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Drug Delivery

Drug Delivery - Posters – Poster Session C

Poster X9 - Functionalization of a meniscus prosthesis enabling the controlled release of anti-inflammatory drugs.

Saturday, October 26, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Knee osteoarthritis (OA) is a complex, degenerative, and chronic joint condition that significantly diminishes quality of life. Despite its rising global incidence, meniscectomy remains the primary treatment, often accelerating the onset of OA over time. An alternative approach involves replacing the entire meniscus with a prosthesis post-meniscectomy, providing a viable option for patients with severe meniscal damage, including the elderly. Additionally, integrating the sustained release of anti-inflammatory drugs directly from the prosthesis can help modulate the knee's pro-inflammatory environment (Fig. 1).

The objective of this study focuses was the functionalization of a meniscus prosthesis with a bilayer system incorporating two anti-inflammatory drugs within biocompatible and biodegradable polymeric coatings. This design ensures distinct and sustained release profiles for each drug (from weeks to months) following implantation in the knee joint. Critical to the success of this approach, the adhesion between the prosthesis and the drug-polymer films was optimized to withstand the high mechanical stresses inherent to the knee joint. The performance of this drug delivery system has been rigorously evaluated through a series of in vitro studies with representative cell lines, bioreactor experiments simulating mechanical forces, and in vivo testing using relevant animal models.

Materials and

Methods:  Screening of Drug-Polymer Combinations
Two anti-inflammatory drugs and several biodegradable polymers were screened to identify the optimal combination for drug-loaded polymeric coatings. These films were created using dip-coating applied to a commercial non-biodegradable meniscus implant. The system resulted in a bilayer polymeric coating, with each layer containing a different anti-inflammatory drug.

Drug Release Studies
Initial drug release studies were performed at 37 °C in PBS with 1% (w/v) Tween 80® to maintain sink conditions. Subsequently, the coated implant was immersed in simulated synovial fluid (SSF) inside a bioreactor simulating the knee joint's mechanical forces. This setup determined the effect of loading cycles on drug release kinetics and polymeric coating stability. Drug release was quantified using reverse phase ultra-performance liquid chromatography (UPLC).

Characterization of Polymeric Coatings
The drug-loaded polymeric coatings were characterized using field-emission scanning electron microscopy (FESEM). Various pre-treatments of the prosthesis were assessed through macroscopic evaluation and dynamic mechanical analysis (DMA).

In Vitro Experiments
In vitro experiments with human monocyte-derived macrophages (HMDMs) were performed to evaluate the toxicity, biocompatibility, and activity of the encapsulated anti-inflammatory drugs along time.

In Vivo Testing
Functionalized prostheses were tested in sheep. The coating was adapted to a sheep meniscus implant, and the coating-to-implant interaction was optimized. Prototypes were implanted in sheep for three months, after which the animals were sacrificed, and the cartilages and knee cavities evaluated.

Results, Conclusions, and Discussions: A prototype of the bilayer coated prosthesis achieved the desired sequential release of the two anti-inflammatory drugs. The fast release of AID1 occurred within 1-4 weeks due to the rapid degradation rate of polymer PA. In contrast, the sustained release of AID2 extended up to 10 months, facilitated by the slow degradation rate and high hydrophobicity of polymers PB and PC (Fig. 2). The released anti-inflammatory drugs demonstrated biocompatibility, non-toxicity, and activity in vitro using a representative cell line of human monocyte-derived macrophages (HMDMs).

To improve coating-to-implant interaction, the prostheses were pre-coated with an adhesive polymer film, creating a binding layer between the prosthesis and the coating. This functionalization significantly improved the interaction, homogeneity and cohesion between the prosthesis surface and the drug-loaded polymeric coatings, as observed during macroscopic evaluation. These findings were corroborated by dynamic mechanical analysis (DMA) characterization.

Evaluation in a bioreactor showed that the polymeric coatings resisted mechanical stimulation while maintaining their structure. The release profile of both drugs remained consistent with that of non-mechanically stimulated coatings, although, as expected, mechanical stimulation slightly accelerated drug release.

In vivo testing involved implanting the coated meniscus prostheses in sheep and evaluating them over three months. The results demonstrated the persistence of the coating post-sacrifice, reduced fibrosis, and improved cartilage scores compared to the uncoated implant.

This project aimed to replace the entire meniscus and address the pro-inflammatory environment within the knee joint. To achieve this, a meniscus prosthesis was functionalized with a bilayer polymeric coating for the controlled release of two anti-inflammatory drugs with distinct release kinetics. Crucially, enhanced interaction between the prosthesis and the drug-loaded polymeric layers was achieved by pre-treating the prosthesis with an adhesive polymer, preventing potential delamination issues post-implantation while maintaining the desired drug release kinetics. These results were validated in vitro, in a bioreactor, and in vivo, confirming the efficacy and stability of the functionalized prosthesis.

Acknowledgements (Optional):  This work has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 814444 (MEFISTO) and Xunta de Galicia’s Grants for the Predoctoral Stage 2022.