Cardiac reperfusion injury is a well-established outcome following treatment of acute myocardial infarction and other types of ischemic heart conditions. Numerous cardioprotection protocols and therapies have been pursued with success in pre-clinical models. Unfortunately, there has been lack of successful large-scale clinical translation, perhaps in part due to the multiple pathways that reperfusion can contribute to cell death. The search continues for new cardioprotection protocols based on what has been learned from past results. One class of cardioprotection protocols that remain under active investigation is that of controlled reperfusion. This class consists of those approaches that modify, in a controlled manner, the content of the reperfusate or the mechanical properties of the reperfusate (e.g., pressure and flow). This review article first provides a basic overview of the primary pathways to cell death that have the potential to be addressed by various forms of controlled reperfusion, including no-reflow phenomenon, ion imbalances (particularly calcium overload), and oxidative stress. Descriptions of various controlled reperfusion approaches are described, along with summaries of both mechanistic and outcome-oriented studies at the pre-clinical and clinical phases. This review will constrain itself to approaches that modify endogenously-occurring blood components. These approaches include ischemic postconditioning, gentle reperfusion, controlled hypoxic reperfusion, controlled hyperoxic reperfusion, controlled acidotic reperfusion, and controlled ionic reperfusion. This review concludes with a discussion of the limitations of past approaches and how they point to potential directions of investigation for the future.

Acoustic droplet vaporization is the ultrasound-mediated phase change of liquid droplets into gas microbubbles. Following the phase change, oxygen diffuses from the surrounding fluid into the microbubble. An in vitro model was used to study the effects of droplet diameter, the presence of an ultrasound contrast agent, ultrasound duty cycle, and droplet concentration on the magnitude of oxygen scavenging in oxygenated deionized water. Perfluoropentane droplets were manufactured through a microfluidic approach at nominal diameters of 1, 3, 5, 7, 9, and 12 µm and studied at concentrations varying from 5.1 × 10−5 to 6.3 × 10−3 mL/mL. Droplets were exposed to an ultrasound transduced by an EkoSonicTM catheter (2.35 MHz, 47 W, and duty cycles of 1.70%, 2.34%, or 3.79%). Oxygen scavenging and the total volume of perfluoropentane that phase-transitioned increased with droplet concentration. The ADV transition efficiency decreased with increasing droplet concentration. The increasing duty cycle resulted in statistically significant increases in oxygen scavenging for 1, 3, 5, and 7 µm droplets, although the increase was smaller than when the droplet diameter or concentration were increased. Under the ultrasound conditions tested, droplet diameter and concentration had the greatest impact on the amount of ADV and subsequent oxygen scavenging occurred, which should be considered when using ADV-mediated oxygen scavenging in therapeutic ultrasounds.

Acoustic droplet vaporization (ADV) is a process that phase transitions liquid droplets into gas microbubbles via ultrasound. ADV results in oxygen scavenging from the surrounding fluid into the microbubbles. The objective of this study was to determine the effect of ultrasound parameters on oxygen scavenging. A microfluidic device was used to produce perfluoropentane droplets with a modal diameter of 1.14 ± 0.04  μm and a polydispersity index of 0.08 ± 0.02. Droplets were diluted to a concentration of 4.7 × 10−4 ± 0.4 × 10−5 ml/ml in 95% oxygenated water. The oxygen partial pressure (pO2) of the water was measured before and during ADV. An EkoSonic ultrasound catheter (2.35 MHz, 1.5 MPa peak negative pressure, 47 W pulse average power) nucleated ADV while either varying burst period or pulse duration (n = 5). Pre-ADV pO2 was 558 ± 5 mm Hg for all experiments. Peri-ADV pO2 dropped to 294 ± 6, 316 ± 10, and 356 ± 12 mmHg for a pulse duration of 17 μs and burst periods of 0.450 ms, 0.725 ms, and 1.000 ms, respectively. The peri-ADV pO2 dropped to 331 ± 14, 342 ± 10, 313 ± 10 mmHg for a burst period of 1.000 ms and pulse durations of 17.0, 23.4, and 37.9 μs, respectively. A significant difference was seen between the amount of oxygen scavenging for the lowest and highest burst periods (p = 0.0012) and pulse durations (p = 0.027).

Nucleating acoustic droplet vaporization reduces the dissolved gas content in a fluid. The objective of this study was to determine if the change in the partial pressure of oxygen (Po2) could be modulated by adjusting the concentration of micron-sized perfluoropentane droplets. The droplets were manufactured using high-speed shaking and size-isolated using differential centrifugation (1 to 6 μm in diameter). Droplets were diluted in saline with a Po2 of 154 mmHg and pumped through a 37°C flow phantom at 40 mL/min. The concentration ranged from 3.5×106 to 3.5×108 droplets/mL. A 5 MHz focused transducer insonified droplets at peak negative pressures of 4.05 MPa with a 500-Hz pulse repetition frequency and 5-cycle pulse duration. The Po2 was measured downstream of the insonation region. At the lowest droplet concentration, the Po2 was reduced to 129 mmHg. As the droplet concentration was increased, the Po2 was reduced further. The reduction was in agreement (intra-class correlation and Pearson correlation coefficients greater than 0.9) with the model reported by Radhakrishnan et al. (2016, Ultrason. Sonochem.). At the highest droplet concentration, the Po2 was reduced to 31 mmHg. These results demonstrate that ADV with varying droplet concentration modulates the oxygen partial pressure in a fluid.