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Parametric Study of Acoustic Droplet Vaporization Thresholds and Payload Release From Acoustically-Responsive Scaffolds.

ABSTRACT: Hydrogels are commonly used for the delivery of bioactive molecules, especially growth factors and cytokines capable of stimulating tissue regeneration. Regenerative processes are regulated by the concentrations and spatiotemporal presentations of these molecules. With conventional hydrogels, these critical delivery parameters cannot be actively modulated after implantation. We have developed composite hydrogel scaffolds where payload release is non-invasively modulated, in an on-demand manner, using ultrasound (US). These acoustically-responsive scaffolds (ARSs) consist of a fibrin matrix doped with a payload-carrying, perfluorocarbon (PFC) double emulsion. Previously, acoustic droplet vaporization (ADV) was used to trigger release of a pro-angiogenic growth factor, encapsulated in the ARS, which stimulated blood vessel formation in vivo. In the present study, we assess how characteristics of the monodispersed emulsion, fibrin matrix, and US impact ADV thresholds and the release efficiency of a dextran payload. ADV thresholds increased with the molecular weight of the PFC in the emulsion and inversely with the volume fraction of emulsion in the ARS. Payload release from ARSs with perfluoroheptane (C7) or perfluorooctane (C8) emulsions was dependent on the number of z-planes of US used to generate ADV and inversely dependent on the lateral spacing. Conversely, release from ARSs with perfluoropentane (C5) or perfluorohexane (C6) emulsions was less dependent on these US exposure parameters. After ADV, payload diffusion decreased significantly in ARSs with C5 or C6 emulsions compared with ARSs with C7 or C8 emulsions. The expansion of the ARS after ADV decreased with the molecular weight of the PFC. Non-selective release increased with the molecular weight of the PFC and thrombin concentration. Overall, these findings can be used for optimization of ARS properties and US parameters in future therapeutic applications.

SUBMITTER: Lu X

PROVIDER: S-EPMC6689245 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Parametric Study of Acoustic Droplet Vaporization Thresholds and Payload Release From Acoustically-Responsive Scaffolds.

Lu Xiaofang X Dong Xiaoxiao X Natla Sam S Kripfgans Oliver D OD Fowlkes J Brian JB Wang Xueding X Franceschi Renny R Putnam Andrew J AJ Fabiilli Mario L ML

Ultrasound in medicine & biology 20190622 9

Hydrogels are commonly used for the delivery of bioactive molecules, especially growth factors and cytokines capable of stimulating tissue regeneration. Regenerative processes are regulated by the concentrations and spatiotemporal presentations of these molecules. With conventional hydrogels, these critical delivery parameters cannot be actively modulated after implantation. We have developed composite hydrogel scaffolds where payload release is non-invasively modulated, in an on-demand manner, ...[more]

PMID: 31235205

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Project description:One of the major challenges in developing acoustic droplet vaporization (ADV)-associated therapy as an effective and safe strategy is the precise determination of the spatial cellular bioeffects after ADV (cell death or cell membrane permeabilization). In this study, we combined high-speed camera imaging and live-cell microscopic imaging to observe the transient dynamics of droplets during ADV and to evaluate the mechanical force on cells. Methods: C6 glioma cells were co-incubated with DiI-labeled droplets (radius: 1.5, 2.25, and 3.0 μm). We used an acousto-optical system for high-speed bright-field (500 kfps) and fluorescence (40 kfps) microscopic imaging in order to visualize the dynamics of droplets under ultrasound excitation (frequency = 5 MHz, pressure = 5-8 MPa, cycle number = 3, pulse number = 1). Live-cell microscopic imaging was used to monitor the cell morphology, cell membrane permeabilization, and cell viability by membrane-anchored Lyn-yellow fluorescence protein, propidium Iodide staining, and calcein blue AM staining, respectively. Results: We discovered that the spatial distribution of ADV-induced bioeffects could be mapped to the physical dynamics of droplet vaporization. For droplets with a 1.5 μm radius, the distance threshold for ADV-induced cell death (5.5±1.9 μm) and reversible membrane permeabilization (11.3±3.5 μm) was well correlated with the distance of ADV-bubble pressing downward to the floor (5.7±1.3 μm) and maximum distance of droplet expansion (11.5±2.6 μm), respectively. These distances were enlarged by increasing the droplet sizes and insonation acoustic pressures. The live-cell imaging results show that ADV-bubbles can directly disrupt the cell membrane layer and induce intensive intracellular substance leakage. Further, the droplets shed the payload onto nearby cells during ADV, suggesting ADV could directly induce adjacent cell death by physical force and enhancement of chemotherapy to distant cells. Conclusion: This study provide new insights into the ADV-mediated physicochemical synergic effect for medical applications.

Project description:Spatiotemporally controlled release of growth factors (GFs) is critical for regenerative processes such as angiogenesis. A common strategy is to encapsulate the GF within hydrogels, with release being controlled via diffusion and/or gel degradation (i.e., hydrolysis and/or proteolysis). However, simple encapsulation strategies do not provide spatial or temporal control of GF delivery, especially non-invasive, on-demand controlled release post implantation. We previously demonstrated that fibrin hydrogels, which are widely used in tissue engineering and GF delivery applications, can be doped with perfluorocarbon emulsion, thus yielding an acoustically responsive scaffold (ARS) that can be modulated with focused ultrasound, specifically via a mechanism termed acoustic droplet vaporization. This study investigates the impact of ARS and ultrasound properties on controlled release of a surrogate payload (i.e., fluorescently-labeled dextran) and fibrin degradation in vitro and in vivo. Ultrasound exposure (2.5MHz, peak rarefactional pressure: 8MPa, spatial peak time average intensity: 86.4mW/cm2), generated up to 7.7 and 21.7-fold increases in dextran release from the ARSs in vitro and in vivo, respectively. Ultrasound also induced morphological changes in the ARS. Surprisingly, up to 2.9-fold greater blood vessel density was observed in ARSs compared to fibrin when implanted subcutaneously, even without delivery of pro-angiogenic GFs. The results demonstrate the potential utility of ARSs in generating controlled release for tissue regeneration.Statement of significanceSimple encapsulation of a molecular payload within a conventional hydrogel scaffold does not provide spatial or temporal control of payload release. Yet, spatiotemporally controlled release of bioactive payloads is critical for tissue regeneration, which often utilizes hydrogel scaffolds to facilitate processes such as angiogenesis. This work investigates the design and performance (both in vitro and in vivo) of hydrogel scaffolds where release of a fluorescent payload is non-invasively and spatiotemporally-controlled using focused ultrasound. We also quantitatively characterize the degradation and vascularization of the scaffolds. Our results may be of interest to groups working on controlled release strategies for implants, especially within the field of tissue engineering.

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Parametric Study of Acoustic Droplet Vaporization Thresholds and Payload Release From Acoustically-Responsive Scaffolds.

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Parametric Study of Acoustic Droplet Vaporization Thresholds and Payload Release From Acoustically-Responsive Scaffolds.

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