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

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

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

Diverse cell therapy approaches constitute prime developmental prospects for managing acute or degenerative cartilaginous tissue affections, synergistically complementing specific surgical solutions. Bone marrow stimulation (i.e., microfracture) remains a standard technique for cartilage repair promotion, despite incurring the adverse generation of fibrocartilagenous scar tissue, while matrix-induced autologous chondrocyte implantation (MACI) and alternative autologous cell-based approaches may partly circumvent this effect. Autologous chondrocytes remain standard cell sources, yet arrays of alternative therapeutic biologicals present great potential for regenerative medicine. Cultured human epiphyseal chondro-progenitors (hECP) were proposed as sustainable, safe, and stable candidates for chaperoning cartilage repair or regeneration. This study describes the development and industrial transposition of hECP multi-tiered cell banking following a single organ donation, as well as preliminary preclinical hECP safety. Optimized cell banking workflows were proposed, potentially generating millions of safe and sustainable therapeutic products. Furthermore, clinical hECP doses were characterized as non-toxic in a standardized chorioallantoic membrane model. Lastly, a MACI-like protocol, including hECPs, was applied in a three-month GLP pilot safety evaluation in a caprine model of full-thickness articular cartilage defect. The safety of hECP transplantation was highlighted in xenogeneic settings, along with confirmed needs for optimal cell delivery vehicles and implantation techniques favoring effective cartilage repair or regeneration

Primary Progenitor Muscle Cells for Regenerative Medicine: Standardization of Therapeutic Protocols and Optimized In Vivo Murine Model For Volumetric Muscle Loss

Skeletal muscle tissue engineering constitutes an emerging therapeutic repair strategy aiming for structural and functional restoration following traumatic injury, deep burns, congenital malformation or surgical tumor removal. As for similar musculoskeletal acute and degenerative affections, allogenic progenitor cell therapy represents a promising clinical approach to synergistically supplement traditional surgical care. Preliminary studies have established the adequation of primary human fetal muscle progenitors (hFMPs) for applications in regenerative medicine. Such therapeutic cell sources combined with bioresorbable scaffolds optimally integrate in murine muscle injury models without causing immune rejection. The present work aimed at functional recovery assessment following standardized application of hFMPs in an optimized murine skeletal muscle wound model. Cryopreserved hFMPs were initiated and culture-expanded before seeding in equine collagen scaffolds. Gastrocnemius muscles of C57BL/6 mice were injured following a standardized protocol. Resulting volume defects were treated with collagen constructs yielding marked hFMPs (105 cells/construct), constructs alone or remained untreated, assorted to appropriate internal controls. Histological and biomechanical analysis of muscle tissue and integrated therapeutic constructs were performed at the time of surgery and during the following 8 weeks. Both therapeutic protocols and in vivo models were optimized and standardized, based on internal experience concerning progenitor cell therapies for cutaneous reconstruction. Results indicated significantly improved function in all study groups treated with hFMPs. In particular, absolute peak twitch tensions measured on injured muscles were relatively superior in value at different time points after progenitor cell therapy application. Engraftment of hFMPs in murine wounded muscle enabled xenogeneic tissue repair stimulation and overall improvement of functional recovery. The combination of murine muscle wound model and therapeutic cell delivery method was determined as optimal for assessing muscle functional characteristic evolution notwithstanding severe tissue injury by volume loss. Such data support further translational investigation of allogenic progenitor cell therapy for human muscle defects and injuries

Grommets and speech at three and six years in children born with total cleft or cleft palate

Grommets may be considered as the treatment of choice for otitis media with effusion (OME) in children born with a cleft. But the timing and precise indications to use them are not well established. The aim of the study is to compare the results of hearing and speech controls at three and six year-old in children born with total cleft or cleft palate in the presence or not of grommets

Banking Progenitor Cells for Hippiatric Regenerative Medicine: Optimized Establishment of Safe and Consistent Cell Sources for Standardized Veterinary Therapeutic Protocols

Acute musculoskeletal injuries in large animals such as horses or camels often result in productivity losses and euthanasia in racing, esthetic or stock animal industries. Bioengineered products for tissue reconstruction and wound healing may supplement traditional veterinary surgical care synergistically. Banked primary fetal progenitor cells can potentially be used towards structural and functional therapeutic restoration in condensed timeframes. Extensive clinical experience exists in our University Hospital working with dermal progenitor fibroblasts for managing burns, donor site grafts and ulcers. By extrapolation, the present study assessed suitability of equine fetal progenitor cell sources for biotechnological processing, robust cell banking and application in tissue engineering strategies for hippiatric regenerative medicine. Diverse fetal equine musculoskeletal tissues were obtained and processed under defined frameworks and protocols for standardized and optimized tiered cell bank establishment and characterization. Consistency, safety and cyto-compatibility of progeny cells with therapeutic delivery systems were assessed. Finally, optimized hippiatric cell therapy protocols were applied for preliminary safety assessments and promoting musculoskeletal wound healing in four equine subjects. Equine progenitor cells were found to optimally adapt to standardized biotechnological processing, rapid extensive cell banking and consistent therapeutic construct bioengineering. Clinical applications of equine allogeneic cell therapies in large animals yielded preliminary evidence of safety and facilitated volumetric defect reconstruction or wound healing. Gathered experience around veterinary wound management using progenitor cells proved highly similar to therapeutic care of human patients suffering acute and chronic musculoskeletal affections. Standardized processing of a single organ donation and establishment of dedicated equine cell banks allows consistent and off-the-freezer allogeneic treatments to potentially be made available for millions of veterinary patients. Prior art in human translational regenerative medicine and preliminary evidence in veterinary settings strongly support the candidacy of equine progenitor cell banking as an optimal tool for efficient therapeutic management of diverse hippiatric musculoskeletal affections

Chondroid cystic malformation of the lung with trisomy 8 mosaicism: a new cystic lung malformation

Neonatal cystic disorders of the lungs are a heterogeneous malformative group including giant lobar hyperinflation, congenital pulmonary airway malformations, intralobar pulmonary sequestration, and bronchogenic cyst. Here, we describe a giant cystic pulmonary malformation in a 5-year-old girl, morphologically characterized by a highly disorganized proliferation of numerous cartilage islands, abundant mesenchymal tissue with abundant adipose differentiation, and epithelium-lined cysts. Cytogenetic analysis revealed an isolated trisomy 8, as the sole karyotype anomaly, a finding further confirmed by a whole-genome single nucleotide polymorphism array genotyping. The trisomy 8 was observed by fluorescent in situ hybridization within the malformation, and also in adjacent pulmonary parenchyma. A search of the literature revealed only 2 cases having similarities with the present case, but bearing different names. We believe that this lesion differs from congenital pulmonary airway malformations and from adult-type pulmonary hamartomas. We propose for this malformative mass the name "chondroid cystic malformation of the lung.

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

Cultured primary progenitor cell types are worthy therapeutic candidates for regenerative medicine. Clinical translation, industrial transposition, and commercial implementation of products based on such cell sources are mainly hindered by economic or technical barriers and stringent regulatory requirements. Applied research in allogenic cellular therapies in the Lausanne University Hospital focuses on cell source selection technique optimization. Use of fetal progenitor cell sources in Switzerland is regulated through Federal Transplantation Programs and associated Fetal Biobanks. Clinical applications of cultured primary progenitor dermal fibroblasts have been optimized since the 1990s as "Progenitor Biological Bandages" for pediatric burn patients and adults presenting chronic wounds. A single organ donation procured in 2009 enabled the establishment of a standardized cell source for clinical and industrial developments to date. Non-enzymatically isolated primary dermal progenitor fibroblasts (FE002-SK2 cell type) served for the establishment of a clinical-grade Parental Cell Bank, based on a patented method. Optimized bioprocessing methodology for the FE002-SK2 cell type has demonstrated that extensive and consistent progenitor cell banks can be established. In vitro mechanistic characterization and in vivo preclinical studies have confirmed potency, preliminary safety and efficacy of therapeutic progenitor cells. Most importantly, highly successful industrial transposition and up-scaling of biobanking enabled the establishment of tiered Master and Working Cell Banks using Good Manufacturing Practices. Successive and successful transfers of technology, know-how and materials to different countries around the world have been performed. Extensive developments based on the FE002-SK2 cell source have led to clinical trials for burns and wound dressing. Said trials were approved in Japan, Taiwan, USA and are continuing in Switzerland. The Swiss Fetal Transplantation Program and pioneer clinical experience in the Lausanne Burn Center over three decades constitute concrete indicators that primary progenitor dermal fibroblasts should be considered as therapeutic flagships in the domain of wound healing and for regenerative medicine in general. Indeed, one single 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

Bullying in Swiss Youth Born with a Unilateral Cleft lip and Palate by Self- and Parent-Report

This study aimed to gain a better understanding of bullying as victims and aggressors in youths born with unilateral cleft lip and palate (UCLP). This is an observational study comparing youths with UCLP (ages 8-16) and their parents with a control group (CG) of children in state schools and their parents. Forty-one youths (43% female; mean age 12.4 ± 2.3 years) and their parents (n = 40) composed the UCLP group and 56 youths (47% female; mean age 12.4 ± 1.2 years) and their parents (n = 33) were in the CG. The Olweus Bully/Victim questionnaire self- and parent-report was used to assess victims and aggressors involved in bullying behaviors. About 30% of all youths reported being a frequent victim of bullying at least 2-3 times a month and an additional 32.3% were bullied 1-2 times in the last 2-3 months. For the total sample, parents significantly (P < .05) underestimated any bullying, both as a victim (youths 62.5% vs parents 45.7%) and as an aggressor (youths 53.1% vs parents 37.1%). There were no significant group differences in experiencing any bullying between the youths with UCLP (52.5%) and the CG youths (69.6%) or in its perception by their parents (43.2% and 48.5%, respectively). There were no group differences between the combinations of victim and aggressor. While there were no differences in bullying prevalence in our sample between youths with UCLP and their peers, this study highlights differences in bullying perceptions between parents and their children