Injectable Thermosensitive Gels: Gelation Behavior, Rheological Properties, and Drug Release Characteristics

Injectable thermosensitive gels are drug delivery systems that remain flowable before injection, undergo in situ gelation near physiological temperature, and form a local drug depot. The technical focus is not merely whether gelation can be induced by heating, but whether continuous and predictable formulation behavior can be established across injection handling, local retention, and drug release. Accordingly, gelation behavior, rheological properties, and drug release characteristics should be analyzed within an integrated technical framework.

Keywords: injectable thermosensitive gel; Pluronic F-127; chitosan; PLGA-PEG-PLGA; gelation behavior; rheological properties; drug release characteristics; in situ gelation

1. Major Injectable Thermosensitive Gel Systems

1.1 Poloxamer-Based Systems

(1) Background

Pluronic F-127 (Poloxamer 407, P407) is one of the most classical representative materials used in injectable thermosensitive gels and belongs to the PEO-PPO-PEO triblock copolymer family. This system remains in solution at low temperature and undergoes a sol-gel transition near physiological temperature due to dehydration of hydrophobic segments, micelle formation, and micellar packing.

(2) Key Characteristics

① Clear thermoresponsive behavior, with relatively straightforward system establishment.

② Good low-temperature fluidity, suitable for withdrawal and injection.

③ Gelation is mainly driven by physical association and does not depend on chemical crosslinking.

(3) Major Advantages

① Relatively low barriers to formulation development, making it suitable as a basic platform for in situ gelation research.

② Certain micellar loading capacity for hydrophobic small molecules.

③ Widely used in local drug delivery, intracavitary administration, and model system construction.

(4) Major Limitations

① Mechanical strength is usually limited when used alone.

② Sensitive to dilution by biological fluids, often resulting in insufficient local shape retention and residence time.

③ Relatively limited ability to control the release of hydrophilic small molecules, with a tendency toward initial burst release.

(5) Suitable Applications

More suitable as a short- to medium-term local drug delivery platform or as a basic framework for composite thermosensitive gels.

1.2 Chitosan-Based Systems

(1) Background

Chitosan and its salt forms, as well as derivative systems with different molecular weights and degrees of deacetylation, constitute an important platform in the study of natural polymer-based thermosensitive gels. In thermosensitive systems, its role extends beyond the formation of a viscous network and also involves charge shielding, hydrogen bond rearrangement, and enhanced chain association.

(2) Key Characteristics

① Gelation behavior is influenced not only by temperature, but also closely by pH, ionic strength, and compatible components.

② Raw material molecular weight, degree of deacetylation, and viscosity grade can markedly affect the rheological window.

③ More suitable for combination with β-glycerophosphate, poloxamers, or functional polymers.

(3) Major Advantages

① Good biocompatibility.

② Better suitability for local tissue repair, protein delivery, and adhesive drug delivery platforms.

③ Precursor viscosity and post-gel network strength can be adjusted relatively flexibly through variation in molecular weight and degree of substitution.

(4) Major Limitations

① Strong environmental sensitivity, with system reproducibility being more dependent on raw material consistency.

② The thermosensitive window of simple chitosan systems is generally less intuitive than that of poloxamer systems.

③ High-viscosity or high-molecular-weight materials may strengthen the network, but can also significantly increase injection resistance.

(5) Suitable Applications

Suitable for local tissue repair, delivery of bioactive molecules, and construction of composite thermosensitive system frameworks.

1.3 Modified Chitosan Systems

(1) Background

Modified materials such as carboxymethyl chitosan, carboxylated chitosan, methacrylated chitosan, and methacrylated carboxymethyl chitosan represent an important direction in the transition of chitosan systems toward designable thermosensitive platforms. Their value lies not in simply replacing chitosan, but in improving water solubility, expanding structural tunability, and enhancing the capacity for composite network formation.

(2) Key Characteristics

① Water solubility and formulation uniformity are usually better than those of native chitosan.

② Gelation and rheological behavior can be tuned through degree of substitution, labeling level, and viscosity range.

③ More readily forms composite networks with other scaffold materials.

(3) Major Advantages

① Beneficial for improving system tunability and formulation optimization flexibility.

② Can simultaneously address thermosensitivity, local adhesiveness, and network stability.

③ Better suited for constructing composite platforms that combine gelation with subsequent structural reinforcement.

(4) Major Limitations

① More material variables and more complex evaluation dimensions.

② Batch-to-batch consistency and control of the degree of modification have more pronounced effects on results.

③ Improper system design may lead to a broadened gelation window, slower structural recovery, or increased injection resistance.

(5) Suitable Applications

Suitable for systems requiring enhanced local adhesion, improved network stability, or functionalized drug delivery design.

1.4 PEG-Polyester Block Copolymer Systems

(1) Background

Block copolymers such as PEG-PLA, PEG-PLGA, and PLGA-PEG-PLGA are important representatives of biodegradable thermosensitive gels. These systems combine thermally induced gelation with degradable network evolution and are more suitable for medium- to long-term local sustained release design.

(2) Key Characteristics

① Gelation usually involves amphiphilic chain rearrangement and microphase separation.

② Post-gel structural retention is generally better than that of simple poloxamer systems.

③ Late-stage drug release is often governed by both diffusion and degradation.

(3) Major Advantages

① Better suited for constructing medium- to long-term local drug depots.

② Degradation and drug release pathways can be modulated through the LA/GA ratio, molecular weight, and block length.

③ Helps reduce the rapid erosion commonly seen in simple physical gel systems.

(4) Major Limitations

① Greater complexity in material design and quality control.

② Different block ratios significantly affect gelation temperature, degradation rate, and late-stage drug release.

③ Formulation development is generally more difficult than for simple physically associated systems.

(5) Suitable Applications

Suitable for medium- to long-term local sustained release, prolonged postoperative drug delivery, and in situ gel platforms requiring relatively stable structural retention.

1.5 Composite Reinforced and Functionalized Systems

(1) Background

In practical development, a single thermosensitive scaffold often cannot simultaneously meet the requirements for gelation rate, mechanical stability, and drug release precision. Therefore, inorganic particles, GelMA-type functional materials, or other composite components are commonly introduced to reinforce the network.

(2) Key Characteristics

① Composite components can increase modulus, improve shape retention, and regulate pore structure.

② The release mechanism shifts from simple diffusion control to combined control by diffusion, network evolution, and interfacial interactions.

③ These systems are closer to actual formulation development scenarios.

(3) Major Advantages

① Improved post-gel structural stability.

② Beneficial for enhancing local residence and modulating the release profile.

③ Better suited for constructing multifunctional local drug delivery platforms.

(4) Major Limitations

① Increased system complexity.

② Particle incorporation may increase injection resistance.

③ Nonlinear coupling may occur among different modules, making evaluation more difficult.

(5) Suitable Applications

Suitable for system design with higher requirements for mechanical reinforcement, local adhesion, long-acting drug release, or functional integration.

Table 1. Comparison of Major Injectable Thermosensitive Gel Systems

System Type	Representative Materials	Basis of Gelation	Major Advantages	Major Limitations	More Suitable Direction
Poloxamer-based system	Pluronic F-127 / P407	Micelle formation and micellar packing	Clear thermoresponsiveness and good low-temperature fluidity	Limited mechanical strength and susceptibility to dilution	Short- to medium-term local drug delivery
Chitosan-based system	Chitosan, chitosan hydrochloride	Temperature-responsive chain association, charge rearrangement, and hydrogen bond reorganization	Good biocompatibility and suitability for composite design	Environmentally sensitive, with reproducibility dependent on raw materials	Tissue repair and bioactive molecule delivery
Modified chitosan system	Carboxymethyl chitosan, CSMA, CMCSMA	Thermoresponsive behavior after modification and composite network formation	Better water solubility and tunability	More variables and more complex evaluation	Functionalized local drug delivery
PEG-polyester system	PLGA-PEG-PLGA	Amphiphilic chain rearrangement and degradable network formation	Suitable for medium- to long-term sustained release	Complex material design and quality control	Sustained local drug delivery
Composite reinforced system	GelMA, silica particles, etc.	Synergistic network formation between thermosensitive scaffold and reinforcing modules	Easier optimization of mechanics and drug release	Increased system complexity	High-performance local drug delivery platforms

2. Gelation Behavior

2.1 Driving Forces for Gelation

(1) Dehydration and Aggregation of Hydrophobic Segments

For poloxamers and most amphiphilic block copolymers, hydration of hydrophobic segments weakens upon heating, and the system progressively evolves from a dispersed state to micellization and then to a continuous network state. This is the most typical gelation basis for injectable thermosensitive gels.

(2) Rearrangement of Hydrogen Bonding, Charge, and Chain Association

For chitosan and its modified systems, gelation depends not only on temperature elevation, but also on charge shielding, hydrogen-bond networks, and changes in chain conformation. Therefore, the gelation behavior of these systems shows stronger environmental dependence.

(3) Synergistic Establishment of Composite Networks

In composite systems, interactions among the primary gelling scaffold, functional polymers, and particulate components collectively determine the rate of network formation and the integrity of the final structure. Accordingly, gelation often shows pronounced formulation dependence.

2.2 Gelation Window

(1) Pre-Injection Flow Window

The system should maintain controllable flowability during storage, withdrawal, and passage through the needle. If marked thickening already occurs at room temperature, the operating window is substantially narrowed.

(2) Post-Injection Gelation Window

After entering the body, the material should establish a continuous network within a short period. If gelation is too slow, the precursor solution may diffuse into surrounding tissues, resulting in an ill-defined local drug depot boundary.

(3) Post-Gel Stability Window

Effective gelation is not equivalent to effective retention. If the gel rapidly swells, is diluted, or erodes after formation, its capacity for local retention and release control remains limited.

2.3 Major Factors Affecting Gelation

(1) Polymer Concentration

An increase in concentration generally enhances the probability of chain contact and association, accelerates gelation, and increases modulus, but also raises injection resistance.

(2) Molecular Weight, Viscosity, and Degree of Substitution

For chitosan-based materials, molecular weight, viscosity grade, degree of deacetylation, and degree of substitution directly determine precursor flowability, the thermal response window, and post-gel network strength.

(3) Compatible Components and Drug-Loaded State

Drug molecules, salt ions, buffer systems, and reinforcing particles may all alter gelation behavior. The gelation behavior of drug-loaded systems cannot be simply extrapolated from blank matrices.

Table 2. Differences in Gelation Behavior Among Typical Systems

System Type	Driving Force for Gelation	Tunability of Gelation Temperature	Pre-Injection Flowability	Post-Gel Structural Retention	Environmental Sensitivity
Poloxamer-based system	Micellization and packing	Good	Good	Moderate	Sensitive to dilution
Chitosan-based system	Temperature + charge + hydrogen bonding	Moderate	Moderate	Moderate	Sensitive to pH and salts
Modified chitosan system	Chain association after modification and composite network formation	Good	Moderately good	Good	Related to degree of substitution
PEG-polyester system	Amphiphilic chain rearrangement	Good	Good	Good	Sensitive to molecular structure
Composite reinforced system	Synergy of multiple interactions	Designable	Formulation-dependent	Good	Highest number of system variables

3. Rheological Properties

3.1 Core Rheological Parameters

(1) Storage Modulus G′ and Loss Modulus G″

G′ reflects the elastic energy storage capability of the system, whereas G″ reflects viscous dissipation behavior. During thermally induced gelation, the system usually shifts from G″-dominant behavior to G′-dominant behavior, indicating a transition from a flow-dominated state to an elasticity-dominated state.

(2) Apparent Viscosity

Viscosity is a direct parameter for evaluating injectability. Its significance lies not only in the absolute value, but also in whether its response to temperature variation and high-shear conditions is stable and predictable.

(3) Structural Recovery Capability

High shear during injection can disrupt the local network. The ability to recover rapidly after shear removal is a key indicator of whether a local drug depot can be re-established after injection.

3.2 Rheological Features Directly Related to the Injection Process

(1) Shear-Thinning

A decrease in viscosity under high shear helps reduce resistance during needle passage and is one of the important advantages of injectable thermosensitive gels.

(2) Rapid Recovery

If the network rebounds rapidly after injection, it is more favorable for reducing leakage and stabilizing local morphology.

(3) Thermally Induced Modulus Transition

An ideal system should show a clear and reproducible modulus increase near the target temperature, rather than slow and dispersed continuous thickening.

3.3 Rheological Targets of Different Systems

(1) Poloxamer-Based Systems

The focus is on increasing post-gel modulus, reducing sensitivity to dilution by biological fluids, and prolonging local residence without substantially sacrificing injectability.

(2) Chitosan and Modified Chitosan Systems

The focus is on stabilizing the gelation window, reducing the influence of environmental fluctuations, and optimizing injectability and structural recovery through molecular weight, degree of substitution, and blending relationships.

(3) PEG-Polyester Systems

The focus is on balancing pre-injection flowability, post-gel structural stability, and consistency of medium- to long-term drug release.

(4) Composite Reinforced Systems

The focus is on maintaining acceptable injection resistance and good post-shear recovery after the introduction of reinforcing modules.

4. Drug Release Characteristics

4.1 Mechanisms of Release Control

(1) Diffusion Control

For most small-molecule drugs, early-stage release is usually dominated by pore diffusion. The denser the network, the lower the drug migration rate is generally.

(2) Swelling and Erosion Control

Physically crosslinked thermosensitive gels often continue to absorb water, swell, and undergo chain exchange in biological fluids. Therefore, the release process is often jointly determined by diffusion and matrix evolution.

(3) Degradation Control

For degradable systems such as PLGA-PEG-PLGA, late-stage release is usually governed simultaneously by diffusion and main-chain degradation.

(4) Drug-Matrix Interaction Control

Hydrophobic interactions, electrostatic adsorption, and hydrogen bonding can markedly affect drug retention and release rate, and are particularly important for protein and peptide cargos.

4.2 Release Characteristics of Different Systems

(1) Poloxamer-Based Systems

These systems more readily provide micellar loading for hydrophobic small molecules, whereas hydrophilic small molecules are more prone to initial burst release.

(2) Chitosan and Modified Chitosan Systems

These systems more readily provide a degree of local microenvironmental protection, but release behavior is often jointly influenced by electrostatic interactions, network rearrangement, and local adhesion.

(3) PEG-Polyester Systems

These systems are more likely to form medium- to long-term release profiles, with late-stage release commonly showing parallel contributions from diffusion and degradation.

(4) Composite Reinforced Systems

After the incorporation of particulate reinforcement modules or functional scaffolds, drug release is no longer determined only by gel pore structure, but instead reflects the combined control of diffusion, network evolution, and interfacial interactions.

4.3 Coupling Relationships Among Gelation, Rheology, and Drug Release

(1) Gelation Rate and Initial Burst Release

The faster the gelation, the more favorable it is generally for reducing precursor leakage and early drug release after administration.

(2) Modulus and Release Rate

A higher G′ usually indicates stronger network confinement, but this does not automatically mean slower release. If subsequent erosion is pronounced, drug release may still accelerate.

(3) Structural Recovery and Sustained Release

The faster the recovery after injection, the more favorable it is for establishing an intact drug depot and achieving a more stable release profile.

Table 3. Differences in Drug Release Characteristics Among Typical Systems

System Type	Main Release Control	Risk of Initial Burst Release	Potential for Long-Acting Release	More Suitable Cargo Type
Poloxamer-based system	Diffusion + erosion	Moderately high	Moderate	Hydrophobic small molecules
Chitosan-based system	Diffusion + network rearrangement	Moderate	Moderate	Proteins, peptides, repair factors
Modified chitosan system	Diffusion + adhesion/local retention	Moderate	Good	Bioactive molecules
PEG-polyester system	Diffusion + degradation	Low to moderate	Good	Medium- to long-term local drug delivery
Composite reinforced system	Diffusion + network evolution + interfacial interactions	Design-dependent	Good	Complex cargos and combination therapy

5. Materials and Products Related to Injectable Thermosensitive Gels

Table 4. Common Basic Materials Used in Injectable Thermosensitive Gel Research

Name	CAS No.	Applicable System/Experimental Stage	Key Use	Notes for Use
Poloxamer 407 (Pluronic F-127)	9003-11-6	F-127 primary gelling systems	Constructs the classical injectable thermosensitive gel framework; used in in situ gelation, local administration, and micellar loading studies of hydrophobic drugs	Usually prepared under low-temperature conditions; concentration directly affects gelation temperature, injection resistance, and initial burst release
Poloxamer 188	9003-11-6	Poloxamer blend systems	Regulates the gelation temperature, low-temperature flowability, and injection handling of F-127 systems	More commonly used as an excipient in blends rather than alone as the primary gelling scaffold
Sodium β-glycerophosphate	13408-09-8	Chitosan/β-GP systems	Co-establishes a thermosensitive gelation environment with chitosan; regulates ionic strength and the gelation window	Addition rate and pH control markedly affect gelation reproducibility
Hydroxypropyl methylcellulose (HPMC)	9004-65-3	Blended thickening/structural reinforcement	Increases system viscosity and post-gel structural retention; compensates for the insufficient modulus of F-127 used alone	Excessive use may increase injection resistance and should be optimized together with gelation temperature and injectability
Methylcellulose	9004-67-5	Cellulose derivative systems	Used as a thermosensitive or auxiliary gelling component to improve viscoelasticity and morphology retention	More suitable as a blended component and should not simply replace the primary gelling material at high concentration
Gelatin	9000-70-8	Natural polymer composite systems	Used to construct composite gel networks combining thermosensitivity and tissue compatibility	Batch variation and the effect of temperature on sol-state stability should be considered
Sodium hyaluronate	9067-32-7	Adhesive/repair-oriented composite systems	Improves local adhesion, water retention, and tissue microenvironment compatibility; commonly used in repair-oriented composite gels	More suitable as a functional component combined with F-127, chitosan, or related materials
Sodium alginate	9005-38-3	Composite network systems	Enhances network integrity and modulates release pathways; suitable for composite gels or particle-gel systems	Not typically a primary thermosensitive system by itself and is commonly used together with thermosensitive scaffolds
Polyethylene glycol (PEG)	25322-68-3	Precursors/modification of PEG-polyester systems	Used to construct precursors for thermosensitive biodegradable systems such as PEG-PLA and PEG-PLGA; improves hydrophilicity and chain balance	Molecular weight selection directly affects gelation temperature, degradation rate, and release behavior
Lactic acid	50-21-5	Polyester precursors/material design	Used as part of the material design background for PLA- or PLGA-related biodegradable thermosensitive systems	More relevant to material synthesis and system origin studies and is not directly used as a gelling excipient
Glycolic acid	79-14-1	Polyester precursors/material design	Used as part of the material design background for PLGA-type biodegradable thermosensitive systems	Changes in the lactic acid/glycolic acid ratio affect degradation rate and late-stage release behavior
Polycaprolactone (PCL)	24980-41-4	PEG-PCL-PEG-type systems	Constructs degradable thermosensitive networks with stronger hydrophobic segments, helping prolong local residence and regulate release	More suitable for medium- to long-term sustained release design; attention should be paid to the prolonged residual period caused by slower degradation
N-Isopropylacrylamide (NIPAM)	2210-25-5	PNIPAM-modified systems	Constructs LCST-type thermoresponsive materials for responsive gel studies	More suitable for mechanistic research or as a comonomer; practical medical systems usually require further composite modification
Sodium bicarbonate	144-55-8	pH/buffer adjustment	Adjusts the initial formulation pH and local buffering environment to assist in optimizing gelation conditions in chitosan-based systems	Should be designed in coordination with the ionic environment of the primary system to avoid pH drift affecting gelation reproducibility

Table 5. Products Related to the Construction and Performance Optimization of Injectable Thermosensitive Gels

Catalog No.	Name	Grade and Purity	Applicable Research Direction/Use
P1440364	PLGA-PEG-PLGA (1500-1500-1500) (LA/GA 15:1)	—	Suitable as a biodegradable primary thermosensitive gelling material for medium- to long-term local sustained release and studies on drug release governed by both diffusion and degradation
P1444975	PLGA-PEG-PLGA (1500-1500-1500) (LA/GA 1:1)	—	Suitable for comparing the effects of different LA/GA ratios on gelation behavior, degradation rate, and late-stage release acceleration
C434553	Chitosan	High molecular weight	Suitable as a basic scaffold for chitosan-based thermosensitive systems to improve post-gel network strength and local residence
C434554	Chitosan	From shrimp shell, practical grade	Suitable for basic formulation screening and process validation experiments
C434547	Chitosan	Low molecular weight	Suitable for reducing system viscosity, improving injectability, and comparing the effects of molecular weight on gelation temperature and rheological behavior
C105802	Chitosan	Medium viscosity, 200-400 mPa.s	Suitable for constructing chitosan thermosensitive formulations that balance injection flowability and post-gel structural retention
C105799	Chitosan	Degree of deacetylation ≥95%, viscosity 100-200 mPa.s	Suitable for studying the effects of degree of deacetylation on the gelation window, ionic response, and local adhesion
C105801	Chitosan	Low viscosity: <200 mPa.s	Suitable for injectable formulations in which needle passage and low-temperature flowability are prioritized
C105803	Chitosan	High viscosity, >400 mPa.s	Suitable for strengthening post-gel network integrity and local shape retention, but injection resistance requires particular attention
B304452	Chitosan hydrochloride	Degree of deacetylation 80.0%-90.0%	Suitable for improving precursor solubility in chitosan systems and evaluating the effects of salt form changes on gelation and drug release
C105800	Carboxylated chitosan	BioReagent, water-soluble	Suitable for constructing water-soluble modified chitosan-based composite thermosensitive systems and improving formulation uniformity and precursor stability
C1501897	Carboxymethyl chitosan	Endotoxin <0.25 EU/mg	Suitable for composite thermosensitive gels and local drug delivery studies with relatively high biocompatibility requirements
C1501899	Carboxymethyl chitosan	Endotoxin <0.05 EU/mg	More suitable for cell- or tissue-related thermosensitive gel studies and experimental systems requiring a low-endotoxin background
C304738	Carboxymethyl chitosan	BioReagent	Suitable as a routine research-grade material for modified chitosan-based thermosensitive systems
C684377	carboxymethyl chitosan	Carboxymethylation ≥80%	Suitable for comparing the effects of the degree of carboxymethylation on system solubility, rheological recovery, and drug release behavior
C304739	Carboxymethyl chitosan	Degree of substitution: ≥90%	Suitable for highly substituted modified chitosan composite gels with enhanced formulation tunability
M768076	Chitosan Methacryloyl	Sterile, degree of substitution: 35-45%; 2% (w/v)	Suitable for constructing composite thermosensitive gel systems that combine a chitosan framework with subsequent network curing capability
M775155	Methylpropenylated chitosan (ChMA)	Viscosity 100-300 mPa.s; labeling rate 10-20%; methacrylate residue ≤100 ppm	Suitable for regulating gelation strength, rheological response, and local structural stability in modified chitosan systems
M398219	Carboxymethyl Chitosan Methacryloyl (CMCSMA)	Labeling rate 10-20%; viscosity ≤100; methacrylate residue ≤100 ppm	Suitable for constructing modified chitosan composite thermosensitive systems with better water solubility and greater formulation flexibility
L768065	Weak Temperature sensitive Gelatin Methacryloyl	Degree of substitution 85-100%	Suitable for constructing composite gel platforms with thermosensitivity, tissue compatibility, and local repair-related properties
S494322	Silica Particles	—	Suitable as an inorganic composite reinforcing component to improve the modulus, structural retention, and release pathway regulation of thermosensitive gels
H396833	High Surface area Silica nanoparticles	—	Suitable for constructing nanocomposite thermosensitive gels, enhancing network compactness, and regulating rheological and drug release behavior
H396821	High Surface area Silica nanoparticles	—	Suitable for combination with poloxamer or chitosan systems to compare the effects of nano-reinforcement on gelation and structural recovery

The research focus of injectable thermosensitive gels should not remain at the single level of whether the system can gel upon heating. Only when a system is operational before injection, capable of rapid and stable gelation after injection, and able to provide predictable structural control during drug release does it truly possess clear value for formulation application.