The interplay between tissue growth and scaffold degradation in engineered tissue constructs

In vitro tissue engineering is emerging as a potential tool to meet the high demand for replacement tissue, caused by the increased incidence of tissue degeneration and damage. A key challenge in this field is ensuring that the mechanical properties of the engineered tissue are appropriate for the in vivo environment. Achieving this goal will require detailed understanding of the interplay between cell proliferation, extracellular matrix (ECM) deposition and scaffold degradation.\ud \ud In this paper, we use a mathematical model (based upon a multiphase continuum framework) to investigate the interplay between tissue growth and scaffold degradation during tissue construct evolution in vitro. Our model accommodates a cell population and culture medium, modelled as viscous fluids, together with a porous scaffold and ECM deposited by the cells, represented as rigid porous materials. We focus on tissue growth within a perfusion bioreactor system, and investigate how the predicted tissue composition is altered under the influence of (i) differential interactions between cells and the supporting scaffold and their associated ECM, (ii) scaffold degradation, and (iii) mechanotransduction-regulated cell proliferation and ECM deposition.\ud \ud Numerical simulation of the model equations reveals that scaffold heterogeneity typical of that obtained from μCT scans of tissue engineering scaffolds can lead to significant variation in the flow-induced mechanical stimuli experienced by cells seeded in the scaffold. This leads to strong heterogeneity in the deposition of ECM. Furthermore, preferential adherence of cells to the ECM in favour of the artificial scaffold appears to have no significant influence on the eventual construct composition; adherence of cells to these supporting structures does, however, lead to cell and ECM distributions which mimic and exaggerate the heterogeneity of the underlying scaffold. Such phenomena have important ramifications for the mechanical integrity of engineered tissue constructs and their suitability for implantation in vivo

A multiscale analysis of nutrient transport and biological tissue growth in vitro

In this paper, we consider the derivation of macroscopic equations appropriate to describe the growth of biological tissue, employing a multiple-scale homogenisation method to accommodate explicitly the influence of the underlying microscale structure of the material, and its evolution, on the macroscale dynamics. Such methods have been widely used to study porous and poroelastic materials; however, a distinguishing feature of biological tissue is its ability to remodel continuously in response to local environmental cues. Here, we present the derivation of a model broadly applicable to tissue engineering applications, characterised by cell proliferation and extracellular matrix deposition in porous scaffolds used within tissue culture systems, which we use to study coupling between fluid flow, nutrient transport and microscale tissue growth. Attention is restricted to surface accretion within a rigid porous medium saturated with a Newtonian fluid; coupling between the various dynamics is achieved by specifying the rate of microscale growth to be dependent upon the uptake of a generic diffusible nutrient. The resulting macroscale model comprises a Darcy-type equation governing fluid flow, with flow characteristics dictated by the assumed periodic microstructure and surface growth rate of the porous medium, coupled to an advection--reaction equation specifying the nutrient concentration. Illustrative numerical simulations are presented to indicate the influence of microscale growth on macroscale dynamics, and to highlight the importance of including experimentally-relevant microstructural information in order to correctly determine flow dynamics and nutrient delivery in tissue engineering applications

Management of Multi Organ Dysfunction in Neonatal Encephalopathy.

Neonatal Encephalopathy (NE) describes neonates with disturbed neurological function in the first post-natal days of life. NE is an overall term that does not specify the etiology of the encephalopathy although it often involves hypoxia-ischaemia. In NE, although neurological dysfunction is part of the injury and is most predictive of long-term outcome, these infants may also have multiorgan injury and compromise, which further contribute to neurological impairment and long-term morbidities. Therapeutic hypothermia (TH) is the standard of care for moderate to severe NE. Infants with NE may have co-existing immune, respiratory, endocrine, renal, hepatic, and cardiac dysfunction that require individualized management and can be impacted by TH. Non-neurological organ dysfunction not only has a negative effect on long term outcome but may also influence the efficacy of treatments in the acute phase. Post resuscitative care involves stabilization and decisions regarding TH and management of multi-organ dysfunction. This management includes detailed neurological assessment, cardio-respiratory stabilization, glycaemic and fluid control, sepsis evaluation and antibiotics, seizure identification, and monitoring and responding to biochemical and coagulation derangements. The emergence of new biomarkers of specific organ injury may have predictive value and improve the definition of organ injury and prognosis. Further evidence-based research is needed to optimize management of NE, prevent further organ dysfunction and reduce neurodevelopmental impairment

The effects of crew resource management on teamwork and safety climate at Veterans Health Administration facilities

Communication failure is a significant source of adverse events in health care and a leading root cause of sentinel events reported to the Joint Commission. The Veterans Health Administration National Center for Patient Safety established Clinical Team Training (CTT) as a comprehensive program to enhance patient safety and to improve communication and teamwork among health care professionals. CTT is based on techniques used in aviation’s Crew Resource Management (CRM) training. The aviation industry has reached a significant safety record in large part related to the culture change generated by CRM and sustained by its recurrent implementation. This article focuses on the improvement of communication, teamwork, and patient safety by utilizing a standardized, CRM‐based, interprofessional, immersive training in diverse clinical areas. The Teamwork and Safety Climate Questionnaire was used to evaluate safety climate before and after CTT. The scores for all of the 27 questions on the questionnaire showed an increase from baseline to 12 months, and 11 of those increases were statistically significant. A recurrent training is recommended to maintain the positive outcomes. CTT enhances patient safety and reduces risk of patient harm by improving teamwork and facilitating clear, concise, specific and timely communication among health care professionals.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145421/1/jhrm21292_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145421/2/jhrm21292.pd

Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation

© Ankers et al. Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NF-κB) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NF-κB and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NF-κB response. In S-phase, the NF-κB response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NF-κB at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NF-κB responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle

Altered inflammasome activation in neonatal encephalopathy persists in childhood

Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)-1 beta, IL-1ra and IL-18 are activated by the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)- and NOD-like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme-linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL-1 beta and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4-7 years were analysed. An increase in serum IL-1ra and IL-18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL-1ra in NE was decreased to normal levels at school age, whereas serum IL-18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school-age NE. NLRP3 and IL-1 beta gene expression were up-regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up-regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention

Using formative research to develop CHANGE! : a curriculum-based physical activity promoting intervention

Background : Low childhood physical activity levels are currently one of the most pressing public health concerns. Numerous school-based physical activity interventions have been conducted with varied success. Identifying effective child-based physical activity interventions are warranted. The purpose of this formative study was to elicit subjective views of children, their parents, and teachers about physical activity to inform the design of the CHANGE! (Children\u27s Health, Activity, and Nutrition: Get Educated!) intervention programme. Methods : Semi-structured mixed-gender interviews (group and individual) were conducted in 11 primary schools, stratified by socioeconomic status, with 60 children aged 9-10 years (24 boys, 36 girls), 33 parents (4 male, 29 female) and 10 teachers (4 male, 6 female). Questions for interviews were structured around the PRECEDE stage of the PRECEDE-PROCEDE model and addressed knowledge, attitudes and beliefs towards physical activity, as well as views on barriers to participation. All data were transcribed verbatim. Pen profiles were constructed from the transcripts in a deductive manner using the Youth Physical Activity Promotion Model framework. The profiles represented analysis outcomes via a diagram of key emergent themes. Results : Analyses revealed an understanding of the relationship between physical activity and health, although some children had limited understanding of what constitutes physical activity. Views elicited by children and parents were generally consistent. Fun, enjoyment and social support were important predictors of physical activity participation, though several barriers such as lack of parental support were identified across all group interviews. The perception of family invested time was positively linked to physical activity engagement. Conclusions : Families have a powerful and important role in promoting health-enhancing behaviours. Involvement of parents and the whole family is a strategy that could be significant to increase children\u27s physical activity levels. Addressing various perceived barriers to such behaviours therefore, remains imperative. <br /

The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

NFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis. assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.These results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone

Resistant Starch: Promise for Improving Human Health

Ongoing research to develop digestion-resistant starch for human health promotion integrates the disciplines of starch chemistry, agronomy, analytical chemistry, food science, nutrition, pathology, and microbiology. The objectives of this research include identifying components of starch structure that confer digestion resistance, developing novel plants and starches, and modifying foods to incorporate these starches. Furthermore, recent and ongoing studies address the impact of digestion-resistant starches on the prevention and control of chronic human diseases, including diabetes, colon cancer, and obesity. This review provides a transdisciplinary overview of this field, including a description of types of resistant starches; factors in plants that affect digestion resistance; methods for starch analysis; challenges in developing food products with resistant starches; mammalian intestinal and gut bacterial metabolism; potential effects on gut microbiota; and impacts and mechanisms for the prevention and control of colon cancer, diabetes, and obesity. Although this has been an active area of research and considerable progress has been made, many questions regarding how to best use digestion-resistant starches in human diets for disease prevention must be answered before the full potential of resistant starches can be realized