Ultrasoft microgels displaying emergent platelet-like behaviours

Brown, Ashley; Stabenfeldt, Sarah E.; Ahn, Byungwook; Hannan, Riley T.; Dhada, Kabir S.; Herman, Emily S.; Stefanelli, Victoria L.; Guzzetta, Nina A.; Alexeev, Alexander; Lam, Wilbur A.; Lyon, L. Andrew; Barker, Thomas H.

doi:10.1038/nmat4066

Cited by 185 publications

(241 citation statements)

References 28 publications

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“…We find that for equivalent ϕ, the resultant colloidal network is identical compared with that obtained with ULC μgels (Fig. 2I), illustrating that the formation of percolated colloidal networks is not specific to the ULC μgels, but rather driven by fibrin polymerization in the absence of any known or observed specific fiber-μgel and μgel-μgel interactions (18). Furthermore, the observed μgel domain organization also enables the fibrin in the μgel-free regions to essentially remain free of distortions due to the particles, a fact that is expected to be favorable given the rigid character of the fibrin fibers.…”

Section: Resultsmentioning

confidence: 52%

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Dynamic assembly of ultrasoft colloidal networks enables cell invasion within restrictive fibrillar polymers

Douglas

Fragkopoulos

Gaines

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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In regenerative medicine, natural protein-based polymers offer enhanced endogenous bioactivity and potential for seamless integration with tissue, yet form weak hydrogels that lack the physical robustness required for surgical manipulation, making them difficult to apply in practice. The use of higher concentrations of protein, exogenous cross-linkers, and blending synthetic polymers has all been applied to form more mechanically robust networks. Each relies on generating a smaller network mesh size, which increases the elastic modulus and robustness, but critically inhibits cell spreading and migration, hampering tissue regeneration. Here we report two unique observations; first, that colloidal suspensions, at sufficiently high volume fraction (ϕ), dynamically assemble into a fully percolated 3D network within high-concentration protein polymers. Second, cells appear capable of leveraging these unique domains for highly efficient cell migration throughout the composite construct. In contrast to porogens, the particles in our system remain embedded within the bulk polymer, creating a network of particle-filled tunnels. Whereas this would normally physically restrict cell motility, when the particulate network is created using ultralow cross-linked microgels, the colloidal suspension displays viscous behavior on the same timescale as cell spreading and migration and thus enables efficient cell infiltration of the construct through the colloidal-filled tunnels.fibrin | microgels | colloidal assemblies | porosity | cell migration D ecoupling stiffness, pore size, and cell infiltration is a critical hurdle in biomaterials design and has been previously addressed in synthetic hydrogels by enabling cell-mediated degradation via protease-specific peptide cross-linkers (1-4). However, even in these highly engineered systems, compared with native extracellular matrices (ECMs), the mesh size remains a critical limiting factor in host integration; this is because cells are incapable of nonproteolytic, i.e., degradation-independent, migration through such small mesh sizes (5), as illustrated in Fig. 1A.Protein-based biomaterials derived from native ECM represent an attractive alternative to synthetic hydrogels, offering significant benefits through their enhanced endogenous bioactivity. The native ECM and its derivatives act as growth factor/cytokine depots, thus providing a multivalent endogenous binding site for growth factor delivery (6). A classic example of this type of biomaterial is fibrin, the endogenous provisional matrix formed at sites of vascular injury as a result of blood coagulation (7,8). Clinically, to reach desirable mechanical properties for sealing tissues/wounds, fibrin is used at supraphysiological concentrations typically containing ∼10× more fibrinogen than physiological concentrations (9-12). When used at these artificially high concentrations, the characteristic mesh size of the network is unfortunately similar to that of synthetic PEG polymers, which is on the order of tens of nanometers, making i...

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Section: Resultsmentioning

confidence: 52%

“…The long migration distances also suggest that the cells rather exploit the long-time viscous behavior of the μgel suspension. of 2 mol % N,N'-methylene(bisacrylamide) (BIS) (16)(17)(18)22). Purified μgels were labeled with AlexaFluor dyes and lyophilized for future use.…”

Section: Methodsmentioning

confidence: 99%

Dynamic assembly of ultrasoft colloidal networks enables cell invasion within restrictive fibrillar polymers

Douglas

Fragkopoulos

Gaines

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…[36][37][38] Current research in the field of platelet-mimetic technologies utilizes a wide variety of strategies including both naturally derived platelet derivatives and synthetic platelet strategies. In subsequent sections, we review various strategies that encompass a large range of approaches to achieve various goals such as wound targeting, drug delivery, and immune system evasion through platelet membrane cloaking.…”

Section: Platelets In Coagulation and Hemostasismentioning

confidence: 99%

“…A study performed by Ravikumar et al 54,55 also involved particles surface-decorated with VWF and collagen-binding ligands, with the purpose of promoting binding to VWF under shear flow and binding to collagen independent of shear flow in order to imitate the dual-binding adhesion and aggregation capability of natural platelets. The platelet-like particles developed by Brown et al 38 use sdFvs, identified through phage display techniques, to obtain a high specificity for fibrin, allowing the particles to target fibrin clots, and therefore secondary hemostasis (Figure 3). These platelet-like particles were found to spread within the fibrin network, and induce collapse of the fibrin network, without binding fibrinogen present in the blood stream or in areas without injured vasculature.…”

Section: Artificial Plateletsmentioning

confidence: 99%

Platelet-mimetic strategies for modulating the wound environment and inflammatory responses

Nandi

Brown

2016

Exp Biol Med (Maywood)

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Platelets closely interface with the immune system to fight pathogens, target wound sites, and regulate tissue repair. Natural platelet levels within the body can be depleted for a variety of reasons, including excessive bleeding following traumatic injury, or diseases such as cancer and bacterial or viral infections. Platelet transfusions are commonly used to improve platelet count and hemostatic function in these cases, but transfusions can be complicated by the contamination risks and short storage life of donated platelets. Lyophilized platelets that can be freeze-dried and stored for longer periods of time and synthetic plateletmimetic technologies that can enhance or replace the functions of natural platelets, while minimizing adverse immune responses have been explored as alternatives to transfusion. Synthetic platelets typically comprise nanoparticles surface-decorated with peptides or ligands to recreate specific biological characteristics of platelets, including targeting of wound and disease sites and facilitating platelet aggregation. Recent efforts in synthetic platelet design have additionally focused on matching platelet shape and mechanics to recreate the marginalization and clot contraction capabilities of natural platelets. The ability to specifically tune the properties of synthetic platelet-mimetic materials has shown utility in a variety of applications including hemostasis, drug delivery, and targeted delivery of cancer therapeutics.

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“…[3][4][5]. These microgels can be environmentally sensitive, and are called "Smart Gels" or "Intelligent Gels", having the ability to sense changes of pH, temperature, humidity, intensity of light, salt concentration, osmotic pressure, surfactants or co-solvents or an electrical or magnetic field [6].…”

Section: Introductionmentioning

confidence: 99%

In situ formation of copper nanoparticles in a p(NIPAM-VAA-AAm) terpolymer microgel that retains the swelling behavior of microgels

Khan¹,

Shaikh²,

Siddiq

et al. 2015

Journal of Polymer Engineering

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Abstract Copper nanoparticles (CuNPs) are formed inside a microgel assembly by an in situ reduction method, confirmed by changes observed in the absorption spectra of CuNPs at different pH values. The presence of CuNPs has been also confirmed by X-ray diffraction (XRD) studies. The terpolymer microgel p(N-isopropylacrylamide-vinyl acetic acid-acrylamide) (p[NIPAM-VAA-AAm]), which is reported for the first time, was synthesized by free radical emulsion polymerization of a temperature-sensitive NIPAM monomer, pH sensitive VAA monomer and a hydrophilic AAm monomer. The effect of temperature below and above the pKa of VAA and the effect of pH at 20°C in the absence and presence of CuNPs on the hydrodynamic radius of microgel was studied. Size of microgel particles is a function of temperature due to the presence of NIPAM, and a function of pH due to the presence of VAA. The presence of CuNPs has little or no effect on the size of microgels by varying pH, which allows these gels to retain their properties with added benefits of CuNPs for possible drug delivery applications.

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Ultrasoft microgels displaying emergent platelet-like behaviours

Cited by 185 publications

References 28 publications

Dynamic assembly of ultrasoft colloidal networks enables cell invasion within restrictive fibrillar polymers

Dynamic assembly of ultrasoft colloidal networks enables cell invasion within restrictive fibrillar polymers

Platelet-mimetic strategies for modulating the wound environment and inflammatory responses

In situ formation of copper nanoparticles in a p(NIPAM-VAA-AAm) terpolymer microgel that retains the swelling behavior of microgels

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