DR is the main cause of blindness in diabetic patients, and the main pathological change in blindness is neovascularization. At present, the main method for the treatment of retinal neovascularization is retinal photocoagulation. Since this century, the research of TRP has increased year by year. Researchers have comprehensively explored the therapeutic effect and safety of TRP on DR through combined treatment, comparative control and other methods ( Table 2 ). In 2009, the University of California reported two cases of UWFFA-assisted targeted laser treatment of diabetic retinopathy (8). For both patients, 532 nm laser was accurately applied to the ischemic area displayed and clearly demarcated by UWFFA for a total of 1000-1400 times. This treatment technology first entered the public eye as an individualized treatment plan: retinal angiography found that TRP successfully regressed retinal neovascularization in two patients. At 9-month follow-up, the patients’ vision was maintained and there was no recurrence of neovascularization and macular edema. In a clinical trial reported in the United Kingdom in 2013 (3), 20 newly treated patients with PDR were treated with TRP alone. The results of the study show that in the short term (12 weeks to 24 weeks), its clinical efficacy and safety are worthy of recognition:76% of patients experienced PDR regression at week 12; patients’ vision and visual field did not worsen or even improved; macular thickness was significantly reduced (mean baseline 251 μm, 12.1 μm at 24 weeks); disease progression was slow, and no TRP-related ocular adverse events occurred during the study period.

The visual field of fluorescein angiography of the standard fundus camera is 30 – 60°. It is necessary to take different images at different times in the study to image the periphery of the retina. This makes it very difficult to accurately delineate retinal capillary non-perfusion and accurately apply photocoagulation within the ischemic boundary. UWFFA is a very useful tool in the diagnosis, staging, management and treatment of DR (22). UWFFA can display more retinal pathology even in eyes judged as normal by 7 standard field (7SF) (16). In 2008, Friberg et al (23). first reported the feasibility of UWFA in 30 eyes of 30 DR patients. Compared with the standard system, they observed that UWFA allowed imaging of a larger area of retinal surface (8.7 ± 1.6 vs 3.4 ± 0.76DD, P<0.001) and retinal ischemia (16.9 ± 15 vs 3.4 ± 4.26 sectors, P<0.05), although the image quality was reduced. Then in 2009, the first case report (8) of TRP and UEFFA mentioned that under UWFFA, the non-perfusion area and its boundary of the patient’s retinal capillaries could be identified very accurately, providing a clearer and more discernible field of vision for the application of TRP. UWFFA can initially and accurately locate the non-perfusion area of retinal capillaries in a 200° field of vision at the early stage of application. In 2013, Muqi et al. (3) evaluated the effect of UWFFA-guided TRP in the eyes of 28 PDR patients. At 12 weeks, 76% of patients had PDR regression, and 37% had complete disease regression at 24 weeks. They found that the thickness of the central retina decreased significantly over time, measured by optical coherence tomography (22). With the gradual maturity of the UWFFA program, as an assistant retinal examination tool, it has been more and more widely used in clinical work. However, the specific use standards for its joint application with TRP still need to be further clarified through large-scale research in the future.

The primary difference between targeted retinal laser and panretinal laser photocoagulation is that the narrowing of the laser range results in a significant reduction in the number of laser spots on the retina. In all randomized controlled clinical trials, regardless of whether the targeted laser range is specified as “optos-guided TRP treatment covered the area of capillary non-perfusion from the ora serrata up to 1 DD into perfused retina (10)”, “navigated, semi-automatic pattern laser application was conducted based on the treatment plan (9)” or “capillary non -perfusion and intermediate ischemic zones posterior to the equator as well as the entire retina anterior to the equator (12)”, the TRP has significantly fewer laser spots (9, 12) or lower power (10). In this regard, the visual analog scale was used to quantify the degree of pain in the treatment of patients, and it was found that the pain of TRP was significantly lower than that of PRP.

For the improvement of visual function, both treatment modalities improved visual acuity and mean visual field defect in the short term (4-12 weeks) but there was no significant difference between the two (10); in the medium and long term (at least 3 months)) The mean best-corrected visual acuity (BCVA) after treatment was significantly decreased, and the difference was not significant (12). DME is a serious complication of DR and one of the main causes of visual loss in DR patients, so central macular thickness (CMT)/central retinal thickness (CRT) is also an important research parameter. CMT decreased in the short term (4-12 weeks) after PTR treatment, and was not significantly different from PRP; although a clinical trial (NCT01232179) (12) reported that TRP or PRP alone was used to treat patients with early or high-risk PDR after 3 months There is an increase in CMT, and CMT thickening after laser treatment has been demonstrated in many other studies (9, 24–26), but there is no difference in results between the two laser modalities. In terms of safety, there were no serious ocular complications or adverse events immediately after TRP treatment, short-term or even mid-to-long term, and there were no signs of intraretinal hemorrhage, vascular damage or traction retinal detachment in the laser treatment area. There is also no adjustment to the treatment regimen for patients treated with TRP, such as switching to PRP.

Comparing the efficacy and safety of the two laser methods, after analyzing many research parameters such as the number of laser points, visual function, UWF, pain level, prognosis, and adverse events, there may be no difference in the efficacy of the two on DR. But TRP reduces retinal damage and preserves more healthy retinas due to fewer laser points, which also improves patient comfort. Therefore, TRP may be a future alternative to PRP to some extent (27)

With the research on the pathophysiology of retinal vascular diseases, the use of anti-VEGF drugs for the treatment of retinal vascular diseases has become more and more popular. Such drugs can bind tightly to VEGF to reduce vascular permeability and then inhibit the formation of new blood vessels. Anti-VEGF is currently the gold standard treatment for veno-occlusive macular edema, especially BRVO (28). However, the short half-life of the drug causes its concentration in the eye to drop rapidly and the concentration in the vitreous cavity is unstable and the treatment effect is short. Retinal neovascularization and macular swelling are prone to recur after a single injection of anti-VEGF drugs (13). Therefore, frequent intravitreal injections of anti-VEGF drugs are required to control macular edema, which increases the likelihood of adverse events such as endophthalmitis and retinal detachment. Researchers have found in clinical trials that Through the combined application of vitreous drug injection and targeted laser therapy, the use of targeted laser can effectively reduce the frequency of drug injections or improve the prognosis, which may achieve the purpose of reducing the number of patient visits, costs and the risk of adverse events.

Current studies have suggested that anti-VEGF drugs can reduce retinal thickness, improve DME, and improve vision in the treatment of DR, but require repeated injections for optimal results. In this regard, in order to reduce the number of injections of anti-VEGF drugs and reduce the occurrence of adverse events, researchers considered the combined application of TRP and intravitreal injection of anti-VEGF drugs. At present, two controlled clinical trials have been completed in Japan (UMIN000007566) and the United States (NCT01552408), involving a total of 81 DME patients. Visual function and CRT were mainly compared between patients receiving TRP and anti-VEGF drugs in combination with patients receiving anti-VEGF drugs alone. However, the results of the two trials are contradictory: after a 6-month study by the Japanese team, it was found that the average best corrected visual acuity (BCVA) of the combined treatment group improved more significantly, And the CRT of the patients in the injection-only group increased to a higher degree at the 3rd, 4th, and 5th months (11);however, after a 3-year Randomized DAVE Trial, the US team found that the combined treatment group was not better than the single injection group in terms of BCVA, visual field, CRT, and the number of injections, but in In terms of safety, there were 5 new cases of new PDR-related neovascularization in the drug injection group but no endophthalmitis in the combined treatment group (13). The difference in results between the two groups may be related to the inclusion criteria, dosing schedule, and sample size. Compared with the US study, the participants in the Japanese trial were injected with bevacizumab (1.25 mg IV bevacizumab: 0.3 mg IV ranibizumab), which may explain the difference in results between the two groups.

In addition, a controlled clinical trial (NCT03904056) (14) reported by the São Paulo State University research team in 2021 compared the effect of PRP combined with intravitreal injection of ranibizumab (IVR) and TRP combined with IVR in the treatment of PDR. The results showed that there were no significant changes in BCVA and central subfield thickness (CSFT) between the two groups; the fluorescein leakage area of active new vessels (FLA) was significantly reduced in the two groups, but there was no between-group difference. In addition, we checked on the International Clinical Trials Registry website (ClinicalTrials.gov) that the Cairo University research team has initiated a RCT (NCT04674254),to compare the changes of macular area in PDR patients receiving anti-VEGF therapy combined with TRP or PRP therapy, and we will continue to pay attention to this.

Overall, TRP helps to improve DME recurrence after vitreous drug injection, additional laser may help to suppress VEGF production in the ischemic area, and combination therapy of TRP and anti-VEGF drugs may help reduce the frequency of vitreous drug injections, patient treatment costs, number of clinic visits, and adverse events (eg, endophthalmitis, retinal detachment).