Physical structuring of injectable polymeric systems to controllably deliver nanosized extracellular vesicles

Extracellular vesicles (EVs) are emerging as a promising alternative approach to cell‐therapies. However, to realize the potential of these nanoparticles as new regenerative tools, healthcare materials that address the current limitations of systemic administration need to be developed. Here, two technologies for controlling the structure of alginate based microgel suspensions are used to develop sustained local release of EVs, in vitro. Microparticles formed using a shearing technique are compared to those manufactured using vibrational technology, resulting in either anisotropic sheet‐like or spheroid particles, respectively. EVs harvested from preosteoblasts are isolated using differential ultracentrifugation and successfully loaded into the two systems, while maintaining their structures. Promisingly, in addition to exhibiting even EV distribution and high stability, controlled release of vesicles from both structures is exhibited, in vitro, over the 12 days studied. Interestingly, a significantly greater number of EVs are released from the suspensions formed by shearing (69.9 ± 10.5%), compared to the spheroids (35.1 ± 7.6%). Ultimately, alterations to the hydrogel physical structures have shown to tailor nanoparticle release while simultaneously providing ideal material characteristics for clinical injection. Thus, the sustained release mechanisms achieved through manipulating the formation of such biomaterials provide a key to unlocking the therapeutic potential held within EVs

Sustained release of decorin to the surface of the eye enables scarless corneal regeneration

Ophthalmology: novel eye drop brings sustained drug delivery to ocular surface An eye drop formulation that applies anti-scarring drugs to the surface of the eye helps reverse infection-induced corneal damage in mice. Hill et al. from the University of Birmingham, UK, formulated a fluid gel loaded with a wound-healing protein called decorin that conforms to the ocular surface and is cleared gradually through blinking. With colleagues in California, they applied the therapeutic eye drop to mice with bacterial eye infections that trigger sight-threatening corneal scarring. Within a matter of days, the team saw improvements in corneal transparency, with reductions in scar tissue and reconstitution of healthy cells. Such a drug delivery system, if successful in humans, could help save many people’s sight and reduce the need for corneal transplantation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Can We Structure Biomaterials to Spray Well Whilst Maintaining Functionality?

Structured fluid biomaterials, including gels, creams, emulsions and particle suspensions, are used extensively across many industries, including great interest within the medical field as controlled release vehicles to improve the therapeutic benefit of delivered drugs and cells. Colloidal forces within these materials create multiscale cohesive interactions, giving rise to intricate microstructures and physical properties, exemplified by increasingly complex mathematical descriptions. Yield stresses and viscoelasticity, typically arising through the material microstructure, vastly improve site-specific retention, and protect valuable therapeutics during application. One powerful application route is spraying, a convenient delivery method capable of applying a thin layer of material over geometrically uneven surfaces and hard-to-reach anatomical locations. The process of spraying is inherently disruptive, breaking a bulk fluid in successive steps into smaller elements, applying multiple forces over several length scales. Historically, spray research has focused on simple, inviscid solutions and dispersions, far from the complex microstructures and highly viscoelastic properties of concentrated colloidal biomaterials. The cohesive forces in colloidal biomaterials appear to conflict with the disruptive forces that occur during spraying. This review explores the physical bass and mathematical models of both the multifarious material properties engineered into structured fluid biomaterials and the disruptive forces imparted during the spray process, in order to elucidate the challenges and identify opportunities for rational design of sprayable, structured fluid biomaterials

Low Acyl Gellan as an Excipient to Improve the Sprayability and Mucoadhesion of Iota Carrageenan in a Nasal Spray to Prevent Infection With SARS-CoV-2

The COVID-19 global pandemic, as well as the widespread persistence of influenza and the common cold, create the need for new medical devices such as nasal sprays to prevent viral infection and transmission. Carrageenan, a sulfated polysaccharide, has a broad, non-pharmacological antiviral capacity, however it performs poorly in two key areas; spray coverage and mucoadhesion. Therefore gellan, another polysaccharide, was investigated as an excipient to improve these properties. It was found that viscoelastic relaxation time was the key predictor of spray coverage, and by reducing this value from 2.5 to 0.25 s, a mix of gellan and carrageenan gave more than four times the coverage of carrageenan alone (p < 0.0001). Gellan also demonstrated enhanced adhesion to a mucus analog that increased significantly with time (p < 0.0001), suggesting the development of specific gellan–mucin interactions. This property was conferred to carrageenan on mixing the two polymers. Together, this data suggests that gellan is a promising excipient to improve both sprayability and mucoadhesion of carrageenan for use in antiviral nasal sprays

Formulation of a Composite Nasal Spray Enabling Enhanced Surface Coverage and Prophylaxis of SARS-COV-2

Airborne pathogens pose high risks in terms of both contraction and transmission within the respiratory pathways, particularly the nasal region. However, there is little in the way of adequate intervention that can protect an individual or prevent further spread. This study reports on a nasal formulation with the capacity to combat such challenges, focusing on severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). Formulation of a polysaccharide‐based spray, known for its mucoadhesive properties, is undertaken and it is characterized for its mechanical, spray distribution, and antiviral properties. The ability to engineer key mechanical characteristics such as dynamic yield stresses and high coverage is shown, through systematic understanding of the composite mixture containing both gellan and λ‐carrageenan. Furthermore, the spray systems demonstrate highly potent capacities to prevent SARS‐CoV‐2 infection in Vero cells, resulting in complete inhibition when either treating, the cells, or the virus, prior to challenging for infection. From this data, a mechanism for both prophylaxis and prevention is proposed; where entrapment within a polymeric coating sterically blocks virus uptake into the cells, inactivating the virus, and allowing clearance within the viscous medium. As such, a fully preventative spray is formulated, targeted at protecting the lining of the upper respiratory pathways against SARS‐CoV‐2

A treatment strategy with nifedipine versus labetalol for women with pregnancy hypertension:study protocol for a randomised controlled trial (Giant PANDA)

BACKGROUND: Approximately one in ten women have high blood pressure during pregnancy. Hypertension is associated with adverse maternal and perinatal outcomes, and as treatment improves maternal outcomes, antihypertensive treatment is recommended. Previous trials have been unable to provide a definitive answer on which antihypertensive treatment is associated with optimal maternal and neonatal outcomes and the need for robust evidence evaluating maternal and infant benefits and risks remains an important, unanswered question for research and clinical communities. METHODS: The Giant PANDA study is a pragmatic, open-label, multicentre, randomised controlled trial of a treatment initiation strategy with nifedipine (calcium channel blocker), versus labetalol (mixed alpha/beta blocker) in 2300 women with pregnancy hypertension. The primary objective is to evaluate if treatment with nifedipine compared to labetalol in women with pregnancy hypertension reduces severe maternal hypertension without increasing fetal or neonatal death or neonatal unit admission. Subgroup analyses will be undertaken by hypertension type (chronic, gestational, pre-eclampsia), diabetes (yes, no), singleton (yes, no), self-reported ethnicity (Black, all other), and gestational age at randomisation categories (11 + 0 to 19 + 6, 20 + 0 to 27 + 6, 28 + 0 to 34 + 6 weeks). A cost-effectiveness analysis using an NHS perspective will be undertaken using a cost-consequence analysis up to postnatal hospital discharge and an extrapolation exercise with a lifetime horizon conditional on the results of the cost-consequence analysis. DISCUSSION: This trial aims to address the uncertainty of which antihypertensive treatment is associated with optimal maternal and neonatal outcomes. The trial results are intended to provide definitive evidence to inform guidelines and linked, shared decision-making tools, thus influencing clinical practice. TRIAL REGISTRATION: EudraCT number: 2020-003410-12, ISRCTN: 12,792,616 registered on 18 November 2020