Ischemic stroke is one of the major causes of severe disability and death worldwide. It is mainly caused by a sudden reduction in cerebral blood flow due to obstruction of the supplying vessel by thrombi and subsequent initiation of a complex cascade of pathophysiological changes, which ultimately lead to brain ischemia and even irreversible infarction. Thus, timely and effective thrombolysis therapy remains a mainstay for acute ischemic stroke treatment. Tissue plasminogen activator (tPA), the only thrombolytic agent approved globally, provides substantial benefits by exerting a fibrinolysis effect, recovering the blood supply in occluded vessels and, thereby, salvaging the ischemic tissue. However, the clinical application of tPA was limited because of a few unsolved issues, such as a narrow therapeutic window, hemorrhagic complications, and limited thrombolytic efficacy, especially, for large thrombi. With the prosperous development of nanotechnology, a series of targeted delivery strategies and nanocomposites have been extensively investigated for delivering thrombolytic agents to facilitate thrombolysis treatment. Excitingly, numerous novel attempts have been reported to be effective in extending the half-life, targeting the thrombus site, and improving the thrombolytic efficacy in preclinical models. This article begins with a brief introduction to ischemic stroke, then describes the current state of thrombolysis treatment and, finally, introduces the application of various nanotechnology-based strategies for targeted delivery of thrombolytic agents. Representative studies are reviewed according to diverse strategies and nano-formulations, with the aim of providing integrated and up-to-date information and to improve the development of thrombolysis treatment for stroke patients.

Background: Experimental evidence suggests that endogenous vascular endothelial growth factor (VEGF) may play a major role in the surgical delay phenomenon. The purpose of this study was to investigate the effect of endogenous VEGF on flap surgical delay. Methods: A total of 82 adult male Sprague-Dawley rats with an average weight of 330 g were used for these experiments. These experiments were then conducted in two parts. In part 1, 32 rats were used to assess the effectiveness of VEGF inhibitor through Western blot assay and enzyme-linked immunosorbent assay. In part 2, 50 rats were used to investigate the effect of VEGF on flap surgical delay by means of arteriography, histologic analysis, and flap viability. Results: The VEGF protein inhibition ratio reached the maximum (approximately 91.6 percent) in 5 to 7 days. The number of transverse arteries and the number of vessels greater than 0.1 mm in diameter on the 3-day delay duration and the 6-day delay duration were significantly greater than those of the normal group. The number of transverse arteries and the number of vessels greater than 0.1 mm in diameter on the 6-day inhibition duration were not significantly changed compared with the normal group. Microvascular density on the 6-day delay duration obviously increased, whereas the 6-day inhibition duration was not significantly changed in comparison to the normal group. Conclusion: Endogenous VEGF is an initiating factor of the surgical delay effect by controlling choke vessel dilation and neovascularization within the choke zones.

Background: Surgical delay can improve flap viability, leading to vasodilation, neovascularization, and vessel reorganization. Experiments suggest a similar positive effect of botulinum toxin type A on pedicled flap viability. However, whether it may convert choke anastomoses into true anastomoses and how to identify the optimal timing for flap transfer remain unclear. Methods: One hundred fifty-four Sprague-Dawley rats were divided into a control group, three saline injection groups, and three botulinum toxin type A injection groups defined by time of injection (2, 3, and 4 weeks before flap harvest). A pedicled 11 × 3-cm flap was marked on the unilateral dorsum of each rat. Before flap harvest, the flap donors were assessed by infrared thermal imaging, postmortem arteriography, immunohistochemical staining of CD31, and enzyme-linked immunosorbent assay. Flap survival area percentage was measured on postoperative day 7. Results: In the control and saline groups, infrared thermography showed three independent white hotspots interspaced by red zones over flaps, whereas it presented a continuous white band in the botulinum toxin type A groups. There was a significant increase in flap survival area, flap surface temperatures, numbers of identifiable vessels in the choke zones, microvascular density, and vascular endothelial growth factor concentration in the botulinum toxin type A groups. Conclusions: Botulinum toxin type A can convert choke anastomoses into true anastomoses, and its preconditioning effect cannot increase over time; it is appropriate to choose the timing point when the infrared thermal images show a continuous white band existing over flaps for flap transfer.

Currently, experimental evidence suggests that the surgical delay can increase flap survival area, but its effect may decrease if the optimal delay period is missed. The aim of this study is to establish a sensitive and objective modality based on the visualized and individualized infrared thermography for identifying the maximal surgical delay effect. A rectangular three‐angiosome flap was designed on the unilateral dorsum of the rat. Ninety‐six rats were randomly divided into six groups according to the various delay time. Both the relative temperature and the relative temperature ratio were measured by the infrared thermography. Arterial density, number of vessels >0.1 mm in diameter, microvessel density, VEGF concentration, and flap viability were measured. Receiving operating characteristic curve with the highest Youden‐Index was used to detect and identify an optimal cutoff point of the relative temperature ratio in the maximal surgical delay effect. The criteria for identifying the flap maximum delay effect based on the infrared thermography included the surface of the postdelayed flaps presented white color (higher temperature) instead of the red and white pattern of the normal skin and the optimal cutoff point of the relative temperature ratio was ≥1.17 with a sensitivity of 84.6% and a specificity of 77.3%. Instead, the sensitivity and specificity of the conventional method based on the delay time were 38.5 and 90.9%, respectively. Infrared thermal imaging can accurately identify the maximum delay effect when combined with the relative temperature ratio.