Photo-mediated Ultrasound Therapy Research Articles

Real-Time Cavitation Monitoring During Optical Coherence Tomography Guided Photo-Mediated Ultrasound Therapy of the Retina.

Photo-mediated ultrasound therapy (PUT) is a novel antivascular therapeutic modality based on cavitation-induced bioeffects. During PUT, synergistic combinations of laser pulses and ultrasound bursts are used to remove the targeted microvessels selectively and precisely without harming nearby tissue. In the current study, an integrated system combining PUT and spectral domain optical coherence tomography (SD-OCT) was developed, where the SD-OCT system was used to guide PUT by detecting cavitation in real time in the retina of the eye. We first examined the capability of SD-OCT in detecting cavitation on a vascular-mimicking phantom and compared the results with those from a passive cavitation detector. The performance of the integrated system in treatment of choroidal microvessels was then evaluated in rabbit eyes in vivo. During the in vivo PUT experiments, several biomarkers at the subretinal layer in the rabbit eye were identified on OCT images. The findings indicate that, by evaluating biomarkers of treatment effect, real-time SD-OCT monitoring could help to avoid micro-hemorrhage, which is a potential major side effect. Real-time OCT monitoring can thus improve the safety and efficiency of PUT in removing the retinal and choroidal microvasculature.

Cutaneous Hypervascularization Treatment Using Photo-Mediated Ultrasound Therapy

Photo-mediated ultrasound therapy (PUT) is a cavitation-based, highly selective antivascular technique. In this study, the effectiveness and safety of PUT on cutaneous vascular malformation was examined through invivo experiments in a clinically relevant chicken wattle model, whose microanatomy is similar to that of port-wine stain and other hypervascular dermal diseases in humans. Assessed by optical coherence tomography angiography, the blood vessel density in the chicken wattle decreased by 73.23% after one session of PUT treatment in which 0.707 J/cm2 fluence laser pulses were applied concurrently with ultrasound bursts (n= 7, P < .01). The effectiveness of removing blood vessels in the skin at depth up to 1 mm was further assessed by H&E-stained histology at multiple time points, which included days 1, 3, 7, 14, and 21 after treatment. Additional immunohistochemical analyses with CD31, caspase-3, and Masson's trichrome stains were performed on day 3 after treatment. The results show that the PUT-induced therapeutic effect was confined and specific to blood vessels only, whereas unwanted collateral damage in other skin tissues such as collagen was avoided. The findings from this study demonstrate that PUT can efficiently and safely remove hypervascular dermal capillaries using laser fluence at a level that is orders of magnitude smaller than that used in conventional laser treatment of vascular lesions, thus offering a safer alternative technique for clinical management of cutaneous vascular malformations.

A review on photo-mediated ultrasound therapy.

Photo-mediated ultrasound therapy (PUT) is a novel therapeutic technique based on the combination of ultrasound and laser. The underlying mechanism of PUT is the enhanced cavitation effect inside blood vessels. The enhanced cavitation activity can result in bio-effects such as reduced perfusion in microvessels. The reduced perfusion effect in microvessels in the eye has the potential to control the progression of eye diseases such as diabetic retinopathy and age-related macular degeneration. Several in vivo studies have demonstrated the feasibility of PUT in removing microvasculature in the eye using rabbit eye model and vasculature in the skin using rabbit ear model. Numerical studies using a bubble dynamics model found that cavitation is enhanced during PUT due to the dramatic increase in size of air/vapor nuclei in blood. In addition, the study conducted to model cavitation dynamics inside a blood vessel during PUT found stresses induced on the vessel wall during PUT are higher than that at normal physiological levels, which may be responsible for bio-effects. The concentration of vasodilators such as nitric oxide and prostacyclin were also found to be affected during PUT in an in vitro study, which may limit blood perfusion in vessels. The main advantage of PUT over conventional techniques is non-invasive, precise, and selective removal of microvessels with high efficiency at relatively low energy levels of ultrasound and laser, without affecting the nearby structures. However, the main limitation of vessel rupture/hemorrhage needs to be overcome through the development of real-time monitoring of treatment effects during PUT. In addition to the application in removing microvessels, PUT-based techniques were also explored in treating other diseases. Studies have found a combination of ultrasound and laser to be effective in removing blood clots inside veins, which has the potential to treat deep-vein thrombosis. The disruption of atherosclerotic plaque using combined ultrasound and laser was also tested, and the feasibility was demonstrated.

Choroidal neovascularization removal with photo-mediated ultrasound therapy.

Age-related macular degeneration (AMD) is a major cause of irreversible central vision loss. The main reason for lost vision due to AMD is choroidal neovascularization (CNV). In the clinic, current treatments for CNV include photodynamic therapy, laser photocoagulation, and anti-vascular endothelial growth factor (VEGF) therapy. This study evaluates a novel treatment technique combining synchronized nanosecond laser pulses and ultrasound bursts, namely photo-mediated ultrasound therapy (PUT) as a potential treatment method for CNV, for its efficacy and safety in the treatment of CNV via the experiments in a clinically-relevant rabbit model in vivo. CNV was created by subretinal injection of Matrigel and vascular endothelial growth factor (M&V) in 10 New Zealand white rabbits. Six rabbits were used in the PUT group. In the control groups, two rabbits were treated by laser-only, and two rabbits were treated by ultrasound-only. The treatment efficacy was evaluated through fundus photography and fluorescein angiography (FA) longitudinally for up to 4weeks. Rabbits were sacrificed for histopathology 3 months after treatment to examine the safety of PUT. The fluorescein leakage on FA was quantified to longitudinally evaluate treatment outcome. Compared with baseline, the relative intensity index was reduced by 26.57%±8.66% at 3 days after treatment, 27.24%±6.21% at 1week after treatment, 27.79%±2.61% at 2weeks after treatment, and 32.12%±3.23% at 4weeks after treatment, all with a statistically significant difference of p<0.01. The comparison between the relative intensity indexes from the two control groups (laser-only treatment and ultrasound-only treatment) did not show any statistically significant difference at all time points. Safety evaluation at 3 months with histopathology demonstrated that the PUT did not result in morphologic changes to the neurosensory retina. This study introduces PUT for the first time for the treatment of CNV. The results demonstrated good efficacy and safety of PUT to treat CNV in a clinically-relevant rabbit model. With a single session of treatment, PUT can safely reduce the leakage of CNV for at least 1 month after treatment.

Cellular response to photo-mediated ultrasound therapy

Photo-mediated ultrasound therapy (PUT) is a novel technique that combines relatively low-pressure focused ultrasound and low-fluence laser to enhance cavitation inside blood vessels. Due to the increased shear and circumferential stresses, the enhanced cavitation activity can achieve anti-vascular effect. The role of endothelial cells in the antivascular effect of PUT was explored by quantifying the release of vasodilators-nitric oxide and prostacyclin from endothelial cells after PUT, laser-only, and ultrasound-only therapies in an in vitro vessel mode. PUT was able to suppress both the vasodilators by more than 5% with concurrently applied 0.5MPa ultrasound pressure at 500 kHz and 15 mJ/cm2 laser fluence at 532 nm. Both the laser-only and ultrasound-only therapies at the similar levels resulted only in elevation of these vasodilators with respect to control. The suppression of vasodilators by PUT was justified with cavitation signals observed using passive cavitation detection and apoptosis observed with Annexin V-fluorescein isothiocyante (FITC), at respective levels. The endothelial cellular response to PUT further motivated us to evaluate the effect of PUT on melanoma cells and evaluate cytotoxic effect through MTT assay. PUT was able to destroy cancer cells through the cavitation effect when compared to laser-only and ultrasound-only therapies at the similar energy levels.

High speed photo-mediated ultrasound therapy integrated with OCTA

Photo-mediated Ultrasound Therapy (PUT), as a new anti-vascular technique, can promote cavitation activity to selectively destruct blood vessels with a significantly lower amount of energy when compared to energy level required by other laser and ultrasound treatment therapies individually. Here, we report the development of a high speed PUT system based on a 50-kHz pulsed laser to achieve faster treatment, decreasing the treatment time by a factor of 20. Furthermore, we integrated it with optical coherence tomography angiography (OCTA) for real time monitoring. The feasibility of the proposed OCTA-guided PUT was validated through in vivo rabbit experiments. The addition of OCTA to PUT allows for quantitative prescreening and real time monitoring of treatment response, thereby enabling implementation of individualized treatment strategies.

A 3D finite element model to study the cavitation induced stresses on blood-vessel wall during the ultrasound-only phase of photo-mediated ultrasound therapy.

Photo-mediated ultrasound therapy (PUT) is a novel technique utilizing synchronized ultrasound and laser to generate enhanced cavitation inside blood vessels. The enhanced cavitation inside blood vessels induces bio-effects, which can result in the removal of micro-vessels and the reduction in local blood perfusion. These bio-effects have the potential to treat neovascularization diseases in the eye, such as age-related macular degeneration and diabetic retinopathy. Currently, PUT is in the preclinical stage, and various PUT studies on in vivo rabbit eye models have shown successful removal of micro-vessels. PUT is completely non-invasive and particle-free as opposed to current clinical treatments such as anti-vascular endothelial growth factor therapy and photodynamic therapy, and it precisely removes micro-vessels without damaging the surrounding tissue, unlike laser photocoagulation therapy. The stresses produced by oscillating bubbles during PUT are responsible for the induced bio-effects in blood vessels. In our previous work, stresses induced during the first phase of PUT due to combined ultrasound and laser irradiation were studied using a 2D model. In this work, stresses induced during the third or last phase of PUT due to ultrasound alone were studied using a 3D finite element method-based numerical model. The results showed that the circumferential and shear stress increased as the bubble moves from the center of the vessel toward the vessel wall with more than a 16 times increase in shear stress from 1.848 to 31.060 kPa as compared to only a 4 times increase in circumferential stress from 211 to 906 kPa for a 2 µm bubble placed inside a 10 µm vessel on the application of 1 MHz ultrasound frequency and 130 kPa amplitude. In addition, the stresses decreased as the bubble was placed in smaller sized vessels with a larger decrease in circumferential stress. The changes in shear stress were found to be more dependent on the bubble–vessel wall distance, and the changes in circumferential stress were more dependent on the bubble oscillation amplitude. Moreover, the bubble shape changed to an ellipsoidal with a higher oscillation amplitude in the vessel’s axial direction as it was moved closer to the vessel wall, and the bubble oscillation amplitude decreased drastically as it was placed in vessels of a smaller size.

Analysis of cavitation induced stresses on blood vessel wall during photo-mediated ultrasound therapy using finite-element based numerical models

Photo-mediated ultrasound therapy (PUT) is a novel technique, which utilizes spatio-temporally synchronized pulsed laser and ultrasound to produce enhanced cavitation inside blood vessels. Vascular bio-effects during PUT, such as reduced perfusion rate and rupture of blood vessel, are thought to be due to shear and circumferential stresses induced on vessel wall. We have developed a 2D axisymmetric and a 3D finite-element method (FEM)-based models in COMSOL Multiphysics to calculate the stresses induced on vessel wall during PUT. The 2D axisymmetric model simulation showed that drastic increase in bubble size with PUT application resulted in higher shear and circumferential stresses as compared with ultrasound application only in the beginning phase of PUT. The 3D model simulation showed increase in stresses when a bubble moves towards the vessel wall, and found relatively higher increase in shear stress as compared to circumferential stress. The 2D results were imperative in understanding of PUT inception resulting in stronger stresses on vessel walls, which were otherwise almost zero for ultrasound-only. The 3D results demonstrated that the stresses on vessel walls further increased during the subsequent phase of PUT, enough to induce vascular bio-effects.

Effect of Photo-Mediated Ultrasound Therapy on Nitric Oxide and Prostacyclin from Endothelial Cells.

Several studies have investigated the effect of photo-mediated ultrasound therapy (PUT) on the treatment of neovascularization. This study explores the impact of PUT on the release of the vasoactive agents nitric oxide (NO) and prostacyclin (PGI2) from the endothelial cells in an in vitro blood vessel model. In this study, an in vitro vessel model containing RF/6A chorioretinal endothelial cells was used. The vessels were treated with ultrasound-only (0.5, 1.0, 1.5 and 2.0 MPa peak negative pressure at 0.5 MHz with 10% duty cycle), laser-only (5, 10, 15 and 20 mJ/cm2 at 532 nm with a pulse width of 5 ns), and synchronized laser and ultrasound (PUT) treatments. Passive cavitation detection was used to determine the cavitation activities during treatment. The levels of NO and PGI2 generally increased when the applied ultrasound pressure and laser fluence were low. The increases in NO and PGI2 levels were significantly reduced by 37.2% and 42.7%, respectively, from 0.5 to 1.5 MPa when only ultrasound was applied. The increase in NO was significantly reduced by 89.5% from 5 to 20 mJ/cm2, when only the laser was used. In the PUT group, for 10 mJ/cm2 laser fluence, the release of NO decreased by 76.8% from 0.1 to 1 MPa ultrasound pressure. For 0.5 MPa ultrasound pressure in the PUT group, the release of PGI2 started to decrease by 144% from 15 to 20 mJ/cm2 laser fluence. The decreases in NO and PGI2 levels coincided with the increased cavitation activities in each group. In conclusion, PUT can induce a significant reduction in the release of NO and PGI2 in comparison with ultrasound-only and laser-only treatments.

Treatment of neovascularization in the eye by photo-mediated ultrasound therapy

Neovascularization in the eye is a common disorder. Abnormal microvessels can develop in the cornea, retina, or choroid of the eye, leading to severe vision loss if left untreated. Current treatment methods carry disadvantages or side effects, such as drug-resistance or damage to the surrounding healthy tissues. By applying synchronized laser pulses and ultrasound bursts, we developed a technique, termed photo-mediated ultrasound therapy (PUT), as a localized antivascular method based on the enhanced cavitation mechanism. PUT takes advantage of the high native optical contrast between blood and surrounding tissues, and has the unique capability to self-target microvessels without damaging surrounding tissues. The technique utilizes nanosecond laser pulses, which is spatially and temporally synchronized with low duty-cycle ultrasound bursts of sub-MHz frequencies at the targeted microvessels. We have tested the feasibility of PUT on the removal of neovascularization in the cornea, retina and choroid in a rabbit eye model. We found that neovascularization in the eye could be greatly reduced after PUT, and the occlusion of microvessels could last up to 4 weeks. In conclusion, PUT holds significant promises as a non-invasive method to precisely remove microvessels in neurovascular eye diseases by more selectively treating vasculature with minimized side-effects.

Photo-Mediated Ultrasound Therapy for the Treatment of Corneal Neovascularization in Rabbit Eyes

PurposeCorneal neovascularization (CNV) is the invasion of new blood vessels into the avascular cornea, leading to reduced corneal transparency and visual acuity, impaired vision, and even blindness. Current treatment options for CNV are limited. We developed a novel treatment method, termed photo-mediated ultrasound therapy (PUT), that combines laser and ultrasound, and we tested its feasibility for treating CNV in a rabbit model.MethodsA suture-induced CNV model was established in New Zealand White rabbits, which were randomly divided into two groups: PUT and control. For the PUT group, the applied light fluence at the corneal surface was estimated to be 27 mJ/cm2 at 1064-nm wavelength with a pulse duration of 5 ns, and the ultrasound pressure applied on the cornea was 0.43 MPa at 0.5 MHz. The control group received no treatment. Red-free photography and fluorescein angiography were utilized to evaluate the efficiency of PUT. Safety was evaluated by histology and immunohistochemistry. For comparison with the PUT safety results, conventional laser photocoagulation (LP) treatment was performed with standard clinical parameters: 532-nm continuous-wave (CW) laser with 0.1-second pulse duration, 450-mW power, and 75-µm spot size.ResultsIn the PUT group, only 1.8% ± 0.8% of the CNV remained 30 days after treatment. In contrast, 71.4% ± 7.2% of the CNV remained in the control group after 30 days. Safety evaluations showed that PUT did not cause any damage to the surrounding tissue.ConclusionsThese results demonstrate that PUT is capable of removing CNV safely and effectively in this rabbit model.Translational RelevancePUT can remove CNV safely and effectively.

Cavitation induced shear and circumferential stresses on blood vessel walls during photo-mediated ultrasound therapy

Photo-mediated ultrasound therapy (PUT) is a novel technique using combined laser and ultrasound to generate enhanced cavitation activity inside blood vessels. The stresses produced by oscillating bubbles during PUT are believed to be responsible for the induced bio-effects in blood vessels. However, the magnitudes of these stresses are unclear. In this study, a two-dimensional axisymmetric finite element method-based numerical model was developed to investigate the oscillating bubble-produced shear and circumferential stresses during PUT. The results showed that increased stresses on the vessel wall were produced during PUT as compared with ultrasound-alone. For a 50-nm radius bubble in a 50-μm radius blood vessel, the produced circumferential and shear stresses were in the range of 100 kPa–400 kPa and 10 Pa–100 Pa, respectively, during PUT with the ultrasound frequency of 1 MHz, ultrasound amplitude of 1400 kPa–1550 kPa, and laser fluence of 20 mJ/cm2, whereas the circumferential and shear stresses produced with ultrasound-alone were less than 2 kPa and 1 Pa, respectively, using the same ultrasound parameters. In addition, the produced stresses increased when the ultrasound pressure and laser fluence were increased but decreased when the ultrasound frequency and vessel size were increased. For bubbles with a radius larger than 100 nm, however, the stresses produced during PUT were similar to those produced during ultrasound-alone, indicating the effect of the laser was only significant for small bubbles.

The Effect of Laser and Ultrasound Synchronization in Photo-Mediated Ultrasound Therapy.

Photo-mediated ultrasound therapy (PUT) is a novel, non-invasive, agent-free, highly selective, and precise anti-vascular technique. PUT removes microvessels through promoting cavitation activity precisely in targeted microvessels by applying synchronized nanosecond laser pulses and ultrasound bursts. The synchronization between laser and ultrasound is critical to the outcome of PUT. Through theoretical simulation and experimental study, the effect of synchronization between laser pulses and ultrasound bursts on cavitation activity during PUT is evaluated. By using a theoretical model, we found that cavitation activity was enhanced when laser pulses and ultrasound bursts were synchronized such that the produced photoacoustic wave overlaid the rarefactional phase of the ultrasound wave. This finding was then verified through in vitro studies where cavitation was monitored by using a passive cavitation detector. Furthermore, we demonstrated that the in vivo treatment outcome of PUT in rabbits was directly related to the synchronization between laser and ultrasound. The anti-vascular effect could only be observed when laser and ultrasound were properly synchronized in vivo. PUT is more efficient when the laser-induced photoacoustic wave overlays the rarefactional phase of the ultrasonic wave. This is a systematic study to investigate the synchronization effect of PUT, which would be significant for further understanding the mechanism and further improving the treatment efficiency of PUT.

Photo-mediated Ultrasound Therapy to Treat Retinal Neovascularization.

This report describes a novel therapeutic technique called photo-mediated ultrasound therapy (PUT). PUT applies synchronized short pulse duration (nanosecond) laser and ultrasound burst on targeted tissue, offering high-precision localized treatment. PUT is based on controlled induction and promotion of micro-cavitation activity in the target tissue. PUT is able to safely and effectively treat retinal neovascularization in rabbits with persistent nonperfusion up to 4 weeks after PUT in the choroidal vasculature.Clinical Relevance- PUT can selectively remove retinal angiogenesis in clinically-relevant disease models in humansized eyes (rabbit) without damaging surrounding tissue.

Enhanced cavitation activity in a slab-shaped optical absorber during photo-mediated ultrasound therapy

Recently, new studies have shown that combined laser and ultrasound, or photo-mediated ultrasound therapy (PUT), can enhance cavitation in optically absorptive targets to disrupt tissues through photoacoustic (PA) effect. These studies, including both experimental and theoretical investigations, have largely focused on blood vessels, which are modeled as cylindrically-shaped optical absorbers for PA wave generation and propagation. However, in many clinical situations, target tissues may not be cylindrically-shaped. In this paper we investigated the effect of PUT on a slab-shaped optical absorber, much larger than the size of the laser beam or the ultrasound focal point. Our results demonstrated that laser light could generate a PA wave that could enhance cavitation not only at the surface of a slab, but also at depths when combined with ultrasound, suggesting that PUT may be effective in enhancing cavitation in a large range of soft tissues. Our results also demonstrated that the cavitation enhancement was based on the optical absorption of the targeted tissue, allowing for self-targeting treatments when optical contrast is present. Additionally, we demonstrated that for the greatest cavitation enhancement in deeper layers a focused laser beam geometry would be most effective.

Real-time photoacoustic sensing for photo-mediated ultrasound therapy.

Photo-mediated ultrasound therapy (PUT) is a novel, noninvasive antimicrovascular approach that can treat neovascularization with high precision. We developed a photoacoustic (PA) sensing (PAS) system for PUT and achieved real-time PAS-guided PUT. Experiments performed on a chicken yolk sac membrane model demonstrated that PAS could monitor the treatment effect in a microvessel during PUT. Vessel shrinkage induced a decrease in the PA signal amplitude, while vessel rupture induced an abrupt increase in the PA signal amplitude. The integrated PUT and PAS system can significantly improve the safety and effectiveness of PUT, and may assist with clinical translation of this novel antimicrovascular technique.

Antivascular photo-mediated ultrasound therapy and its application in the eye

Antivascular therapy can improve the prognosis of a variety of pathological conditions, including cancer and many eye diseases. By synergistically applying laser pulses and ultrasound bursts, we developed a photo-mediated ultrasound therapy (PUT) technique as a localized antivascular method. PUT takes advantage of the high native optical contrast among biological tissues and has the unique capability to self-target microvessels without damaging surrounding tissue. The technique utilizes an integrated therapeutic ultrasound and laser system. The laser system emits 5-ns, 10-Hz pulses, which is synchronized with 10-ms, 10-Hz ultrasound bursts. Experiments were carried out on chicken yolk sac membrane and rabbit eyes. With radiant exposures around 5 mJ/cm2at 532 nm and ultrasound pressures around 0.4 MPa at 1 MHz or 0.5 MHz, microvessels were able to be removed. Furthermore, ex vivo tests with human blood demonstrated that cavitation was induced when laser and ultrasound were utilized synergistically. On the rabbit eye model, the blood flow in microvessels could be greatly reduced after PUT, and the occlusion of microvessels could last up to 4 weeks. In conclusion, PUT holds significant promises as a non-invasive method to precisely remove microvessels in neurovascular eye diseases by more selectively treating vasculature with minimized side-effects.

Removal of choroidal vasculature using concurrently applied ultrasound bursts and nanosecond laser pulses

Pathologic microvasculature plays a crucial role in innumerable diseases causing death and major organ impairment. A major clinical challenge is the development of selective therapies to remove these diseased microvessels without damaging surrounding tissue. This report describes our development of novel photo-mediated ultrasound therapy (PUT) technology for precisely removing choroidal blood vessels in the eye. PUT selectively removes microvessels by concurrently applying nanosecond laser pulses with ultrasound bursts. In PUT experiments on rabbit eyes in vivo, we applied 55–75 mJ/cm2 of light fluence at the retinochoroidal surface at 532-nm and 0.5 MPa of ultrasound pressure at 0.5 MHz. PUT resulted in significantly reduced blood perfusion in the choroidal layer which persisted to four weeks without causing collateral tissue damage, demonstrating that PUT is capable of removing choroidal microvasculature safely and effectively. With its unique advantages, PUT holds potential for the clinical management of eye diseases associated with microvessels and neovascularization.

Bubble growth in cylindrically-shaped optical absorbers during photo-mediated ultrasound therapy

Photo-mediated ultrasound therapy (PUT) is a non-invasive, agent-free technique to shut down microvessels with high precision by promoting cavitation activity precisely in the targeted microvessels. PUT is based on the photoacoustic (PA) cavitation generated through concurrently applied nanosecond laser pulses and ultrasound bursts. In this study, a PA cavitation model is employed to understand the enhanced cavitation activity during PUT, with full consideration of the optical absorption of blood vessels. Bubble size evolution in cylindrically-shaped optical absorbers (vessels) due to rectified diffusion is simulated. Results show that the ultrasound pressure required for bubble growth decreases dramatically with the increased laser fluence. At a relatively low ultrasound driving pressure, bubble equilibrium radius increases rapidly due to concurrently applied nanosecond laser pulses and ultrasound bursts, resulting in a transition from inertial cavitation to stable cavitation. This inertial to stable transition is verified by the experimentally measured results on 0.76 mm silicone tubes filled with human whole blood with 0.5 MHz ultrasound at 0.243 MPa. This study demonstrated the potential to induce stable bubbles in blood vessels by PUT non-invasively.

Innovations in Retinal Laser Technology

Retinal laser photocoagulation is a proven, effective treatment for various retinal disorders, including diabetic retinopathy, retinal vein occlusions, and sickle cell retinopathy. To minimize iatrogenic retinal damage while maintaining therapeutic effects, retinal laser technology has evolved significantly since its introduction in ophthalmology more than half a century ago. These innovations have included both optimizations of laser parameters in addition to the development of novel laser delivery systems. This review summarizes recent innovations in retinal laser technology, including subthreshold micropulse laser, selective retinal therapy and nanosecond laser, innovative modes of laser delivery including pattern scanning laser, endpoint management, navigated laser, and newly described photo-mediated ultrasound therapy.