1. Biodegradable Cisplatin-Eluting Tracheal Stent for Malignant Airway Obstruction In Vivo and In Vitro Studies Yin-Kai Chao, MD, PhD ; Kuo-Sheng Liu, MD ; Yi-Chuan Wang, MS ; Yen-Lin Huang, MD, PhD ; and Shih-Jung Liu, PhD CHEST 2013; 144(1):193–199 R2 홍인택

2. Introduction  Approximately 30% of patients with lung cancer have central airway obstruction. Self-expandable metallic stents (SEMSs) are commonly used in these patients for the palliation of the symptom.  SEMS are also notorious for various troublesome complications, including stent fracture, migration, impaired mucociliary clearance, and increased bacterial infection

3. Introduction  We believe that an ideal airway stent possess sufficient strength to perform its mechanical function be biodegradable (no need for removal after serving its purpose) be biocompatible so that the material breakdown process will not cause any tissue irritation, provide effective pharmaceuticals for a sustained period of time.

4. Introduction  In this report we aimed to develop biodegradable drug-eluting stents that can provide a sustainable release of cisplatin, which is the most commonly used antitumor medication in lung cancer for the treatment of malignant tracheal obstruction.

5. Method

6. Composition of Biodegradable Stents  The biodegradable polymers used were poly( ‐ caprolactone), with a molecular weight of 80,000 Da (Sigma-Aldrich Co LLC).

7. Fabrication of Bare PCL Stents  To fabricate a biodegradable stent, a stent element design, as shown in Figure 1A, was first developed  After molding, each stent element was interconnected with another stent element ( Fig 1B ).

8. Fabrication of Bare PCL Stents  By interconnecting six and 10 elements, respectively, the assembly was rolled into mesh tubes, and the final connecting points were welded by a hot spot welding.  Biodegradable stents of two different external diameters (6 mm and 10 mm) were obtained ( Fig 1C ).

9. Spray Coating of Cisplatin  After the assembly process, the PCL stents were coated with cisplatin by a spray coating device, which was designed and built in our laboratory.  Poly ( d,l )-lactide-co-glycolide (PLGA) (75:25, Resomer RG 756; Boehringer Ingelheim GmbH) and cisplatin (Sigma-Aldrich Co LLC) were first dissolved in acetonitrile at predetermined ratios (90/10, 80/20, 70/30, 50/50, weight/weight) and were then delivered by the spray coater with a volumetric flow rate of 4 mL/h.

10. Mechanical Properties of PCL Stents  To compare the PCL stents manufactured in this study with the commercial 10-mm-covered Ultraflex SEMSs (Boston Scientific), both PCL (10 mm in diameter) and Ultraflex stents were compressed by a 1-N force, and the deformation rates were recorded.

11. In Vitro Elution of Cisplatin From the Stents  An in vitro elution method was used to determine the release characteristics of cisplatin from the stents.  The stents’ elements were placed in glass test tubes with 1 mL of phosphate buffer.  The dissolution medium was collected daily for subsequent HPLC analyses  Fresh phosphate buffer (1 mL) was then added for the next 24-h period, and this procedure was repeated for 6 weeks.

12. In Vivo Animal Model  Fifteen New Zealand white rabbits (Banqiao Animal Center), with an average weight of 3.0 kg, were divided into five groups in this study.  The 6-mm PCL stent was implanted under direct vision.  Blood concentrations of cisplatin were collected by syringes via puncture on the marginal ear vein on postoperative days 1, 4, and 7.

13. In Vivo Animal Model  Animals were killed by intravascular injection of lethal- dose lidocaine at postoperative 1, 2, 3, 4, and 5 weeks.  The cervical trachea (at the stented and adjacent unstented areas), lung tissue from the right upper lobe, and the liver were excised and submitted for histologic examination and HPLC analysis.

14. Result

15. Mechanical Properties of the PCL Stent vs SEMs  Figure 2 shows the deformation of both PCL stents and commercial SEMs subjected to a 1-N load.  Furthermore, when subjected to repeated dynamic loads, the PCL stents exhibited good flexibility and fully regained their shapes as the loads were removed. Approximately 90% of the strength of SEMs.

16. In Vitro Release of Cisplatin From the PCL Stents

17. In Vivo Animal Study and Cisplatin Level in Blood and Tissue  No animal died of airway complications during the period of study.  Figure 4 shows the bronchoscopic findings 1, 3, and 4 weeks after stent insertion

18. In Vivo Animal Study and Cisplatin Level in Blood and Tissue

19. In Vivo Animal Model

20. Histologic Examination  Figure 6 displays the trachea with stent in place.

21. Histologic Examination

22. Discussion  SEMSs have been of great value in palliation of malignant airway obstruction but are also notorious for various troublesome complications.  In the current study, we successfully demonstrated that the biodegradable PCL stents have mechanical strength comparable to the strength of SEMSs, with minimal tissue reaction.  Through the combined use of PLGA materials and the spray coating technique, a controlled amount of cisplatin could be released locally over a few weeks with minimal systemic concentration.

23. Discussion  First, this drug-releasing model was constructed on nondiseased rabbit trachea. The actual response of the stent to endobronchial cancerous tissue remains unknown.  Second, our stent was inserted surgically but not via endobronchial route, which is not similar to the current clinical practice.  All these will be topics of future research in our laboratory.

24. Conclusion  Our study demonstrated that the biodegradable stents provided physical properties comparable to the properties of SEMSs and a sustained release of cisplatin for 5 weeks, which showed great potential in the treatment of malignant airway obstruction.