Poster O13 - Nano-structured, degradable thin films improve airway perfusion in a rodent tracheal autotransplantation model of lung transplantation

Introduction: Lung transplantation has the lowest long-term survival rates among solid organ transplants (5.8 years). Airway complications, driven by ischemia and hypoxia from bronchial vasculature sacrifice and immune-mediated microvasculature destruction, significantly contribute to morbidity and mortality post-lung transplantation. There is a need for therapeutic options that improve upon clinical data showing the benefit of promoting vascularization post-operatively and can do so while maintaining the existing surgical workflow. There is interest in therapeutics that upregulate local angiogenic transcription factors such as hypoxia inducible factor (HIF). This includes iron chelating agent deferoxamine (DFO) which stabilizes HIF-1α to stimulate angiogenic pathways. We hypothesized that drug-loaded, nanofiber-based thin films may provide a combination of material (nanoarchitecture, porosity, stiffness) and chemical (DFO) cues to promote vascularization synergistically to improve post-operative perfusion. We tested whether degradable, nano-structured thin films, with or without DFO, could enhance vascularization and perfusion in a rat tracheal autotransplantation (RTA) model.

Materials and

Methods: Nanofiber-based films (~50 µm thick) were electrospun with polyglycolide (PGS; 12% w/v) and varied DFO concentrations (0%, 10%, 20% w/w) in hexafluoroisopropanol. Smooth PGS films were made via solvent casting. Films were characterized for fiber diameter (N=100), orientation, porosity, drug release/loading (N=3), and strength (N=4) through scanning electron microscopy (SEM), high-performance liquid chromatography, and tensile tests. Films were applied post-operatively in the RTA model (N=4) which mimics airway ischemia. Airway perfusion was evaluated on day 10 using laser speckle contrast analysis (LASCA) to compare perfusion units between non-transplanted and transplanted tracheal segments.

Results, Conclusions, and Discussions: Characterization showed manufacture of thin films with varied surface patterning (fiber diameter) and strength: smooth PGS, nano-PGS (847 ± 250 nm, 0.39 ± 0.04 N), nano-PGS-10% DFO (335 ± 110 nm, 0.41 ± 0.17 N), and nano-PGS-20% DFO (131 ± 36 µm, 0.23 ± 0.70 N) (Figure 1). 10% and 20% nano-PGS films had DFO loading of 17 ± 1 and 35 ± 1 µg/mg, respectively, and 10% films demonstrated sustained release over 7 days. Smooth PGS films did not improve perfusion in the RTA model. In contrast, nano-structured films showed improved perfusion, and nano-PGS-10% DFO and nano-PGS-20% DFO significantly increased vascularization at the anastomosis site and provided the lowest perfusion difference in comparison to native trachea. (p < 0.005) (Figure 2).

Several engineering approaches have been developed to provide local proangiogenic cues post-operatively, primarily focused on local drug administration; however, each has its own limitations for use, including off-target side effects from lack of localization, poor residence time or inability to sustain release, poor potency or stability of active agents, high cost, or incompatibility with the surgical workflow. In contrast, nano-structured thin films at the anastomosis site could provide a scalable, low cost, and simple-to-administer approach that fits into the existing surgical workflow. Nanofiber-based thin films are attractive due to their sustained drug delivery functionality, biocompatibility, biomimetic architecture, and high surface area-to-volume ratio, thereby enhancing endothelial cell adhesion and proliferation while providing a template for vascular network growth. The DFO-loaded, nano-structured thin films we describe could provide surgeons with a novel tool that integrates at the anastomosis site to improve wound healing, provide local, sustained delivery of proangiogenic agents, and promote vascularization prior to safely degrading.

We successfully applied electrospinning to manufacture defect-free fibrous films with varied topography without or with different concentrations of DFO. Nano-structured, degradable PGS thin films loaded with DFO improved the local angiogenic response and achieved near-native levels of perfusion, demonstrating the potential to improve post-operative lung transplant outcomes.

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