Sticky Patches Research Articles

Engineering multifunctional adhesive hydrogel patches for biomedical applications

AbstractTraditional patches, such as sticking plaster or acrylic adhesives used for over a hundred years, lack functionality. To address this issue of poor functionality, adhesive hydrogel patches have emerged as an efficient bioactive multifunctional alternative. Hydrogels are three‐dimensional, water‐swellable, and polymeric materials closely resembling the native tissue architecture. The physicochemical properties of hydrogels can be modified easily, allowing them to be suitable for various biomedical applications. Moreover, adhesive properties can be imparted to hydrogels through physicochemical manipulations, making them ideal candidates for supplementing or replacing traditional sticking plaster. As a result, sticky hydrogel patches are widely used for transdermal drug delivery and have even found commercial purposes. Beyond transdermal delivery, such hydrogel patches have also found applications in cardiac therapy, cancer research, and biosensing, among other applications. In this mini‐review, we critically discuss the challenges of fabricating multifunctional adhesive hydrogel patches. Furthermore, we introduce some of the chemical strategies involved with fabricating the patches. We also review their emerging biomedical applications. Finally, we explore their potential future in the flourishing field of tissue engineering and drug delivery.

Inverting ice surface elevation and velocity for bed topography and slipperiness beneath Thwaites Glacier

Abstract. There is significant uncertainty over how ice sheets and glaciers will respond to rising global temperatures. Limited knowledge of the topography and rheology of the ice–bed interface is a key cause of this uncertainty as models show that small changes in the bed can have a large influence on predicted rates of ice loss. Most of our detailed knowledge of bed topography comes from airborne and ground-penetrating radar observations. However, these direct observations are not spaced closely enough to meet the requirements of ice-sheet models, so interpolation and inversion methods are used to fill in the gaps. Here we present the results of a new inversion of surface elevation and velocity data over Thwaites Glacier, West Antarctica, for bed topography and slipperiness (i.e. the degree of basal slip for a given level of drag). The inversion is based on a steady-state linear perturbation analysis of the shallow-ice-stream equations. The method works by identifying disturbances to surface flow which are caused by obstacles or sticky patches in the bed and can therefore be applied wherever the shallow-ice-stream equations hold and where surface data are available, even where the ice thickness is not well known. We assess the performance of the inversion for topography with the available radar data. Although the topographic output from the inversion is less successful where the bed slopes steeply, it compares well with radar data from the central trunk of the glacier for medium-wavelength features (5–50 km). This method could therefore be useful as an independent test of other interpolation methods such as mass conservation and kriging. We do not have data to allow us to assess the success of the slipperiness results from our inversions, but we provide maps that may guide future seismic data collection across Thwaites Glacier. The methods presented here show significant promise for using high-resolution satellite datasets, calibrated by sparser field datasets, to generate high-resolution bed topography products across the ice sheets and therefore contribute to reduced uncertainty in predictions of future sea-level rise.

Basal hydrofractures near sticky patches

Basal crevasses are macroscopic structural discontinuities at the base of ice sheets and glaciers that arise by fracture. Motivated by observations and by the mechanics of elastic fracture, we hypothesise that spatial variations in basal stress (in the presence of basal water pressure) can promote and localise basal crevassing. We quantify this process in the theoretical context of linear elastic fracture mechanics. We develop a model evaluating the effect of shear-stress variation on the growth of basal crevasses. Our results indicate that sticky patches promote the propagation of basal crevasses, increase their length of propagation into the ice and, under some conditions, give them curved trajectories that incline upstream. A detailed exploration of the parameter space is conducted to gain a better understanding of the conditions under which sticky-patch-induced basal crevassing is expected beneath ice sheets and glaciers.

An Intrinsically-Adhesive Family of Injectable and Photo-Curable Hydrogels with Functional Physicochemical Performance for Regenerative Medicine.

Attaching hydrogels to soft internal tissues is crucial for the development of various biomedical devices. Tough sticky hydrogel patches present high adhesion, yet with lack of injectability and the need for treatment of contacting surface. On the contrary, injectable and photo-curable hydrogels are highly attractive owing to their ease of use, flexibility of filling any shape, and their minimally invasive character, compared to their conventional preformed counterparts. Despite recent advances in material developments, a hydrogel that exhibits both proper injectability and sufficient intrinsic adhesion is yet to be demonstrated. Herein, a paradigm shift is proposed toward the design of intrinsically adhesive networks for injectable and photo-curable hydrogels. The bioinspired design strategy not only provides strong adhesive contact, but also results in a wide window of physicochemical properties. The adhesive networks are based on a family of polymeric backbones where chains are modified to be intrinsically adhesive to host tissue and simultaneously form a hydrogel network via a hybrid cross-linking mechanism. With this strategy, adhesion is achieved through a controlled synergy between the interfacial chemistry and bulk mechanical properties. The functionalities of the bioadhesives are demonstrated for various applications, such as tissue adhesives, surgical sealants, or injectable scaffolds.

Colloidal diamond.

Self-assembling colloidal particles in the cubic diamond crystal structure could potentially be used to make materials with a photonic bandgap1-3. Such materials are beneficial because they suppress spontaneous emission of light1 and are valued for their applications as optical waveguides, filters and laser resonators4, for improving light-harvesting technologies5-7 and for other applications4,8. Cubic diamond is preferred for these applications over more easily self-assembled structures, such as face-centred-cubic structures9,10, because diamond has a much wider bandgap and is less sensitive to imperfections11,12. In addition, the bandgap in diamond crystals appears at a refractive index contrast of about 2, which means that a photonic bandgap could be achieved using known materials at optical frequencies; this does not seem to be possible for face-centred-cubic crystals3,13. However, self-assembly of colloidal diamond is challenging. Because particles in a diamond lattice are tetrahedrally coordinated, one approach has been to self-assemble spherical particles with tetrahedral sticky patches14-16. But this approach lacks a mechanism to ensure that the patchy spheres select the staggered orientation of tetrahedral bonds on nearest-neighbour particles, which is required for cubic diamond15,17. Here we show that by using partially compressed tetrahedral clusters with retracted sticky patches, colloidal cubic diamond can be self-assembled using patch-patch adhesion in combination with a steric interlock mechanism that selects the required staggered bond orientation. Photonic bandstructure calculations reveal that the resulting lattices (direct and inverse) have promising optical properties, including a wide and complete photonic bandgap. The colloidal particles in the self-assembled cubic diamond structure are highly constrained and mechanically stable, which makes it possible to dry the suspension and retain the diamond structure. This makes these structures suitable templates for forming high-dielectric-contrast photonic crystals with cubic diamond symmetry.

Capillary Force Driving Directional 1D Assembly of Patchy Colloidal Discs.

Self-assembly from individual colloidal building units to complex superstructures provides a simple yet effective way for the fabrication of functional materials. A rational design of the unit interactions is essential for it to proceed in a desired manner. Here we show that nondirectional capillary force can be used for directional one-dimensional (1D) assembly of colloidal discs having a designed patch distribution, and colloidal discs with two liquid patches can assemble into long colloidal chains where the stacked colloidal discs have a well-matched configuration with parallel orientation. The length of the chains can be controlled by controlling the experimental parameters. We also found when liquid patches gradually turn into sticky patches, hydrophobic attraction comes into play and becomes dominant, which can also result in chains with continuously increasing length. This method opens an effective avenue for obtaining colloidal chains (or fibers), which can be adapted for the fabrication of other superstructures.

Generation of large pollution patches via collisions of sticky floating parcels driven by wind and surface currents

We study the evolution of large systems of sticky patches of pollution that float on the sea surface and are moved around by realistic wind and simulated surface currents. The study area is the Gulf of Finland in the eastern Baltic Sea that hosts extremely heavy cargo and tanker traffic. It is assumed that patches merge at collision. Collisions are enhanced by wind impact that depends on the patch size. We implement a space partitioning algorithm for fast simulations of large systems of >8000 patches and perform a series of simulations with different initial size and location of the patches. The resulting empirical distribution of the number of patches of different size is governed universally by a stretched-exponential power law f(x) = A exp (−xb). This indicates that the evolution of large systems of pollution patches on the sea surface exhibits classic self-organization and scale invariance properties. This may be the key effect explaining how the patchiness of waste in marine environment is formed under the impact of different drivers.

Criticality of colloids with three distinct interaction patches: As simple as A,B,C?

We systematically study the phase behavior of a simple model of associating fluids which consists of hard spherical particles with three short-ranged attractive sites on their surfaces (sticky spots or patches), of types A,B, and C, that can form bonds with energy ε_{ij} (i,j=A,B,C). We consider realizations of the model with one, two, or three nonzero ε_{ij}. Using Wertheim's first order perturbation theory of association, we establish the minimum requirements on the bond energies for the model to exhibit a liquid-vapor critical point, and investigate the nature of criticality in each case. As a preliminary, we rigorously show that, within this theory, particles with M identical sites do not condense if M<3, a result that was previously conjectured, but never proved.

The "Sticky Patch" Model of Crystallization and Modification of Proteins for Enhanced Crystallizability.

Crystallization of macromolecules has long been perceived as a stochastic process, which cannot be predicted or controlled. This is consistent with another popular notion that the interactions of molecules within the crystal, i.e., crystal contacts, are essentially random and devoid of specific physicochemical features. In contrast, functionally relevant surfaces, such as oligomerization interfaces and specific protein-protein interaction sites, are under evolutionary pressures so their amino acid composition, structure, and topology are distinct. However, current theoretical and experimental studies are significantly changing our understanding of the nature of crystallization. The increasingly popular "sticky patch" model, derived from soft matter physics, describes crystallization as a process driven by interactions between select, specific surface patches, with properties thermodynamically favorable for cohesive interactions. Independent support for this model comes from various sources including structural studies and bioinformatics. Proteins that are recalcitrant to crystallization can be modified for enhanced crystallizability through chemical or mutational modification of their surface to effectively engineer "sticky patches" which would drive crystallization. Here, we discuss the current state of knowledge of the relationship between the microscopic properties of the target macromolecule and its crystallizability, focusing on the "sticky patch" model. We discuss state-of-the-art in silico methods that evaluate the propensity of a given target protein to form crystals based on these relationships, with the objective to design variants with modified molecular surface properties and enhanced crystallization propensity. We illustrate this discussion with specific cases where these approaches allowed to generate crystals suitable for structural analysis.

Gadolinium induced effects on mammalian cell motility, adherence and chromatin structure.

The toxicity of gadolinium is reduced by chelating agents that render this heavy metal into contrast complexes used for medical magnetic resonance imaging. However, the dissociation of gadolinium chelates is known to generate Gd3+ ions, the cellular toxicity of which has not been tested in details. The cytotoxic effects of Gd(III) ions were evaluated by monitoring the proliferation, measuring the cellular motility and following chromatin changes in various cell lines upon Gd3+ treatment. Measurements applied long-term scanning microscopy and a perfusion platform that replaced the medium with test solutions, bypassed physical contact with the cell culture during experiments, and provided uninterrupted high time-resolution time-lapse photomicrography for an extended period of time. Genotoxicity specific chromatin changes characteristic to Gd(III) were distinguished in human skin keratinocytes (HaCaT), human limbal stem cells (HuLi), colorectal adenocarcinoma (CaCO2), murine squamous carcinoma (SCC) and Indian muntjac (IM) cell lines. Characteristic features of Gd(III) toxicity were: loss of cellular motility, irreversible attachment of cells to the growth surface and cell death. Injury-specific chromatin changes manifested at micromolar Gd3+ concentrations as premature chromatin condensation and highly condensed sticky chromatin patches. Gd(III) concentration- and cell type-dependent reduction of normal adherence, as well as premature chromatin condensation confirmed apoptosis. The risk related to the release of toxic Gd3+ ions from gadolinium complexes and their effects on mono- and multi-layer cellular barriers have to be reconsidered when these chelated complexes are used as contrasting agents especially in relation to possible blood-brain barrier damages.

Sticky Patches on Lipid Nanoparticles Enable the Selective Targeting and Killing of Untargetable Cancer Cells.

Effective targeting by uniformly functionalized nanoparticles is limited to cancer cells expressing at least two copies of targeted receptors per nanoparticle footprint (approximately ≥2 × 10(5) receptor copies per cell); such a receptor density supports the required multivalent interaction between the neighboring receptors and the ligands from a single nanoparticle. To enable selective targeting below this receptor density, ligands on the surface of lipid vesicles were displayed in clusters that were designed to form at the acidic pH of the tumor interstitium. Vesicles with clustered HER2-targeting peptides within such sticky patches (sticky vesicles) were compared to uniformly functionalized vesicles. On HER2-negative breast cancer cells MDA-MB-231 and MCF7 {expressing (8.3 ± 0.8) × 10(4) and (5.4 ± 0.9) × 10(4) HER2 copies per cell, respectively}, only the sticky vesicles exhibited detectable specific targeting (KD ≈ 49-69 nM); dissociation (0.005-0.009 min(-1)) and endocytosis rates (0.024-0.026 min(-1)) were independent of HER2 expression for these cells. MDA-MB-231 and MCF7 were killed only by sticky vesicles encapsulating doxorubicin (32-40% viability) or α-particle emitter (225)Ac (39-58% viability) and were not affected by uniformly functionalized vesicles (>80% viability). Toxicities on cardiomyocytes and normal breast cells (expressing HER2 at considerably lower but not insignificant levels) were not observed, suggesting the potential of tunable clustered ligand display for the selective killing of cancer cells with low receptor densities.

Overturned folds in ice sheets: Insights from a kinematic model of traveling sticky patches and comparisons with observations

AbstractOverturned folds are observed in regions of the Greenland ice sheet where driving stress is highly variable. Three mechanisms have been proposed to explain these folds: freezing subglacial water, traveling basal slippery patches, and englacial rheological contrasts. Here we explore how traveling basal sticky patches can produce overturned folds. Transitions from low to high stress cause a tradeoff in ice flow between basal slip and internal deformation that deflects ice stratigraphy vertically. If these transitions move, the slip‐deformation tradeoff can produce large folds. Those folds record the integrated effects of time‐varying basal slip. To understand how dynamic changes in basal slip influence ice sheet stratigraphy, we develop a kinematic model of ice flow in a moving reference frame that follows a single traveling sticky patch. The ice flow field forms a vortex when viewed in the moving reference frame, and this vortex traps ice above the traveling patch and produces overturned folds. Sticky patches that travel downstream faster produce larger overturned folds. We use the model as an interpretive tool to infer properties of basal slip from three example folds. Our model suggests that the sticky patches underneath these folds propagated downstream at rates between one half and the full ice velocity. The regional flow regime for the smaller two folds requires substantial internal deformation whereas the regime for the largest fold requires substantially more basal slip. The distribution and character of stratigraphic folds reflect the evolution and propagation of individual sticky patches and their effects on ice sheet flow.

Sticky Patches on Lipid Nanoparticles Generate Binding Geometries that Enable Effective Targeting of Otherwise Untargetable Cancers

The majority of breast cancer patients (70%) have tumors designated as ‘HER2-negative’ (<1+ HER2-expression evaluated by immunohistochemistry or < 200,000 HER2-copies per cell). For these patients there are no targeted therapeutic options utilizing the HER2 receptor. The ability of conventionally targeted nanoparticles for specific targeting stops to hold on cancer cells expressing less than 200,000 copies of HER2 per cell or less than two receptors per nanoparticle's projected area (for particles of 100 nm in-diameter). This geometry corresponds to the limit of multivalent interactions (avidity) loosely defined as multiple contacts between neighboring same-cell receptors with ligands from a single nanoparticle. An alternative therapeutic approach is needed, therefore, to enable selective targeting and effective killing of cancer cells with low or too low HER2 expression.Towards this goal we designed targeted lipid nanoparticles (vesicles) that contain HER2-targeting short peptides densely conjugated (for high local multivalency) within sticky patches. Sticky patches are phase-separated raft-like lipid-domains of high local multivalency which is induced by preferential partitioning of peptide-functionalized lipids. To enable selectivity in binding, sticky patches are exclusively triggered to form in mildly acidic environments matching the tumor interstitium. Lipid phase-separation with lowering pH is a result of the interplay of decreasing (pH-tunable) electrostatic repulsion and attractive hydrogen bonding among the domain-forming lipids.We show that lipid nanoparticles with sticky patches selectively associate with and kill HER2-negative and triple negative breast cancer cells (MCF-7 and MDA-MB-231, respectively, with 60,000 and 90,000 HER2-copies per cell) while do not affect cardiomyocytes and breast normal cells. Systematic studies of association, dissociation and internalization rates of nanoparticles by cells will be presented, and a mechanistic mathematical model will be discussed with the aim to explain the observed high avidity.

Patterns without patches: hierarchical self-assembly of complex structures from simple building blocks.

Nanoparticles with “sticky patches” have long been proposed as building blocks for the self-assembly of complex structures. The synthetic realizability of such patchy particles, however, greatly lags behind predictions of patterns they could form. Using computer simulations, we show that structures of the same genre can be obtained from a solution of simple isotropic spheres, with control only over their sizes and a small number of binding affinities. In a first step, finite clusters of well-defined structure and composition emerge from natural dynamics with high yield. In effect a kind of patchy particle, these clusters can further assemble into a variety of complex superstructures, including filamentous networks, ordered sheets, and highly porous crystals.

Polymer patchy colloids with sticky patches

Patchy particles (PPs) are considered as interesting building blocks for the fabrication of novel structures with enhanced complexity and functionality. However, their development is primarily limited by the fact that there is no reliable method to prepare PPs on a large scale. Herein, a one-pot strategy to prepare PPs relying on polymerization-induced phase separation in monomer-embedded polymer nanoparticles is demonstrated. The surface is found to be composed of sticky patches embedded in a hard matrix by adhesion and force–distance measurements performed by atomic force microscopy. The patch sizes could be easily tuned by controlling the monomer conversion or varying the composition between the polymer and the monomer. This study presents the possibility to develop a simple, low-cost and scalable method for preparing large quantities of PPs from homopolymers. It may also pave the way to new PPs for functional materials and devices.

Entropy stabilizes open crystals

Open crystalline configurations self-assembled from colloids with sticky patches have recently been shown to be unexpectedly stable. A theory that accounts for the entropy of the colloids' thermal fluctuations now explains why.

Immiscible lipids control the morphology of patchy emulsions

We study the phase behavior of immiscible mixtures of phospholipids and cholesterol at the interface of oil-in-water emulsions, which governs the surface morphology of patchy droplets. Emulsification with lipid mixtures leads to domain formation with a variety of shapes, such as spots, disordered stripes, hemispheres and rings. We map out the ternary immiscibility diagram of our system, which allows one to control the geometry of patches on the droplet surface. By contrast to short-lived domains on liposomes, image analysis of the individual domains shows that emulsion spots grow towards a steady state size distribution and remain stable over weeks. These domains are functionalized with biotinylated lipids, which makes them useful candidates for directed self-assembly through specific interactions via streptavidin. Here we bind streptavidin coated beads to these lipids and find that the binder diffusion constant depends on the morphology of the droplet. These fluid patchy particles offer a versatile system in which the geometry and the dynamics of the sticky patches are under control.

Self-assembly gets new direction

By controlling the placement of 'sticky' patches on particles, assemblies can be made that mimic atomic bonding in molecules. This greatly expands the range of structures that can be assembled from small components. See Article p.51 Chemists routinely use atoms that can form directional bonds to assemble complex and useful molecular structures. But larger colloidal particles have proved less conducive to rational assembly because they lack specific directional bonds. David Pine and colleagues now report a way around this problem that could lead to the creation of a rich variety of new micro-structured colloidal materials with technologically useful properties. Using microsphere clusters as intermediates, they create colloidal particles with chemically distinct and precisely located 'sticky patches' on the surface — up to 7 per particle — that enable specific and highly directional bonding. Using this system, they assemble 'colloidal molecules' exhibiting a wide range of bonding symmetries.

Neutrophils cast slings against the flow

During inflammation neutrophils roll slowly on microvessel walls, prior to their extravasation. Cell flattening and long rear membrane tethers maintain slow neutrophil rolling at high shear stress. Here, Sundd et al. report that 'slings' forming at the front of rolling neutrophils can also act as potent breaks during rolling. In vitro and in vivo imaging showed that detached tethers swing to the front of rolling neutrophils to form long slings that contain 'sticky patches' of the P-selectin ligand PSGL1. As neutrophils roll over the sling and transfer load between consecutive PSGL1 patches, the interaction between LFA1 on slings and ICAM2 on the neutrophil surface ensures tight neutrophil wrapping by slings, thereby retaining them close to the microvessel wall. Interestingly, measurements of the forces applied by tethers and slings on rolling neutrophils indicate that these structures could be sufficient for slow neutrophil rolling at high shear stress.

‘Slings’ enable neutrophil rolling at high shear

Most leukocytes can roll along the walls of venules at low shear stress (1 dyn/cm2), but neutrophils have the ability to roll at 10-fold higher shear stress in microvessels in vivo1,2. The mechanisms involved in this shear-resistant rolling are known to involve cell flattening3 and pulling of long membrane tethers at the rear4–6. Here, we show that these long tethers do not retract as postulated6,7, but instead persist and appear as ‘slings’ at the front of rolling cells. We demonstrate slings in a model of acute inflammation in vivo and on P-selectin in vitro, where P-selectin-glycoprotein-ligand-1 (PSGL-1) is presented as discrete sticky patches while LFA-1 is expressed over the entire length on slings. As neutrophils roll forward, slings wrap around the rolling cells and undergo a step-wise peeling from the P-selectin substrate enabled by the failure of PSGL-1 patches under hydrodynamic forces. The ‘step-wise peeling of slings’ is distinct from the ‘pulling of tethers’ reported previously4–6,8. Each sling effectively lays out a cell-autonomous adhesive substrate in front of neutrophils rolling at high shear stress during inflammation.