Using individualized three-dimensional printed airway models to guide airway stent implantation.

Airway stents are used to manage central airway obstructions by restoring airway patency. Current manufactured stents are limited in shape and size, which pose issues in stent fenestrations needed to be manually created to allow collateral ventilation to airway branches. The precise location to place these fenestrations can be difficult to predict based on 2-dimensional computed tomography images. Inspiratory computed tomography scans were obtained from 3 patients and analysed using 3D-Slicer™, Blender™ and AutoDesk® Meshmixer™ programmes to obtain working 3D-airway models, which were 3D printed. Stent customizations were made based on 3D-model dimensions, and fenestrations into the stent were cut. The modified stents were then inserted as per usual technique. Two patients reported improved airway performance; however, stents were later removed due to symptoms related to in-stent sputum retention. In a third patient, the stent was removed a few weeks later due to the persistence of fistula leakage. The use of a 3D-printed personalized airway model allowed for more precise stent customization, optimizing stent fit and allowing for cross-ventilation of branching airways. We determine that an airway model is a beneficial tool for stent optimization but does not prevent the development of some stent-related complications such as airway secretions.

Paclitaxel-eluting silicone airway stent for preventing granulation tissue growth and lung cancer relapse in central airway pathologies.

BACKGROUND: Airway stents are used to treat obstructive central airway pathologies including palliation of lung cancer, but face challenges with granulation tissue growth. Paclitaxel is a chemotherapy drug that also suppresses growth of granulation tissue. Yet, side effects arise from administration with toxic solubilizers. By incorporating paclitaxel in silicone stents, delivery of paclitaxel can be localized, and side effects minimized. METHODS: Paclitaxel was incorporated into Liquid Silicone Rubber (LSR) containing polydimethylsiloxane, either as a powder or solution, prior to curing. Drug release study was compared in vitro at 37°C over 10 days. Drug release was quantified using HPLC, and bronchial cell lines were grown on LSR to investigate drug cytotoxicity, and expression of inflammatory markers, specifically interleukin-6 and interleukin-8. RESULTS: Release rate of paclitaxel incorporated into silicone rubber was consistent with the Korsmeyer and Weibull models (R2 > 0.96). Paclitaxel exposure reduced IL-8 levels in cancer cell lines, whilst no cytotoxic effect was observed in all cell lines at treatment concentration levels (≤ 0.1% (w/v) paclitaxel in silicone). CONCLUSIONS: Incorporating paclitaxel into a silicone matrix for future use in a tracheobronchial stent was investigated. Drug release from silicone was observed and is a promising avenue for future treatments of central airway pathologies.

The utility of 3D-printed airway stents to improve treatment strategies for central airway obstructions.

Airway stents are commonly used in the management of patients suffering from central airway obstruction (CAO). CAO may occur directly from airway strictures, obstructing airway cancers, airway fistulas or tracheobronchomalacia, resulting from the weakening and dynamic collapse of the airway wall. Current airway stents are constructed from biocompatible medical-grade silicone or from a nickel-titanium (nitinol) alloy with fixed geometry. The stents are inserted via the mouth during a bronchoscopic procedure. Existing stents have many shortcomings including the development of obstructing granulation tissue in the weeks and months following placement, mucous build up within the stent, and cough. Furthermore, airway stents are expensive and, if improperly sized for a given airway, may be easily dislodged (stent migration). Currently, in Australia, it is estimated that approximately 12,000 patients will develop CAO annually, many of whom will require airway stenting intervention. Of all stenting procedures, the rate of failure is currently reported to be at 22%. With a growing incidence of lung cancer prevalence globally, the need for updating airway stent technology is now greater than ever and personalizing stents using 3D-printing technology may offer the best chance of addressing many of the current limitations in stent design. This review article will assess what represents the gold standard in stent manufacture with regards to treatment of tracheobronchial CAO, the challenges of current airway stents, and outlines the necessity and challenges of incorporating 3D-printing technology into personalizing airway stents today.

Long-term prognosis and cost-effectiveness of left ventricular assist device as bridge to transplantation: A systematic review.

BACKGROUND: This systematic review aimed to evaluate the clinical outcomes and cost-effectiveness of left ventricular assist devices (LVADs) used as bridge to transplantation (BTT), compared to orthotopic heart transplantation (OHT) without a bridge. METHOD: Systematic searches were performed in electronic databases with available data extracted from text and digitized figures. Meta-analysis of short and long-term term post-transplantation outcomes was performed with summation of cost-effectiveness analyses. RESULTS: Twenty studies reported clinical outcomes of 4575 patients (1083 LVAD BTT and 3492 OHT). Five studies reported cost-effectiveness data on 837 patients (339 VAD BTT and 498 OHT). There was no difference in long-term post-transplantation survival (HR 1.24, 95% CI 1.00-1.54), acute rejection (HR 1.10, 95% CI 0.93-1.30), or chronic rejection and cardiac allograft vasculopathy (HR 0.99, 95% CI 0.73-1.36). No differences were found in 30-day post-operative mortality (OR 0.91, 95% CI 0.42-2.00), stroke (OR 1.64, 95% CI 0.43-6.27), renal failure (OR 1.43, 95% CI 0.58-3.54), bleeding (OR 1.56, 95% CI 0.78-3.13), or infection (OR 2.44, 95% CI 0.81-7.38). Three of the five studies demonstrated incremental cost-effectiveness ratios below the acceptable maximum threshold. The total cost of VAD BTT ranged from $316,078 to $1,025,500, and OHT ranged from $179,051 to $802,200. CONCLUSION: LVADs used as BTT did not significantly alter post-transplantation long-term survival, rejection, and post-operative morbidity. LVAD BTT may be cost-effective, particularly in medium and high-risk patients with expected prolonged waiting times, renal dysfunction, and young patients.

Coronary Artery Bypass Grafting With and Without Manipulation of the Ascending Aorta: A Network Meta-Analysis.

BACKGROUND: Coronary artery bypass grafting (CABG) remains the standard of treatment for 3-vessel and left main coronary disease, but is associated with an increased risk of post-operative stroke compared to percutaneous coronary intervention. It has been suggested that CABG techniques that eliminate cardiopulmonary bypass and reduce aortic manipulation may reduce the incidence of post-operative stroke. OBJECTIVES: A network meta-analysis was performed to compare post-operative outcomes between all CABG techniques, including anaortic off-pump CABG (anOPCABG), off-pump with the clampless Heartstring device (OPCABG-HS), off-pump with a partial clamp (OPCABG-PC), and traditional on-pump CABG with aortic cross-clamping. METHODS: A systematic search of 6 electronic databases was performed to identify all publications reporting the outcomes of the included operations. Studies reporting the primary endpoint, 30-day post-operative stroke rate, were included in a Bayesian network meta-analysis. RESULTS: There were 13 included studies with 37,720 patients. At baseline, anOPCABG patients had higher previous stroke than did the OPCABG-PC (7.4% vs. 6.5%; p = 0.02) and CABG (7.4% vs. 3.2%; p = 0.001) patients. AnOPCABG was the most effective treatment for decreasing the risk of post-operative stroke (-78% vs. CABG, 95% confidence interval [CI]: 0.14 to 0.33; -66% vs. OPCABG-PC, 95% CI: 0.22 to 0.52; -52% vs. OPCABG-HS, 95% CI: 0.27 to 0.86), mortality (-50% vs. CABG, 95% CI: 0.35 to 0.70; -40% vs. OPCABG-HS, 95% CI: 0.38 to 0.94), renal failure (-53% vs. CABG, 95% CI: 0.31 to 0.68), bleeding complications (-48% vs. OPCABG-HS, 95% CI: 0.31 to 0.87; -36% vs. CABG, 95% CI: 0.42 to 0.95), atrial fibrillation (-34% vs. OPCABG-HS, 95% CI: 0.49 to 0.89; -29% vs. CABG, 95% CI: 0.55 to 0.87; -20% vs. OPCABG-PC, 95% CI: 0.68 to 0.97), and shortening the length of intensive care unit stay (-13.3 h; 95% CI: -19.32 to -7.26; p < 0.0001). CONCLUSIONS: Avoidance of aortic manipulation in anOPCABG may decrease the risk of post-operative stroke, especially in patients with higher stroke risk. In addition, the elimination of cardiopulmonary bypass may reduce the risk of short-term mortality, renal failure, atrial fibrillation, bleeding, and length of intensive care unit stay.

Mechanical Versus Bioprosthetic Aortic Valve Replacement in Middle-Aged Adults: A Systematic Review and Meta-Analysis.

The choice of a bioprosthetic valve (BV) or mechanical valve (MV) in middle-aged adults undergoing aortic valve replacement is a complex decision that must account for numerous prosthesis and patient factors. A systematic review and meta-analysis was performed to compare long-term survival, major adverse prosthesis-related events, anticoagulant-related events, major bleeding, reoperation, and structural valve degeneration in middle-aged patients receiving a BV or MV. A comprehensive search from six electronic databases was performed from their inception to February 2016. Results from patients aged less than 70 years undergoing aortic valve replacement with a BV or MV were included. There were 12 studies involving 8,661 patients. Baseline characteristics were similar. There was no significant difference in long-term survival among patients aged 50 to 70 or 60 to 70 years. Compared with MVs, BVs had significantly fewer long-term anticoagulant-related events (hazard ratio [HR] 0.54, p = 0.006) and bleeding (HR 0.48, p < 0.00001) but significantly greater major adverse prosthesis-related events (HR 1.82, p = 0.02), including reoperation (HR 2.19, p < 0.00001). The present meta-analysis found no significant difference in survival between BVs and MVs in patients aged 50 to 70 or 60 to 70 years. Compared with MVs, BVs have reduced risk of major bleeding and anticoagulant-related events but increased risk of structural valve degeneration and reoperation. However, the mortality consequences of reoperation appear lower than that of major bleeding, and recent advances may further lower the reoperation rate for BV. Therefore, this review supports the current trend of using BVs in patients more than 60 years of age.

Plasma Ion Activated Expanded Polytetrafluoroethylene Vascular Grafts with a Covalently Immobilized Recombinant Human Tropoelastin Coating Reducing Neointimal Hyperplasia.

Expanded polytetrafluoroethylene (ePTFE) vascular conduits with less than or equal to 6 mm internal diameter typically occlude due to a combination of thrombus formation and neointimal hyperplasia. We hypothesized that by layering the polymerized elastin precursor, human tropoelastin, in the synthetic vessel lumen we could mimic the internal elastic lamina and so maintain low thrombogenicity while significantly reducing smooth muscle cell proliferation. The luminal surfaces of ePTFE conduits were activated with plasma immersion ion implantation (PIII) treatment to facilitate covalent attachment of tropoelastin. Multilayered tropoelastin vessels (2TE) enhanced endothelial cell attachment and proliferation in vitro and were superior to materials lacking the protein. In an ovine carotid interposition model of graft compatibility, partially tropoelastin coated vessels (1TE) thrombosed at a greater rate than control ePTFE, but 2TE maintained the same patency as controls. 2TE showed a significant reduction in neointimal area down to 9.7 ± 5.2% (p < 0.05) in contrast to 32.3 ± 3.9% for ePTFE alone. This reduction was due to a halving of the number of smooth muscle cells present and a corresponding reduction in their proliferation. 2TE, but not 1TE, enhanced the vascular compatibility of these materials: while both tropoelastin presentations increased in vitro endothelialization, only 2TE displayed the dual benefits of maintained hemocompatibility and simultaneously suppressed neointimal hyperplasia in vivo. We conclude that 2TE surface modification provides a significant improvement over ePTFE vascular conduits in a pilot large animal model study and presents an attractive path toward clinical applications for reduced diameter vessels.

Surgery for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetically determined cardiac disease characterised by otherwise unexplained myocardial hypertrophy of the left ventricle, and may result in left ventricular outflow tract obstruction. It is the most common cause of sudden cardiac death in young adults due to arrhythmias. Septal myectomy is a surgical treatment for HCM with moderate to severe outflow tract obstruction, and is indicated for patients with severe symptoms refractory to medical therapy. The surgical approach involves obtaining access to the interventricular septum via transaortic, transapical or transmitral approaches, and excising a portion of the hypertrophied myocardium to relieve the outflow tract obstruction. Large, contemporary series from centres experienced in septal myectomy patients have demonstrated a low early mortality of <2 %, excellent long-term survival that matches the general population, and durable relief of symptoms.

Biomechanics and biocompatibility of the perfect conduit-can we build one?

No currently available conduit meets the criteria for an ideal coronary artery bypass graft. The perfect conduit would combine the availability and complication-free harvest of a synthetic vessel with the long-term patency performance of the internal mammary artery. However, current polymer conduits suffer from inelastic mechanical properties and especially poor surface biocompatibility, resulting in early loss of patency as a coronary graft. Approaches to manufacture an improved conduit using new polymers or polymer surfaces, acellular matrices, or cellular constructs have to date failed to achieve a commercially successful alternative. Elastin, by mimicking the native extracellular environment as well as providing elasticity, provides the 'missing link' in vascular conduit design and brings new hope for realization of the perfect conduit.

A multilayered synthetic human elastin/polycaprolactone hybrid vascular graft with tailored mechanical properties.

Small-diameter synthetic vascular graft materials fail to match the patency of human tissue conduits used in vascular bypass surgery. The foreign surface retards endothelialization and is highly thrombogenic, while the mismatch in mechanical properties induces intimal hyperplasia. Using recombinant human tropoelastin, we have developed a synthetic vascular conduit for small-diameter applications. We show that tropoelastin enhances endothelial cell attachment (threefold vs. control) and proliferation by 54.7 ± 1.1% (3 days vs. control). Tropoelastin, when presented as a monomer and when cross-linked into synthetic elastin for biomaterials applications, had low thrombogenicity. Activation of the intrinsic pathway of coagulation, measured by plasma clotting time, was reduced for tropoelastin (60.4 ± 8.2% vs. control). Platelet attachment was also reduced compared to collagen. Reductions in platelet interactions were mirrored on cross-linked synthetic elastin scaffolds. Tropoelastin was subsequently incorporated into a synthetic elastin/polycaprolactone conduit with mechanical properties optimized to mimic the human internal mammary artery, including permeability, compliance, elastic modulus and burst pressure. Further, this multilayered conduit presented a synthetic elastin internal lamina to circulating blood and demonstrated suturability and mechanical durability in a small scale rabbit carotid interposition model.

Animal models for the assessment of novel vascular conduits.

The development of an ideal small-diameter conduit for use in vascular bypass surgery has yet to be achieved. The ongoing innovation in biomaterial design generates novel conduits that require preclinical assessment in vivo, and a number of animal models have been used for this purpose. This article examines the rationale behind animal models used in the assessment of small-diameter vascular conduits encompassing the commonly used species: baboons, sheep, pigs, dogs, rabbits, and rodents. Studies on the comparative hematology for these species relative to humans are summarized, and the hydrodynamic values for common implant locations are also compared. The large- and small-animal models are then explored, highlighting the characteristics of each that determine their relative utility in the assessment of vascular conduits. Where possible, the performance of expanded polytetrafluoroethylene is given in each animal and in each location to allow direct comparisons between species. New challenges in animal modeling are outlined for the assessment of tissue-engineered graft designs. Finally, recommendations are given for the selection of animal models for the assessment of future vascular conduits.

Covalent immobilisation of tropoelastin on a plasma deposited interface for enhancement of endothelialisation on metal surfaces.

Currently available endovascular metallic implants such as stents exhibit suboptimal biocompatibility in that they re-endothelialise poorly leaving them susceptible to thrombosis. To improve the interaction of these implants with endothelial cells we developed a surface coating technology, enabling the covalent attachment of biomolecules to previously inert metal surfaces. Using horseradish peroxidase as a probe, we demonstrate that the polymerised surface can retain the presentation and activity of an immobilised protein. We further demonstrated the attachment of tropoelastin, an extracellular matrix protein critical to the correct arrangement and function of vasculature. Not only it is structurally important, but it plays a major role in supporting endothelial cell growth, while modulating smooth muscle cell infiltration. Tropoelastin was shown to bind to the surface in a covalent monolayer, supplemented with additional physisorbed multilayers on extended incubation. The physisorbed tropoelastin layers can be washed away in buffer or SDS while the first layer of tropoelastin remains tightly bound. The plasma coated stainless steel surface with immobilised tropoelastin was subsequently found to have improved biocompatibility by promoting endothelial cell attachment and proliferation relative to uncoated stainless steel controls. Tropoelastin coatings applied to otherwise inert substrates using this technology could thus have broad applications to a range of non-polymeric vascular devices.