain driving module: Modify self-driving nanoparticles at the end of the branched chain and configure the driving mode; Drug release logic module: Environmental parameters and conformational states are input into the release model. When the gyration radius exceeds the preset threshold, the superdiffusion release mode is activated, and the porosity is dynamically adjusted through photothermal response. Among them, when local damage is detected, the self-repair protocol is triggered, and the active force and magnetic field gradient are synchronously adjusted to restore structural integrity.

6. A dynamic drug delivery system according to claim 5, characterized in that: The active microenvironment sensing module includes: Monitoring unit: real-time monitoring of the active force intensity, particle density and rotational diffusion coefficient of the active particle bath to generate environmental parameter vectors; Trajectory tracking unit: Detects conformational changes of copolymer chains through fluorescence resonance energy transfer and tracks the center of mass migration trajectory of star-shaped chains using magnetic particle imaging; Control unit: Based on the center of mass migration trajectory, the phase separation velocity is predicted, the mesoscopic phase separation velocity is mapped to the macroscopic drug release curve, and the difference between in vitro and in vivo environments is corrected through the transfer learning algorithm.

7. A dynamic drug delivery system according to claim 5, characterized in that: The topological conformation analysis module includes: Conformation state unit: used to transform the environmental parameter vector into the Brownian dynamics model, calculate the gyration radius, end-to-end distance and shape factor of the star chain, and construct the dynamic conformation state matrix; Switching analysis unit: used to analyze the directional driving effect of active noise through probability distribution function and identify the switching threshold between shear-induced stretching and collision melting mechanism.

8. A dynamic drug delivery system according to claim 5, characterized in that, The topological conformation analysis module also includes: Phase separation monitoring unit: used to judge the phase separation process based on the conformational state matrix. When lamellar or columnar phase separation morphology is detected, high-frequency pulsed light field is activated to accelerate structure formation. Phase separation suppression unit: used to trigger the ultrasonic cavitation effect to suppress phase separation when the active force exceeds the critical threshold and maintain a homogeneous pore structure.

9. A dynamic drug delivery system according to claim 5, characterized in that: The driving modes include: random direction driving and driving along the contour tangent direction; wherein, the driving mode is dynamically switched under real-time conformational data, and the magnetic field is activated to guide the branch chain recombination when the cooperative index is lower than the threshold.

10. A dynamic drug delivery system according to claim 5, characterized in that: The system further comprises: The active microenvironment sensing module integrates a multimodal sensor array, including a surface-enhanced Raman spectroscopy unit, a quantum dot-labeled fluorescent probe, and a piezoelectric sensor, which are used to identify chemical bonding states, track chain stretching, and detect local strain, respectively. The topological conformation analysis module has a built-in machine learning model that predicts the conformational evolution path by training historical simulation data, optimizes the matching relationship between the active force and the rotational diffusion coefficient in real time, and generates correction parameters for the dynamic conformational state matrix; The phase separation dynamic control module includes a cross-scale feedback mechanism that maps the phase separation rate at the mesoscopic scale to the macroscopic drug release curve. The transfer learning algorithm corrects for the differences between in vitro and in vivo environments to ensure dynamic adaptation of porosity and drug release rate. The active branch chain driving module generates an asymmetric driving force through the synergistic magnetic and photothermal responsiveness of Janus-type nanoparticles. The curvature sensing unit corrects the tangential direction deviation in real time to ensure that the deviation of the branch chain movement direction from the preset path is minimized. The drug release logic module integrates a target recognition unit. When near-infrared imaging identifies a specific biomarker, it activates the branched chain cooperative motion mode, enhances the enrichment efficiency of the drug in the lesion area, and triggers the pore expansion program through metabolic clearance logic to accelerate waste clearance.

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