Poloxamer-based injectable hydrogels as matrices for localized anti-inflammatory drug delivery in meniscus injuries

Abstract

Poloxamer-based hydrogels, composed of thermoreversible triblock copolymers, are promising drug delivery systems due to their ability to transition from a liquid to a gel state at physiological temperatures, enabling minimally invasive injection and localized, sustained release of therapeutic agents. In this study, poloxamer hydrogels were prepared with diclofenac sodium salt and paracetamol as model anti-inflammatory drugs, and characterized for morphology, osmolarity, pH, and temperature sensitivity. Drug loading optimization was performed to ensure homogeneous dispersion, and release kinetics were evaluated by spectrophotometric analysis, with mathematical modeling used to describe and predict drug release mechanisms from the hydrogel matrix. The optimized poloxamer gels exhibited an appropriate sol–gel transition near body temperature (26–37 °C), stable pH, and osmolarity suitable for biomedical use. Drug release profiles showed controlled, sustained release of both diclofenac sodium and paracetamol over extended periods, with mathematical modeling indicating that diffusion-based mechanisms predominated in drug release from the hydrogel matrix, validating the system design for targeted, localized therapy. These findings demonstrate that poloxamer-based injectable hydrogels effectively deliver anti-inflammatory agents with controlled release, representing a versatile platform for localized drug delivery in regenerative medicine and orthopedic applications, particularly for intra-articular treatment of musculoskeletal disorders, thereby supporting improved therapeutic outcomes while minimizing systemic exposure and associated side effects.

Introduction

Drug delivery systems are designed to control the release and distribution of therapeutic agents, improving therapeutic efficacy while minimizing systemic side effects.1,2 Hydrogel matrices have emerged as particularly promising carriers due to their hydrophilic, crosslinked polymer networks, which can hold large volumes of water while maintaining structural integrity.3,4 Their softness, porosity, high biocompatibility, and stimuli-responsive behavior, such as sol–gel transitions triggered by temperature, pH, or enzymatic activity, enable precise control of drug release in vivo. Thermosensitive hydrogels have attracted significant attention due to their ability to undergo phase transitions as ambient temperature changes. This property enhances drug delivery systems by improving local drug penetration, providing better spatial and temporal control, and increasing drug bioavailability.4,5

Poloxamer-based hydrogels, composed of nonionic triblock copolymers of poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (PEO–PPO–PEO), exhibit thermoreversible gelation behavior, remaining liquid at room temperature and transitioning to a gel at physiological temperatures.6,7 These polymers, known commercially as Pluronics, Synperonics, or Lutrol, include a variety of liquids, pastes, and solids. Their molecular weights range from 1100 to 14[thin space (1/6-em)]000, and the ethylene oxide to propylene oxide weight ratios vary from 1[thin space (1/6-em)]:[thin space (1/6-em)]9 to 8[thin space (1/6-em)]:[thin space (1/6-em)]2.8

Aqueous poloxamer 407 undergoes a solution-to-gel transition as temperature increases, caused by the formation and organization of micelles into periodic lattices.9 This property allows for minimally invasive administration via injection, followed by in situ gelation at the target site.10,11 Recent advances have addressed the inherent limitations of poloxamer hydrogels, including weak mechanical properties and rapid gel erosion, by employing chemical crosslinking strategies that extend drug release profiles to 70 days while maintaining biocompatibility. The nature, composition, and concentration of poloxamers are the most critical factors defining drug release rates, with hydrophobic gel matrices exhibiting compact micellar arrangements that slow diffusion and erosion.12 Incorporating drug-loaded particles into poloxamer gels extends drug release by establishing multiple barriers that limit the release rate. Meanwhile, chemical modification of poloxamers offers a promising approach to achieve prolonged sustained release for parenteral use, without sacrificing the gel’s rheological properties.1

Hydrophobic small molecules can be encapsulated inside poloxamer matrices, but these additives often adversely affect the rheological properties and reduce the gelation temperatures of the hydrogels, which may limit their clinical use. Studies employing differential scanning calorimetry, rheology, and small-angle X-ray scattering have demonstrated that small molecule addition lowers thermal transition temperatures and increases micelle size, providing fundamental understanding for tuning the mechanical and structural properties of drug-loaded formulations.13 As demonstrated in studies on poloxamer formulations, increasing gelling viscosity reduces the drug release rate and gel dissolution time, thereby prolonging the drug’s duration of action in disease treatment.

In orthopedic and musculoskeletal applications, injectable hydrogels have demonstrated significant therapeutic potential as delivery vehicles for diverse bioactive agents, including growth factors, anti-inflammatory drugs, steroids, and cells.14 The meniscus, a fibrocartilaginous structure with limited intrinsic healing capacity due to its avascular nature, particularly benefits from localized delivery of therapeutic agents.11 Recent studies have validated the use of anti-inflammatory agents in thermosensitive hydrogels for intra-articular applications, demonstrating regenerated cartilage profiles and superior anti-inflammatory effects in osteoarthritis models. Injectable hydrogel drug delivery platforms offer many benefits for osteoarthritis treatment, including enhanced biocompatibility, biodegradability, and low immunogenicity, with mechanisms such as anti-inflammation, anti-oxidative stress, and promotion of cartilage regeneration.15,16 The concentration and composition of poloxamers greatly influence their biomedical applications. Triblock copolymer systems offer desirable features for surgical use, including rapid sol–gel transition and biocompatibility, indicating their potential for osteoarticular regeneration.17

Diclofenac sodium salt (Fig. 1a), a phenylacetic acid derivative, exerts its therapeutic effects primarily by inhibiting cyclooxygenase enzymes (COX-1 and COX-2), thereby preventing the conversion of arachidonic acid into prostaglandins.18–20 Paracetamol (N-acetyl-p-aminophenol) (Fig. 1b) is among the most extensively utilized agents with antipyretic, analgesic, and anti-inflammatory properties.21,22 Poloxamer formulations enhance the solubility of both agents and enable sustained release profiles. Combining these agents with poloxamer-based hydrogel systems allows localized, sustained, and controlled release at the injury site, enhancing tissue integration and reducing systemic exposure.5,23

Fig. 1 (a) Chemical structure of diclofenac sodium salt, (b) chemical structure of paracetamol.

Mathematical modeling is essential for analyzing and predicting drug release behavior from hydrogel matrices.16,24 The field originated with Higuchi’s seminal model in 1961, and models have been categorized as empirical/semi-empirical or mechanistic. Mechanistic models, based on physical and chemical processes such as diffusion, dissolution, swelling, and degradation, offer deeper insights and better predictive power for optimizing system design. Recent studies confirm that diffusion-based mechanisms predominate in drug release from poloxamer matrices, with gel erosion and polymer dissolution ultimately controlling release kinetics.25–29

This study aimed to prepare poloxamer-based hydrogel matrices loaded with diclofenac sodium salt and paracetamol, as model anti-inflammatory drugs, with a primary focus on evaluating controlled-release behavior and functional performance. The obtained drug-loaded gels were characterized for morphology, osmolarity, pH, temperature sensitivity, and drug loading to optimize drug dispersion and release properties. Release kinetics were assessed by spectrophotometric analysis, and mathematical models were applied to describe and predict drug release mechanisms from the poloxamer-based hydrogel matrix.

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Materials

Kolliphor® K407 (K407), Poloxamer 188 Pro (P188), and Synperonic® F108 (F108) were purchased from MERCK Sigma-Aldrich (St. Louis, MO, USA). N-(4-Hydroxyphenyl)acetamide (paracetamol) and diclofenac sodium salt were kindly offered by the NOVA FCT University (MERCK Sigma-Aldrich). All chemicals were used as received without additional purification. Ultra-pure water was produced in-house using a Milli-Q water purification system (Millipore, Merck, Darmstadt, Germany).

Marta Tuszynska, Adriana Gonçalves, Joanna Skopinska-Wisniewska, Paula I. P. Soares and Anna Bajek, Poloxamer-based injectable hydrogels as matrices for localized anti-inflammatory drug delivery in meniscus injuries, DOI: 10.1039/D6RA02085B (Paper) RSC Adv., 2026, 16, 21333-21345, Received 11th March 2026 , Accepted 27th March 2026, First published on 1st May 2026