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The foreign body response (FBR) to implanted materials culminates in the deposition of a hypo-permeable, collagen rich fibrotic capsule by myofibroblast cells at the implant site. The fibrotic capsule can be deleterious to the function of some medical implants as it can isolate the implant from the host environment. Modulation of fibrotic capsule formation has been achieved using intermittent actuation of drug delivery implants, however the mechanisms underlying this response are not well understood. Here, we use analytical, computational, and in vitro models to understand the response of human myofibroblasts (WPMY-1 stromal cell line) to intermittent actuation using soft robotics and investigate how actuation can alter the secretion of collagen and pro/anti-inflammatory cytokines by these cells. Our findings suggest that there is a mechanical loading threshold that can modulate the fibrotic behaviour of myofibroblasts, by reducing the secretion of soluble collagen, transforming growth factor beta-1 and interleukin 1-beta, and upregulating the anti-inflammatory interleukin-10. By improving our understanding of how cells involved in the FBR respond to mechanical actuation, we can harness this technology to improve functional outcomes for a wide range of implanted medical device applications including drug delivery and cell encapsulation platforms. A major barrier to the successful clinical translation of many implantable medical devices is the foreign body response (FBR) and resultant deposition of a hypo-permeable fibrotic capsule (FC) around the implant. Perturbation of the implant site using intermittent actuation (IA) of soft-robotic implants has previously been shown to modulate the FBR and reduce FC thickness. However, the mechanisms of action underlying this response were largely unknown. Here, we investigate how IA can alter the activity of myofibroblast cells, and ultimately suggest that there is a mechanical loading threshold within which their fibrotic behaviour can be modulated. These findings can be harnessed to improve functional outcomes for a wide range of medical implants, particularly drug delivery and cell encapsulation devices. [Display omitted] [ABSTRACT FROM AUTHOR]

The incorporation of the RGD peptide (arginine-glycine-aspartate) into biomaterials has been proposed to promote cell adhesion to the matrix, which can influence and control cell behaviour and function. While many studies have utilised RGD modified biomaterials for cell delivery, few have examined its effect under the condition of reduced oxygen and nutrients, as found at ischaemic injury sites. Here, we systematically examine the effect of RGD on hMSCs in hyaluronic acid (HA) hydrogel under standard and ischaemic culture conditions, to elucidate under what conditions RGD has beneficial effects over unmodified HA and its effectiveness in improving cell viability. Results demonstrate that under standard culture conditions, RGD significantly increased hMSC spreading and the release of vascular endothelial factor-1 (VEGF) and monocyte chemoattractant factor-1 (MCP-1), compared to unmodified HA hydrogel. As adhesion is known to influence cell survival, we hypothesised that cells in RGD hydrogels would exhibit increased cell viability under ischaemic culture conditions. However, results demonstrate that cell viability and protein release was comparable in both RGD modified and unmodified HA hydrogels. Confocal imaging revealed cellular morphology indicative of weak cell adhesion. Subsequent investigations found that RGD was could exert positive effects on encapsulated cells under ischaemic conditions but only if hMSCs were pre-cultured under standard conditions to allow strong adhesion to RGD before exposure. Together, these results provide novel insight into the value of RGD introduction and suggest that the adhesion of hMSCs to RGD prior to delivery could improve survival and function at ischaemic injury sites. The development of a biomaterial scaffold capable of maintaining cell viability while promoting cell function is a major research goal in the field of cardiac tissue engineering. This study confirms the suitability of a modified HA hydrogel whereby stem cells in the modified hydrogel showed significantly greater cell spreading and protein secretion compared to cells in the unmodified HA hydrogel. A pre-culture period allowing strong adhesion of the cells to the modified hydrogel was shown to improve cell survival under conditions that mimic the myocardium post-MI. This finding may have a significant impact on the use and timelines of modifications to improve stem cell survival in harsh environments like the injured heart. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Histidine containing dipeptides (HCDs: carnosine, anserine and balenine) have numerous therapeutic and ergogenic properties, but there is a lack of consensus on the mechanistic pathways through which they function. Potential roles include intracellular buffering, neutralisation of reactive species, and calcium regulation. Comparative investigations of the HCD content of various species provide unique insight into their most likely mechanisms of action. This review chronologically describes how the comparative physiology studies, conducted since the beginning of the 20th century, have shaped our understanding of the physiological roles of HCDs. The investigation of a wide range of physiologically distinct species indicates that those species with a strong reliance on non-oxidative forms of energy production are abundant in HCDs. These include: whales who experience long periods of hypoxia while diving; racehorses and greyhound dogs who have highly developed sprint abilities, and chickens and turkeys whose limited capacity for flight is largely fuelled by their white, glycolytic, muscle. Additionally, a higher HCD content in the Type 2 muscle fibres of various species (which have greater capacity for non-oxidative metabolism) was consistently observed. The pKa of the HCDs render them ideally suited to act as intracellular physicochemical buffers within the pH transit range of the skeletal muscle. As such, their abundance in species which show a greater reliance on non-oxidative forms of energy metabolism, and which experience regular challenges to acid–base homeostasis, provides strong evidence that intracellular proton buffering is an important function of the HCDs in skeletal muscle. Unlabelled Image • Potential HCD roles include intracellular buffering, neutralisation of reactive species, and calcium regulation. • We reviewed how comparative investigations have enhanced understanding of the HCD role in skeletal muscle metabolism. • The HCDs pKa render them ideally suited to act as buffers across the pH transit range of the skeletal muscle. • HCDs are abundant in species who rely on non-oxidative metabolism, e.g., whales, racehorses, greyhounds and chickens. • We conclude that acid-base regulation is an important HCD function in the skeletal muscle. [ABSTRACT FROM AUTHOR]

The Constrained Model of Total Energy Expenditure predicts that increased physical activity may not influence total energy expenditure, but instead, induces compensatory energetic savings in other processes. Much remains unknown, however, about concepts of energy expenditure, constraint and compensation in different populations, and it is unclear whether this model applies to endurance athletes, who expend very large amounts of energy during training and competition. Furthermore, it is well-established that some endurance athletes consciously or unconsciously fail to meet their energy requirements via adequate food intake, thus exacerbating the extent of energetic stress that they experience. Within this review we A) Describe unique characteristics of endurance athletes that render them a useful model to investigate energy constraints and compensations, B) Consider the factors that may combine to constrain activity and total energy expenditure, and C) Describe compensations that occur when activity energy expenditure is high and unmet by adequate energy intake. Our main conclusions are as follows: A) Higher activity levels, as observed in endurance athletes, may indeed increase total energy expenditure, albeit to a lesser degree than may be predicted by an additive model, given that some compensation is likely to occur; B) That while a range of factors may combine to constrain sustained high activity levels, the ability to ingest, digest, absorb and deliver sufficient calories from food to the working muscle is likely the primary determinant in most situations and C) That energetic compensation that occurs in the face of high activity expenditure may be primarily driven by low energy availability i.e., the amount of energy available for all biological processes after the demands of exercise have been met, and not by activity expenditure per se. [Display omitted] • The Constrained Theory predicts that energy spent in physical activity will induce compensatory energetic savings elsewhere. • Endurance athletes have high energy expenditure, indicating that compensation to increased physical activity is partial. • The ability to ingest, digest, absorb and deliver sufficient calories is fundamental to sustaining high activity levels. • Low energy availability may be the primary driver of compensatory energy savings when physical activity levels are high. [ABSTRACT FROM AUTHOR]

Exercise physiologists and evolutionary biologists share a research interest in determining patterns of energy allocation during times of acute or chronic energetic scarcity. Within sport and exercise science, this information has important implications for athlete health and performance. For evolutionary biologists, this would shed new light on our adaptive capabilities as a phenotypically plastic species. In recent years, evolutionary biologists have begun recruiting athletes as study participants and using contemporary sports as a model for studying evolution. This approach, known as human athletic palaeobiology, has identified ultra-endurance events as a valuable experimental model to investigate patterns of energy allocation during conditions of elevated energy demand, which are generally accompanied by an energy deficit. This energetic stress provokes detectable functional trade-offs in energy allocation between physiological processes. Early results from this modelsuggest thatlimited resources are preferentially allocated to processes which could be considered to confer the greatest immediate survival advantage (including immune and cognitive function). This aligns with evolutionary perspectives regarding energetic trade-offs during periods of acute and chronic energetic scarcity. Here, we discuss energy allocation patterns during periods of energetic stress as an area of shared interest between exercise physiology and evolutionary biology. We propose that, by addressing the ultimate " why " questions, namely why certain traits were selected for during the human evolutionary journey, an evolutionary perspective can complement the exercise physiology literature and provide a deeper insight of the reasons underpinning the body's physiological response to conditions of energetic stress. • Evolutionary biologists have recently begun to use ultra-endurance events to study mechanisms of adaptation to energetic scarcity. • Life history theory, a branch of evolutionary theory, describes the competitive allocation of finite energy between physiological processes. • Early results suggest that limited resources are preferentially allocated to processes conferring the greatest immediate survival advantage. • The investigation of energy allocation is also of fundamental importance within the field of sport and exercise science. • Here, we propose that an evolutionary perspective can complement the exercise physiology literature and provide a deeper mechanistic insight of the reasons underpinning toward why the body's physiological responds the way it does to conditions of energetic stress. [ABSTRACT FROM AUTHOR]

Venous grafts have been used to bypass stenotic arteries for many decades. However, this “gold standard” treatment is far from optimal, with long-term vein graft patency rates reported to be as low as 50% at >15 years. These results could be a result of the structural and functional differences of veins compared to arteries. In this study we developed a new protocol for manufacturing reinforced fresh veins with a decellularized porcine arterial scaffold. This novel method was designed to be replicated easily in a surgical setting, and manufactured reinforced constructs were robust and easier to handle than the veins alone. Furthermore, we demonstrate that these Reinforced Venous-Arterial Conduits have comparable mechanical properties to native arteries, in terms of ultimate tensile strength (UTS) (2.36 vs. 2.24 MPa) and collagen dominant phase (11.04 vs. 12.26 MPa). Therefore, the Reinforced Venous-Arterial Conduit combines the benefits of using the current gold standard homogenous venous grafts composed of a confluent endothelial surface, with an “off-the-shelf” decellularized artery to improve the mechanical properties to closely mimic those of native arteries, while maintaining the self-repairing characteristics of native tissue. In conclusion in this study we have produced a construct and a new technique that combines the mechanical properties of both a natural vein and a decellularized artery to produce a reinforced venous graft that closely mimics the mechanical response of an arterial segment. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the use of online delivery as a pedagogical approach to teach the practical and theoretical skills required for resting ECG electrode placement and interpretation. Results Comparable results were found for all variables between the two groups, apart from electrode placement, whereby students in the classroom based group were significantly more accurate than their counterparts in the online group (p < 0.05). The effect size of this difference was large (0.91), whereas the effect size for all other measured variables were classified as small (0–0.49). Conclusion Online learning is an effective study mode in both theoretical and practical application; however consideration must be taken of the types of practical skills which it is used for. More complex practical skills requiring haptic awareness may best be delivered within a classroom setting if feasible, whereby the instructor can provide immediate feedback. [ABSTRACT FROM AUTHOR]

Freshwater turtles found in higher latitudes can experience extreme challenges to acid-base homeostasis while overwintering, due to a combination of cold temperatures along with the potential for environmental hypoxia. Histidine-containing dipeptides (HCDs; carnosine, anserine and balenine) may facilitate pH regulation in response to these challenges, through their role as pH buffers. We measured the HCD content of three tissues (liver, cardiac and skeletal muscle) from the anoxia-tolerant painted turtle (C. picta bellii) acclimated to either 3 or 20 °C. HCDs were detected in all tissues, with the highest content shown in the skeletal muscle. Turtles acclimated to 3 °C had more HCD in their skeletal muscle than those acclimated to 20 °C (carnosine = 20.8 ± 4.5 vs 12.5 ± 5.9 mmol·kg DM−1; ES = 1.59 (95%CI: 0.16–3.00), P = 0.013). The higher HCD content shown in the skeletal muscle of the cold-acclimated turtles suggests a role in acid-base regulation in response to physiological challenges associated with living in the cold, with the increase possibly related to the temperature sensitivity of carnosine's dissociation constant. [Display omitted] • pH regulation is a major challenge for overwintering freshwater turtles. • Histidine containing dipeptides are important intracellular buffers. • Turtles acclimated to 3 °C had higher HCD content than those at 20 °C. • HCDs may be important pH regulators in cold-acclimated turtles. [ABSTRACT FROM AUTHOR]