Cutaneous Cell Therapy Manufacturing Timeframe Rationalization: Allogeneic Off-the-Freezer Fibroblasts for Dermo-Epidermal Combined Preparations (DE-FE002-SK2) in Burn Care
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethical Compliance of the Study
2.2. Materials and Consumables Used for the Study
2.3. Equipment Used for the Study
2.4. Primary Cell Sourcing and Cellular Raw Material Manufacture
2.5. Dermal Template Preparation: In Vitro Collagen Synthesis Induction Conditions
2.6. Allogeneic Dermal Template Preparation: In Vitro Manufacturing Optimization
2.7. Dermal Template Characterization Assay: Sirius Red Staining and Collagen Quantification
2.8. Combined DE-FE002-SK2 Construct Manufacturing Process
2.9. Combined DE-FE002-SK2 Construct Structural Characterization: Histology and Immunohistochemistry Assays
2.10. Combined DE-FE002-SK2 Construct Functional Characterization: Ex Vivo De-Epidermalized Dermis Model
2.11. Statistical Analyses and Data Presentation
3. Results
3.1. FE002-SK2 Primary Progenitor Fibroblasts Are Functionally Superior to Patient Fibroblasts for In Vitro Collagen Synthesis
3.2. DE-FE002-SK2 Constructs Can Be Manufactured for Clinical Use in Three Weeks
3.3. DE-FE002-SK2 Constructs Display Structural Attributes Which Are Equivalent or Superior to Fully Autologous CDEAs
3.4. DE-FE002-SK2 Constructs Display Enhanced Bio-Adhesive Functions on DED Compared to CEAs
4. Discussion
4.1. Historical Evolution and Technical Bottlenecks in Burn Patient Cytotherapeutic Care
4.2. Transitioning to Complex Cutaneous Grafts for Enhanced Burn Victim Clinical Outcomes
4.3. Dermal Components Are Necessary for High-Quality Closure of Extensive and Deep Burns
4.4. Allogeneic FE002-SK2 Primary Progenitor Fibroblasts Have Been Extensively Clinically Tested
4.5. DE-FE002-SK2 Constructs: Technically Enhanced Modern Alternatives to Standard CDEA Protocols
4.6. Study Limitations and Future Perspectives
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CDEA | cultured dermo-epidermal autograft |
CEA | cultured epithelial autograft |
CHUV | Centre Hospitalier Universitaire Vaudois |
DED | de-epidermalized dermis |
DE-FE002-SK2 | bioengineered skin graft based on cultured allogeneic fibroblasts and autologous keratinocytes |
DMEM | Dulbecco’s modified Eagle medium |
DMSO | dimethyl sulfoxide |
ECM | extracellular matrix |
EDTA | ethylenediaminetetraacetic acid |
EOPCB | end of production cell bank |
FBS | fetal bovine serum |
FE002-SK2 | clinical grade primary progenitor fibroblast cell source |
GMP | good manufacturing practices |
H&E | hematoxylin and eosin |
MCB | master cell bank |
PBB | progenitor biological bandages |
PBS | phosphate-buffered saline |
PCB | parental cell bank |
TBSA | total body surface area |
UK | United Kingdom |
USA | United States of America |
WCB | working cell bank |
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Parameters | Values/Results | |||
---|---|---|---|---|
Cell seeding density (viable cells/cm2) | 1500 | 3000 | 6000 | 20,000 |
Time to confluency (days) | 12 ± 2 | 10 ± 2 | 7 ± 1 | 4 ± 0.5 |
Medium exchange procedures (n) | 5 | 4 | 3 | 2 |
Seeding lot size 1 (106 cells) | 2.8 | 5.6 | 11.3 | 37.5 |
Process Phase | Parameters | Targets | Methods | Gradings 1 | |
---|---|---|---|---|---|
CDEA Group | DE-FE002-SK2 Group | ||||
1. Dermal Template | Manufacturing timeframe | Two weeks of culture | Operator assessment | − | +++ |
Fibroblast monolayer formation after expansion | Formation of a homogeneous cellular layer | Operator assessment; microscopy | ++ | +++ | |
Dermal template sheet formation after vitamin C induction | Formation of a dermal template by collagen synthesis | Operator assessment; collagen staining | ++ | +++ | |
Homogeneity of the dermal template sheet | Consistency of dermal template attributes over the whole surface | Operator assessment; histology | ++ | +++ | |
Robustness of the dermal template sheet | Possibility to detach and manipulate the dermal template | Operator assessment; handling | + | +++ | |
2. Combined Construct | Manufacturing timeframe | One week of culture | Operator assessment | + | +++ |
Compatibility between the dermal template and autologous keratinocytes | Passive combination of components in co-culture | Operator assessment; histology | ++ | +++ | |
Stratification of the epidermal component | Formation of a stratified epidermal component | Operator assessment; histology | + | +++ | |
Homogeneity of the construct | Consistency of construct attributes over the whole surface | Operator assessment; histology | + | ++ | |
Robustness of the construct | Possibility to detach and manipulate the construct | Operator assessment; handling | + | ++ |
Attribute Type | Parameters | Targets | Methods | Gradings 1 | |
---|---|---|---|---|---|
CEA Group | DE-FE002-SK2 Group | ||||
1. Translational Attributes | Transfer of the construct to a Vaseline gauze | Possibility to manipulate and transport the construct using the gauze | Operator assessment | ++ | +++ |
Application of the construct on the DED model | Simple topical application on the DED surface | Operator assessment | +++ | +++ | |
Applied construct structural integrity maintenance | Maintenance of construct structural integrity on the DED model | Operator assessment | ++ | ++ | |
2. Functional Attributes | Initial adhesion of the construct to the DED model | Construct adheres rapidly to the DED model | Operator assessment | ++ | ++ |
Endpoint homogeneous adhesion of the construct to the DED model | Construct adheres homogeneously to the DED model | Operator assessment; MTT | − | ++ | |
Endpoint homogeneous metabolic activity throughout of the construct on the DED model | Cellular metabolic activity is significant and homogeneous throughout the construct on the DED model | Operator assessment; MTT | ± | +++ |
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Chen, X.; Laurent, A.; Liao, Z.; Jaccoud, S.; Abdel-Sayed, P.; Flahaut, M.; Scaletta, C.; Raffoul, W.; Applegate, L.A.; Hirt-Burri, N. Cutaneous Cell Therapy Manufacturing Timeframe Rationalization: Allogeneic Off-the-Freezer Fibroblasts for Dermo-Epidermal Combined Preparations (DE-FE002-SK2) in Burn Care. Pharmaceutics 2023, 15, 2334. https://doi.org/10.3390/pharmaceutics15092334
Chen X, Laurent A, Liao Z, Jaccoud S, Abdel-Sayed P, Flahaut M, Scaletta C, Raffoul W, Applegate LA, Hirt-Burri N. Cutaneous Cell Therapy Manufacturing Timeframe Rationalization: Allogeneic Off-the-Freezer Fibroblasts for Dermo-Epidermal Combined Preparations (DE-FE002-SK2) in Burn Care. Pharmaceutics. 2023; 15(9):2334. https://doi.org/10.3390/pharmaceutics15092334
Chicago/Turabian StyleChen, Xi, Alexis Laurent, Zhifeng Liao, Sandra Jaccoud, Philippe Abdel-Sayed, Marjorie Flahaut, Corinne Scaletta, Wassim Raffoul, Lee Ann Applegate, and Nathalie Hirt-Burri. 2023. "Cutaneous Cell Therapy Manufacturing Timeframe Rationalization: Allogeneic Off-the-Freezer Fibroblasts for Dermo-Epidermal Combined Preparations (DE-FE002-SK2) in Burn Care" Pharmaceutics 15, no. 9: 2334. https://doi.org/10.3390/pharmaceutics15092334
APA StyleChen, X., Laurent, A., Liao, Z., Jaccoud, S., Abdel-Sayed, P., Flahaut, M., Scaletta, C., Raffoul, W., Applegate, L. A., & Hirt-Burri, N. (2023). Cutaneous Cell Therapy Manufacturing Timeframe Rationalization: Allogeneic Off-the-Freezer Fibroblasts for Dermo-Epidermal Combined Preparations (DE-FE002-SK2) in Burn Care. Pharmaceutics, 15(9), 2334. https://doi.org/10.3390/pharmaceutics15092334