In-vivo efficacy of biodegradable ultrahigh ductility Mg-Li-Zn alloy tracheal stents for pediatric airway obstruction

Tracheal stenosis, a debilitating condition limits air passage to lungs affecting pediatric and adult populations. Current biodegradable polymeric stent therapies are far from ideal. An ultrahigh ductility biodegradable magnesium based alloy (LZ61-KBMS) developed herein may offer a viable solution.

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Fig. 1. (A). Endoscopic images of the stented airway right after implantation, and after 4, 8 and 12 weeks of implantation; (B). Tracheal lumen area calculated based on the cross-section of optical coherence tomography (OCT) images collected at 4, 8 and 12 weeks. **denotes a significant difference between alloy groups (p <0.01, n=3); (C). The 3D structures of 316L SS stents and LZ61-KBMS stents based on µCT scans collected at different time points indicating the stents remaining after implantation in vivo.

Trachea (windpipe), a key component of the human respiratory system, is a flexible air tube that extends from the larynx to the bronchi and allows air to flow to the lungs. Tracheal stenosis is a condition involving narrowing or constriction of the trachea and occurs due to injury caused by many events such as after prolonged intubation, tumors pressing on the trachea, infections and certain autoimmune diseases. In most cases, laryngotracheal stenosis is acquired, but for pediatric patients, tracheal stenosis can also be congenital. Most common treatments for tracheal stenosis include surgical resection and reconstruction, laser-based bronchoscopy, contact electrocautery, argon plasma coagulation, cryotherapy, photodynamic therapy, and brachytherapy.

Airway stenting is a valuable adjunct to the other therapeutic bronchoscopic techniques as stenting provides mechanical support to maintain the patency of airway lumen and therefore, secures long-term effectiveness. Various types of tracheal stents are available for airway stenting ranging from silicone tubes and metallic stents while the decision to select a certain type of stent is made based on individual clinical symptoms. Even though all these stents exhibit efficient short-term palliation, none of the stents provide satisfactory long-term effectiveness and there is a significant clinical need for the generation and use of a biodegradable medical device which maintains airway patency while also totally degrading overtime within a predetermined time period. Various biodegradable polymers (e.g. PLGA, PCL, polydioxanone, etc.) based stent have been tested in preclinical and clinical settings but the results however, are far from ideal and their clinical use is also controversial. 

In the year 2010, our team realized that instead of using degradable polymers, tracheal stents made from magnesium-based alloy could be used [1]. Magnesium (Mg) alloy is unique as a biodegradable material because among metals, magnesium-based alloys provide better mechanical support when compared to conventional polymers. On the other hand, due to the biodegradable nature, magnesium alloy-based implants will dissolve overtime obviating secondary surgeries needed to retrieve non-biodegradable stents or need for surgical interventions for stents implanted permanently in patients. Mg being the second most abundant intracellular cation and the fourth most abundant cation in the body, the alloy itself as well as its degradation products are well tolerated and easily excreted by the human body.

A variety of magnesium-based alloy systems have been developed. However, to meet the design requirement of tracheal stent applications the following important principles/criteria need to be meet: (1) achieve appropriate biodegradation rate in aqueous environment; (2) good ductility to achieve high plastic deformation to endure the stent crimping and expansion processes during stent deployment; (3) display adequate strength to maintain the mechanical support against the vascular wall during degradation of the device; and finally (4) exhibit no significant short-term and long-term toxicity of the alloying elements as well as the related degradation products.

Various Mg alloys systems have been studied for stent applications, however, the ductility of these magnesium-based alloys is severely limited posing many difficulties in the balloon expandable stent design and manufacture of magnesium stents. In addition, the degradation is significantly accelerated when the alloys matrices are exposed to flow or cyclic stresses. We therefore realized that there is a critical need to develop new magnesium alloys specifically for tracheal stent applications which are expected to meet the following: (1) provide strong mechanical support with much improved ductility; (2) offer resistance to corrosion under flow and cyclic stresses; (3) ensure safety due to the judicious selection of non-toxic alloying elements aided by empirical and first principles theoretical understanding.

As a first step, we developed six ultra-high ductility alloys containing lithium (Li), aluminum (Al) and zinc (Zn). We also extensively studied their mechanical properties, in-vitro and in-vivo corrosion and biocompatibility [2, 3]. Of the six alloys, LZ61 showed the slowest corrosion rate and contains only Mg, Li (L) and Zn (Z) which are highly biocompatible to human and therefore, they were selected for tracheal stent fabrication and in-vivo testing which was the main objective of this current paper.  In this work (Nature Communications Biology 2020; 10.1038/s42003-020-01400-7), we demonstrate superior response of a balloon expandable ultra-high ductility (UHD) biodegradable LZ61 tracheal stent (LZ61-KBMS) contrasted with traditional non-degradable 316L stainless steel stents. The results obtained from the stent implanted in rabbit trachea clearly demonstrates complete degradation of LZ61-KBMS without impacting further airway growth (Fig. 1). On the other hand, the 316L stainless steel stent show distinct airway narrowing due to severe stenosis formation. The LZ61-KBMS stents, therefore, have obvious advantages over the 316L SS stent due to the favorable degradation observed over time and more importantly, the non-induction of any noticeable stenosis on the surrounding tracheal tissue. Histological analysis clearly demonstrates the excellent biocompatibility of the biodegradable LZ61-KBMS stents as the tracheal mucosa was also fully restored at 8 weeks for the LZ61-KBMS stent and this is critical, since any mucosa scarring can drive the stenotic tissue formation.

These results reported here are encouraging for the potential future application of this degradable metal tracheal stent, particularly among pediatric patients. However, for clinical translation of this innovative technology several questions need to be answered using various animal models including exploring the performance of the LZ61-KBMS stent in a tracheal stenosis model combined with the design and development of a better non-invasive delivery system such as a balloon-based catheter with placement and expansion under imaging such that the LZ61-KBMS stent could be endoscopically implanted. As a first step, we have also recently developed a stenosis induction apparatus that reliably induced stenosis with a low mortality rate as compared with that of other methods reported in the literature [4]. This method we believe sets the stage for the creation of a much needed clinically relevant and reproducible subglottic stenosis disease model that is amenable to testing of minimally invasive treatment modalities including implanting and assessing the efficacy of our LZ61-KBMS stents.

References:

  1. S.A. Luffy, D.T. Chou, J. Waterman, P.D. Wearden, P.N. Kumta, and T.W. Gilbert, Evaluation of magnesium-yttrium alloy as an extraluminal tracheal stent. Journal of Biomedical Materials Research Part A, 2014. 102(3): p. 611-620.
  2. J.Y. Wu, D.L. Zhao, J.M. Ohodnicki, B. Lee, A. Roy, R. Yao, S.N. Chen, Z.Y. Dong, W.R. Heineman, and P.N. Kumta, In Vitro and in Vivo Evaluation of Multiphase Ultrahigh Ductility Mg-Li-Zn Alloys for Cardiovascular Stent Application. Acs Biomaterials Science & Engineering, 2018. 4(3): p. 919-932.
  3. J.Y. Wu, D.L. Zhao, B. Lee, A. Roy, R. Yao, S.N. Chen, Z.Y. Dong, W.R. Heineman, and P.N. Kumta, Effect of Lithium and Aluminum on the Mechanical Properties, In Vivo and In Vitro Degradation, and Toxicity of Multiphase Ultrahigh Ductility Mg-Li-Al-Zn Quaternary Alloys for Vascular Stent Application. Acs Biomaterials Science & Engineering, 2020. 6(4): p. 1950-1964.
  4. L.J. Mady, M. Criado, J. Park, K. Baddour, A.M. Aral, A. Roy, L.H. Rigatti, P.N. Kumta, and D.H. Chi, Subglottic Stenosis: Development of a Clinically Relevant Endoscopic Animal Model. Otolaryngology-Head and Neck Surgery, 2020. 162(6): p. 905-913.

Prashant Kumta

Edward R. Weidlein Chair Professor, University of Pittsburgh

Biomaterials, energy storage, energy conversion, non-viral gene delivery, biodegradable metals, ceramics and polymers, lithium ion batteries, additive manufacturing, biosensors, tissue engineering

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