3D Printable Vascular Networks Generated by Accelerated Constrained Constructive Optimization for Tissue Engineering.

One of the greatest challenges in fabricating artificial tissues and organs is the incorporation of vascular networks to support the biological requirements of the embedded cells, encouraging tissue formation and maturation. With the advent of 3D printing technology, significant progress has been made with respect to generating vascularized artificial tissues. Current algorithms to generate arterial/venous trees are computationally expensive and offer limited freedom to optimize the resulting structures. Furthermore, there is no method for algorithmic generation of vascular networks that can recapitulate the complexity of the native vasculature for more than two trees, and export directly to a 3D printing format. Here, we report such a method, using an accelerated constructive constrained optimization approach, by decomposing the process into construction, optimization, and collision resolution stages. The new approach reduces computation time to minutes at problem sizes where previous implementations have reported days. With the optimality criterion of maximizing the volume of useful tissue which could be grown around such a network, an approach of alternating stages of construction and batch optimization of all node positions is introduced and shown to yield consistently more optimal networks. The approach does not place a limit on the number of interpenetrating networks that can be constructed in a given space; indeed we demonstrate a biomimetic, liver-like tissue model. Methods to account for the limitations of 3D printing are provided, notably the minimum feature size and infill at sharp angles, through padding and angle reduction, respectively.EPSRC Doctoral Training Partner-ship Award (EP/N509620/1) EPSRC (EP/R511675/1 & EP/N509620/1) Isaac Newton Trust Rosetrees Trust (M787). Cambridge Trust CONACyT (Mexico) EPSRC Cambridge & Cranfield Doctoral Training Centre in Ultra Precision (EP/K503241/1

Physical and biological characterization of ferromagnetic fiber networks: effect of fibrin deposition on short-term in vitro responses of human osteoblasts.

Ferromagnetic fiber networks have the potential to deform in vivo imparting therapeutic levels of strain on in-growing periprosthetic bone tissue. 444 Ferritic stainless steel provides a suitable material for this application due to its ability to support cultures of human osteoblasts (HObs) without eliciting undue inflammatory responses from monocytes in vitro. In the present article, a 444 fiber network, containing 17 vol% fibers, has been investigated. The network architecture was obtained by applying a skeletonization algorithm to three-dimensional tomographic reconstructions of the fiber networks. Elastic properties were measured using low-frequency vibration testing, providing globally averaged properties as opposed to mechanical methods that yield only local properties. The optimal region for transduction of strain to cells lies between the ferromagnetic fibers. However, cell attachment, at early time points, occurs primarily on fiber surfaces. Deposition of fibrin, a fibrous protein involved in acute inflammatory responses, can facilitate cell attachment within this optimal region at early time points. The current work compared physiological (3 and 5 g·L(-1)) and supraphysiological fibrinogen concentrations (10 g·L(-1)), using static in vitro seeding of HObs, to determine the effect of fibrin deposition on cell responses during the first week of cell culture. Early cell attachment within the interfiber spaces was observed in all fibrin-containing samples, supported by fibrin nanofibers. Fibrin deposition influenced the seeding, metabolic activity, and early stage differentiation of HObs cultured in the fibrin-containing fiber networks in a concentration-dependant manner. While initial cell attachment for networks with fibrin deposited from low physiological concentrations was similar to control samples without fibrin deposition, significantly higher HObs attached onto high physiological and supraphysiological concentrations. Despite higher cell numbers with supraphysiological concentrations, cell metabolic activities were similar for all fibrinogen concentrations. Further, cells cultured on supraphysiological concentrations exhibited lower cell differentiation as measured by alkaline phosphatase activity at early time points. Overall, the current study suggests that physiological fibrinogen concentrations would be more suitable than supraphysiological concentrations for supporting early cell activity in porous implant coatings.This is the author accepted manuscript. The final version is available from Mary Ann Liebert at http://online.liebertpub.com/doi/abs/10.1089/ten.TEA.2014.0211?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

Processes and coastal dynamics in the Ensenada de Marbella: recent morphosedimentary evolution

La Ensenada de Marbella ha experimentado en las últimas décadas cambios físicos y socio-económicos sustanciales debidos fundamentalmente a una transformación en el modelo económico y un desarrollo acusado del turismo residencial y todos los impactos en los usos del suelo relacionado con ello. Sin embargo, las causas de la alteración de la dinámica litoral también hay que buscarlas en cambios en la morfología del nearshore y en la dinámica sedimentaria. Para analizar la morfodinámica de la ensenada en varios escenarios temporales, simulaciones de oleaje sobre batimetrías del 1888 y actuales revelan cambios importantes en los patrones dispersión de la energía y el funcionamiento de la bahía a través de complejas células litorales de transporte. El análisis de los procesos dinámicos en la zona del nearshore y el estudio volumétrico a través de modelos de batimetrías secuenciales muestran como dichos cambios morfológicos de los fondos costeros pueden o no estar relacionados con cambios a largo plazo en la línea de costa, y por tanto ser co-responsables de los procesos de erosión y acreción acelerados evidentes a lo largo de la Ensenada

Socio-demographic characteristics associated with emotional and social loneliness among older adults

Background: International studies provide an overview of socio-demographic characteristics associated with loneliness among older adults, but few studies distinguished between emotional and social loneliness. This study examined socio-demographic characteristics associated with emotional and social loneliness. Methods: Data of 2251 community-dwelling older adults, included at the baseline measure of the Urban Health Centers Europe (UHCE) project, were analysed. Loneliness was measured with the 6-item De Jong-Gierveld Loneliness Scale. Multivariable logistic regression models were used to evaluate associations between age, sex, living situation, educational level, migration background, and loneliness. Results: The mean age of participants was 79.7 years (SD = 5.6 years); 60.4% women. Emotional and social loneliness were reported by 29.2 and 26.7% of the participants; 13.6% experienced emotional and social loneliness simultaneously. Older age (OR: 1.16, 95% CI: 1.06–1.28), living without a partner (2.16, 95% CI: 1.73–2.70), and having a low educational level (OR: 1.82, 95% CI: 1.21–2.73), were associated with increased emotional loneliness. Women living with a partner were more prone to emotional loneliness than men living with a partner (OR: 1.78, 95% CI: 1.31–2.40). Older age (OR: 1.11, 95% CI: 1.00–1.22) and having a low educational level (OR: 1.77, 95% CI: 1.14–2.74) were associated with increased social loneliness. Men living without a partner were more prone to social loneliness than men living with a partner (OR: 1.94, 95% CI: 1.35–2.78). Conclusions: Socio-demographic characteristics associated with emotional and social loneliness differed regarding sex and living situation. Researchers, policy makers, and healthcare professionals should be aware that emotional and social loneliness may affect older adults with different socio-demographic characteristics

Reconstruction of the mouse extrahepatic biliary tree using primary human extrahepatic cholangiocyte organoids

Treatment of common bile duct disorders such as biliary atresia or ischaemic strictures is limited to liver transplantation or hepatojejunostomy due to the lack of suitable tissue for surgical reconstruction. Here, we report a novel method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree and we explore the potential of bioengineered biliary tissue consisting of these extrahepatic cholangiocyte organoids (ECOs) and biodegradable scaffolds for transplantation and biliary reconstruction in vivo. ECOs closely correlate with primary cholangiocytes in terms of transcriptomic profile and functional properties (ALP, GGT). Following transplantation in immunocompromised mice ECOs self-organize into tubular structures expressing biliary markers (CK7). When seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary marker expression (CK7) and function (ALP, GGT). This bioengineered tissue can reconstruct the wall of the biliary tree (gallbladder) and rescue and extrahepatic biliary injury mouse model following transplantation. Furthermore, it can be fashioned into bioengineered ducts and replace the native common bile duct of immunocompromised mice, with no evidence of cholestasis or lumen occlusion up to one month after reconstruction. In conclusion, ECOs can successfully reconstruct the biliary tree following transplantation, providing proof-of-principle for organ regeneration using human primary cells expanded in vitro

The effectiveness of a coordinated preventive care approach for healthy ageing (UHCE) among older persons in five European cities: A pre-post controlled trial

Background: Older persons often have multiple health and social problems and need a variety of health services. A coordinated preventive approach that integrates the provision of health and social care services could promote healthy ageing. Such an approach can be organised differently, depending on the availability and organizational structures in the local context. Therefore, it is important to evaluate the effectiveness of a coordinated preventive care approach in various European settings. Objectives: This study explored the effects of a coordinated preventive health and social care approach on the lifestyle, health and quality of life of community-dwelling older persons in five European cities. Design: International multi-center pre-post controlled trial. Setting: Community settings in cities in the United Kingdom, Greece, Croatia, the Netherlands and Spain. Participants: 1844 community-dwelling older persons (mean age = 79.5; SD = 5.6). Methods: The Urban Health Centres Europe (UHCE) approach consisted of a preventive multidimensional health assessment and, if a person was at-risk, coordinated care-pathways targeted at fall risk, appropriate medication use, loneliness and frailty. Intervention and control sites were chosen based on their location in distinct neighbourhoods in the participating cities. Persons in the catchment area of the intervention sites ‘the intervention group’ received the UHCE a

Stimulation of Human Osteoblast Differentiation in Magneto-Mechanically Actuated Ferromagnetic Fiber Networks

There is currently an interest in “active” implantable biomedical devices that include mechanical stimulation as an integral part of their design. This paper reports the experimental use of a porous scaffold made of interconnected networks of slender ferromagnetic fibers that can be actuated in vivo by an external magnetic field applying strains to in-growing cells. Such scaffolds have been previously characterized in terms of their mechanical and cellular responses. In this study, it is shown that the shape changes induced in the scaffolds can be used to promote osteogenesis in vitro. In particular, immunofluorescence, gene and protein analyses reveal that the actuated networks exhibit higher mineralization and extracellular matrix production, and express higher levels of osteocalcin, alkaline phosphatase, collagen type 1α1, runt-related transcription factor 2 and bone morphogenetic protein 2 than the static controls at the 3-week time point. The results suggest that the cells filling the inter-fiber spaces are able to sense and react to the magneto-mechanically induced strains facilitating osteogenic differentiation and maturation. This work provides evidence in support of using this approach to stimulate bone ingrowth around a device implanted in bone and can pave the way for further applications in bone tissue engineering

Stimulation of Human Osteoblast Differentiation in Magneto-Mechanically Actuated Ferromagnetic Fiber Networks.

There is currently an interest in "active" implantable biomedical devices that include mechanical stimulation as an integral part of their design. This paper reports the experimental use of a porous scaffold made of interconnected networks of slender ferromagnetic fibers that can be actuated in vivo by an external magnetic field applying strains to in-growing cells. Such scaffolds have been previously characterized in terms of their mechanical and cellular responses. In this study, it is shown that the shape changes induced in the scaffolds can be used to promote osteogenesis in vitro. In particular, immunofluorescence, gene and protein analyses reveal that the actuated networks exhibit higher mineralization and extracellular matrix production, and express higher levels of osteocalcin, alkaline phosphatase, collagen type 1α1, runt-related transcription factor 2 and bone morphogenetic protein 2 than the static controls at the 3-week time point. The results suggest that the cells filling the inter-fiber spaces are able to sense and react to the magneto-mechanically induced strains facilitating osteogenic differentiation and maturation. This work provides evidence in support of using this approach to stimulate bone ingrowth around a device implanted in bone and can pave the way for further applications in bone tissue engineering.This research was supported by the EPSRC (EP/R511675/1), the Blavatnik Family Foundation and the European Research Council (Grant No. 240446). Financial support for G.K.L. has been provided via the Blavatnik Family Foundation and Reuben Foundation. Financial support for R.A.B. has been provided via the National Institute for Health Research (NIHR)