Immune-Instructive Polymers Control Macrophage Phenotype and Modulate the Foreign Body Response In Vivo

© 2020 The Author(s) Implantation of medical devices can result in inflammation. A large library of polymers is screened, and a selection found to promote macrophage differentiation towards pro- or anti-inflammatory phenotypes. The bioinstructive properties of these materials are validated within a rodent model. By identifying novel materials with immune-instructive properties, the relationship between material-immune cell interactions could be investigated, and this offers exciting possibilities to design novel bioinstructive materials that can be used for numerous clinical applications including medical implants

Innate immune cell instruction using micron-scale 3D objects of varied architecture and polymer chemistry: The ChemoArchiChip

To design effective immunomodulatory implants, innate immune cell interactions at the surface of biomaterials need to be controlled and understood. The architectural design freedom of two-photon polymerization is used to produce arrays of surface-mounted, geometrically diverse 3D polymer objects. This reveals the importance of the interplay between architecture and materials chemistry in determining human macrophage fate in vitro. The ChemoArchiChip identifies key structure-function relationships and design rules from machine learning models to build a mechanistic understanding of cell attachment and polarization. Object shape, vertex/cone angle, and size are key drivers of attachment. Particular shapes are found to heavily modulate pro- or anti-inflammatory cell polarization, while triangular pyramids drastically reduce or even eliminate attachment. Caveola-dependent endocytosis is a principal mechanism by which cells respond to objects with sharp points; i.e., low vertex/cone angles. The discovery of these putative design rules points to surfaces decorated with architectures to augment implant performance

Immune instructive materials for dendritic cell modulation

With most cytokine-based immunotherapies not fulfilling the promise of efficacy seen in pre-clinical experiments and often being associated with severe dose-limiting toxicities, biomaterial-based immunotherapies have emerged as powerful tools in different clinical settings including cancer vaccines and inflammatory diseases. Dendritic cells (DCs) play a central role in regulating adaptive immune responses making them ideal targets for immune modulation. To study the effect of polymer chemistry on DCs a screening of a polymer library constituted of acrylates, methacrylates and acrylamides was performed. Both stimulatory and regulatory polymers that instructed or inhibited DC activation respectively were identified. Stimulatory polymers instructed an immunogenic DC phenotype in the absence of any other exogenous stimuli leading to improved interaction with T cells, while regulatory polymers rendered DCs less responsive to TLR-4 stimulation and induced limited T cell proliferation. To elucidate the mechanisms of the observed polymer induced modulation in behaviour and phenotype of DCs, the coating stiffness and thickness of adsorbed proteins from serum supplemented culture medium on scaled up polymers were investigated. Two stimulatory hit polymers were additionally tested in an in vitro breast cancer-based tumour assay, showing the successful induction of tumour specific cytotoxic T lymphocytes that killed breast cancer cells efficiently. To investigate molecular changes of DCs cultured on stimulatory polymers, microarray analysis was performed to detect the expression levels of more than 21,000 genes. A short study into topography-induced DC modulations revealed that certain topographies render DC less responsive to LPS stimulus as well as slowed down DC motility, presenting a clear relationship between feature spacing and speed. In summary, findings from this study demonstrate the ability of polymer surfaces to modulate DC phenotype and function. The observations presented and discussed in this study provide a framework through which immune-instructive therapeutics for vaccine adjuvants, cancer therapies or auto-immune diseases could be developed

Immune instructive materials for dendritic cell modulation

With most cytokine-based immunotherapies not fulfilling the promise of efficacy seen in pre-clinical experiments and often being associated with severe dose-limiting toxicities, biomaterial-based immunotherapies have emerged as powerful tools in different clinical settings including cancer vaccines and inflammatory diseases. Dendritic cells (DCs) play a central role in regulating adaptive immune responses making them ideal targets for immune modulation. To study the effect of polymer chemistry on DCs a screening of a polymer library constituted of acrylates, methacrylates and acrylamides was performed. Both stimulatory and regulatory polymers that instructed or inhibited DC activation respectively were identified. Stimulatory polymers instructed an immunogenic DC phenotype in the absence of any other exogenous stimuli leading to improved interaction with T cells, while regulatory polymers rendered DCs less responsive to TLR-4 stimulation and induced limited T cell proliferation. To elucidate the mechanisms of the observed polymer induced modulation in behaviour and phenotype of DCs, the coating stiffness and thickness of adsorbed proteins from serum supplemented culture medium on scaled up polymers were investigated. Two stimulatory hit polymers were additionally tested in an in vitro breast cancer-based tumour assay, showing the successful induction of tumour specific cytotoxic T lymphocytes that killed breast cancer cells efficiently. To investigate molecular changes of DCs cultured on stimulatory polymers, microarray analysis was performed to detect the expression levels of more than 21,000 genes. A short study into topography-induced DC modulations revealed that certain topographies render DC less responsive to LPS stimulus as well as slowed down DC motility, presenting a clear relationship between feature spacing and speed. In summary, findings from this study demonstrate the ability of polymer surfaces to modulate DC phenotype and function. The observations presented and discussed in this study provide a framework through which immune-instructive therapeutics for vaccine adjuvants, cancer therapies or auto-immune diseases could be developed

Immune-instructive materials as new tools for immunotherapy

Immune instructive materials, are materials with the ability to modulate or mimic the function of immune cells, provide exciting opportunities for developing new therapies in many areas including medical devices, chronic inflammation, cancer, and autoimmune diseases. In this review we highlight some of the latest research involving material-based strategies for modulating macrophage phenotype and dendritic cell function, as well as a brief description on biomaterial use in T cell and natural killer cell engineering. We highlight studies on material topography, size, shape and surface chemistry to reduce inflammation, along with scaffold and hydrogel delivery systems that are used for modulating DC phenotype and influencing T cell polarization. Artificial antigen presenting cells are also reviewed as a promising approach to cancer immunotherapy

Occurrence of Babesia species in captive reindeer (Rangifer tarandus) in Germany

Two cases of acute babesiosis in captive reindeer (Rangifer tarandus) in two German zoos in 2009 and 2012 triggered this study to investigate the occurrence and species diversity of Babesia parasites infecting reindeer in different zoos and deer parks in Germany. Between June and December 2013, blood samples were taken from 123 clinically inapparent reindeer from 16 different facilities. Samples were tested for the presence of Babesia species DNA by conventional PCR and sequence analysis of part of the 18S rRNA gene. Also, Giemsa-stained smears of reindeer blood samples were examined for parasitaemia by light microscopy. The overall PCR-prevalence in blood samples was 23.6% (n=29). Comparison of sequenced amplicons with GenBank entries possibly revealed up to five different Babesia species: B. venatorum (n=19), B. capreoli (n=2) and B. capreoli-like (n=4), B. odocoilei-like (n=2) and B. divergens (n=1), while one sample turned out to be a Theileria sp. Out of the 16 facilities in the study, 12 housed at least one positive animal. In Giemsa-stained blood smears, intra-erythrocytic Babesia parasites were detected in samples of three reindeer from three locations. The high prevalence of Babesia infections implicates babesiosis to be a relevant infectious disease threat for captive reindeer in Germany. Consequently, reindeer with clinical signs compatible to those of acute babesiosis should either be tested for the presence of Babesia spp. DNA or blood smears should be examined for parasitaemia

Mitigating the foreign body response through ‘immune-instructive’ biomaterials

ObjectivesBiomaterials are routinely used in clinical applications. A key to the clinical success of implanted biomaterials is not eliciting detrimental immune responses. In this article, we provide an overview of immune responses to biomaterials, along with biomaterial-based approaches to mitigate the adverse host reactions while supporting pro-healing immune responses. We also review existing in-vitro models used to assess the biocompatibility of biomaterials.Key findingsOnce implanted, biomaterials are often detected as foreign bodies by the immune system, triggering detrimental immune responses. Such responses could damage host tissues and impair the function of implanted materials or devices. Therefore, there is substantial interest in developing new materials and tools with the ability to modulate immune responses to support tissue regeneration and healing processes. However, the bioengineering of immune responses through biomaterials requires detailed understanding of how the immune system typically responds to foreign materials. This knowledge can inform designing materials with bio-instructive chemistries and/or surface attributes. In this review, first we briefly discuss basic aspects of the foreign body response followed by different strategies for developing ‘immune-instructive’ biomaterials, models to test their efficacy and examples of their clinical applications.ConclusionsPromising progress has been made in the field of biomaterial engineering however, how different immune cells interact with biomaterials is yet to be fully elucidated. A better understanding of cell-material interactions, and particularly the impact of inter-individual variations, will allow the development of new generation of more personalised ‘immune-instructive’ biomaterials and medical devices to modulate immune responses towards anti-inflammatory and pro-healing phenotypes