Beyond Encapsulation: Exploring Macrophage-Fibroblast Cross Talk in Implant-Induced Fibrosis.

The foreign body response (FBR) and organ fibrosis are complex biological processes involving the interaction between macrophages and fibroblasts. Understanding the molecular mechanisms underlying macrophage-fibroblast cross talk is crucial for developing strategies to mitigate implant encapsulation, a major cause of implant failure. This article reviews the current knowledge on the role of macrophages and fibroblasts in the FBR and organ fibrosis, highlighting the similarities between these processes. The FBR is characterized by the formation of a fibrotic tissue capsule around the implant, leading to functional impairment. Various factors, including material properties such as surface chemistry, stiffness, and topography, influence the degree of encapsulation. Cross talk between macrophages and fibroblasts plays a critical role in both the FBR and organ fibrosis. However, the precise molecular mechanisms remain poorly understood. Macrophages secrete a wide range of cytokines that modulate fibroblast behavior such as abundant collagen deposition and myofibroblast differentiation. However, the heterogeneity of macrophages and fibroblasts and their dynamic behavior in different tissue environments add complexity to this cross talk. Experimental evidence from in vitro studies demonstrates the impact of material properties on macrophage cytokine secretion and fibroblast physiology. However, the correlation between in vitro response and in vivo encapsulation outcomes is not robust. Adverse outcome pathways (AOPs) offer a potential framework to understand and predict process complexity. AOPs describe causal relationships between measurable events leading to adverse outcomes, providing mechanistic insights for in vitro testing and predictive modeling. However, the development of an AOP for the FBR does require a comprehensive understanding of the molecular initiating events and key event relationships to identify which events are essential. In this article, we describe the current knowledge on macrophage-fibroblast cross talk in the FBR and discuss how targeted research can help build an AOP for implant-related fibrosis.

Dynamic adaptation of mesenchymal stem cell physiology upon exposure to surface micropatterns.

Human mesenchymal stem (hMSCs) are defined as multi-potent colony-forming cells expressing a specific subset of plasma membrane markers when grown on flat tissue culture polystyrene. However, as soon as hMSCs are used for transplantation, they are exposed to a 3D environment, which can strongly impact cell physiology and influence proliferation, differentiation and metabolism. Strategies to control in vivo hMSC behavior, for instance in stem cell transplantation or cancer treatment, are skewed by the un-physiological flatness of the standard well plates. Even though it is common knowledge that cells behave differently in vitro compared to in vivo, only little is known about the underlying adaptation processes. Here, we used micrometer-scale defined surface topographies as a model to describe the phenotype of hMSCs during this adaptation to their new environment. We used well established techniques to compare hMSCs cultured on flat and topographically enhanced polystyreneand observed dramatically changed cell morphologies accompanied by shrinkage of cytoplasm and nucleus, a decreased overall cellular metabolism, and slower cell cycle progression resulting in a lower proliferation rate in cells exposed to surface topographies. We hypothesized that this reduction in proliferation rate effects their sensitivity to certain cancer drugs, which was confirmed by higher survival rate of hMSCs cultured on topographies exposed to paclitaxel. Thus, micro-topographies can be used as a model system to mimic the natural cell micro-environment, and be a powerful tool to optimize cell treatment in vitro.

Geometric constraints of endothelial cell migration on electrospun fibres.

Biomaterial scaffolds that can form a template for tissue growth and repair forms the basis of many tissue engineering paradigms. Cell migration and colonisation is an important, and often overlooked, first step. In this study, fibrous guidance structures were produced via electrospinning and the effect of physical features such as fibre diameter (ranging from 500 nm to 10 µm) on endothelial cell migration was assessed. Using a modified wound healing assay, fibre diameter was found to have a significant effect on the rate of wound closure and the peak migration velocity of the cells with scaffold diameter shown to influence both morphology and alignment of the migrating cells. The expression, phosphorylation and distribution of focal adhesion kinase (FAK) was disrupted on the different scaffolds with small-diameter scaffolds exhibiting increased FAK phosphorylation with the kinase present in the cytosol whereas on large-diameter scaffolds FAK was largely restricted to focal adhesions at the cell periphery. This study demonstrates that electrospun scaffolds can be used to model cell migration on fibrous substrates, and particularly for the studying effects of physical features of the substrate, and that FAK is a key mediator of cell-scaffold interactions on migrating cells.

The cytokine secretion profile of mesenchymal stromal cells is determined by surface structure of the microenvironment.

Mesenchymal stromal cells (MSC) secrete factors that contribute to organ homeostasis and repair in a tissue specific manner. For instance, kidney perivascular mesenchymal stromal cells (kPSCs) can facilitate renal epithelial repair through secretion of hepatocyte growth factor (HGF) while the secretome of bone marrow MSCs gives rise to immunosuppression. Stromal cells function in a complex 3-dimensional (3D) connective tissue architecture that induces conformational adaptation. Here we tested the hypothesis that surface topography and associated cell adaptations dictate stromal cell function through tuning of the cytokines released. To this end, we cultured human bone marrow and kidney perivascular stromal cells in the TopoWell plate, a custom-fabricated multi-well plate containing 76 unique bioactive surface topographies. Using fluorescent imaging, we observed profound changes in cell shape, accompanied by major quantitative changes in the secretory capacity of the MSCs. The cytokine secretion profile was closely related to cell morphology and was stromal cell type specific. Our data demonstrate that stromal cell function is determined by microenvironment structure and can be manipulated in an engineered setting. Our data also have implications for the clinical manufacturing of mesenchymal stromal cell therapy, where surface topography during bioreactor expansion should be taken into account to preserve therapeutic properties.

Definition and classification of disasters : Introduction of a disaster severity scale

In disaster medicine, a meaningful definition of the word disaster is lacking. A simple definition, using only two criteria, is proposed. Added to this, a classification scheme is formulated. Based on this definition and classification, a disaster severity scale is introduced. The methodology used is described, and the significance of these proposals is discussed.(AU)

An attempt at more accurate estimation of the number of ambulances needed at disasters in the Netherlands

A more accurated estimation of the number of ambulances needed at disasters prevents vehicles from being withdrawn unnecessary from their "normal" duties, thereby curtailing needless expense and helping to ensure that disaster sites are not overcrowded with emergency workers impeding each other's effectiveness. This article discusses a formula for determining the number of ambulances needed at a disaster (AU)

Methodology : Tools for evaluating disaster : Preliminary results of some hundreds of disasters

Epidemiology research of disasters is hampered by a lack of uniformity and standardization in describing these events. By applying a classification and scoring system, which recently became available, an analisys could by performed of 416 disasters from the past 40 years. Only 79 references were useful in obtaining reliable figures for a scoring on the Disasters Severity Scale (DSS). The various disaster types show a relationship between the DSS-scoring on the one hand, and the severity factor (S)and the number of the dead and wounded (n) on the other. It is concluded that the classification and scoring system used could serve as a tool for evaluating the majority of disasters. A small improvement of this system is recommended (AU)

Criteria for the assessment of disaster preparedness

The assessment of disaster preparedness of certain areas is to a large extent liable to subjectivity. For a modern society, however, objectivity is a prereqisite. A methodology is presented calculating the disaster preparedness of municipalities, counties, provinces, states, or even countries. Standardization of this methodology could allow comparison of disaster preparedness between these areas (AU)

Assesment of the medical services'commitment capacity, of a disaster medical gravity index and of disaster preparedness

During a disaster, the synchronization of the different links in the rescue chain and their respective capacities is decisive if the progressive medical treatment is to be adequate. The calculation of a disaster's medical gravity index and the comparison of this with the total available capacity of medical services make it possible to assess the commitment required on the part of the emergency medical aid both in planning and managing the response to a disaster(AU)

The medical severity index of disasters

In 1980 an international working party postulated a definition for a disaster. later this concept was formulated into a classification and scoring system. This system has now been refined to be used prospectively during the management stage of a calamity. By calculating the medical severity index, which is the product of the casualty load and the severity of the incident, and comparing this figure with the available total capacity of the medical services, which is the medical rescue capacity, the medical transport capacity and the hospital treatment capacity, the dispatcher at the control center can fairly quickly and precisely identify if a calamity is to be regarded as a disaster or not and if the region can cope with the situation. Moreover a calculation of the hospital treatment capacity in the dimensions needed for the medical rescue capacity and medical transport capcity when planning how to deal with a disaster.(AU)