Unplanned Rehospitalisation due to Medication Harm following an Acute Myocardial Infarction.

INTRODUCTION: The contribution of medication harm to rehospitalisation and adverse patient outcomes after an acute myocardial infarction (AMI) needs exploration. Rehospitalisation is costly to both patients and the healthcare facility. Following an AMI, patients are at risk of medication harm as they are often older and have multiple comorbidities and polypharmacy. This study aimed to quantify and evaluate medication harm causing unplanned rehospitalisation after an AMI. METHODS: This was a retrospective cohort study of patients discharged from a quaternary hospital post-AMI. All rehospitalisations within 18 months were identified using medical record review and coding data. The primary outcome measure was medication harm rehospitalisation. Preventability, causality, and severity assessments of medication harm were conducted. RESULTS: A total of 1,564 patients experienced an AMI, and 415 (26.5%) were rehospitalised. Eighty-nine patients (5.7% of total population; 6.0% of those discharged) experienced a total of 101 medication harm events. Those with medication harm were older (p = 0.007) and had higher rates of heart failure (p = 0.005), chronic kidney disease (p = 0.046), chronic obstructive pulmonary disease (p = 0.037), and a prior history of ischaemic heart disease (p = 0.005). Gastrointestinal bleeding, acute kidney injury, and hypotension were the most common medication harm events. Forty percent of events were avoidable, and 84% were classed as "serious." Furosemide, antiplatelets, and angiotensin-converting enzyme inhibitors were the most commonly implicated medications. The median time to medication harm rehospitalisation was 79 days (interquartile range: 16-200 days). CONCLUSION: Medication harm causes unplanned rehospitalisation in 5.7% of all AMI patients (1 in 17 patients; 6.0% of those discharged). The majority of harm was serious and occurred within the first 200 days of discharge. This study highlights that measures to attenuate the risk of medication harm rehospitalisation are essential, including post-discharge medication management.

Effects of a culturally informed model of care for Aboriginal and Torres Strait Islander patients with acute coronary syndrome in a tertiary hospital in Australia: a pre-post, quasi-experimental, interventional study.

BACKGROUND: Aboriginal and Torres Strait Islander (Indigenous) peoples with cardiac disease in Australia have worse outcomes than non-Indigenous people with cardiac disease. We hypothesised that the implementation of a culturally informed model of care for Indigenous patients hospitalised with acute coronary syndrome (ACS) would improve their clinical outcomes. METHODS: For this pre-post, quasi-experimental, interventional study, cohorts of Indigenous patients before and after the implementation of a model of care were compared. The novel, culturally informed, multidisciplinary-team model of care was a local programme of care developed to reduce morbidity and mortality from cardiac conditions among Indigenous Australians. All index admissions in the 24-month pre-implementation period (Jan 1 2013, to Dec 31, 2014) were analysed, as were all index admissions in the 12-month post-implementation period (Oct 1, 2015, to Sept 30, 2016). Comparisons were also made with non-Indigenous cohorts in the same timeframes. Admissions were excluded if the patient did not survive to hospital discharge. The study was conducted at Princess Alexandra Hospital, a tertiary hospital in metropolitan Brisbane (QLD, Australia). Data on presentation, comorbidities, investigations, treatment, and for outcomes were manually collected from a consolidated clinical information application. Mortality data were obtained from the Queensland Registry of Births, Deaths, and Marriages. The primary outcome was a composite of death, acute myocardial infarction, unplanned revascularisation, and cardiac readmission at 90 days after index admission, assessed in all patients. FINDINGS: The Indigenous cohorts included 199 patients admitted with ACS before the model of care was implemented (85 [43%] were female and 114 [57%] were male) and 119 admitted post-implementation (62 [52%] were female and 57 [48%] were male). The non-Indigenous cohorts included 440 patients with ACS before the model of care was implemented (140 [32%] were female and 300 [68%] were male) and 467 admitted post-implementation (143 [31%] were female and 324 [69%] were male). Compared with the pre-implementation group, Indigenous patients admitted post-implementation had a significant reduction in the primary outcome (67 [34%] of 199 vs 24 [20%] of 119; hazard ratio 0·60, 95% CI 0·40-0·90; p=0·012), which was driven by a reduction in unplanned cardiac readmissions (64 [32%] of 199 vs 21 [18%] of 119; 0·55, 0·35-0·85; p=0·0060). There was no significant change in non-Indigenous patients between the pre-implementation and post-implementation timeframes in the composite endpoint at 90 days (81 [18%] of 440 vs 93 [20%] of 467; 1·08, 0·83-1·41; p=0·54). Pre-implementation, there was significantly more incidence of the primary outcome in Indigenous patients than non-Indigenous patients (p<0·0001), with no significant difference in the post-implementation period (p=0·92). INTERPRETATION: Clinical outcomes for Indigenous patients admitted to a tertiary hospital in Australia improved after implementation of a culturally informed model of care, with a reduction in the disparity in incidence of primary endpoints that existed between Indigenous and non-Indigenous patients before implementation. FUNDING: Queensland Department of Health Aboriginal and Torres Strait Islander Health Division (now First Nations Health Office).

Mechanical Intercellular Communication via Matrix-Borne Cell Force Transmission During Vascular Network Formation.

Intercellular communication is critical to the formation and homeostatic function of all tissues. Previous work has shown that cells can communicate mechanically via the transmission of cell-generated forces through their surrounding extracellular matrix, but this process is not well understood. Here, mechanically defined, synthetic electrospun fibrous matrices are utilized in conjunction with a microfabrication-based cell patterning approach to examine mechanical intercellular communication (MIC) between endothelial cells (ECs) during their assembly into interconnected multicellular networks. It is found that cell force-mediated matrix displacements in deformable fibrous matrices underly directional extension and migration of neighboring ECs toward each other prior to the formation of stable cell-cell connections enriched with vascular endothelial cadherin (VE-cadherin). A critical role is also identified for calcium signaling mediated by focal adhesion kinase and mechanosensitive ion channels in MIC that extends to multicellular assembly of 3D vessel-like networks when ECs are embedded within fibrin hydrogels. These results illustrate a role for cell-generated forces and ECM mechanical properties in multicellular assembly of capillary-like EC networks and motivates the design of biomaterials that promote MIC for vascular tissue engineering.

Gender differences in cardiovascular disease risk: Adolescence to young adulthood.

BACKGROUND AND AIMS: Gender differences in cardiovascular disease (CVD) have been well documented but rarely for young adults and the extent to which gender related lifestyle differences may contribute to gender differences in CVD risk experienced by young adults have not been reported. METHODS AND RESULTS: Data are from a long-running cohort study, the Mater-University of Queensland Study of Pregnancy (MUSP). We track gender differences in CVD related behaviours at 21 and 30 years (consumption of a Western Diet/Health-Oriented Diet, cigarette smoking, vigorous physical exercise, heavy alcohol consumption). At 30 years we compare males and females for CVD risk, and the extent to which lifestyle behaviours at 21 and 30 years contribute to CVD risk. At both 21 and 30 years of age, males more frequently consume a Western Diet and less often a Health Oriented Diet. By contrast, males are also much more likely to report engaging in vigorous physical activity. On most CVD markers, males exhibit much higher levels of risk than do females at both 21 and 30 years. At 30 years of age males have about five times the odds of being at high risk of CVD. Some lifestyle behaviours contribute to this additional risk. CONCLUSION: Young adult males much more frequently engage in most CVD related risk behaviours and males have a higher level of CVD risk. Gender differences in CVD risk remain high even after adjustment for CVD lifestyles, though dietary factors independently contribute to CVD risk at 30 years.

Dietary patterns explaining variations in blood biomarkers in young adults are associated with the 30-year predicted cardiovascular disease risks in midlife: A follow-up study.

BACKGROUND AND AIMS: To examine a combined effect of dietary intakes, blood lipid and insulin resistance in young adulthood on the risk of predicted CVD through midlife. METHODS AND RESULTS: Data of young adults from a birth cohort study in Australia were used. Reduced rank regression (RRR) and partial least squares (PLS) methods identified dietary patterns rich in meats, refined grains, processed and fried foods, and high-fat dairy and low in whole grains and low-fat dairy from dietary intakes obtained at 21-years, and blood lipids and measures of insulin resistance measured at 30-years of age. Using standard CVD risk factors measured at 30-years of age, the Framingham Heart Study risk-prediction algorithms were used to calculate the 30-year predicted Framingham CVD risk scores. The scores represent Hard CVD events; coronary death, myocardial infarction and stroke and Full CVD events; Hard CVD plus coronary insufficiency and angina pectoris, transient ischaemic attack, intermittent claudication, and congestive heart failure in midlife. Sex-specific upper quartiles of CVD risk scores were used to define high-risk groups. Modified Poisson regression models were used to estimate relative risks (RRs) with 95% CI. Greater adherence to the diet identified applying RRR in young adulthood was associated with higher risks of predicted Hard CVD (RR: 1.60; 1.14, 2.25) and Full CVD (RR: 1.46; 1.04, 2.05) events in midlife. The diet from PLS showed similar trend of association for the risk of predicted Hard CVD events (RR: 1.49; 1.03, 2.16) in adjusted models. CONCLUSION: Dietary patterns associated with variations in blood lipids and insulin resistance in young adulthood are associated with increased risks of predicted CVD events in midlife. The findings suggest that diet induced altered blood lipids and insulin resistance in the life course of young adulthood could increase the risks of CVD events in later life.

Dietary patterns and young adult body mass change: A 9-year longitudinal study.

PURPOSE: While excessive weight gain is highest during young adulthood, the extent to which specific dietary patterns are associated with changes in measures of body mass in this course of life remains unknown. We aimed to examine the associations of dietary patterns at 21 years with changes in body weight and body mass index (BMI) between 21 and 30 years. METHODS: We used data on young adults from a long-running birth cohort in Australia. Western and prudent dietary patterns were identified applying principal component analysis to 33 food groups obtained by a food frequency questionnaire at 21 years. Body weight and height were measured at 21 and 30 years. Multivariable regression models, using generalized estimating equations, were adjusted for concurrent changes in sociodemographic and lifestyle variables in evaluating the effect of identified dietary patterns on changes in weight and BMI over time. RESULTS: In the fully adjusted model, young adults in the highest tertile of the Western pattern had a mean weight gain of 9.9 (95% CI 8.5, 11.3) kg compared to those in the lowest that had a mean weight gain of 7.1 (95% CI 5.6, 8.5) kg, P-for linear trend = 0.0015. The corresponding values for mean gains in BMI were 3.1 (95% CI 2.7, 3.6) kg/m2 for young adults in the highest tertile compared to 2.4 (95% CI 1.9, 2.9) kg/m2 for those in lowest, P-for linear trend = 0.0164. There was no evidence of a significant association between the prudent pattern and mean changes in each outcome over time in this study. CONCLUSIONS: The findings of the current study show that greater adherence to the Western diet at 21 years was positively associated with increases in body weight and BMI from 21 to 30 years of age, whereas the prudent diet had no significant association with these outcomes. The findings provide evidence that the adverse effects of the Western diet on weight gain in young adulthood could partly be prevented through optimising diet in the early course of life.

Fiber density and matrix stiffness modulate distinct cell migration modes in a 3D stroma mimetic composite hydrogel.

The peritumoral stroma is a complex 3D tissue that provides cells with myriad biophysical and biochemical cues. Histologic observations suggest that during metastatic spread of carcinomas, these cues influence transformed epithelial cells, prompting a diversity of migration modes spanning single cell and multicellular phenotypes. Purported consequences of these variations in tumor escape strategies include differential metastatic capability and therapy resistance. Therefore, understanding how cues from the peritumoral stromal microenvironment regulate migration mode has both prognostic and therapeutic value. Here, we utilize a synthetic stromal mimetic in which matrix fiber density and bulk hydrogel mechanics can be orthogonally tuned to investigate the contribution of these two key matrix attributes on MCF10A migration mode phenotypes, epithelial-mesenchymal transition (EMT), and invasive potential. We develop an automated computational image analysis framework to extract migratory phenotypes from fluorescent images and determine 3D migration metrics relevant to metastatic spread. Using this analysis, we find that matrix fiber density and bulk hydrogel mechanics distinctly contribute to a variety of MCF10A migration modes including amoeboid, single mesenchymal, clusters, and strands. We identify combinations of physical and soluble cues that induce a variety of migration modes originating from the same MCF10A spheroid and use these settings to examine a functional consequence of migration mode -resistance to apoptosis. We find that cells migrating as strands are more resistant to staurosporine-induced apoptosis than either disconnected clusters or individual invading cells. Improved models of the peritumoral stromal microenvironment and understanding of the relationships between matrix attributes and cell migration mode can aid ongoing efforts to identify effective cancer therapeutics that address cell plasticity-based therapy resistances. STATEMENT OF SIGNIFICANCE: Stromal extracellular matrix structure dictates both cell homeostasis and activation towards migratory phenotypes. However decoupling the effects of myriad biophysical cues has been difficult to achieve. Here, we encapsulate electrospun fiber segments within an amorphous hydrogel to create a fiber-reinforced hydrogel composite in which fiber density and hydrogel stiffness can be orthogonally tuned. Quantification of 3D cell migration reveal these two parameters uniquely contribute to a diversity of migration phenotypes spanning amoeboid, single mesenchymal, multicellular cluster, and collective strand. By tuning biophysical and biochemical cues to elicit heterogeneous migration phenotypes, we find that collective strands best resist apoptosis. This work establishes a composite approach to modulate fibrous topography and bulk hydrogel mechanics and identified biomaterial parameters to direct distinct 3D cell migration phenotypes.

Rapid magnetically directed assembly of pre-patterned capillary-scale microvessels.

Capillary scale vascularization is critical to the survival of engineered 3D tissues and remains an outstanding challenge for the field of tissue engineering. Current methods to generate micro-scale vasculature such as 3D printing, two photon hydrogel ablation, angiogenesis, and vasculogenic assembly face challenges in rapidly creating organized, highly vascularized tissues at capillary length-scales. Within metabolically demanding tissues, native capillary beds are highly organized and densely packed to achieve adequate delivery of nutrients and oxygen and efficient waste removal. Here, we adopt two existing techniques to fabricate lattices composed of sacrificial microfibers that can be efficiently and uniformly seeded with endothelial cells (ECs) by magnetizing both lattices and ECs. Ferromagnetic microparticles (FMPs) were incorporated into microfibers produced by solution electrowriting (SEW) and fiber electropulling (FEP). By loading ECs with superparamagnetic iron oxide nanoparticles (SPIONs), the cells could be seeded onto magnetized microfiber lattices. Following encapsulation in a hydrogel, the capillary templating lattice was selectively degraded by a bacterial lipase that does not impact mammalian cell viability or function. This work introduces a novel approach to rapidly producing organized capillary networks within metabolically demanding engineered tissue constructs which should have broad utility for the fields of tissue engineering and regenerative medicine.

Dietary patterns and the risks of metabolic syndrome and insulin resistance among young adults: Evidence from a longitudinal study.

BACKGROUND AND AIMS: Whether early young adulthood dietary patterns predict the risk of metabolic syndrome (MetS) and diabetes-related endpoints prior to middle age remains unknown. We examined the prospective associations of dietary patterns in early young adulthood with MetS and diabetes-related endpoints at later young adulthood. METHODS: We used data of young adults from a long running birth cohort in Australia. The Western dietary pattern rich in meats, refined grains, processed and fried foods and the prudent dietary pattern rich in fruits and vegetables, whole grains and legumes were derived using principal component analysis at the 21-year follow-up from dietary data obtained by a food frequency questionnaire. Fasting blood samples at 30 years were collected from each participant and their blood biomarkers, anthropometric and blood pressure were measured. MetS, insulin resistance, and prediabetes were based on clinical cut-offs; increased ß-cell function and insulin resistance were based on upper quartiles. Log-binomial models were used to estimate diet-related risks of each outcome adjusting for potential confounders. RESULTS: Greater adherence to the Western pattern predicted higher risks of MetS (RR: 2.32; 95% CI: 1.34, 4.00), increased insulin resistance (1.69; 1.07, 2.65), high ß-cell function (1.60; 1.10, 2.31) and less likelihood of increased insulin sensitivity (0.57; 0.39, 0.84) in adjusted models. Conversely, adhering more to the prudent pattern predicted lower risks of MetS (RR: 0.47; 95% CI: 0.29, 0.75), increased insulin resistance (0.57; 0.39, 0.82), high ß-cell function (0.69; 0.50, 0.93) and a greater likelihood of increased insulin sensitivity (1.84; 1.30, 2.60). CONCLUSION: This prospective study of young adults indicates greater adherence to unhealthy Western diet predicted higher risks of MetS and increased insulin resistance, whereas healthy prudent diet predicted lower risks. Optimizing diets to improve later cardiometabolic health needs to occur in early adulthood.

Dietary patterns and the risk of abnormal blood lipids among young adults: A prospective cohort study.

BACKGROUND AND AIMS: The extent to which dietary patterns influence the risk of abnormal blood lipids throughout young adulthood remains unclear. The aim was to investigate whether early young adulthood dietary patterns predict the risk of abnormal blood lipids during later young adulthood. METHODS AND RESULTS: We used data from a long running birth cohort study in Australia. Western dietary pattern rich in meats, processed foods and high-fat dairy products and prudent pattern rich in fruit, vegetables, fish, nuts, whole grains and low-fat dairy products were derived using principal component analysis at the 21-year follow-up from dietary data obtained using a food frequency questionnaire. After 9-years, fasting blood samples of all participants were collected and their total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterols and triglyceride (TG) levels were measured. Abnormal blood lipids were based on clinical cut-offs for total, LDL and HDL cholesterols, and TG and relative distributions for total:HDL and TG:HDL cholesterols ratios. Log-binomial models were used to estimate risk of each outcome in relation to dietary patterns. Greater adherence to the Western pattern predicted increased risks of high LDL (RR: 1.47; 95%CI: 1.06, 2.03) and TG (1.90; 1.25, 2.86), and high ratios of total:HDL (1.48; 1.00, 2.19) and TG:HDL (1.78; 1.18, 2.70) cholesterols in fully adjusted models. Conversely, a prudent pattern predicted reduced risks of low HDL (0.58; 0.42, 0.78) and high TG (0.66; 0.47, 0.92) and high total:HDL (0.71; 0.51, 0.98) and TG:HDL (0.61; 0.45, 0.84) cholesterols ratios. CONCLUSION: This is the first prospective study to show greater adherence to unhealthy Western diet predicted increased risks of abnormal blood lipids, whereas healthy prudent diet predicted lower such risks in young adults. Addressing diets in early course may improve cardiovascular health of young adults.

Direct comparison of angiogenesis in natural and synthetic biomaterials reveals that matrix porosity regulates endothelial cell invasion speed and sprout diameter.

Vascularization of large, diffusion-hindered biomaterial implants requires an understanding of how extracellular matrix (ECM) properties regulate angiogenesis. Sundry biomaterials assessed across many disparate angiogenesis assays have highlighted ECM determinants that influence this complex multicellular process. However, the abundance of material platforms, each with unique parameters to model endothelial cell (EC) sprouting presents additional challenges of interpretation and comparison between studies. In this work we directly compared the angiogenic potential of commonly utilized natural (collagen and fibrin) and synthetic dextran vinyl sulfone (DexVS) hydrogels in a multiplexed angiogenesis-on-a-chip platform. Modulating matrix density of collagen and fibrin hydrogels confirmed prior findings that increases in matrix density correspond to increased EC invasion as connected, multicellular sprouts, but with decreased invasion speeds. Angiogenesis in synthetic DexVS hydrogels, however, resulted in fewer multicellular sprouts. Characterizing hydrogel Young's modulus and permeability (a measure of matrix porosity), we identified matrix permeability to significantly correlate with EC invasion depth and sprout diameter. Although microporous collagen and fibrin hydrogels produced lumenized sprouts in vitro, they rapidly resorbed post-implantation into the murine epididymal fat pad. In contrast, DexVS hydrogels proved comparatively stable. To enhance angiogenesis within DexVS hydrogels, we incorporated sacrificial microgels to generate cell-scale pores throughout the hydrogel. Microporous DexVS hydrogels resulted in lumenized sprouts in vitro and enhanced cell invasion in vivo. Towards the design of vascularized biomaterials for long-term regenerative therapies, this work suggests that synthetic biomaterials offer improved size and shape control following implantation and that tuning matrix porosity may better support host angiogenesis. STATEMENT OF SIGNIFICANCE: Understanding how extracellular matrix properties govern angiogenesis will inform biomaterial design for engineering vascularized implantable grafts. Here, we utilized a multiplexed angiogenesis-on-a-chip platform to compare the angiogenic potential of natural (collagen and fibrin) and synthetic dextran vinyl sulfone (DexVS) hydrogels. Characterization of matrix properties and sprout morphometrics across these materials points to matrix porosity as a critical regulator of sprout invasion speed and diameter, supported by the observation that nanoporous DexVS hydrogels yielded endothelial cell sprouts that were not perfusable. To enhance angiogenesis into synthetic hydrogels, we incorporated sacrificial microgels to generate microporosity. We find that microporosity increased sprout diameter in vitro and cell invasion in vivo. This work establishes a composite materials approach to enhance the vascularization of synthetic hydrogels.

Dynamic Endothelial Stalk Cell-Matrix Interactions Regulate Angiogenic Sprout Diameter.

Angiogenesis is a complex, multicellular process that involves bidirectional interactions between extracellular matrix (ECM) and collectively invading endothelial cell (EC) sprouts that extend the microvasculature during development, wound healing, and disease processes. While many aspects of angiogenesis have been well studied, the relationship between endothelial sprout morphology and subsequent neovessel function remains relatively unknown. Here, we investigated how various soluble and physical matrix cues that regulate endothelial sprouting speed and proliferation correspond to changes in sprout morphology, namely, sprout stalk diameter. We found that sprout stalk cells utilize a combination of cytoskeletal forces and proteolysis to physically compact and degrade the surrounding matrix, thus creating sufficient space in three-dimensional (3D) ECM for lateral expansion. As increasing sprout diameter precedes lumenization to generate perfusable neovessels, this work highlights how dynamic endothelial stalk cell-ECM interactions promote the generation of functional neovessels during sprouting angiogenesis to provide insight into the design of vascularized, implantable biomaterials.

Stromal cell identity modulates vascular morphogenesis in a microvasculature-on-a-chip platform.

Supportive stromal cells of mesenchymal origins regulate vascular morphogenesis in developmental, pathological, and regenerative contexts, contributing to vessel formation, maturation, and long-term stability, in part via the secretion of bioactive molecules. In this work, we adapted a microfluidic lab-on-a-chip system that enables the formation and perfusion of microvascular capillary beds with connections to arteriole-scale endothelialized channels to explore how stromal cell (SC) identity influences endothelial cell (EC) morphogenesis. We compared and contrasted lung fibroblasts (LFs), dermal fibroblasts (DFs), and bone marrow-derived mesenchymal stem cells (MSCs) for their abilities to support endothelial morphogenesis and subsequent perfusion of microvascular networks formed in fibrin hydrogels within the microfluidic device. We demonstrated that while all 3 SC types supported EC morphogenesis, LFs in particular resulted in microvascular morphologies with the highest total network length, vessel diameter, and vessel interconnectivity across a range of SC-EC ratio and density conditions. Not only did LFs support robust vascular morphology, but also, they were the only SC type to support functional perfusion of the resultant capillary beds. Lastly, we identified heightened traction stress produced by LFs as a possible mechanism by which LFs enhance endothelial morphogenesis in 3D compared to other SC types examined. This study provides a unique comparison of three different SC types and their role in supporting the formation of microvasculature that could provide insights for the choice of cells for vascular cell-based therapies and the regulation of tissue-specific vasculature.

Stable and transient bubble formation in acoustically-responsive scaffolds by acoustic droplet vaporization: theory and application in sequential release.

Acoustically-responsive scaffolds (ARSs), which are fibrin hydrogels containing monodispersed perfluorocarbon (PFC) emulsions, respond to ultrasound in an on-demand, spatiotemporally-controlled manner via a mechanism termed acoustic droplet vaporization (ADV). Previously, ADV has been used to control the release of bioactive payloads from ARSs to stimulate regenerative processes. In this study, we used classical nucleation theory (CNT) to predict the nucleation pressure in emulsions of different PFC cores as well as the corresponding condensation pressure of the ADV-generated bubbles. According to CNT, the threshold bubble radii above which ADV-generated bubbles remain stable against condensation were 0.4 µm and 5.2 µm for perfluoropentane (PFP) and perfluorohexane (PFH) bubbles, respectively, while ADV-generated bubbles of any size in perfluorooctane (PFO) condense back to liquid at ambient condition. Additionally, consistent with the CNT findings, stable bubble formation from PFH emulsion was experimentally observed using confocal imaging while PFO emulsion likely underwent repeated vaporization and recondensation during ultrasound pulses. In further experimental studies, we utilized this unique feature of ADV in generating stable or transient bubbles, through tailoring the PFC core and ultrasound parameters (excitation frequency and pulse duration), for sequential delivery of two payloads from PFC emulsions in ARSs. ADV-generated stable bubbles from PFH correlated with complete release of the payload while transient ADV resulted in partial release, where the amount of payload release increased with the number of ultrasound exposure. Overall, these results can be used in developing drug delivery strategies using ARSs.

Optical coherence tomography and fluorescence microscopy dual-modality imaging for in vivo single-cell tracking with nanowire lasers.

Emerging cell-based therapies such as stem cell therapy and immunotherapy have attracted broad attention in both biological research and clinical practice. However, a long-standing technical gap of cell-based therapies is the difficulty of directly assessing treatment efficacy via tracking therapeutically administered cells. Therefore, imaging techniques to follow the in vivo distribution and migration of cells are greatly needed. Optical coherence tomography (OCT) is a clinically available imaging technology with ultrahigh-resolution and excellent imaging depth. It also shows great potential for in vivo cellular imaging. However, due to the homogeneity of current OCT cell labeling contrast agents (such as gold and polymer nanoparticles), only the distribution of entire cell populations can be observed. Precise tracking of the trajectory of individual single cells is not possible with such conventional contrast agents. Microlasers may provide a route to track unique cell identifiers given their small size, high emission intensities, rich emission spectra, and narrow linewidths. Here, we demonstrate that nanowire lasers internalized by cells provide both OCT and fluorescence signal. In addition, cells can be individually identified by the unique lasing emission spectra of the nanowires that they carry. Furthermore, single cell migration trajectories can be monitored both in vitro and in vivo with OCT and fluorescence microscopy dual-modality imaging system. Our study demonstrates the feasibility of nanowire lasers combined with the dual-modality imaging system for in vivo single cell tracking with a high spatial resolution and identity verification, an approach with great utility for stem cell and immunomodulatory therapies.

Fiber Crimp Confers Matrix Mechanical Nonlinearity, Regulates Endothelial Cell Mechanosensing, and Promotes Microvascular Network Formation.

Mechanical interactions between cells and their surrounding extracellular matrix (ECM) guide many fundamental cell behaviors. Native connective tissue consists of highly organized, 3D networks of ECM fibers with complex, nonlinear mechanical properties. The most abundant stromal matrix component is fibrillar type I collagen, which often possesses a wavy, crimped morphology that confers strain- and load-dependent nonlinear mechanical behavior. Here, we established a new and simple method for engineering electrospun fibrous matrices composed of dextran vinyl sulfone (DexVS) with controllable crimped structure. A hydrophilic peptide was functionalized to DexVS matrices to trigger swelling of individual hydrogel fibers, resulting in crimped microstructure due to the fixed anchorage of fibers. Mechanical characterization of these matrices under tension confirmed orthogonal control over nonlinear stress-strain responses and matrix stiffness. We next examined ECM mechanosensing of individual endothelial cells (ECs) and found that fiber crimp promoted physical matrix remodeling alongside decreases in cell spreading, focal adhesion area, and nuclear localization of Yes-associated protein (YAP). These changes corresponded to an increase in migration speed, along with evidence for long-range interactions between neighboring cells in crimped matrices. Interestingly, when ECs were seeded at high density in crimped matrices, capillary-like networks rapidly assembled and contained tube-like cellular structures wrapped around bundles of synthetic matrix fibers due to increased physical reorganization of matrix fibers. Our work provides an additional level of mechanical and architectural tunability to synthetic fibrous matrices and implicates a critical role for mechanical nonlinearity in EC mechanosensing and network formation.