Topology Optimization and 3D printing of Large Deformation Compliant Mechanisms for Straining Biological Tissues

This paper presents a synthesis approach in a density-based topology optimization setting to design large deformation compliant mechanisms for inducing desired strains in biological tissues. The modelling is based on geometrical nonlinearity together with a suitably chosen hypereleastic material model, wherein the mechanical equilibrium equations are solved using the total Lagrangian finite element formulation. An objective based on least-square error with respect to target strains is formulated and minimized with the given set of constraints and the appropriate surroundings of the tissues. To circumvent numerical instabilities arising due to large deformation in low stiffness design regions during topology optimization, a strain-energy based interpolation scheme is employed. The approach uses an extended robust formulation i.e. the eroded, intermediate and dilated projections for the design description as well as variation in tissue stiffness. Efficacy of the synthesis approach is demonstrated by designing various compliant mechanisms for providing different target strains in biological tissue constructs. Optimized compliant mechanisms are 3D-printed and their performances are recorded in a simplified experiment and compared with simulation results obtained by a commercial software.Comment: 23 pages, 14 figure

Application of high resolution DLP stereolithography for fabrication of tricalcium phosphate scaffolds for bone regeneration

Bone regeneration requires porous and mechanically stable scaffolds to support tissue integration and angiogenesis, which is essential for bone tissue regeneration. With the advent of additive manufacturing process, production of complex porous architecture has become feasible. However, a balance has to be sorted between porous architecture and mechanical stability which facilitates bone regeneration for load bearing applications. 
 Current study evaluates used of high resolution digital light processing (DLP) -based additive manufacturing to produce complex but mechanical stable scaffolds based on β-tricalcium phosphate (β-TCP) for bone regeneration. 
 Four different geometries, a rectilinear Grid, hexagonal Kagome, schwart primitive and hollow Schwarz are designed with 400 µm pores and 75 or 50 vol.% porosity. However after initial screening for design stability and mechanical properties, only a rectilinear Grid structure, a hexagonal Kagome structure are found to be reproducible and showed higher mechanical properties. 
 Micro computed tomography (µ-CT) analysis shows < 2 vol.% error in porosity and < 6 % relative deviation of average pore sizes for the Grid structures. At 50 vol.% porosity, this architecture also has the highest compressive strength of 44.7 MPa (Weibull modulus is 5.28), while bulk specimens reach 235 ± 37 MPa. 
 To evaluate suitability of 3D scaffolds produce by DLP methods for bone regeneration, scaffolds were cultured with murine preosteoblastic MC3T3-E1 cells. Short term study showed cells growth over 14 days, with more than two-fold increase of alkaline phosphatase (ALP) activity compared to cells on 2D tissue culture plastic. Collagen deposition was increased by a factor of 1.5 – 2 when compared to the 2D controls. This confirm retention of biocompatible and osteo-inductive properties of β-TCP following DLP process. 
 This study has implications for designing of the high resolution porous scaffolds for bone regenerative applications and contributes to understanding of DLP based additive manufacturing process for medical applications

Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2.

Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high-dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies

Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation

SummaryMacrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease

Publisher Correction: Tumor-necrosis factor impairs CD4⁺ T cell–mediated immunological control in chronic viral infection (Nature Immunology, (2016), 17, 5, (593-603), 10.1038/ni.3399).

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Enzymatic activity of HPGD in Treg cells Suppresses Tconv cells to maintain adipose tissue homeostasis and prevent metabolic dysfunction

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into the metabolite 15-keto PGE2, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.Lisa Schmidleithner, Yasser Thabet, Eva Schonfeld, Maren Kohne, Daniel Sommer ... Simon C. Barry ... et al