Our present results have demonstrated that PTT via an AuNP-coated SEMS under NIR laser irradiation will successfully treat granulation tissue formation after stent placement in the rat esophagus. The granulation tissue was significantly decreased in the PTT groups compared to a control group. PTT-induced cell apoptosis was significantly elevated in the heated esophageal mucosa, and markers of cellular proliferation were significantly decreased after PTT when compared to the control animals. Increases in HSP expression and thermal induced-apoptosis are well-characterized features of the heat shock response, and previous studies have reported that HSP70 is an indicator of heat stress in different species.22, 23
Our study groups were evaluated for the rebound effect. The group C rats treated once at 4 weeks after stent placement had a significant increase in granulation tissue formation at 8 weeks compared to the group D animals treated twice at 4 and 8 weeks after stent placement. The tissue-hyperplasia area and number of epithelial layers in group C were found to have gradually increased compared with the group D rats. Our results confirmed that the PTT was more effective when administered every 4 weeks and indicated therefore that periodic PTT seems to be necessary to treat stent-induced granulation tissue formation after stent placement. Further studies with a long-term follow-up are required to confirm our present findings.
Although PTT has been previously reported to successfully treat granulation tissue formation, there is no consensus regarding the optimal temperature for local heating for the treatment of stent-induced granulation tissue formation.11, 20, 24–26 Several studies have reported that at 43 °C to 65 °C can help inhibit tissue hyperplasia but that an increase to 70 °C induced immediate tissue burn.11, 19, 25 In our current study, stent-induced granulation tissue formation in the rat esophagus was effectively treated with AuNP coated SEMS-mediated local heating at 65 °C, which may effectively burn the granulation tissues generated around the stent. Taken together, our present results demonstrated that local heat treatment at 65 °C was optimal for successful PTT.
Our previous studies have reported that an AuNP-coated SEMS can be easily fabricated using simple synthesis steps and is rapidly heated to therapeutic temperatures within a few seconds of NIR laser irradiation.11, 20 The AuNP-coated SEMS used in our current experiments thus rapidly reached a high temperature, which increased in proportion to the NIR power. Hence, the PT properties could be easily controlled by adjusting the NIR irradiation levels. These properties can be attributed to the anisotropic structural characteristics of AuNP, consistent with our prior results.11, 20 Our previous studies involved local heat treatment via the AuNP-coated stent under NIR irradiation at one week after stent placement to prevent stent-induced tissue hyperplasia. In our current study, local heat treatment was performed at 4 weeks after granulation tissue formation had already occurred. Restenosis caused by stent-induced granulation tissue formation occurs as an excessive proliferative response within 4 weeks to the mechanical injury caused by stent placement.10, 11, 21 Taken together with previous evidence, our current findings support the notion that local heat treatment via the NIR irradiation of an AuNP-coated stent is an effective therapeutic option for the prevention as well as the treatment of granulation tissue formation after stent placement.
Advances in stent technologies have resulted in a decrease in complications and a prolonged stent patency period. Although a stent has been commonly used as a minimally invasive method to treat malignant and benign esophageal strictures, tissue hyperplasia through the mesh or around the edges of esophageal stents has been reported after the placement of up to 60% of bare stents and 13% of covered stents.27 – 29 Hence, permanent stent placement in patients with a relatively long life expectancy has not yet become widespread due to the likelihood of late adverse events, including the development of new strictures caused by stent-induced granulation tissue formation, stent migration, and esophageal ulceration.30, 31 We believe however that our therapeutic strategy using AuNP-coated SEMS could be applied also to an uncovered SEMS to treat granulation tissue growth, and may prolong stent patency by reducing stent-induced tissue hyperplasia, thus improving the patients' quality of life.
There were some limitations to our study of note. First, our findings may not reflect all of the pathological mechanisms occurring in humans following a stent placement. Second, it is necessary to determine the optimal timing for local heating after stent placement to treat stent-induced granulation tissue formation. Third, we did not evaluate the depth penetration of the AuNP-coated SEMS in the rat esophageal model. Although additional studies will be required to further validate our current data, our study supports the premise that PTT via an AuNP-coated stent can successfully treated stent-induced tissue hyperplasia.
An AuNP-coated SEMS appears to be an effective approach for the local treatment of stent-induced granulation tissue formation in the rat esophagus. An AuNP-coated stent-mediated local PTT protocol could be used for not only to treat granulation tissue formation but also tumor ingrowth or overgrowth though the stent meshes. Although further preclinical studies are needed to investigate its efficacy and safety, this therapeutic strategy shows considerable promise for the treatment of granulation tissue formation after stent placement.