Bringing Safe and Standardized Cell Therapies to Industrialized Processing for Burns and Wounds

Abstract

organ donation potentially enables millions of patients to benefit from high-quality, safe and effective regenerative therapies. This work presents a technical and translational overview of the described progenitor cell technology harnessed in Switzerland as cellular therapies for treatment of burns and wounds around the globe.

Holistic Approach of Swiss Fetal Progenitor Cell Banking: Optimizing Safe and Sustainable Substrates for Regenerative Medicine and Biotechnology

“…Regulatory vetting and GMP constraints relative to traceable tissue procurement, testing, and bioprocessing favor an up-stream medical and serological testing approach (i.e., repeated bloodwork for HIV-1/2, HTLV-1/2, hCMV, EBV, HHV-6/7/8, HSV, HBV, HCV, HPV, West Nile virus, syphilis) of motherdonors for inclusion in the Program, positively impacting longterm testing costs ( Supplementary Figure 1; Quintin et al, 2007;Applegate et al, 2013). Practically, optimized workflows and specifications eventually enabled traceable simultaneous isolation of various FPC types (i.e., FPCs isolated from fetal tissues such as skin, cartilage, tendon, bone, muscle, intervertebral disc, lung) from a single fetal organ donation (i.e., codename FE002, 2009) for rapid and efficient PCB establishment and subsequent industrial GMP processing (Laurent et al, 2020e). Specific bioprocessing methodologies enable safe and sustained use of original cell sources for extended periods, as adequate testing implementation ensures maximal safety of the end-products or substrates (De Buys Roessingh et al, 2015).…”

“…Bioengineered PBB constructs were observed to promote proliferation, adhesion, and migration of endogenous cells, without atrophic skin formation (Ramelet et al, 2009). Over two decades of clinical experience and multicentric studies have shown the safety or beneficial therapeutic effects of dermal FPCs in PBBs, notably within phase I and II clinical trials in Switzerland and Asia (i.e., ClinicalTrials.gov identifiers: NCT02737748 & NCT03624023) (Hohlfeld et al, 2005;Ramelet et al, 2009;Laurent et al, 2020e). In view of further optimization of burn wound or ulcer care in particular, high therapeutic benefits may be gained by stabilizing and formulating active cell-derivative components in pharmaceutical creams, ointments, or gels, as these are used for the maintenance therapy to accelerate wound healing (i.e., potentially scarlessly) after primary wound closure.…”

“…For industrial-scale manufacturing of cell bank lots, stringent optimization must be conducted regarding raw materials, reagents, and contact-process consumable selection. In particular, the make, model, and lot identity of culture vessels and nutrient supplements must be optimized by thorough benchmarking before use in a GMP environment, as these elements may bear significant impacts on endpoint cell yields or population doubling times, thereby tangibly affecting the overall cost of production (Laurent et al, 2020e). Novel culture vessel systems may be investigated for two-dimensional (e.g., Corning R HYPERFlasks R , Nunc TM Cell Factories TM , or Greiner CELLdiscs TM ) or three-dimensional (e.g., Terumo Quantum R , roller bottles, spinner flasks) cell culture efficiency, but should be thoroughly validated before adoption at industrial scales.…”

“…Such limits comprise, without being limited to, operator-related cell quantification, relatively important occupied volumes in conventional incubators with limited airflow and oxygenation, or relative contamination risks (e.g., open vessels for cryopreservation).FPCs are sufficient for industrial-scale GMP manufacturing with minimal processing requirements. Standardized multi-tiered cell banking model establishment (i.e., sub-tiering cryopreserved cell stocks in Parental, Master, Working, and End of Production Cell Banks, PCB-MCB-WCB-EOPCB, with tier nomenclature based on in vitro passages) allows for efficient constitution, transposition, and utilization of consistent biological sources of high therapeutic value(Figures 6, 7; De Buys Roessingh et al,Laurent et al, 2020e)…”

“…Photographic representations of the lesions at the beginning of treatment, after six days, and after 14 days. Figures modified with permission fromLapp et al (2013) andLaurent et al (2020e).…”