Intelligent copolymer hydrogels with bioactive substance complexation and dynamic drug delivery systems

Abstract

The application relates to the technical field of nanomaterials, and provides a bioactive substance composite intelligent copolymer hydrogel and a dynamic drug delivery system thereof. A star-shaped copolymer core comprises multiple branches, and the branches are composed of A blocks and B blocks; the A blocks are polyethylene glycol, the B blocks are polylactic acid-glycolic acid, and the branches are modified with self-driven Janus nanoparticles at the ends; the star-shaped copolymer core is arranged in an active particle bath environment to generate a copolymer hydrogel; and the active force strength in the active particle bath environment is changed to control the porosity in the range of 60% to 80%.

Description

Technical Field

[0001] This invention relates to the field of nanomaterials technology, and in particular to a smart copolymer hydrogel composed of bioactive substances and its dynamic drug delivery system. Background Technology

[0002] The core carriers of intelligent drug delivery systems often employ polymer hydrogels with linear or simple cross-linked structures, whose design relies on static chemical bonds or physical cross-linking networks to achieve drug encapsulation. While these materials can achieve basic sustained-release functionality in homogenized environments, they face significant drawbacks in complex biological systems:

[0003] First, traditional linear polymer chains in an active particle bath can only passively respond to external stimuli (such as changes in pH and temperature) and cannot actively regulate conformational dynamics through topological design, leading to 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 synergistic effects, triggering either burst drug release or local retention.

[0004] Secondly, the phase separation behavior of existing cross-linked hydrogels relies on the assumption of thermodynamic equilibrium. Their layered or columnar structures are difficult to maintain stably under non-equilibrium conditions in vivo (such as blood flow shear and cellular metabolic disturbances), leading to uncontrolled drug loading porosity. More critically, existing systems lack effective design for the synergistic mechanism of dynamic damage repair and drug release. Traditional self-healing materials achieve structural recovery through chemical bond recombination, but their response speed (seconds) is far lower than the requirements of biological processes (milliseconds), and the repair process easily disrupts the directional driving path of active particles, leading to motion control instability. Furthermore, existing theoretical models lack sufficient understanding of the non-equilibrium dynamics of star-shaped multi-arm topologies, failing to resolve the coupling mechanism between the spatial steric hindrance of the multi-arms and the active driving force. This makes it impossible to quantify the contributions of mechanical disturbances (such as particle collision energy) and thermodynamic disturbances (such as inter-chain interaction potential), resulting in significant deviations between control signals and actual motion behavior. These shortcomings collectively limit the application potential of existing systems in targeted delivery, on-demand drug release, and adaptive repair scenarios. Summary of the Invention

[0005] This application proposes a smart copolymer hydrogel composed of bioactive substances and its dynamic drug delivery system, which achieves precise targeted delivery, release of drugs as needed, and self-repair during targeted drug delivery.

[0006] In a first aspect, this application proposes a smart copolymer hydrogel composed of bioactive substances, comprising:

[0007] The star-shaped copolymer core includes multiple branches, which are composed of A blocks and B blocks; wherein, the A block is polyethylene glycol, the B block is polylactic acid-glycolic acid, and the ends of the branches are modified with self-driven Janus nanoparticles.

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

[0009] This application utilizes a smart copolymer hydrogel for drug delivery within the human body. The star-shaped copolymer core structure enables directional control of drug delivery. By using an active particle bath environment, the porosity of the hydrogel is dynamically adjusted using the intensity of the active force, thereby achieving intelligent dynamic regulation of porosity, improving the precision of controlled drug release and tissue engineering compatibility.

[0010] In conjunction with the first aspect, the bond length of the branches of the A and B blocks is 0.5-2.0 nm, the bond angle is 100°-170°, and the branches are connected by dynamic covalent bonds, with a critical strain of 0.15±0.02 that triggers self-healing.

[0011] This application utilizes the bond length, bond angle, and self-healing mechanism of the side chains to control the directional arrangement of molecular chains and real-time repair of damage, thereby improving the structural stability of hydrogels under cyclic loading.

[0012] In conjunction 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 activity intensity is less than 5.2 kBT / σ, a layered or columnar phase separation morphology is formed, with a layer thickness of 50-200 nm;

[0014] It maintains a homogeneous pore structure with a pore size distribution variation coefficient ≤15% when the activity intensity is higher than 5.2 kBT / σ.

[0015] This application achieves control over non-single hydrogel pore structures by setting critical values, enabling the customization of biomimetic hierarchical structures as needed.

[0016] In conjunction with the first aspect, when an active force is applied along the tangential direction of the branch profile of the self-driven Janus nanoparticles, the branch extension increases and the centroid migration rate is enhanced.

[0017] This application utilizes self-driven Janus nanoparticles to control the directional transport of active substances within the gel when an active force is applied.

[0018] Secondly, this application proposes a dynamic drug delivery system applicable to the aforementioned smart copolymer hydrogel composed of a bioactive substance, the system comprising:

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

[0020] Topological conformation analysis module: Receives the environmental parameter vector, constructs a dynamic conformation state matrix, and identifies the switching threshold between shear-induced stretching and collision melting mechanisms;

[0021] Active branched-chain driven module: Self-driven nanoparticles are modified at the ends of the branches to configure the driving mode;

[0022] Drug release logic module: Input environmental parameters and conformational state into the release model. When the cyclotron radius exceeds the preset threshold, the super-diffusion release mode is activated. The porosity is dynamically adjusted through photothermal response. When local damage is detected, a self-repair protocol is triggered, and the activity force and magnetic field gradient are adjusted simultaneously to restore structural integrity.

[0023] This application achieves precise drug delivery based on the lesion microenvironment while simultaneously ensuring the integrity of the carrier structure.

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

[0025] Monitoring unit: Real-time monitoring of the activity intensity, particle density, and rotational diffusion coefficient of the active particle bath, generating an environmental parameter vector;

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

[0027] Regulation unit: Based on the centroid migration trajectory, predict the phase separation rate, map the mesoscale phase separation rate to the macroscopic drug release curve, and correct the differences between in vitro and in vivo environments through transfer learning algorithms.

[0028] This application controls the dynamic mapping of the drug release curve by adjusting the mesoscopic phase separation rate, thereby achieving precise delivery by mimicking the deviation between the simulated and real in vivo environments.

[0029] In conjunction with the second aspect, the topological configuration resolution module includes:

[0030] Conformational state unit: used to calculate the gyration radius, end-to-end distance and shape factor of the star chain in the Brownian dynamics model, and to construct the dynamic conformational state matrix by applying environmental parameter vectors;

[0031] Switching Analysis Unit: Used to analyze the directional driving effect of active noise through probability distribution functions and identify the switching threshold between shear-induced stretching and collision melting mechanisms.

[0032] This application constructs a three-dimensional conformational state matrix by synchronously calculating the gyration radius, end-point distance, and shape factor using Brownian dynamics. Based on the probability distribution function, it quantitatively analyzes the switching critical point between shear-induced stretching and collisional melting mechanisms, thereby achieving accurate prediction of microsecond-level conformational changes.

[0033] In conjunction with the second aspect, the topological configuration resolution module further includes:

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

[0035] Phase separation suppression unit: used to suppress phase separation by triggering ultrasonic cavitation effect when the activity exceeds the critical threshold, thus maintaining a homogeneous porous structure.

[0036] This application achieves accelerated phase separation by promoting layered / columnar phase separation through bidirectional intelligent control of phase separation using a high-frequency pulsed light field; it also constructs an inhibition mechanism by maintaining homogeneous pores through ultrasonic cavitation, thereby achieving dynamic switching of acceleration / inhibition modes based on the conformational state matrix. Compared with traditional techniques, the phase separation structure formation time is improved, and the structure is more stable than a single chain.

[0037] In conjunction with the second aspect, the driving mode includes: random direction driving and driving along the contour tangent direction; wherein, the driving mode is dynamically switched under real-time conformational data, and when the coordination index is lower than the threshold, the magnetic field is activated to guide the reorganization of the branches.

[0038] This application activates magnetic field-oriented recombination when quantifying conformational synergy by using a real-time switching logic between random direction-driven and contour tangent direction-driven approaches, thereby improving the efficiency of branch 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 extension, and detect local strain, respectively.

[0041] The topological conformation analysis module has a built-in machine learning model that predicts conformational evolution paths by training on historical simulation data, optimizes the matching relationship between activity force and 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 mesoscale to the macroscopic drug release curve. It uses a transfer learning algorithm to correct for differences between in vitro and in vivo environments, ensuring dynamic adaptation between porosity and drug release rate.

[0043] The active branch drive 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 between the branch motion direction and 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 cooperative motion mode, enhancing the drug accumulation efficiency in the lesion area, and triggers a pore expansion procedure through metabolic clearance logic to accelerate waste removal.

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

[0046] Other features and advantages of the invention will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the invention. The objects and other advantages of the invention may be realized and obtained by means of the structures particularly pointed out in the written description and the accompanying drawings.

[0047] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0048] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings:

[0049] Figure 1 This is a comparison of the structure of a smart copolymer hydrogel composed of bioactive substances and a traditional hydrogel structure, along with a drug delivery efficiency curve, in an embodiment of the present invention.

[0050] Figure 2 This is a diagram illustrating the composition of the dynamic drug delivery system in an embodiment of the present invention.

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

[0052] Figure 4 This is a diagram showing the composition of the topological configuration analysis module in an embodiment of the present invention. Detailed Implementation

[0053] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0054] Example 1:

[0055] See Figure 1 , Figure 1 In the middle, the top left corner shows the structural diagram of a traditional linear hydrogel, whose drug delivery efficiency is as follows: Figure 1The parallel circuit diagram shown indicates a relatively consistent efficiency during drug delivery. The lower left corner shows the structure of the hydrogel corresponding to this application, where efficiency continuously improves during drug delivery. This application proposes a smart copolymer hydrogel composed of bioactive substances, comprising:

[0056] The star-shaped copolymer core includes multiple branches, which are composed of A blocks and B blocks; wherein, the A block is polyethylene glycol, the B block is polylactic acid-glycolic acid, and the ends of the branches are modified with self-driven Janus nanoparticles.

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

[0058] The star-shaped copolymer core of this application adopts an AB-block branched structure. The combination of the A-block of polyethylene glycol and the B-block of polylactic-co-glycolic acid achieves dynamic phase separation regulation through the attraction-repulsion interaction between the blocks. The multi-branched structure of the star-shaped copolymer core, formed by atom transfer radical polymerization, can improve 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-co-glycolic acid is used to impart controllable degradation and regulate the drug release rate. The non-equilibrium oriented force field of the active particle bath in this application forms a spatial coupling mechanism with the self-driving direction of Janus particles, which solves the problem that the passive response of porosity in traditional hydrogels cannot improve the drug release rate or reduce the repulsion ability.

[0059] Janus nanoparticles modified with branched ends serve as self-driving units, controlling drug delivery through directional driving along the contour tangent via the coupling mechanism between the active direction and the chain structure.

[0060] This application uses Janus nanoparticles as self-driven units, which accelerate polymer chain rearrangement through directional force field coupling in an active particle bath environment, thereby increasing the dynamic response speed of porosity to 300%.

[0061] The B-block combination of the star-shaped copolymer core and 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, and automatically compensates for porosity when degradation accelerates.

[0062] The A-block and Janus nanoparticles form a hydration layer. The autonomous movement of the Janus particles disrupts the continuity of the biomembrane, reduces the biomembrane adhesion resistance, and increases the drug delivery rate by 40%.

[0063] In actual real-time processes, the angle between the propulsion direction of Janus nanoparticles and the force field direction coupled with the directional field of the active particle bath does not exceed 90° but is higher than 45°, driving the branches to produce asymmetric folding.

[0064] The star-shaped copolymer core structure of this application can induce ordered movement of branches, thereby regulating the crosslinking density and mechanical response of the hydrogel network through the driving mechanism of active branches. Compared with traditional linear chains, the non-equilibrium fluctuation characteristics of the star-shaped topology make it easier to form a dynamic adaptive structure in an active environment.

[0065] The porosity regulation of the active particle bath in this application is based on the mechano-thermodynamic synergistic effect between active particles and copolymer chains. The conformational equilibrium of the copolymer chains is altered by the directional collisions or shearing effects of the active particles. Under low activity, particle perturbation promotes interchain phase separation, accelerating self-assembly and leading to a decrease in porosity. Conversely, under high activity, strong mechanical perturbation disrupts phase separation stability, controlling the loosening of the network structure and increasing porosity. The non-monotonic dependence of active particle density on driving force provides a physical basis for the precise control of porosity within the range of 60%–80%.

[0066] Example 2:

[0067] The A and B blocks of this application define the bond length of the branches as 0.5-2.0 nm and the bond angle as 100°-170°. The branches are connected by dynamic covalent bonds, and the critical strain for self-healing is set as 0.15±0.02. In actual implementation, in the active particle bath, the critical strain triggers the self-healing process, and Janus nanoparticles drive the chain rearrangement to restore the bond angle to no less than 95% of the initial value. The specific degree of restoration needs to be combined with the actual situation.

[0068] In this application, the bond length limitation can control the extension degree of the branches and avoid pore blockage caused by entanglement. The bond angle setting can control the direction of the branches and improve the permeability of the diffusion channels of active substances.

[0069] The setting of branch bond lengths (0.5-2.0 nm) and bond angles (100°-170°) allows for dynamic adjustability of the network structure by regulating the balance between the rigidity and flexibility of the chains. Shorter bond lengths (e.g., 0.5 nm) combined with larger bond angles (e.g., 170°) form highly extensible branches, enhancing the mechanical strength of the network; longer bond lengths (2.0 nm) and smaller bond angles (100°) allow for local bending of the branches, improving the inter-chain entanglement effect. For example, in actual implementation, if the bond length is ≤1 nm, a disulfide bond is used in a dynamic covalent position; when the bond length is >1 nm, an imine bond is used.

[0070] Example 3:

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

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

[0073] It maintains a homogeneous pore structure with a pore size distribution variation coefficient ≤15% when the activity intensity is higher than 5.2 kBT / σ.

[0074] The variation coefficients for layer thickness and pore size distribution in this application are designed to prevent the uniformity of pore structures in traditional hydrogels. Therefore, a customized biomimetic hierarchical structure is required to control the directional migration of cells with enhanced heterogeneous structures under active conditions without structural instability.

[0075] In practical implementation, this application sets a phase separation threshold of 5.2 kBT / σ to control the activity force below the critical value Fac. When the activity force is below the critical value Fac, the active particles enhance the inter-block interaction effect and form a layered / columnar structure through the microphase separation dynamics accelerated by spatial fluctuations. If the activity force exceeds Fac, the active particles will collide with the dominant system to dissipate energy, thereby destroying the long-range order.

[0076] Example 4:

[0077] When active force is applied along the tangential direction of the branch profile in the self-driven Janus nanoparticles of this application, the branch extension increases and the centroid migration rate is enhanced. The effect is that the force field direction is parallel to the branch direction, avoiding chain entanglement. Combined with the structure of the star copolymer core, the efficiency of branch synergistic extension is improved. In the case of centroid migration, combined with the active particle bath, the dynamic response time of porosity can be shortened.

[0078] When a self-driven Janus particle is subjected to an active force along the tangential direction of the branch profile, the direction of its driving force is matched with the local curvature of the chain conformation.

[0079] The increase in branch extension is due to the continuous energy input of tangential driving force: the motion direction of Janus particles forms a positive feedback with the conformational evolution of branches—branch extension reduces local curvature.

[0080] Example 5:

[0081] This application proposes a dynamic drug delivery system applicable to the aforementioned smart copolymer hydrogel containing a bioactive substance. (See attached document.) Figure 2 The system includes:

[0082] Active microenvironment sensing module: used to acquire environmental parameter vectors of copolymer hydrogel when the target drug uses copolymer hydrogel as a carrier; this application implements the acquisition of parameter vectors such as pH value, temperature, enzyme concentration, etc. In this process, the main hardware for acquiring environmental parameter vectors can be a micro-sensor array 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 threshold between 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 thresholds by identifying the shear force and the intensity of 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 driven module: Self-driven nanoparticles are modified at the ends of the branches to configure the driving mode; the main driving modes configured in this application include dual-mode driving of magnetic field gradient and chemical gradient, realizing delay switching. In the specific implementation process, the delay is less than 2 seconds. The magnetic field formed on the surface of Janus particles can realize the triggering of the drive.

[0085] The drug release logic module inputs environmental parameters and conformational state into the release model. When the cyclotron radius exceeds a preset threshold, a super-diffusion release mode is activated, dynamically adjusting porosity through photothermal response. Specifically, when local damage is detected, a self-repair protocol is triggered, simultaneously adjusting the activity and magnetic field gradients to restore structural integrity. During drug release, when the cyclotron radius exceeds the preset threshold, the super-diffusion release mode is activated, initiating a near-infrared photothermal response, instantly increasing porosity. The self-repair protocol, after damage detection, synchronously adjusts the ATP concentration and corresponding magnetic field gradient to achieve self-repair. In practice, electrical impedance tomography (EIT) is used to locate the area requiring repair, and repair factors are injected via a microfluidic pump to achieve repair.

[0086] The active microenvironment sensing module of this application is based on the conformation-environment coupling characteristics of star-shaped copolymer branches. Specific conformation-environment coupling characteristics include the selective swelling of A / B blocks in response to pH and temperature. In practical implementation, this application monitors the dynamic changes of the radius of gyration (Rg) and shape factor (S) during execution, capturing the chemical gradient of the target tissue microenvironment in real time, such as the acidic environment of a tumor. Specifically, environmental parameter vectors encode the local state of the active particle bath, such as Fa and ρ. This application uses the previously established conformation-kinetic correlation equation (Rg∝Fa^α) to determine the inputs in the control process based on inverse analysis of the microenvironment perturbation intensity.

[0087] The topological conformation analysis module in this application constructs deviation characteristics based on the non-equilibrium scaling law through a dynamic conformation state matrix. The shear-induced stretching mechanism in this application corresponds to the directional deformation of the chain at low Dr, specifically related to the MSAD angular displacement, through a collisional melting mechanism. Specifically, at high Dr, it corresponds to the random fluctuations of the chain segments, specifically related to the MSD super-diffusion decay. The switching threshold is identified by analyzing the causal relationship between the kinetic energy of active particles and chain conformation fluctuations. When the contribution of mechanical disturbance exceeds that of thermodynamic disturbance, such as in the Fac determination in previous phase separation studies, the switching mechanism is triggered to ensure that the control strategy matches the physical mechanism.

[0088] The active branched-chain driven module, in this application, configures the driving mode of the self-driven nanoparticles based on the heterogeneous surface characteristics of Janus particles, specifically including:

[0089] In stochastic-driven mode, isotropic active forces are used to enhance drug diffusion and penetration, and biomembrane barriers are destroyed based on collisional melting mechanisms.

[0090] In tangential-driven mode, anisotropic active forces are used for directional migration, utilizing centroid superdiffusion to cross the intervascular wall space.

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

[0092] Example 6:

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

[0094] The monitoring unit of this application can monitor the activity 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 active particles and copolymer chains. For example, in 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 intensity of activity is detected by utilizing the chemotactic response of Janus particles, such as the linear relationship between velocity and Fa.

[0097] 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 considering the particle orientation-dependent time, specifically the anisotropic decay of fluorescence, to determine the rotational diffusion coefficient in the dynamic light scattering process.

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

[0100] FRET conformational analysis involves labeling the A / B block interface of a star-shaped chain with donor-acceptor fluorophores. If the branch extension leads to a decrease in FRET efficiency, it can be determined that the chain conformation changes from a globular to a coiled state. The transition data during the transition process is directly related to the cyclotron radius threshold-triggered release in previous simulations. In the specific implementation of this application, nanoscale chain folding is captured by FRET, macroscopic migration is located by MPI, and the data from both are then fused to achieve modeling, which has a multi-scale effect.

[0101] The magnetic Janus grain of this application uses dipole moment-spatial coding characteristics to reconstruct the trajectory of the centroid motion through the MPI signal intensity-phase relationship. Combined with the superdiffusion model, it is used for reverse analysis of the driving mode and for switching the driving mode.

[0102] The regulatory unit of this application predicts the phase separation rate based on the centroid migration trajectory, maps the mesoscopic phase separation rate to the macroscopic drug release curve, and corrects the differences between the in vitro and in vivo environments through a transfer learning algorithm.

[0103] Specifically, this application establishes a phase separation rate equation through mesoscale 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 real-time input environmental parameters, it predicts the growth rate of the layered phase. In this 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 100 nm, a continuous percolation channel is formed, and the release rate increases sharply. By constructing an in vitro-in vivo feature migration network, the low-dimensional data such as the active force intensity, particle density and rotational diffusion coefficient monitored in vitro are aligned with multimodal data such as in vivo MRI images and tissue elasticity. Combined with the domain adaptation algorithm to compensate for blood flow shear force, the interference on phase separation dynamics is reduced.

[0104] Example 7:

[0105] See Figure 4 The topological conformation resolution module of this application includes:

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

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

[0108] In practical implementation, the calculation of the gyration radius (Rg) and end distance (Re) is performed using the multibody correlation integral method: Rg^2=(1 / 2N 2 )Σ<(r_i-r_j) 2 This leads to dynamic evolution and vitality intensity, exhibiting a power-law scaling in specific effects. In the calculation process, the shape factor S = <Rg 2 > / <Re 2 The introduction of the '>' parameter effectively distinguishes the topological states of the chain: S≈0.3 corresponds to a compact spherical conformation, i.e., collisional melting is dominant; S>0.6 indicates an extended coil state, i.e., shear stretching is dominant. The dynamic conformational state matrix can be mapped to the percolation threshold model of drug release rate by updating the three-dimensional phase space coordinates of Rg, Re, and S in real time, thereby achieving drug delivery control.

[0109] In practical implementation, the switching analysis unit of this application analyzes the directional driving effect of active noise through probability distribution function to identify the switching threshold between shear-induced stretching and collision melting mechanisms.

[0110] The specific probability distribution function (PDF) is used to analyze focusing activity noise, thereby achieving a directional driving effect:

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

[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 PDF morphological differences. When the KL distance between the two mechanisms exceeds the critical value (D_KL≥1.2bit), mechanism switching is triggered.

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

[0115] This application combines a three-dimensional conformation matrix with active noise analysis, i.e., by using initial state parameters to reduce noise perturbation intensity, thereby jointly reducing computational complexity. Through shape factor and self-healing protocol, the self-healing function is triggered upon the occurrence of abrupt changes, earlier than damage occurs, reducing the misjudgment of damage.

[0116] Example 8:

[0117] See Figure 4 The topological conformation resolution module of this application also includes:

[0118] The phase separation monitoring unit of this application determines the phase separation process based on the conformational state matrix. When a layered or columnar phase separation morphology is detected, a high-frequency pulsed light field is activated to accelerate structure formation.

[0119] In the specific implementation process, the B block, mainly polylactic acid-hydroxyacetic acid, contains conjugated groups that can selectively absorb photons, thereby increasing the local temperature rise and controlling the enhanced chain segment mobility. In the specific implementation, the glass transition temperature Tg is dynamically reduced, which can accelerate the phase domain coarsening kinetics.

[0120] In this application, pulsed light field excites the A block. Since polyethylene glycol is mainly present, the nitrobenzene ester group at the end undergoes a [2+2] ring addition reaction. At the phase interface, a dynamic covalent network can be formed, thereby locking the size (50-200nm) of the layered / columnar phase domains and their orientation along the polarization direction of the light field. This can prevent overgrowth caused by Ostwald ripening.

[0121] The phase separation suppression unit of this application is used to trigger ultrasonic cavitation effect to suppress phase separation when the activity exceeds the critical threshold, maintain a homogeneous pore structure, and generate microjets through ultrasonic control to break the pre-ordered structure, thereby achieving the effect of maintaining a homogeneous pore structure.

[0122] Example 9:

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

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

[0125] If real-time conformational data indicates that the side chain is in a compact folded state, it will induce local melting of the chain segment through a random-driven mode combined with Brownian collisions of Janus particles, thereby promoting the diffusion of drug molecules from the dense core to the outside.

[0126] In this application, under low cooperative state, the magnetic field gradient applies magnetic moment orientation force through the magnetic components of Janus particles, inducing the reorganization of branches along the direction of magnetic field lines.

[0127] In this application, the dual-mode switching can randomly drive nucleation, and then the corresponding tangential driving acceleration of molecular chain orientation can be determined by phase separation monitoring, thereby increasing the speed of layered structure formation.

[0128] Example 10:

[0129] The system in this application also includes:

[0130] The active microenvironment sensing module of this 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 used to identify chemical bonding states, track chain extension, and detect local strain, respectively. Through the multimodal sensor array, chemical bonds and local strain can be monitored simultaneously. The PVDF piezoelectric film detects micro-strain, thereby realizing the detection of chemical bonding states, tracking chain extension, and local strain. The piezoelectric sensor array is embedded in a 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, it outputs the matching of the activity force and the diffusion coefficient, optimizes the matching relationship between the activity force and the rotational diffusion coefficient in real time, and generates the correction parameters of the dynamic conformational state matrix.

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

[0133] The active branch drive 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 between the branch motion direction and the preset path is minimized.

[0134] The drug release logic module of this application integrates a target recognition unit. When a specific biomarker is identified by near-infrared imaging, the branched cooperative motion mode is activated to enhance the enrichment efficiency of the drug in the lesion area. The metabolic clearance logic triggers a pore expansion procedure to accelerate waste clearance.

[0135] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A smart copolymer hydrogel composed of bioactive substances, characterized in that, include: The star-shaped copolymer core includes multiple branches, which are composed of A blocks and B blocks; wherein, the A block is polyethylene glycol, the B block is polylactic acid-glycolic acid, and the ends of the branches are modified with self-driven Janus nanoparticles. A star-shaped copolymer core is configured in an active particle bath environment to generate a copolymer hydrogel; wherein, the porosity is controlled within the range of 60% to 80% by the change in the activity intensity in the active particle bath environment. The bond lengths of the branches of the A and B blocks are 0.5-2.0 nm, the bond angles are 100°-170°, and the branches are connected by dynamic covalent bonds. The critical strain that triggers self-healing is 0.15±0.

02. The active particle bath environment is configured with a phase separation threshold; wherein, the phase separation threshold is 5.2 kBT / σ; When the activity intensity is less than 5.2 kBT / σ, a layered or columnar phase separation morphology is formed, with a layer thickness of 50-200 nm; It maintains a homogeneous pore structure with a pore size distribution variation coefficient ≤15% when the activity intensity is higher than 5.2kBT / σ.

2. The smart copolymer hydrogel composed of bioactive substances as described in claim 1, characterized in that, When active forces are applied along the tangential direction of the branch profile, the self-driven Janus nanoparticles exhibit increased branch extension and enhanced centroid migration rate.

3. A dynamic drug delivery system, applicable to a smart copolymer hydrogel composed of a bioactive substance according to any one of claims 1 to 2, characterized in that, The system includes: Active microenvironment sensing module: used to acquire the environmental parameter vector of the copolymer hydrogel when the target drug uses the copolymer hydrogel as a carrier; Topological conformation analysis module: Receives the environmental parameter vector, constructs a dynamic conformation state matrix, and identifies the switching threshold between shear-induced stretching and collision melting mechanisms; Active branched-chain driven module: Self-driven nanoparticles are modified at the ends of the branches to configure the driving mode; Drug release logic module: Input environmental parameters and conformational state into the release model. When the cyclotron radius exceeds the preset threshold, the super-diffusion release mode is activated. The porosity is dynamically adjusted through photothermal response. When local damage is detected, a self-repair protocol is triggered, and the activity force and magnetic field gradient are adjusted simultaneously to restore structural integrity.

4. A dynamic drug delivery system as described in claim 3, characterized in that, The active microenvironment sensing module includes: Monitoring unit: Real-time monitoring of the activity intensity, particle density, and rotational diffusion coefficient of the active particle bath, generating an environmental parameter vector; Trajectory tracking unit: Detects conformational changes in copolymer chains through fluorescence resonance energy transfer and tracks the centroid migration trajectory of star-shaped chains using magnetic particle imaging; Regulation unit: Based on the centroid migration trajectory, predict the phase separation rate, map the mesoscale phase separation rate to the macroscopic drug release curve, and correct the differences between in vitro and in vivo environments through transfer learning algorithms.

5. A dynamic drug delivery system as described in claim 3, characterized in that, The topological configuration resolution module includes: Conformational state unit: used to calculate the gyration radius, end-to-end distance and shape factor of the star chain in the Brownian dynamics model, and to construct the dynamic conformational state matrix by applying environmental parameter vectors; Switching Analysis Unit: Used to analyze the directional driving effect of active noise through probability distribution functions and identify the switching threshold between shear-induced stretching and collision melting mechanisms.

6. A dynamic drug delivery system as described in claim 5, characterized in that, The topological configuration resolution module also includes: Phase separation monitoring unit: used to determine the phase separation process based on the conformational state matrix; when a layered or columnar phase separation morphology is detected, a high-frequency pulsed light field is activated to accelerate structure formation. Phase separation suppression unit: used to suppress phase separation by triggering ultrasonic cavitation effect when the activity exceeds the critical threshold, thus maintaining a homogeneous porous structure.

7. A dynamic drug delivery system as described in claim 3, 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 when the coordination index is lower than the threshold, the magnetic field is activated to guide the reorganization of the branches.

8. A dynamic drug delivery system as described in claim 3, characterized in that, The system also includes: 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 extension, and detect local strain, respectively. The topological conformation analysis module has a built-in machine learning model that predicts conformational evolution paths by training on historical simulation data, optimizes the matching relationship between activity force and rotational diffusion coefficient in real time, and generates correction parameters for the dynamic conformational state matrix. The active branch drive module generates an asymmetric driving force through the synergistic magnetic and photothermal responsiveness of Janus-type nanoparticles. The tangential direction deviation is corrected in real time by the curvature sensing unit to ensure that the deviation between the branch motion direction and 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 cooperative motion mode, enhancing the drug accumulation efficiency in the lesion area, and triggers a pore expansion procedure through metabolic clearance logic to accelerate waste removal.

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