Industrial Development of Standardized Fetal Progenitor Cell Therapy for Tendon Regenerative Medicine: Preliminary Safety in Xenogeneic Transplantation

Abstract

Tendon defects require multimodal therapeutic management over extensive periods and incur high collateral burden with frequent functional losses. Specific cell therapies have recently been developed in parallel to surgical techniques for managing acute and degenerative tendon tissue affections, to optimally stimulate resurgence of structure and function. Cultured primary human fetal progenitor tenocytes (hFPT) have been preliminarily considered for allogeneic homologous cell therapies, and have been characterized as stable, consistent, and sustainable cell sources in vitro. Herein, optimized therapeutic cell sourcing from a single organ donation, industrial transposition of multi-tiered progenitor cell banking, and preliminary preclinical safety of an established hFPT cell source (i.e., FE002-Ten cell type) were investigated. Results underlined high robustness of FE002-Ten hFPTs and suitability for sustainable manufacturing upscaling within optimized biobanking workflows. Absence of toxicity or tumorigenicity of hFPTs was demonstrated in ovo and in vitro, respectively. Furthermore, a 6-week pilot good laboratory practice (GLP) safety study using a rabbit patellar tendon partial-thickness defect model preliminarily confirmed preclinical safety of hFPT-based standardized transplants, wherein no immune reactions, product rejection, or tumour formation were observed. Such results strengthen the rationale of the multimodal Swiss fetal progenitor cell transplantation program and prompt further investigation around such cell sources in preclinical and clinical settings for musculoskeletal regenerative medicine.

Hypoxic Incubation Conditions for Optimized Manufacture of Tenocyte-Based Active Pharmaceutical Ingredients of Homologous Standardized Transplant Products in Tendon Regenerative Medicine

“…Therein, allogenic homologous therapeutic approaches and products may be devised with highly limited risks of tumor formation or eliciting immune responses. Notably, hFPTs manufactured in normoxia conditions were recently documented as preliminarily safe for implantation in a rabbit patellar tendon defect model, wherein hyaluronic acid served as a functional delivery scaffold [ 5 ]. The proof of concept of progenitor tenocyte-based APIs for homologous allogenic treatment of tendon defects or affections has been established, albeit with a remaining margin of improvement for the technical optimization of the manufacturing process.…”

“…Human fetal progenitor tenocytes (hFPT) produced in vitro under defined multi-tiered cell bank systems have recently been characterized (i.e., in vitro and in preclinical models) and qualified as potential therapeutic cell sources in tendon regenerative medicine [ 1 , 2 , 3 , 4 , 5 ]. Potential therapeutic uses of such novel tenocyte-based therapies or products include the management of local inflammation-mediated tissue degeneration, partial tendon ruptures, or volumetric tissue defects related to traumatic injuries.…”

“…Potential therapeutic uses of such novel tenocyte-based therapies or products include the management of local inflammation-mediated tissue degeneration, partial tendon ruptures, or volumetric tissue defects related to traumatic injuries. Therein, allogenic applications of homologous cell-based or cell-derived preparations are considered based on the intrinsic advantages of the biological active pharmaceutical ingredients (API) of interest, such as technical simplicity of manufacture, a defined and stable tissue-specific phenotype in vitro, extensive stability, and the verifiable absence of immunogenic or tumorigenic risk factors [ 1 , 2 , 5 ]. The appropriate conjugation of hFPTs with suitable delivery vehicles (e.g., hyaluronan-based hydrogels) or tissue engineering scaffolds (e.g., synthetic polymer-based constructs, decellularized human or equine tendon tissues) represents a cornerstone in tangible therapeutic combination product development [ 2 , 4 , 6 ].…”

“…Within the establishment of scalable hFPT (i.e., cellular API) manufacturing processes, multiple parameters require appropriate technical optimization and validation phases in order to comply with the current systematic requirements of a risk-based, process-oriented, and quality-driven production approach [ 5 ]. Key or critical workflow parameters to be taken into consideration during API manufacturing process design and validation phases include specified contact-process consumables (e.g., proliferation medium, culture vessels, dissociation reagents, and cryopreservation medium), the technical specifications for hFPT culture-expansion (e.g., cell seeding and harvest procedures, media exchanges, total culture periods), as well as incubation parameters (e.g., incubator temperature, humidity levels, gaseous mix composition) [ 7 , 8 ].…”

“…In view of eventual clinical translation, robust and sustainable hFPT manufacturing processes have already been technically optimized and established in traditionally used and defined normoxic cell culture conditions (i.e., 21% O 2 , 5% CO 2 ) following a single organ donation [ 1 , 5 ]. However, healthy human tendons are constituted by poorly vascularized tissues, physiologically exposed to oxygen levels far below 21% O 2 , contrasting with standard and artificial in vitro normoxic culture environments.…”