Nanolatex architectonics: influence of cationic charge density and size on their adsorption onto surfaces with a 2D or 3D distribution of anionic groups

Hypothesis: It is theoretically predicted and hypothesized that the charge density and size of spherical nanoparticles are the key factors for their adsorption onto oppositely charged surfaces. It is also hypothesized that the morphology and charge of the surface are of great importance. In-plane 2D (silica) or a volumetric 3D (regenerated TEMPO-oxidized cellulose model surfaces) distribution of charged groups is expected to influence charge compensation and, thus, the adsorption behavior. Experiments: In this work, self-stabilized nanolatexes with a range of cationic charge densities and sizes were synthesized through reversible addition fragmentation chain-transfer (RAFT) polymerization coupled with polymerization-induced self-assembly (PISA). Their adsorption onto silica and anionic cellulose model surfaces was investigated using stagnation point adsorption reflectometry (SPAR) and quartz crystal microbalance with dissipation (QCM-D). Findings: Experiments and theory agree and show that the size of the nanolatex and the difference in charge density compared to the substrate determine the charge compensation and, thus, the surface coverage. Highly charged or large nanolatexes overcompensate the surface charge of non-porous substrates leading to a significant repulsive zone where other particles cannot adsorb. For porous substrates like cellulose, the vertical distribution of charged groups in the 3D volume prevents overcompensation and thus increases the adsorption. This systematic study investigates the isolated effect of surface charge and size and paves the way for on-demand particles specifically designed for a surface with particular characteristics.Published versionThe authors acknowledge funding from the Knut and Alice Wallenberg Foundation (KAW) through the Wallenberg Wood Science Center and a personal fellowship for Tobias Benselfelt

Elastoplastic behavior of anisotropic, physically crosslinked hydrogel networks comprising stiff, charged fibrils in an electrolyte

Fibrillar hydrogels are remarkably stiff, low-density networks that can hold vast amounts of water. These hydrogels can easily be made anisotropic by orienting the fibrils using different methods. Unlike the detailed and established descriptions of polymer gels, there is no coherent theoretical framework describing the elastoplastic behavior of fibrillar gels, especially concerning anisotropy. In this work, the swelling pressures of anisotropic fibrillar hydrogels made from cellulose nanofibrils were measured in the direction perpendicular to the fibril alignment. This experimental data was used to develop a model comprising three mechanical elements representing the network and the osmotic pressure due to non-ionic and ionic surface groups on the fibrils. At low solidity, the stiffness of the hydrogels was dominated by the ionic swelling pressure governed by the osmotic ingress of water. Fibrils with different functionality show the influence of aspect ratio, chemical functionality, and the remaining amount of hemicelluloses. This general model describes physically crosslinked hydrogels comprising fibrils with high flexural rigidity - that is, with a persistence length larger than the mesh size. The experimental technique is a framework to study and understand the importance of fibrillar networks for the evolution of multicellular organisms, like plants, and the influence of different components in plant cell walls.The Knut and Alice Wallenberg Foundation are acknowledged for funding through the Wallenberg Wood Science Center (WWSC) and an individual fellowship for Tobias Benselfelt (KAW 2019.0564). Stefan B. Lindstroem works within the Neopulp research profile financed by the Knowledge Foundation, and also thanks SCA for financial support

Photocross-Linkable and Shape-Memory Biomaterial Hydrogel Based on Methacrylated Cellulose Nanofibres

In the context of three-dimensional (3D) cell culture and tissue engineering, 3D printing is a powerful tool for customizing in vitro 3D cell culture models that are critical for understanding the cell-matrix and cell-cell interactions. Cellulose nanofibril (CNF) hydrogels are emerging in constructing scaffolds able to imitate tissue in a microenvironment. A direct modification of the methacryloyl (MA) group onto CNF is an appealing approach to synthesize photocross-linkable building blocks in formulating CNF-based bioinks for light-assisted 3D printing; however, it faces the challenge of the low efficiency of heterogenous surface modification. Here, a multistep approach yields CNF methacrylate (CNF-MA) with a decent degree of substitution while maintaining a highly dispersible CNF hydrogel, and CNF-MA is further formulated and copolymerized with monomeric acrylamide (AA) to form a super transparent hydrogel with tuneable mechanical strength (compression modulus, approximately 5-15 kPa). The resulting photocurable hydrogel shows good printability in direct ink writing and good cytocompatibility with HeLa and human dermal fibroblast cell lines. Moreover, the hydrogel reswells in water and expands to all directions to restore its original dimension after being air-dried, with further enhanced mechanical properties, for example, Young’s modulus of a 1.1% CNF-MA/1% PAA hydrogel after reswelling in water increases to 10.3 kPa from 5.5 kPa.</p

Mathematical Model Predicts that Acceleration of Diabetic Wound Healing is Dependent on Spatial Distribution of VEGF-A mRNA (AZD8601)

Introduction Pharmacologic approaches for promoting angiogenesis have been utilized to accelerate healing of chronic wounds in diabetic patients with varying degrees of success. We hypothesize that the distribution of proangiogenic drugs in the wound area critically impacts the rate of closure of diabetic wounds. To evaluate this hypothesis, we developed a mathematical model that predicts how spatial distribution of VEGF-A produced by delivery of a modified mRNA (AZD8601) accelerates diabetic wound healing. Methods We modified a previously published model of cutaneous wound healing based on coupled partial differential equations that describe the density of sprouting capillary tips, chemoattractant concentration, and density of blood vessels in a circular wound. Key model parameters identified by a sensitivity analysis were fit to data obtained from an in vivo wound healing study performed in the dorsum of diabetic mice, and a pharmacokinetic model was used to simulate mRNA and VEGF-A distribution following injections with AZD8601. Due to the limited availability of data regarding the spatial distribution of AZD8601 in the wound bed, we performed simulations with perturbations to the location of injections and diffusion coefficient of mRNA to understand the impact of these spatial parameters on wound healing. Results When simulating injections delivered at the wound border, the model predicted that injections delivered on day 0 were more effective in accelerating wound healing than injections delivered at later time points. When the location of the injection was varied throughout the wound space, the model predicted that healing could be accelerated by delivering injections a distance of 1-2 mm inside the wound bed when compared to injections delivered on the same day at the wound border. Perturbations to the diffusivity of mRNA predicted that restricting diffusion of mRNA delayed wound healing by creating an accumulation of VEGF-A at the wound border. Alternatively, a high mRNA diffusivity had no effect on wound healing compared to a simulation with vehicle injection due to the rapid loss of mRNA at the wound border to surrounding tissue. Conclusions These findings highlight the critical need to consider the location of drug delivery and diffusivity of the drug, parameters not typically explored in pre-clinical experiments, when designing and testing drugs for treating diabetic wounds.Funding Agencies|AstraZenecaAstraZeneca; National Institutes of HealthUnited States Department of Health &amp; Human ServicesNational Institutes of Health (NIH) - USA [HL116449, HL137755, AR069393, EY028868, T32LM012416]; National Science FoundationNational Science Foundation (NSF) [1842490, 1716537]; Allen Discovery Center at Stanford University</p

Photocross-Linkable and Shape-Memory Biomaterial Hydrogel Based on Methacrylated Cellulose Nanofibres

In the context of three-dimensional (3D) cell cultureand tissueengineering, 3D printing is a powerful tool for customizing in vitro3D cell culture models that are critical for understanding the cell-matrixand cell-cell interactions. Cellulose nanofibril (CNF) hydrogelsare emerging in constructing scaffolds able to imitate tissue in amicroenvironment. A direct modification of the methacryloyl (MA) grouponto CNF is an appealing approach to synthesize photocross-linkablebuilding blocks in formulating CNF-based bioinks for light-assisted3D printing; however, it faces the challenge of the low efficiencyof heterogenous surface modification. Here, a multistep approach yieldsCNF methacrylate (CNF-MA) with a decent degree of substitution whilemaintaining a highly dispersible CNF hydrogel, and CNF-MA is furtherformulated and copolymerized with monomeric acrylamide (AA) to forma super transparent hydrogel with tuneable mechanical strength (compressionmodulus, approximately 5-15 kPa). The resulting photocurablehydrogel shows good printability in direct ink writing and good cytocompatibilitywith HeLa and human dermal fibroblast cell lines. Moreover, the hydrogelreswells in water and expands to all directions to restore its originaldimension after being air-dried, with further enhanced mechanicalproperties, for example, Young's modulus of a 1.1MA/10.3 kPa from5.5 kPa.Peer reviewe

The Combination of Vascular Endothelial Growth Factor A (VEGF-A) and Fibroblast Growth Factor 1 (FGF1) Modified mRNA Improves Wound Healing in Diabetic Mice: An Ex Vivo and In Vivo Investigation

Background: Diabetic foot ulcers (DFU) pose a significant health risk in diabetic patients, with insufficient revascularization during wound healing being the primary cause. This study aimed to assess microvessel sprouting and wound healing capabilities using vascular endothelial growth factor (VEGF-A) and a modified fibroblast growth factor (FGF1). Methods: An ex vivo aortic ring rodent model and an in vivo wound healing model in diabetic mice were employed to evaluate the microvessel sprouting and wound healing capabilities of VEGF-A and a modified FGF1 both as monotherapies and in combination. Results: The combination of VEGF-A and FGF1 demonstrated increased vascular sprouting in the ex vivo mouse aortic ring model, and topical administration of a combination of VEGF-A and FGF1 mRNAs formulated in lipid nanoparticles (LNPs) in mouse skin wounds promoted faster wound closure and increased neovascularization seven days post-surgical wound creation. RNA-sequencing analysis of skin samples at day three post-wound creation revealed a strong transcriptional response of the wound healing process, with the combined treatment showing significant enrichment of genes linked to skin growth. Conclusion: f-LNPs encapsulating VEGF-A and FGF1 mRNAs present a promising approach to improving the scarring process in DFU