Corona-induced transition from molecular to particle motion in biological media

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Light signatures generated by particles in a nanoscopeIn last month’s post [see ‘Nanoparticle motion through heterogeneous hydrogels’ on November 6th, 2024], I described our recent work on tracking nanoparticles through a model of the vitreous humour and mentioned it was the first of two articles published in the Nature journal, Scientific Reports.  In the second article, we explored the use of caustics in an optical microscope [see ‘Seeing the invisible’ on October 29th, 2014] to track nanoparticles in biofluids.  Nanoparticles are below the resolution of an optical microscope because they are substantially smaller than the wavelength of visible light; hence, they are usually tracked using fluorescent markers or tags attached chemically to the nanoparticles.  These tags can influence both the motion of the particles and biological activity so caustics provide a label-free technique that allows particles to be tracked in real-time using a standard optical microscope.  In most of our previous research, we have tracked nanoparticles in transparent fluids such as water, glycerol-water mixtures, or the hydrogels described in last month’s post.  In our latest work, we have tracked small nanoparticles with diameters from 10 to 100 nm in common cell culture media with different concentrations of serum proteins.  These fluids are a ‘soup’ of complex protein molecules that interact with one another and the gold nanoparticles being tracked.  We found that the presence of proteins caused a reduction in the rate of diffusion for both positively- and negatively-charged particles and we concluded that the proteins form a corona around each nanoparticle effectively enlarging its diameter.  For larger nanoparticles, and those positively-charged, the enlargement appears to cause a transition from molecular motion, in which particle diameter is unimportant, to particle motion where larger particles diffuse more slowly.  We first explored this transition from fractional to classical Stokes-Einstein behaviour in simple fluids in 2017 [‘Slow moving nanoparticles‘ on December 13th 2017] and it seems likely to be complicated in these complex fluids.  Hence, understanding protein dynamics as well nanoparticle dynamics will be essential to the development of nanotechnologies applicable in biological environments.  So, we have lots more work to do!

Sources:

Schleyer G, Patterson EA, Curran JM. Label free tracking to quantify nanoparticle diffusion through biological media. Scientific Reports. 2024 Aug 13;14(1):18822.

Coglitore D, Edwardson SP, Macko P, Patterson EA, Whelan MP, Transition from fractional to classical Stokes-Einstein behaviour in simple fluids, Royal Society Open Science, 4:170507, 2017.

Nanoparticle motion through heterogeneous hydrogels

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Over the last couple of years, we have been transitioning a technique, which we developed for tracking the motion of nanoparticles using caustics [see ‘Slow moving nanoparticles‘ on December 13th 2017], from its initial use in exploring mechanics at the nanoscale to applications in nanobiology [See ‘Label-free real-time tracking of individual bacterium‘ on January 25th, 2023] where it has the advantages of functioning in real-time and being label-free (chemical labels can impact motion, protein interactions and cell behaviour).  In the summer, we had couple of articles published in consecutive issues of the Nature journal, Scientific Reports which describe our recent work.  In the first, we have explored the diffusion of nanoparticles through a synthetic analogue of the vitreous humour in order to support the design of novel therapeutics for retinal diseases.  Retinal diseases, such as macular degeneration and diabetic retinopathy, affects millions of people globally and treatment often involves frequent intravitreal injections of anti-vascular endothelium growth factor agents and corticoids.  Delivery of the appropriate dose to the retinal cell layer is challenging due to the complex nature of the vitreous and functionalised nanoparticles offer a potential solution.  In vivo animal testing is inappropriate because of the ethical concerns and poor representation of human eyes and ex vivo testing of cadaveric eyes is unreliable due to the instability of biomechanical and biochemical properties of the vitreous humour.  Hence, we used agar-hyaluronic acid hydrogels as an in vitro model of the vitreous and employed the caustic technique to track the motion of nanoparticles through the hydrogels.  The hydrogels had been validated as a representative model of the vitreous humour by other research groups.  Our tracking technique revealed that the electric charge on the nanoparticles did not affect their diffusion through the hydrogel; however, both the diameter of the particles and the heterogeneous nature of the gel influenced the diffusion.  Nanoparticles with diameters of 200, 100 and 50 nm moved progressively more quickly and over a larger area.  The diffusion rates in hydrogels with a high viscosity (about 450  Pa.s) were consistent throughout the gel implying that the gel was homogeneous, while gels with medium (about 40 Pa.s) to low (about 3 Pa.s) viscosity generated diffusion rates that were distributed bi-modally suggesting a heterogeneous gel with zones of low and high density in which the particles moved more or less freely.  The heterogeneity of a gel renders a global value for viscosity somewhat meaningless and makes comparisons difficult with the vitreous humour because it is also heterogeneous; however, global values of viscosity for porcine vitreous humour are typically 1 Pa.s.  We are continuing this research; however, our published work has demonstrated that the use of caustics in an optical microscope is a reproducible and inexpensive technique for exploring the design of novel nanoscale drug delivery systems for the eye.

Source: Lorenzo Lopez M, Kearns VR, Curran JM, Patterson EA. Diffusion of nanoparticles in heterogeneous hydrogels as vitreous humour in vitro substitutes. Scientific reports. 2024 Jul 29;14(1):1744.

Image: Random track of a nanoparticle superimposed on its image generated in the microscope using a pin-hole and narrowband filter.

Emergence of ideas leading to a lack of deep insights

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Decorative imageIn Surrealism, which emerged after World War 1, artists attempted to allow the subconscious mind to express itself and resulted in illogical montages or dreamlike scenes and ideas.  Some surrealists championed the subconscious because they thought it would release society from the oppressive rationality of capitalism.  Anna Wiele Kjaer of the University of Copenhagen has suggested that instead our subconscious has been colonised by capitalism and is being shaped the endless of streams of disconnected images flowing from our phones, which are as incongruous as any surrealist montage.  To decolonise our subconscious and to replenish our creativity many of us need a digital detox involving time away from our electronic devices [see ‘Digital detox with deep vacation’ on August 10th, 2016] allowing our brains to switch into mind wandering mode for long uninterrupted periods [see ‘Mind wandering’ on September 3rd, 2014].  Cormac McCarthy has described how ideas struggle against their own realisation and come with their own innate scepticism that acts like a steering mechanism for their emergence from our subconscious.  He also suggests that all ideas come to an end when they lose lustre becoming a tool, perhaps as a theory, strategy or plan, and you can no longer entertain the illusion that they hold some deep insight into reality.  Many of my thoughts never coalesce into an emergent idea but remain as illogical and disconnected as a surrealist montage and the few that do emerge don’t provide deep insights into reality that I recognise.

Sources:

Anya Harrison, Another Surrealism, 2022

Cormac McCarthy, The Passenger, Pan MacMillan, 2023.

Jackie Wullschläge, Surrealism at 100: does it still have the power to disrupt?, FT Weekend, 27 January 2024.

Image: Ceramic tile by Pablo Picasso in museum in Port de Sóller Railway Station, Mallorca.

Meaningless on holiday

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Decorative photograph of ruins of Cornish tin mineI spent a substantial proportion of last month enjoying a summer holiday in Cornwall walking sections of the South-west Coast Path (see ‘The Salt Path’ on August 14th, 2019), sampling local beers and reading books.  The books were mainly fiction.  So it should be no surprise that a recurring theme in the books was relationships because no one exists independent of their relationships with others.  This was very apparent in the first two books I read in Cornwall: ‘River East River West’ by Aube Rey Lescure about the interface of modern Chinese culture with American colonialism and exceptionalism in the context of parenthood and teenagers growing up; and in ‘The Crooked Plow’’’ by Itamar Vieira Junior, a horrific, heart-warming and, for me educational, family saga in the face of brutal exploitation of former slave communities in Brazil.  However, as I read deeper into the pile of holiday reading, a theme of meaninglessness started to emerge.  A hint appeared in ‘Scaffolding’ by Lauren Elkin when one character says, ‘I have always taken great comfort in the chaos of the universe, that nothing is meant to be and History means nothing but what we decide on its behalf.’  It started to crystallize, at least in my mind, when I read ‘How Life Works’ by Philip Ball who referred to Wienberg’s version of a universe without purpose or meaning before discussing at length that there is no blueprint or plan for life and that our genome contains the instructions that allow our cells to make between eighty thousand and four hundred thousand proteins but our cells decide when,  which and what quantity of each protein to produce as a consequence of their relationships with their neighbours and the environment.  However, in ‘Orbital’ by Samantha Harvey, a novel set in the space station orbiting the Earth, the meaningless of our lives is boldly stated: ‘We matter greatly and not at all. To reach some pinnacle of human achievement only to discover that your achievements are next to nothing and that to understand this is the greatest achievement of any life, which itself is nothing, and also much more than everything.’  This sentiment was re-iterated succinctly in ‘Your absence is darkness’ by Jon Kalman Stefansson, as ‘We come out of nowhere, disappear into nothingness, and, in the end, everything is erased‘.  There was a brief respite when I read ‘Slow Productivity’ by Cal Newman who encourages us to give ourselves time to produce something great, citing Isaac Newton’s ‘Principia’ and ‘On the Road’ by Jack Kerouac; however, I hardly expect to leave such works for future generations so I was not much cheered.  The meaninglessness of life reappeared in ‘Baumgartner’ by Paul Auster, in which a semi-retired professor is writing an essay about Kierkegaard, the existentialist philosopher, and describes his obligation as a professor ‘to ask good questions about what it means to be alive, even if he knows he will never be able to answer them.’  In the last book I managed to finish before we left Cornwall, ‘Close to Home’ by Michael Magee, a leading character decides to steal a copy of Knut Hamsun’s ‘Hunger’ from a bookshop because it was an existential novel with an afterword by Paul Auster, whose last novel I had just read, and foreword by Jo Nesbo, who’s crime thriller, Redeemer, I had read earlier in the holiday but had not yet managed to weave into this post! Perhaps someone had carefully selected my summer reading to ensure that I got the message that all victories are trivial, all wealth is valueless and that happiness is to be found in our relationships with others.  Alternatively, all of these books were published in the last twelve months so maybe all of the authors were possessed by sense of meaninglessness induced by the current geo-political situation.

BTW the only book I read on holiday that I did not manage to mention above was ‘The Premonition’ by Banana Yoshimoto – a beautifully written short novel about relationships and loneliness.

The Books:

‘River East River West’ by Aube Rey Lescure, Duckworth Books, 2024.

‘The Crooked Plow’ by Itamar Vieira Junior, translated by Johnny Lorenz, Verso Books, 2023.

‘Scaffolding’ by Lauren Elkin, Penguin Books, 2024.

‘How Life Works’ by Philip Ball, Pan MacMillan, 2024.

‘Orbital’ by Samantha Harvey, Grove Atlantic Publishing, 2024.

‘Your absence is darkness’ by Jon Kalman Stefansson, translated by Philip Roughton, Hachette, 2024.

‘Slow Productivity’ by Cal Newman, Penguin Books, 2024.

‘Baumgartner’ by Paul Auster, Faber & Faber, 2024.

‘Close to Home’ by Michael Magee, Penguin Books, 2024.

‘Redeemer’ by Jo Nesbo, Penguin Books, 2022.

‘The Premonition’ by Banana Yoshimoto, translated Asa Yoneda, Faber & Faber, 2023.