Immunogenicity | EPFL Graph Search

Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:

Wanted immunogenicity typically relates to vaccines, where the injection of an antigen (the vaccine) provokes an immune response against the pathogen, protecting the organism from future exposure. Immunogenicity is a central aspect of vaccine development.
Unwanted immunogenicity is an immune response by an organism against a therapeutic antigen. This reaction leads to production of anti-drug-antibodies (ADAs), inactivating the therapeutic effects of the treatment and potentially inducing adverse effects.

A challenge in biotherapy is predicting the immunogenic potential of novel protein therapeutics. For example, immunogenicity data from high-income countries are not always transferable to low-income and middle-income countries. Another challenge is considering how the immunogenicity of vaccines changes with a

Effect of temporal onsets of mechanical loading on bone formation inside a tissue engineering scaffold combined with cell therapy

Tanja Cloé Hausherr, Dominique Pioletti

Several approaches to combine bone substitutes with biomolecules, cells or mechanical loading have been explored as an alternative to the limitation and risk-related bone auto- and allo-grafts. In particular, human bone progenitor cells seeded in porous poly(L-lactic acid)/tricalcium phosphate scaffolds have shown promising results. Furthermore, the application of mechanical loading has long been known to be a key player in the regulation of bone architecture and mechanical properties. Several in vivo studies have pointed out the importance of its temporal offset. When an early mechanical loading was applied a few days after scaffold implantation, it was ineffective on bone formation, whereas a delayed mechanical loading of several weeks was beneficial for bone tissue regeneration. No information is reported to date on the effectiveness of applying a mechanical loading in vivo on cell-seeded scaffold with respect to bone formation in a bone site. In our study, we were interested in human bone progenitor cells due to their low immunogenicity, sensitivity to mechanical loading and capacity to differentiate into osteogenic human bone progenitor cells. The latest capacity allowed us to test two different bone cell fates originating from the same cell type. Therefore, the general aim of this study was to assess the outcome on bone formation when human bone progenitor cells or pre-differentiated osteogenic human bone progenitor cells are combined with early and delayed mechanical loading inside bone tissue engineering scaffolds. Scaffolds without cells, named cell-free scaffold, were used as control. Surprisingly, we found that (1) the optimal solution for bone formation is the combination of cell-free scaffolds and delayed mechanical loading and that (2) the timing of the mechanical application is crucial and dependent on the cell type inside the implanted scaffolds.

2018

Engineering Dynamic Hydrogels For In Vitro Organoid Culture

Delphine Lorraine Perle Blondel

Over the past decade, methods to culture stem cells in three dimensions have opened up a plethora of new opportunities for basic and translational research in the life sciences. In particular, the use of natural extracellular matrix (ECM) surrogates, such as mouse tumour-derived Matrigel, unleashed the possibility to recapitulate complex multicellular behaviours in vitro, culminating in the successful derivation of miniaturized organs, termed organoids. While organoids hold tremendous potential as model systems in basic biology, the translational potential of these systems is hampered by their strict dependency on animal-derived matrices that suffer from batch-to-batch variability, potential immunogenicity, and ethical concerns. Recent efforts in engineering covalently crosslinked synthetic hydrogels have attempted to substitute these ill-defined organoid culture systems. However, although these bio-artificial matrices have shown significant potential for 3D organoid culture, their stability and their inherent elastic nature hamper organoid development. Indeed, the native ECM, just like Matrigel, is a highly viscoelastic and dynamic 3D milieu that can relax in response to tissue-induced stress by breaking and subsequently rearranging its network, thus permitting cellular remodelling without compromising the macroscopic stability of the material over time. Therefore, there is a need to develop the next generation of synthetic organoid culture matrices, exhibiting in vivo-like stress-relaxation properties. This thesis provides a perspective on how chemically defined, bio-inspired hydrogels can be designed as potential replacements for native ECM-based matrices for 3D organoid culture. In contrast to traditional synthetic hydrogels that cannot accommodate the dynamic mechanical changes occurring during organoid development, four types of synthetic matrices were developed that are crosslinked, either fully or partially, through dynamic physical bonds. The introduction of such network dynamics is shown to facilitate key morphogenetic processes, such as tissue budding, that are normally absent in purely elastic networks. A unifying hypothesis emerging from these results is that stress relaxation is a crucial requirement for 3D organoid culture. The mechanisms by which stress relaxation influence ISC fate and organoid development remain to be further studied. Preliminary experiments indicated that the stem cells may sense and respond to these characteristics through differential activation of mechanosensing pathways including the transcriptional co-activator YAP. The dynamic hydrogels developed in this thesis hold great promise as tunable environments for stem cell-based self-organization, enabling morphogenetic processes that may be suppressed in conventional synthetic hydrogels systems predominantly used in 3D cell culture applications.

EPFL2019

In vivo mechanical loading combined with cell therapy in a bone tissue engineering scaffold

Tanja Cloé Hausherr

Bone defects generate a worldwide high demand for bone repair and reconstruction. The incidence of bone defect repair in our aging society is expected to increase in the next decades. As bone auto- and allografting solutions often suffer from limited supplies, there is a clinical need for alternative bone substitutes, challenging researchers in bone tissue engineering to find novel approaches. To address this challenge, several biomaterials have been combined with different approaches, such as various biomolecules delivery, cell therapy or the application of mechanical loading. In the present PhD thesis, we assessed for the first time the effect of temporal onsets of mechanical loading combined with cell therapy in a tissue engineering scaffold implanted in a bone site. For this purpose, we used a poly(L-lactic acid)/ß-tricalcium phosphate scaffold, human bone progenitor cells and two mechanical loading conditions. The choice of the scaffold was motivated by its reinforced porous structure and enhanced bioactivity, whereas, for the choice of cells, we were driven by their low immunogenicity and high capacity for osteogenic differentiation. This capacity allowed us to evaluate two different bone cell fates originating from the same cell type. We then used the same mechanical loading parameters as in previous studies on scaffolds without cells. When loading was applied a few days post-implantation (early loading) and a few weeks post-implantation (delayed loading), moderate and advantageous effects for bone repair could respectively be observed. We focused our work on (1) the investigation of a potential immune reaction triggered by xenograft cells at an early stage of implantation in immuno-competent rats and (2) the evaluation of early and delayed mechanical loadings on bone formation when combined with cell therapy. Three scaffold conditions were used: human bone progenitor cell-seeded, osteogenic human bone progenitor cell-seeded and cell-free scaffolds. Each scaffold condition was implanted bilaterally in both femoral condyles of rats. In the first part of this thesis, early immune reaction was evaluated on implanted scaffolds based on histology. The results indicated that, unlike cell-free scaffolds, both cell-seeded types of scaffolds affected the surrounding tissue by forming fibrous tissue but without triggering particular specific immune reaction. In the second part, we followed static and dynamic bone parameters inside scaffolds based on microCT scans. We showed that, independently of mechanical loading conditions, a significantly higher amount of bone was formed within cell-free scaffolds than within the two cell-seeded ones. Depending on the cell-seeded scaffold conditions, early mechanical loading had different effects on bone formation. We concluded that the timing of mechanical loading and the cell types, as well as specific combinations thereof, are crucial for a beneficial bone repair. Overall, however, cell-free scaffolds used in this study could be considered as the best solution when combined with delayed mechanical loading, as it is simple and safe from a clinical point of view without increasing regulatory restriction due to the use of cells.

EPFL2016