Table 4.

Summary of the effect of altering ultrasound parameters on drug delivery efficacy and adverse effects on tissue.

Ultrasound parameter	Method of ultrasound	Range of parameters studied and (majority of parameters studied)	Parameters directly compared	Effect of changing a given parameter on safety	Effect of changing a given parameter on delivery
Frequency	MBPEXO	0.3-3 MHz (1 MHz)	---------------------------------------------Not directly compared---------------------------------------------
	AS and MBPENDO	0.02-3 MHz (0.88-1 MHz)	0.04, 0.5, 1 and 3 MHz [72]0.4, 0.5, 0.8, 1.0 MHz [70]0.4 and 0.6 MHz [16]1 and 3 MHz [61]1 and 3.3 MHz 74	Reducing frequency increases epithelial damage at higher pressures and durations 16, 70, 74.	Transscleral delivery: Penetration depth through sclera increased with decreasing frequency 16, 61, 70, 72, 74.
Power	MBPEXO	0.15-3 W/cm2(0.5 or 2 W/cm2)	0.5, 1, 2 and 2.5 W/cm2 [33]1, 1.5 and 2 W/cm2 36	Increasing power significantly increases vascular and epithelial damage, and results in inflammatory infiltrates, particularly when using continuous ultrasound 33, 36.	Increasing power does not appear to improve transfection efficacy 33, 36.
	AS and MBPENDO	0.002-2.5 W/cm2 (0.05, 0.5 and 1 W/cm2) 0.05 or 105 W/cm2 using HIFU	0.002, 0.01, 0.05, 0.12, 0.38 and 1.8 W/cm2 [73]0.07, 0.31 and 1.22 W/cm2 [43]0.19, 0.34 and 0.56 W/cm2 [60, 62]0.3, 0.5, 0.8 and 1.0 W/cm2 [70]0.5 and 1 W/cm2 [64]1, 1.3 and 1.5 W/cm2 45	Increasing power increases scleral temperature and the presence of corneal pitting and debridement, however structural changes appear rapidly reversable 73.	Scleral penetration is maximised when inducing stable cavitation in the topical media, but higher intensities, where inertial cavitation predominates appears to decrease penetration 43, 60, 62, 64, 73.Increasing power improves permeability at lower frequencies 70. When increasing power improves penetration, molecule retention in the sclera is prolonged 45.
Peak Negative Pressure	MBPEXO	Not measured using planar transducers,0.36-1.1MPa using HIFU	0.81, 0.88 and 1.1 MPa 66	Increasing PNP increases vascular damage 66.	Increasing PNP improves BRB permeation 66
	AS and MBPENDO	0.041-0.165MPa (0.08-0.13MPa)15.7Mpa using HIFU	0.08, 0.1 and 0.13 MPa [60, 62]0.041, 0.082 and 0.165 MPa 43	Results as for power assessments 43, 60, 62.	Results as for power assessments 43, 60, 62
Sonication duration	MBPEXO	4-300 s(60-300 s)60 or 120 s using HIFU	---------------------------------------------Not directly compared---------------------------------------------
	AS and MBPENDO	30-3600 s(300-600 s)30 or 100 s using HIFU	30 and 120 s [64]60 and 240 s 42 600, 1800 and 3600 s [69]600 and 1800 s 43	Longer sonication durations resulted in clouding of the lens, tissue dehydration and retinal delamination 42.	Increasing the sonication duration increased the vitreoretinal delivery of small (53nm), and medium (131nm) but not larger (218nm) nanospheres [64]Increasing sonication duration further improved transscleral and corneoscleral delivery 43, 69.
Pulse repetition frequency	MBPEXO	1 - 100 Hz or continuous(100 Hz)	---------------------------------------------Not directly compared---------------------------------------------
	AS and MBPENDO	0.1428-1 Hz or continuous(continuous)
Duty cycle	MBPEXO	1 - 50% or continuous(50%)	---------------------------------------------Not directly compared---------------------------------------------
	AS and MBPENDO	14.3% - 50% or continuous(50% or continuous)	50% and continuous 64	-	Decreasing the duty cycle from continuous to 50% doubled the delivery of smaller (53 nm), but not larger (131 nm) nanospheres into retinal pigment epithelial cells through the neural retina 64.
Pulse duration	MBPEXO	5-50 ms or continuous(5 or 10 ms)	---------------------------------------------Not directly compared---------------------------------------------
	AS and MBPENDO	5-1000ms or continuous (continuous)10-100ms using HIFU	10, 20, 50 and 100 ms using HIFU 49	Increasing the pulse duration caused erosion of the corneal surface 49.	Increasing pulse duration increased transscleral penetration distance 49.