Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Reagents and Consumables Used in the Study
2.2. Equipment and Instruments Used in the Study
2.3. Lyophilized FE002 Primary Chondroprogenitor Preparation and Characterization
2.4. HA-L-PNIPAM Polymer Synthesis and Characterization
2.5. HA-L-PNIPAM and HA-Based Hydrogel Formulation with Lyophilized FE002 Primary Chondroprogenitors
2.6. Determination of the Intrinsic Antioxidant Capacity of Lyophilized FE002 Primary Chondroprogenitors
2.7. Rheological Characterization of the Combination Products
2.8. Combination Product Accelerated Degradation Assays with Rheological Readouts
2.9. Combination Product Rotational Tribology Characterization
2.10. Combination Product Injectability Assessment
2.11. Combination Product In Vitro Cytocompatibility with Primary Fibroblast-like Synoviocytes
2.12. Combination Product In Vivo Efficacy Assessment in a Rodent Model of Knee Osteoarthritis
2.12.1. Knee Osteoarthritis Model and Surgical Procedure
2.12.2. Investigative Product Groups and Product Administration Modalities
2.12.3. Terminal Procedure and Sampling of Posterior Knee Joints
2.12.4. Micro-CT Data Acquisition and Data Analysis by Scoring
2.12.5. Histological Analyses and Histopathological Chondral Defect Grading
2.12.6. Histomorphometry Evaluation of Osteoarthritis Progression
2.13. Statistical Analyses and Presentation of Experimental Data
3. Results and Discussion
3.1. Lyophilized FE002 Chondroprogenitors Possess Intrinsic Antioxidant Properties and Functionalize Hydrogels through Stability Enhancement
3.2. Thermo-Responsive Hydrogels May Be Simply Synthetized and Autoclave-Sterilized before Inclusion of Cell Lyophilizates
3.3. Combination Products Display Optimal Thermo-Responsive Behaviors and Lubricating Effects In Vitro
3.4. Combination Products Present Significantly Improved Stability against Oxidative Degradation
3.5. The Use of HA-L-PNIPAM Efficiently Improves HA-Based Hydrogel Resistance toward Enzymatic Degradation
3.6. The Studied Combination Products Display No Cytotoxicity In Vitro and Are Easily Injectable
3.7. The Studied Combination Products Did Not Cause Adverse Reactions In Vivo and Procured Multi-Parameter Beneficial Trends in a Rodent Model of Knee OA
3.8. Novel Orthopedic Combination Product Preclinical Assessment: Current Insights and Bottlenecks around Efficacy Evaluation
3.9. A Historical Landmark in Clinical Allogeneic Cell-Based Management of Orthopedic Conditions: The Disruptive Case of Invossa
3.10. Study Limitations and Perspectives for Future Development Work
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACLT | anterior cruciate ligament transection |
Da | Daltons |
HA | hyaluronic acid |
H2O2 | hydrogen peroxide |
FRAP | ferric reducing antioxidant power |
GLP | good laboratory practices |
HES | hematoxilin/eosin/saffron |
hMnx | hemi-meniscectomy |
LVE | linear viscoelastic region |
MD | medical device |
MW | molecular weight |
OA | osteoarthritis |
OARSI | Osteoarthritis Research Society International |
Pa | Pascals |
Pa·s | Pascal seconds |
PBS | phosphate-buffered saline |
Ph.Eur. | European pharmacopoeia |
PNIPAM | poly(N-isopropylacrylamide) |
PRP | platelet-rich plasma |
ROS | reactive oxygen species |
SF | synovial fluid |
TB | Toluidine blue |
TEAC | Trolox equivalent antioxidant capacity |
USA | United States of America |
UV | ultraviolet |
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Formulation Type | Gross (Co-)Polymer Concentration (mg/mL) | Net HA Concentration (mg/mL) 2 | Lyophilized FE002 Chondroprogenitor Presence (Y/N) |
---|---|---|---|
HA | 10 | 10 | N |
HA-L-PNIPAM | 37 | 10 | N |
HA + Cells | 10 | 10 | Y (3 × 106 cells/vial) |
HA-L-PNIPAM + Cells | 37 | 10 | Y (3 × 106 cells/vial) |
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Porcello, A.; Gonzalez-Fernandez, P.; Jeannerat, A.; Peneveyre, C.; Abdel-Sayed, P.; Scaletta, C.; Raffoul, W.; Hirt-Burri, N.; Applegate, L.A.; Allémann, E.; et al. Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis. Pharmaceutics 2023, 15, 1528. https://doi.org/10.3390/pharmaceutics15051528
Porcello A, Gonzalez-Fernandez P, Jeannerat A, Peneveyre C, Abdel-Sayed P, Scaletta C, Raffoul W, Hirt-Burri N, Applegate LA, Allémann E, et al. Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis. Pharmaceutics. 2023; 15(5):1528. https://doi.org/10.3390/pharmaceutics15051528
Chicago/Turabian StylePorcello, Alexandre, Paula Gonzalez-Fernandez, Annick Jeannerat, Cédric Peneveyre, Philippe Abdel-Sayed, Corinne Scaletta, Wassim Raffoul, Nathalie Hirt-Burri, Lee Ann Applegate, Eric Allémann, and et al. 2023. "Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis" Pharmaceutics 15, no. 5: 1528. https://doi.org/10.3390/pharmaceutics15051528
APA StylePorcello, A., Gonzalez-Fernandez, P., Jeannerat, A., Peneveyre, C., Abdel-Sayed, P., Scaletta, C., Raffoul, W., Hirt-Burri, N., Applegate, L. A., Allémann, E., Laurent, A., & Jordan, O. (2023). Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis. Pharmaceutics, 15(5), 1528. https://doi.org/10.3390/pharmaceutics15051528