Development and clinical evaluation of laser-sintered ankle foot orthoses

Ankle foot orthoses (AFOs) are traditionally manufactured using vacuum thermoforming as shaping technology. Additive manufacturing has the potential to disruptively change the way these orthopaedic devices are produced. In this study, AFOs are developed which are virtually designed and produced with laser sintering as shaping technology. The mechanical and clinical performances of these laser-sintered AFOs are compared with traditionally manufactured AFO by asking seven patients (both children and adults) to walk with each type of AFO

Engineering cytokine therapeutics

Cytokines have pivotal roles in immunity, making them attractive as therapeutics for a variety of immune-related disorders. However, the widespread clinical use of cytokines has been limited by their short blood half-lives and severe side effects caused by low specificity and unfavourable biodistribution. Innovations in bioengineering have aided in advancing our knowledge of cytokine biology and yielded new technologies for cytokine engineering. In this Review, we discuss how the development of bioanalytical methods, such as sequencing and high-resolution imaging combined with genetic techniques, have facilitated a better understanding of cytokine biology. We then present an overview of therapeutics arising from cytokine re-engineering, targeting and delivery, mRNA therapeutics and cell therapy. We also highlight the application of these strategies to adjust the immunological imbalance in different immune-mediated disorders, including cancer, infection and autoimmune diseases. Finally, we look ahead to the hurdles that must be overcome before cytokine therapeutics can live up to their full potential

Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells.

Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.We thank M. Jaeger (Radboudumc) for kindly providing flourescein isothiocyanate-labelled Candida albicans. D. Williams (East Tennessee State University) provided the β-glucan we used in our initial experiments. H. Lemmers (Radboudumc) kindly prepared the purified lipopolysaccharide used for stimulation of primary human monocytes and macrophages. Part of the figures were prepared using (among other software) Biorender.com. B.N. is supported by a National Health and Medical Research Council (Australia) Investigator Grant (APP1173314). This work was supported by National Institutes of Health grants R01 HL144072, R01 CA220234 and P01 HL131478, as well as a Vici grant from the Dutch Research Council NWO and an ERC Advanced Grant (all to W.J.M.M.). M.G.N. was supported by a Spinoza grant from Dutch Research Council NWO and an ERC Advanced Grant (#833247).S

ENDOGLIN is dispensable for vasculogenesis, but required for vascular endothelial growth factor-induced angiogenesis

ENDOGLIN (ENG) is a co-receptor for transforming growth factor-β (TGF-β) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA-mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis

Performance of isogeometric analysis for 2D Helmholtz problems: A study of dispersion characteristics, convergence rates and efficient quadrature

This work studies the potential of NURBS-based IsoGeometric Analysis (IGA) for use in dynamic problems, more specifically 2D Helmholtz problems. The dispersion characteristics of IGA discretizations are investigated and compared to those of classical Finite Element Analysis (FEA). This is done by studying both the eigenvalues and the eigenmodes of simple 2D domains governed by a Helmholtz equation. It is found that IGA exhibits advantageous properties as compared to standard FEA discretizations, but that both the domain geometry and the parametrization have a large influence on the dispersion error for IGA. Simulations are also carried out on a less trivial problem domain – with boundary geometries that cannot be exactly described by standard FEA discretizations. Multiple frequencies are investigated and frequency response functions computed. Convergence rates are studied, both on a per-degree-of-freedom basis and on a computation time basis. Results are each time benchmarked against standard FEA results. In order to more fully exploit the higher continuity of IGA discretizations, a nearly optimal quadrature rule for NURBS-based IGA developed by Auricchio et al. is implemented, and the computational efficiency is compared to that obtained when using a standard Gauss rule. The results show that the higher complexity introduced by this nearly optimal quadrature compensates for the lower required number of quadrature points, and seems to limit its practical use.status: publishe