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Tissue formation and healing both require cell proliferation and migration, but also extracellular matrix production and tensioning. In addition to restricting proliferation of damaged cells, increasing evidence suggests that cellular senescence also has distinct modulatory effects during wound healing and fibrosis. Yet, a direct role of senescent cells during tissue formation beyond paracrine signaling remains unknown. We here report how individual modules of the senescence program differentially influence cell mechanics and ECM expression with relevance for tissue formation. We compared DNA damage-mediated and DNA damage-independent senescence which was achieved through over-expression of either p16Ink4a or p21Cip1 cyclin-dependent kinase inhibitors in primary human skin fibroblasts. Cellular senescence modulated focal adhesion size and composition. All senescent cells exhibited increased single cell forces which led to an increase in tissue stiffness and contraction in an in vitro 3D tissue formation model selectively for p16 and p21-overexpressing cells. The mechanical component was complemented by an altered expression profile of ECM-related genes including collagens, lysyl oxidases, and MMPs. We found that particularly the lack of collagen and lysyl oxidase expression in the case of DNA damage-mediated senescence foiled their intrinsic mechanical potential. These observations highlight the active mechanical role of cellular senescence during tissue formation as well as the need to synthesize a functional ECM network capable of transferring and storing cellular forces.

Nutrient supply via a functional vasculature is essential during regenerative processes, tissue growth, and homeostasis. 3D bioprinting offers the opportunity to engineer vascularized constructs by combining cells and biocompatible materials in specifically designed fashions. However, the complexity of microvascular dynamic networks can hardly be recapitulated yet, even by sophisticated 3D manufacturing. Ideally, the natural organizational competences of endothelial cells will be harnessed such that engineered vascular networks self‐assemble to form complex, controllable microvascular patterns. Here, a bioengineering approach is presented to control microvascular structure formation and to steer cellular self‐assembly of endothelial and supporting cells within a multi‐material stereolithographic 3D bioprinting concept. Bioengineered vascularized constructs are generated by controlled cell deposition in an enzymatically degradable or a non‐degradable material. In vitro, the microvascular structures are regulated in distribution, network orientation, vessel length and branching behavior and developed lumen, signs of vascular stabilization and an interconnected vascular network including anastomosis. This novel biofabrication approach demonstrates the capability to control microvascular network formation by using cellular and spatial cues allowing the generation of distinctly yet precisely vascularized constructs. Such novel approach of controlled microvascular formation may play a fundamental role in the development of vascularized implants or in vitro screening models.

Successful fracture healing requires a tight interplay between mechanical and biological cues. In vitro studies illustrated that mechanical loading modulates bone morphogenetic protein (BMP) signaling. However, in the early phases of large bone defect regeneration in vivo, the underlying mechanisms leading to this mechanosensation remained unknown. We investigated the interaction of BMP2 stimulation and mechanical boundary conditions in a rat critical-sized femoral defect model (5 mm) stabilized with three distinctly different external fixator stiffness. Defects were treated with 5 μg rhBMP2 loaded on an absorbable collagen sponge. Early matrix alignment was monitored by second-harmonic generation imaging. Bony bridging of defects and successive healing was monitored by histology at day 7 and day 14 as well as in vivo microCT at days 10, 21, and 42 post-operation. Femora harvested at day 42 were characterized mechanically assessing torsional load to failure ex vivo. At tissue level, differences between groups were visible at day 14 with manifest bone formation in the microCT. Histologically, we observed prolonged chondrogenesis upon flexible fixation, whereas osteogenesis started earlier after rigid and semirigid fixation. At later time points, there was a boost of bone tissue formation upon flexible fixation, whereas other groups already displayed signs of tissue maturation. Based on gene expression profiling, we analyzed the mechanobiological interplay. Already at day 3, these analyses revealed differences in expression pattern, specifically of genes involved in extracellular matrix formation. Gene regulation correlating with fixator stiffness was pronounced at day 7 comprising genes related to immunological processes and cellular contraction. The influence of loading on matrix contraction was further investigated and confirmed in a 3D bioreactor. Taken together, we demonstrate an early onset of mechanical conditions influencing BMP2-induced defect healing and shed light on gene regulatory networks associated with extracellular matrix organization and contraction that seemed to directly impact healing outcomes. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

The prospects of survival and changes in function (need for care) are evaluated after a two-year period for the 1486 persons resident in the geriatric institution “De Gamles By”, Copenhagen, on January 15, 1967. It is shown that the logarithm of the survival percentages is approximately a linear function of the time. The prospect of survival is slightly better for the females than for the males because of a significantly higher mortality among the dependent men than among the dependent women. There is no difference as regards sex in the mortality rate for the independent patients (25%). The prospect of survival is poorest in the heavily dependent patients, regardless of sex. Only 5% of the patients were discharged to their homes or transferred to a hospital or some other institution. There was an improvement in the care status, regardless of sex, in 4%, the condition was unchanged in 61%, and there was deterioration in 35% of the 870 patients who survived the two-year period. On the basis of the prospects of surviving whilst waiting for admittance, the saving in institutional places is discussed. The increased need for more accommodation in geriatric institutions is emphasized in order to reduce the unfortunate consequences of the time spent in waiting for admission.

Two cross-sectional studies, carried out at an interval of exactly 2 years at a geriatric institution accommodating about 1400 residents, show an increase in the age of the patients and in the need for care after the 2 years. An analysis of the conditions shows that the changes are due to the surviving patients becoming older and in need of more care, without adequate compensation for this trend having been taken into account when admitting new patients. The admittance and staff aspects connected with these changes are discussed.

Oral health status and dental treatment needs were investigated in 50 randomly selected patients in the geriatric department of a Danish district hospital. All the participants were examined clinically and radiologically. Oral health status was generally poor. Ten participants required no dental treatment. The remaining 40 participants needed some kind of treatment, mainly prosthetic and surgical. The 40 participants requiring treatment were all asked whether or not they wanted the proposed treatment. Only 18 were interested. The participants were divided into three groups according to their medical status. 28 participants had a poor medical status. It was estimated that these patients once having left the hospital would never be able to visit a dentist on their own initiative, and therefore should be treated institutionally.

With the aim of demonstrating prognostics as regards death in a geriatric population, the mortality among 1486 patients (516 men and 970 women) in De Gamles By, Copenhagen, was observed over a 2-year period. The mortality curves for the groups examined were found to be rectilinear in logarithmic form and could therefore be described with sufficient certainty by one value, viz. the probability of death in any one year. The probability of death was just over 20% and was the same for both sexes. Of the parameters examined, particularly high mortality was found where there was urinary incontinence, severe mental abnormality, a great need for nursing, and poor physical mobility (especially inability to walk). On the other hand, there was no particular relationship with age. Where the degree of the handicapping factors was severe, there was generally greater mortality among the men than among the women, but this was not so in the less severe cases. The length of stay in the institution had no effect on the mortality. The results of the present study are in good agreement with previous findings reported from New York (7).

International audience; 1 INTRODUCTION The perception of musical performers with regard to their acoustical environment, which has received increasing attention since the late 1980s 1, 2 , is different from the perception on the part of the audience. The motor activity of the musician, which absorbs much of his attention, the proximity of his instrument and other instruments as sound source(s), as well as the need to hear him-or herself and other ensemble players sufficiently well for a high quality performance can entail substantially different needs and expectations towards the room acoustical conditions on stage. Recent research has also addressed the question, to what extent and in which way not only the perception but also the way of playing of musical performers depends on the acoustical environment 3-5. In one of these studies, musicians were exposed to different acoustical environments simulated by a multichannel loudspeaker system in an anechoic chamber. As a result, significant differences in terms of tempo, vibrato, and sound level were observed under the different acoustical conditions 6. A comparison of features extracted from the audio signal with the response of the musicians given in questionnaires filled out after the recording indicated that many of the adaptations of the interpretation style were made consciously, such as a more pronounced staccato and longer pauses between notes with increasing reverberation time 7. Another study 8 has been carried out in seven real halls in which a cellist played the same musical program during a concert tour. Room acoustical measurements were performed in the empty rooms, and computer simulations were conducted to estimate the acoustics in the occupied condition. The musical recordings were analyzed in terms of tempo, dynamics, loudness, and timbre characteristics. A statistical analysis of the relationship between room acoustical parameters according to ISO-3382-1 9 and audio features representing qualities of the musical performance revealed that more than 50% of the variance in performance features could be explained by the acoustical properties of the environment. With a similar test design, the same authors invited 12 musical performers playing six musical instruments to perform the same pieces of music in different acoustical conditions, simulated by dynamic binaural synthesis, thus avoiding the confusion with other influencing factors such as the visual impression, audience reactions, or the design of the stage 10. The statistical analysis again revealed a significant influence of room acoustical parameters on the way of playing, but also very individual patterns of reaction, which strongly varied not only between different musical instruments but also between different performers on the same instrument. The interaction of singers with their room acoustical environment was investigated mainly in the context of choir performance. Marshall and Meyer placed an ensemble of singers in a semi-anechoic room, where they were exposed to synthetic sound fields including discrete reflections arriving from the side and rear, combined with an artificial reverberation tail 11. The experiment demonstrated the strong influence of reverberation on the comfort of singers. Early reflections were appreciated if their time delay did not exceed 40 ms, beyond which they became unpleasant. A more recent work 12 focused on the effect of early reflections when singing in small ensembles (2 to 4 singers) in a church. Artificial early reflections were added to the natural acoustics of the venue by means of microphones and loudspeakers. The different groups of singers performed musical pieces