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Acoustic droplet-hydrogel composites for spatial and temporal control of growth factor delivery and scaffold stiffness.

ABSTRACT: Wound healing is regulated by temporally and spatially restricted patterns of growth factor signaling, but there are few delivery vehicles capable of the "on-demand" release necessary for recapitulating these patterns. Recently we described a perfluorocarbon double emulsion that selectively releases a protein payload upon exposure to ultrasound through a process known as acoustic droplet vaporization (ADV). In this study, we describe a delivery system composed of fibrin hydrogels doped with growth factor-loaded double emulsion for applications in tissue regeneration. Release of immunoreactive basic fibroblast growth factor (bFGF) from the composites increased up to 5-fold following ADV and delayed release was achieved by delaying exposure to ultrasound. Releasates of ultrasound-treated materials significantly increased the proliferation of endothelial cells compared to sham controls, indicating that the released bFGF was bioactive. ADV also triggered changes in the ultrastructure and mechanical properties of the fibrin as bubble formation and consolidation of the fibrin in ultrasound-treated composites were accompanied by up to a 22-fold increase in shear stiffness. ADV did not reduce the viability of cells suspended in composite scaffolds. These results demonstrate that an acoustic droplet-hydrogel composite could have broad utility in promoting wound healing through on-demand control of growth factor release and/or scaffold architecture.

SUBMITTER: Fabiilli ML

PROVIDER: S-EPMC3746980 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Acoustic droplet-hydrogel composites for spatial and temporal control of growth factor delivery and scaffold stiffness.

Fabiilli Mario L ML Wilson Christopher G CG Padilla Frédéric F Martín-Saavedra Francisco M FM Fowlkes J Brian JB Franceschi Renny T RT

Acta biomaterialia 20130325 7

Wound healing is regulated by temporally and spatially restricted patterns of growth factor signaling, but there are few delivery vehicles capable of the "on-demand" release necessary for recapitulating these patterns. Recently we described a perfluorocarbon double emulsion that selectively releases a protein payload upon exposure to ultrasound through a process known as acoustic droplet vaporization (ADV). In this study, we describe a delivery system composed of fibrin hydrogels doped with grow ...[more]

PMID: 23535233

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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:Ultrasonically actuated microbubble oscillations hold great promise for minimally invasive therapeutic interventions. While several preclinical studies have demonstrated the potential of this technology, real-time methods to control the amplitude and type of microbubble oscillations (stable vs inertial acoustic cavitation) and ensure that cavitation occurs within the targeted region are needed for their successful translation to the clinic. In this paper, we propose a real-time nonlinear state controller that uses specific frequency bands of the microbubble acoustic emissions (harmonic, ultra-harmonic, etc.) to control cavitation activity (observer states). To attain both spatial and temporal control of cavitation activity with high signal to noise ratio, we implement a controller using fast frequency-selective passive acoustic mapping (PAM) based on the angular spectrum approach. The controller includes safety states based on the recorded broadband signal level and is able to reduce sensing inaccuracies with the inclusion of multiple frequency bands. In its simplest implementation the controller uses the peak intensity of the passive acoustic maps, reconstructed using the 3rd harmonic (4.896 × 0.019 MHz) of the excitation frequency. Our results show that the proposed real-time nonlinear state controller based on PAM is able to reach the targeted level of observer state (harmonic emissions) in less than 6 seconds and remain within 10 % of tolerance for the duration of the experiment (45 seconds). Similar response was observed using the acoustic emissions from single element passive cavitation detection, albeit with higher susceptibility to background noise and lack of spatial information. Importantly, the proposed PAM-based controller was able to control cavitation activity with spatial selectivity when cavitation existed simultaneously in multiple regions. The robustness of the controller is demonstrated using a range of controller parameters, multiple observer states concurrently (harmonic, ultra-harmonic, and broadband), noise levels (°6 to 12 dB SNR), and bubble concentrations (0.3 to 180 × 103 bubbles per microliter). More research in this direction under preclinical and clinical conditions is warranted.

Dataset Information

Acoustic droplet-hydrogel composites for spatial and temporal control of growth factor delivery and scaffold stiffness.

Publications

Acoustic droplet-hydrogel composites for spatial and temporal control of growth factor delivery and scaffold stiffness.

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