Poly (N-isopropylacrilamide) (pNIPAm) microgels (microgels) are colloidal particles that have been used extensively for biomedical applications. Typically, these particles are synthesized in the presence of an exogenous cross-linker, such as N, N′-Methylenebis (acrylamide) (BIS); however, recent studies have demonstrated that pNIPAm microgels can be synthesized in the absence of an exogenous crosslinker, resulting in the formation of ultra-low crosslinked (ULC) particles, which are highly deformable. Microgel deformability has been linked in certain cases to enhanced bioactivity when ULC microgels are used for the creation of biomimetic particles. We hypothesized that ultrasound stimulation of microgels would enhance particle deformation and that the degree of enhancement would negatively correlate with the degree of particle crosslinking. Here, we demonstrate in tissue-mimicking phantoms that using ultrasound insonification causes deformations of ULC microgel particles. Furthermore, the amount of deformation depends on the ultrasound excitation frequency and amplitude, and on the concentration of ULC microgel particles. We observed that the amplitude of deformation increases with increasing ULC microgel particle concentration up to 2.5 mg / 100 ml, but concentrations higher than 2.5 mg / 100 ml result in reduced amount of deformation. In addition, we observed that the amplitude of deformation was significantly higher at 1 MHz insonification frequency. We also report that increasing the degree of microgel crosslinking reduces the magnitude of the deformation and increases the optimal concentration required to achieve the largest amount of deformation. Stimulated ULC microgel particle deformation has numerous potential biomedical applications, including enhancement of localized drug delivery and biomimetic activity. These results demonstrate the potential of ultrasound stimulation for such applications.
Ultrasound contrast agents (UCA), such as microbubbles, enhance the scattering properties of blood, which is otherwise hypoechoic. The multiple scattering interactions of the acoustic field with UCA are poorly understood due to the complexity of the multiple scattering theories and the nonlinear microbubble response. The majority of bubble models describe the behavior of UCA as single, isolated microbubbles suspended in infinite medium. Multiple scattering models such as the independent scattering approximation can approximate phase velocity and attenuation for low scatterer volume fractions. However, all current models and simulation approaches only describe multiple scattering and nonlinear bubble dynamics separately. Here we present an approach that combines two existing models: (1) a full-wave model that describes nonlinear propagation and scattering interactions in a heterogeneous attenuating medium and (2) a Paul–Sarkar model that describes the nonlinear interactions between an acoustic field and microbubbles. These two models were solved numerically and combined with an iterative approach. The convergence of this combined model was explored in silico for 0.5 × 106 microbubbles ml−1, 1% and 2% bubble concentration by volume. The backscattering predicted by our modeling approach was verified experimentally with water tank measurements performed with a 128-element linear array transducer. An excellent agreement in terms of the fundamental and harmonic acoustic fields is shown. Additionally, our model correctly predicts the phase velocity and attenuation measured using through transmission and predicted by the independent scattering approximation.
We propose a method to quantify the vascular density in vascular networks using contrast-enhanced multiple scattering. We measured the diffusion constant D and transport mean free path L* from the time evolution of the incoherent intensity in a rat model of cancer. An 8 MHz linear transducer array was used to record the backscattered signals from subcutaneous fibrosarcoma tumors and control tissue. The coherent and incoherent contributions to the backscattered intensity were separated, and the growth rate of the incoherent contribution was measured, giving the D and L*, knowing the effective speed of sound. By translating the linear array along the tumor, mapping of L* was achieved. Tumors were implanted in the right flank of four rats, and the contralateral side served as control. Acoustic angiography and measurements of the incoherent intensity were performed. The mean L* values in control and tumor tissue were significantly different (105.27 + /- 30.96 micron and 41.28+ /- 14.23 micron, respectively, p = 8.4033 × 10-49). The mean distance between vessels was estimated from acoustic angiography images using Monte-Carlo simulations, and was in agreement with the experimentally calculated values of L* (r = 0.9507, p = 1.4957 × 10-9).
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