Progress in material design for biomedical applications

Biomaterials that interface with biological systems are used to deliver drugs safely and efficiently; to prevent, detect, and treat disease; to assist the body as it heals; and to engineer functional tissues outside of the body for organ replacement. The field has evolved beyond selecting materials that were originally designed for other applications with a primary focus on properties that enabled restoration of function and mitigation of acute pathology. Biomaterials are now designed rationally with controlled structure and dynamic functionality to integrate with biological complexity and perform tailored, high-level functions in the body. The transition has been from permissive to promoting biomaterials that are no longer bioinert but bioactive. This perspective surveys recent developments in the field of polymeric and soft biomaterials with a specific emphasis on advances in nano- to macroscale control, static to dynamic functionality, and biocomplex materials.National Institutes of Health. National Heart, Lung, and Blood Institute (Ruth L. Kirschstein National Research Service Award (F32HL1220090)

Cerebral blood flow and Aβ-amyloid estimates by WARM analysis of [¹¹C]PiB uptake distinguish among and between neurodegenerative disorders and aging

Background: We report results of the novel Washout Allometric Reference Method (WARM) that uses estimates of cerebral blood flow and amyloid load from the same [C]Pittsburgh Compound B ([C]PiB) retention maps in brain to distinguish between patients with different forms dementia, including Alzheimer's disease, and healthy volunteers. The method introduces two approaches to the identification of brain pathology related to amyloid accumulation, (1) a novel analysis of amyloid binding based on the late washout of the tracer from brain tissue, and (2) the simultaneous estimation of absolute cerebral blood flow indices (sCBF) from the early accumulation of the tracer in brain tissue. Objective: We tested the hypothesis that a change of cerebral blood flow is correlated with the degree of tracer [C]PiB retention, reflecting dendritic spine pathology and consequent inhibition of brain energy metabolism and reduction of blood flow by neurovascular coupling in neurodegenerative disorders, including Alzheimer's disease. Methods: Previously reported images of [C]PiB retention in brain of 29 subjects with cognitive impairment or dementia [16 Alzheimer's Disease (AD), eight subjects with dementia with Lewy bodies (DLB), five patients with frontotemporal lobar degeneration (FTLD), five patients with mild cognitive impairment, and 29 age-matched healthy control subjects (HC)], underwent analysis of PiB delivery and retention by means of WARM for quantitation of [C]PiB's binding potentials (BP) and correlated surrogate cerebral blood flow (sCBF) estimates, based on the [C]PiB images, compared to estimates by conventional Standard Uptake Value Ratio (SUVR) of [C]PiB retention with cerebellum gray matter as reference. Receiver Operating Characteristics (ROC) revealed the power of discrimination among estimates. Results: For AD, the discriminatory power of [C]PiB binding potential (BP) by WARM exceeded the power of SUVR that in turn exceeded the power of sCBF estimates. Differences of [C]PiB binding and sCBF measures between AD and HC both were highly significant (p < 0.001). For all the dementia groups as a whole, sCBF estimates revealed the greatest discrimination between the patient and HC groups. WARM resolves a major issue of amyloid load quantification with [C]PiB in human brain by determining absolute sCBF and amyloid load measures from the same images. The two parameter approach provides key discriminary information in AD for which [C]PiB traditionally is used, as well as for the distinct flow deficits in FTLD, and the marked parietal and occipital lobe flow deficits in DLB. Conclusion: We conclude that WARM yields estimates of two important variables that together discriminate among patients with dementia, including AD, and healthy volunteers, with ROC that are superior to conventional methods of analysis. The distinction between estimates of flow and amyloid load from the same dynamic emission tomograms provides valuable pathogenetic information

Measurement of glomerular filtration rate reveals that subcapsular injection of shear‐thinning hyaluronic acid hydrogels does not impair kidney function in mice

The continued development of minimally invasive therapeutic implants, such as injectable hydrogels, necessitates the concurrent advancement of methods to best assess their biocompatibility via functional outcomes in vivo. Biomaterial implants have been studied to treat kidney disease; however, assessment of biocompatibility has been limited to biomarker and histological assessments. Techniques now exist to measure kidney function serially in vivo in murine studies via transcutaneous measurements of glomerular filtration rate (tGFR). In this study, adult male and female wild-type BalbC mice underwent right unilateral nephrectomy. The remaining solitary left kidney was allowed 4 weeks to recover via compensatory hypertrophy, after which subcapsular injection of either saline or shear-thinning hyaluronic acid hydrogel was performed. Serial tGFR measurements before and after treatment were used to assess the effect of hydrogel injection on kidney filtration. Urine and serum biomarkers of kidney function, and kidney histology were also quantified. Hydrogel injection did not affect kidney function, as assessed by tGFR. Results were in agreement with standard metrics of serum and urine biomarkers of injury as well as histological assessment of inflammation. The model developed provides a direct functional assessment of implant compatibility for the treatment of kidney disease and impact on kidney function

Computational Sensitivity Investigation of Hydrogel Injection Characteristics for Myocardial Support

Biomaterial injection is a potential new therapy for augmenting ventricular mechanics after myocardial infarction (MI). Recent in vivo studies have demonstrated that hydrogel injections can mitigate the adverse remodeling due to MI. More importantly, the material properties of these injections influence the efficacy of the therapy. The goal of the current study is to explore the interrelated effects of injection stiffness and injection volume on diastolic ventricular wall stress and thickness. To achieve this, finite element models were constructed with different hydrogel injection volumes (150 µL and 300 µL), where the modulus was assessed over a range of 0.1 kPa to 100 kPa (based on experimental measurements). The results indicate that a larger injection volume and higher stiffness reduce diastolic myofiber stress the most, by maintaining the wall thickness during loading. Interestingly, the efficacy begins to taper after the hydrogel injection stiffness reaches a value of 50 kPa. This computational approach could be used in the future to evaluate the optimal properties of the hydrogel

Tunable Blood Shunt for Neonates With Complex Congenital Heart Defects

Despite advancements in procedures and patient care, mortality rates for neonatal recipients of the Norwood procedure, a palliation for single ventricle congenital malformations, remain high due to the use of a fixed-diameter blood shunt. In this study, a new geometrically tunable blood shunt was investigated to address limitations of the current treatment paradigm (e.g., Modified Blalock-Taussig Shunt) by allowing for controlled modulation of blood flow through the shunt to accommodate physiological changes due to the patient’s growth. First, mathematical and computational cardiovascular models were established to investigate the hemodynamic requirements of growing neonatal patients with shunts and to inform design criteria for shunt diameter changes. Then, two stages of prototyping were performed to design, build and test responsive hydrogel systems that facilitate tuning of the shunt diameter by adjusting the hydrogel’s degree of crosslinking. We examined two mechanisms to drive crosslinking: infusion of chemical crosslinking agents and near-UV photoinitiation. The growth model showed that 15–18% increases in shunt diameter were required to accommodate growing patients’ increasing blood flow; similarly, the computational models demonstrated that blood flow magnitudes were in agreement with previous reports. These target levels of diameter increases were achieved experimentally with model hydrogel systems. We also verified that the photocrosslinkable hydrogel, composed of methacrylated dextran, was contact-nonhemolytic. These results demonstrate proof-of-concept feasibility and reflect the first steps in the development of this novel blood shunt. A tunable shunt design offers a new methodology to rebalance blood flow in this vulnerable patient population during growth and development

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Multi-model evaluation of the sensitivity of the global energy budget and hydrological cycle to resolution

This study undertakes a multi-model comparison with the aim to describe and quantify systematic changes of the global energy and water budgets when the horizontal resolution of atmospheric models is increased and to identify common factors of these changes among models. To do so, we analyse an ensemble of twelve atmosphere-only and six coupled GCMs, with different model formulations and with resolutions spanning those of state-of-the-art coupled GCMs, i.e. from resolutions coarser than 100 km to resolutions finer than 25 km. The main changes in the global energy budget with resolution are a systematic increase in outgoing longwave radiation and decrease in outgoing shortwave radiation due to changes in cloud properties, and a systematic increase in surface latent heat flux; when resolution is increased from 100 to 25 km, the magnitude of the change of those fluxes can be as large as 5 W m−2. Moreover, all but one atmosphere-only model simulate a decrease of the poleward energy transport at higher resolution, mainly explained by a reduction of the equator-to-pole tropospheric temperature gradient. Regarding hydrological processes, our results are the following: (1) there is an increase of global precipitation with increasing resolution in all models (up to 40 × 103 km3 year−1) but the partitioning between land and ocean varies among models; (2) the fraction of total precipitation that falls on land is on average 10% larger at higher resolution in grid point models, but it is smaller at higher resolution in spectral models; (3) grid points models simulate an increase of the fraction of land precipitation due to moisture convergence twice as large as in spectral models; (4) grid point models, which have a better resolved orography, show an increase of orographic precipitation of up to 13 × 103 km3 year−1 which explains most of the change in land precipitation; (5) at the regional scale, precipitation pattern and amplitude are improved with increased resolution due to a better simulated seasonal mean circulation. We discuss our results against several observational estimates of the Earth's energy budget and hydrological cycle and show that they support recent high estimates of global precipitation

State of the climate in 2018

In 2018, the dominant greenhouse gases released into Earth’s atmosphere—carbon dioxide, methane, and nitrous oxide—continued their increase. The annual global average carbon dioxide concentration at Earth’s surface was 407.4 ± 0.1 ppm, the highest in the modern instrumental record and in ice core records dating back 800 000 years. Combined, greenhouse gases and several halogenated gases contribute just over 3 W m−2 to radiative forcing and represent a nearly 43% increase since 1990. Carbon dioxide is responsible for about 65% of this radiative forcing. With a weak La Niña in early 2018 transitioning to a weak El Niño by the year’s end, the global surface (land and ocean) temperature was the fourth highest on record, with only 2015 through 2017 being warmer. Several European countries reported record high annual temperatures. There were also more high, and fewer low, temperature extremes than in nearly all of the 68-year extremes record. Madagascar recorded a record daily temperature of 40.5°C in Morondava in March, while South Korea set its record high of 41.0°C in August in Hongcheon. Nawabshah, Pakistan, recorded its highest temperature of 50.2°C, which may be a new daily world record for April. Globally, the annual lower troposphere temperature was third to seventh highest, depending on the dataset analyzed. The lower stratospheric temperature was approximately fifth lowest. The 2018 Arctic land surface temperature was 1.2°C above the 1981–2010 average, tying for third highest in the 118-year record, following 2016 and 2017. June’s Arctic snow cover extent was almost half of what it was 35 years ago. Across Greenland, however, regional summer temperatures were generally below or near average. Additionally, a satellite survey of 47 glaciers in Greenland indicated a net increase in area for the first time since records began in 1999. Increasing permafrost temperatures were reported at most observation sites in the Arctic, with the overall increase of 0.1°–0.2°C between 2017 and 2018 being comparable to the highest rate of warming ever observed in the region. On 17 March, Arctic sea ice extent marked the second smallest annual maximum in the 38-year record, larger than only 2017. The minimum extent in 2018 was reached on 19 September and again on 23 September, tying 2008 and 2010 for the sixth lowest extent on record. The 23 September date tied 1997 as the latest sea ice minimum date on record. First-year ice now dominates the ice cover, comprising 77% of the March 2018 ice pack compared to 55% during the 1980s. Because thinner, younger ice is more vulnerable to melting out in summer, this shift in sea ice age has contributed to the decreasing trend in minimum ice extent. Regionally, Bering Sea ice extent was at record lows for almost the entire 2017/18 ice season. For the Antarctic continent as a whole, 2018 was warmer than average. On the highest points of the Antarctic Plateau, the automatic weather station Relay (74°S) broke or tied six monthly temperature records throughout the year, with August breaking its record by nearly 8°C. However, cool conditions in the western Bellingshausen Sea and Amundsen Sea sector contributed to a low melt season overall for 2017/18. High SSTs contributed to low summer sea ice extent in the Ross and Weddell Seas in 2018, underpinning the second lowest Antarctic summer minimum sea ice extent on record. Despite conducive conditions for its formation, the ozone hole at its maximum extent in September was near the 2000–18 mean, likely due to an ongoing slow decline in stratospheric chlorine monoxide concentration. Across the oceans, globally averaged SST decreased slightly since the record El Niño year of 2016 but was still far above the climatological mean. On average, SST is increasing at a rate of 0.10° ± 0.01°C decade−1 since 1950. The warming appeared largest in the tropical Indian Ocean and smallest in the North Pacific. The deeper ocean continues to warm year after year. For the seventh consecutive year, global annual mean sea level became the highest in the 26-year record, rising to 81 mm above the 1993 average. As anticipated in a warming climate, the hydrological cycle over the ocean is accelerating: dry regions are becoming drier and wet regions rainier. Closer to the equator, 95 named tropical storms were observed during 2018, well above the 1981–2010 average of 82. Eleven tropical cyclones reached Saffir–Simpson scale Category 5 intensity. North Atlantic Major Hurricane Michael’s landfall intensity of 140 kt was the fourth strongest for any continental U.S. hurricane landfall in the 168-year record. Michael caused more than 30 fatalities and $25 billion (U.S. dollars) in damages. In the western North Pacific, Super Typhoon Mangkhut led to 160 fatalities and$6 billion (U.S. dollars) in damages across the Philippines, Hong Kong, Macau, mainland China, Guam, and the Northern Mariana Islands. Tropical Storm Son-Tinh was responsible for 170 fatalities in Vietnam and Laos. Nearly all the islands of Micronesia experienced at least moderate impacts from various tropical cyclones. Across land, many areas around the globe received copious precipitation, notable at different time scales. Rodrigues and Réunion Island near southern Africa each reported their third wettest year on record. In Hawaii, 1262 mm precipitation at Waipā Gardens (Kauai) on 14–15 April set a new U.S. record for 24-h precipitation. In Brazil, the city of Belo Horizonte received nearly 75 mm of rain in just 20 minutes, nearly half its monthly average. Globally, fire activity during 2018 was the lowest since the start of the record in 1997, with a combined burned area of about 500 million hectares. This reinforced the long-term downward trend in fire emissions driven by changes in land use in frequently burning savannas. However, wildfires burned 3.5 million hectares across the United States, well above the 2000–10 average of 2.7 million hectares. Combined, U.S. wildfire damages for the 2017 and 2018 wildfire seasons exceeded $40 billion (U.S. dollars)