No abstract

Wound healing in fetal skin is characterized by the absence of scar tissue formation, which is not dependent on the intrauterine environment and amniotic fluid. Fetal cells have the capacity of extraordinary expansion and we describe herein the development of a fetal skin cell bank where from one organ donation (2-4 cm2) it is possible to produce several hundred million fetal skin constructs of 9 x 12 cm2. Fetal cells grow three to four times more rapidly than older skin cells cultured in the same manner and these banked fetal cells are very resistant against physical and oxidative stress when compared to adult skin cells under the same culture conditions. They are up to three times more resistant to UVA radiation and two times more resistant towards hydrogen peroxide treatment. This mechanism may be of major importance for fetal cells when they are delivered to hostile wound environments. For fetal cell delivery to patients, cells were associated with a collagen matrix to form a three-dimensional construct in order to analyze the capacity of these cells for treating various wounds. We have seen that fetal cells can modify the repair response of skin wounds by accelerating the repair process and reducing scarring in severe bums and wounds of various nature in children. Hundreds of thousands of patients could potentially be treated for acute and chronic wounds from one standardized and controlled cell bank.

Nitric oxide (NO) is synthesized from l-arginine by the Ca(2+)/calmodulin-sensitive endothelial NO synthase (NOS) isoform (eNOS). The present study assesses the role of Ca(2+)/calmodulin-dependent protein kinase II (CaMK II) in endothelium-dependent relaxation and NO synthesis. The effects of three CaMK II inhibitors were investigated in endothelium-intact aortic rings of normotensive rats. NO synthesis was assessed by a NO sensor and chemiluminescence in culture medium of cultured porcine aortic endothelial cells stimulated with the Ca(2+) ionophore A23187 and thapsigargin. Rat aortic endothelial NOS activity was measured by the conversion of l-[(3)H]arginine to l-[(3)H]citrulline. Three CaMK II inhibitors, polypeptide 281-302, KN-93, and lavendustin C, attenuated the endothelium-dependent relaxation of endothelium-intact rat aortic rings in response to acetylcholine, A23187, and thapsigargin. None of the CaMK II inhibitors affected the relaxation induced by NO donors. In a porcine aortic endothelial cell line, KN-93 decreased NO synthesis and caused a rightward shift of the concentration-response curves to A23187 and thapsigargin. In rat aortic endothelial cells, KN-93 significantly decreased bradykinin-induced eNOS activity. These results suggest that CaMK II was involved in NO synthesis as a result of Ca(2+)-dependent activation of eNOS.

Swiss Fetal Progenitor Cell Banking is proposed, achieving sustained standards and potential production of billions of affordable and efficient therapeutic doses. Thereby, the aim is to validate the core therapeutic value proposition, to increase awareness and use of standardized protocols for translational regenerative medicine, potentially impacting millions of patients suffering from cutaneous and musculoskeletal diseases. Alternative applications of FPC banking include biopharmaceutical therapeutic product manufacturing, thereby indirectly and synergistically enhancing the power of modern therapeutic armamentariums. It is hypothesized that a single qualifying fetal organ donation is sufficient to sustain decades of scientific, medical, and industrial developments, as technological optimization and standardization enable high efficiency.

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.

Treatment of congenital diaphragmatic hernia (CDH) challenges obstetricians, pediatric surgeons, and neonatologists. Persistent pulmonary hypertension (PPHT) associated with lung hypoplasia in CDH leads to a high mortality rate at birth. PPHT is principally due to an increased muscularization of the arterioles. Management of CDH has been greatly improved by the introduction of prenatal surgical intervention with tracheal obstruction (TO) and by more appropriate postnatal care. TO appears to accelerate fetal lung growth and to increase the number of capillary vessels and alveoli. Improvement of postnatal care over the last years is mainly due to the avoidance of lung injury by applying low peak inflation pressure during ventilation. The benefits of other drugs or technical improvements such as the use of inhaled nitric oxide or extracorporeal membrane oxygenation (ECMO) are still being debated and no single strategy is accepted worldwide. Despite intensive clinical and experimental research, the treatment of newborn with CDH remains difficult.

Progenitor Biological Bandages (PBB) have been continuously applied clinically in the Lausanne Burn Center for over two decades. Vast translational experience and hindsight have been gathered, specifically for cutaneous healing promotion of donor-site grafts and second-degree pediatric burns. PBBs constitute combined Advanced Therapy Medicinal Products, containing viable cultured allogeneic fetal dermal progenitor fibroblasts. Such constructs may partly favor repair and regeneration of functional cutaneous tissues by releasing cytokines and growth factors, potentially negating the need for subsequent skin grafting, while reducing the formation of hypertrophic scar tissues. This retrospective case-control study (2010–2018) of pediatric second-degree burn patients comprehensively compared two initial wound treatment options (i.e., PBBs versus Aquacel® Ag, applied during ten to twelve days post-trauma). Results confirmed clinical safety of PBBs with regard to morbidity, mortality, and overall complications. No difference was detected between groups for length of hospitalization or initial relative burn surface decreasing rates. Nevertheless, a trend was observed in younger patients treated with PBBs, requiring fewer corrective interventions or subsequent skin grafting. Importantly, significant improvements were observed in the PBB group regarding hypertrophic scarring (i.e., reduced number of scar complications and related corrective interventions). Such results establish evidence of clinical benefits yielded by the Swiss fetal progenitor cell transplantation program and favor further implementation of specific cell therapies in highly specialized regenerative medicine.

The complex management of severe burn victims requires an integrative collaboration of multidisciplinary specialists in order to ensure quality and excellence in healthcare. This multidisciplinary care has quickly led to the integration of cell therapies in clinical care of burn patients. Specific advances in cellular therapy together with medical care have allowed for rapid treatment, shorter residence in hospitals and intensive care units, shorter durations of mechanical ventilation, lower complications and surgery interventions, and decreasing mortality rates. However, naturally fluctuating patient admission rates increase pressure towards optimized resource utilization. Besides, European translational developments of cellular therapies currently face potentially jeopardizing challenges on the policy front. The aim of the present work is to provide key considerations in burn care with focus on architectural and organizational aspects of burn centers, management of cellular therapy products, and guidelines in evolving restrictive regulations relative to standardized cell therapies. Thus, based on our experience, we present herein integrated management of risks and costs for preserving and optimizing clinical care and cellular therapies for patients in dire need.