Bench and initial preclinical results of a novel 8 mm diameter double opposed helical biodegradable stent.

BACKGROUND: Metallic endovascular stents are utilized off-label in congenital heart disease. Biodegradable stents (BDS) offer potential advantages in a growing child. We have previously reported double opposed helical (DH) BDS up to 6 mm diameter (DH-6). The objectives are to investigate the bench characteristics of larger 8 mm diameter BDS (DH-8) manufactured with increasing strut thicknesses and the inflammatory profile in a porcine model. METHODS: DH-8 were manufactured with strut thicknesses 0.10, 0.12, and 0.18 mm and mechanical testing performed. Stents were deployed into the infrarenal descending aorta (DAO) of nine minipigs. At insertion (nonsurvival = 2), 1 week (n = 2), 1 month (n = 2), and 9 months (n = 3) follow-up angiography, intravascular ultrasound and histopathology were performed. RESULTS: There was superior recoil and collapse pressure with increasing strut thickness, with 0.18 mm having 1.0% elastic recoil and collapse pressure 0.75 Atmospheres. There was good wall apposition at insertion with 5 BDS (4 DH-8 and 1 DH-6) but suboptimal in 4 as the minipigs infrarenal DAO were >8 mm (deployed at iliac bifurcation). Structural integrity was maintained in 8 BDS with 1 DH-8 collapsed at 9 months, secondary to strut damage at insertion. No thrombosis was seen. There was mild inflammation and neointimal proliferation at 1 week and 1 month, but a moderate inflammatory response at 9 months. CONCLUSIONS: DH-8 with increased strut thickness had acceptable mechanical properties at the cost of an increased inflammatory response. Miniaturization to improve delivery and further investigation on the long-term inflammatory profile of thicker struts, including through degradation, is needed. © 2016 Wiley Periodicals, Inc.

A novel design biodegradable stent for use in congenital heart disease: mid-term results in rabbit descending aorta.

OBJECTIVES: This study evaluates the feasibility of delivery and deployment of low and medium molecular weight (LMW and MMW, respectively) double-opposing helical (DH) poly-l-lactic acid biodegradable stent (BDS) in rabbit descending aorta (DAO). Secondary objectives were to assess patency and inflammation of stented vessels at 9 months and to investigate safety following intentional embolization of stent fragments in DAO. BACKGROUND: A BDS that will relieve aortic obstruction and disappears as the child grows older allowing for preservation of aortic wall elasticity and natural growth of aorta will be ideal to treat Coarctation (CoA). BDS have never been evaluated in the DAO. METHODS: Seven New Zealand white rabbits underwent implantation of DH-LMW (n = 7), DH-MMW (n = 3), and metal stents (n = 7) in DAO. BDS fragments were intentionally embolized into DAO in two rabbits. RESULTS: All stents were deployed via a 6-French sheath. Five BDS covered the origin of major DAO side branches. Angiography and intravascular ultrasound showed good stent apposition to the wall of DAO with minimal luminal loss at 9 months follow-up. All stents had minimal neointimal hyperplasia on histopathology. Adverse events included 1 death, 1 aortic aneurysm, and lower extremity ulceration due to self-mutilation in an embolization rabbit. CONCLUSIONS: Pilot study confirms the feasibility of delivery and deployment of up to 6-millimeter diameter DH BDS in rabbit DAO. Stent integrity with DH design was maintained at 9 months with minimal vessel inflammation. Potential morbidity due to embolized BD fragments cannot be ruled out and needs further evaluation.

A novel biodegradable stent applicable for use in congenital heart disease: bench testing and feasibility results in a rabbit model.

OBJECTIVES: A novel double opposed helical (DH) biodegradable stent was designed and fabricated for CHD applications. The primary objective was to evaluate the feasibility of DH stent delivery and deployment in rabbit external iliac arteries (EIA). Secondary objectives were to assess stent patency, thrombosis and inflammation at 1-week and 1-month follow-up. BACKGROUND: Biodegradable stents have largely been designed for adult cardiovascular indications, to avoid long term complications of permanent implants. A growing child with congenital heart disease (CHD) would especially derive substantial benefit from this technology. METHODS: DH stents were manufactured to 3, 4, 5, and 6-mm diameter with poly-l-lactic acid (PLLA) fibers. Bench test analysis was performed. Six DH stents were implanted in rabbit EIA. Vessel patency was assessed at 1-week and 1-month follow-up with repeat angiography, intravascular ultrasound (IVUS). Histopathological evaluation was performed. RESULTS: The elastic recoil and collapse pressure of DH stents were comparable to conventional metal stents. All DH stents were successfully delivered and implanted with good apposition to the vessel wall and no collapse of the proximal, mid or distal ends. All stented vessels remained patent. No acute or early stent thrombosis was noted. Histopathology showed minimal inflammatory response and mild neointimal proliferation at 1 month follow-up. CONCLUSIONS: In vitro results of DH PLLA biodegradable stents are comparable to conventional metal stents. The pilot animal study confirms the delivery and deployment of the DH stents to the desired location. The DH design can be used to fabricate larger diameter stents needed for CHD.

Three-dimensional printing of poly(glycerol sebacate fumarate) gadodiamide-poly(ethylene glycol) diacrylate structures and characterization of mechanical properties for soft tissue applications.

Bioresorbable materials have been frequently used to three-dimensional (3D) print biomedical structures. In this study, we developed a technique to 3D print poly(glycerol sebacate fumarate) gadodiamide (Rylar)-poly(ethylene glycol) diacrylate (PEGDA) samples and investigated their mechanical and thermal properties as a function of (PS) and ultraviolet intensity (UVI). The Young's modulus (E), ultimate tensile strength (UTS), failure strain (ɛF ), and glass transition temperature (Tg ) showed strong correlation with PS and UVI. Results showed E to be between 1.31 and 3.12 MPa, UTS between 0.07 and 0.43 MPa, and ɛF between 7 and 20% with brittle failure. The Tg was observed to lie between -54.48 and -49.10 °C without secondary/tertiary transitions. Dominant elastic behavior was observed from the dynamic mechanical testing viscoelastic data. Testing results were used to develop a regression predictive model for E as a function of PS and UVI. The model performance was evaluated experimentally with an average absolute error of 3.62%. The E and stress-strain response of our 3D printed samples show agreement with published data for human tracheal cartilage, and the mechanical properties were comparable to other published soft polymeric scaffolds/patches. The E' moduli were also similar to bovine articular cartilage. We have successfully demonstrated that Rylar, a novel bioresorbable radiopaque polymer, when blended with PEGDA can be 3D printed controllably for soft tissue applications such as airway obstructions. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 664-671, 2019.

Biodegradable Stents for Congenital Heart Disease.

The quest for an ideal biodegradable stent for both adult coronary and pediatric congenital heart disease applications continues. Over the past few years, a lot of progress has been made toward development of a dedicated pediatric biodegradable stent that can be used for congenital heart disease applications. At present, there are no biodegradable stents available for use in congenital heart disease. In this article, the authors review the different biodegradable materials and their limitations and provide an overview of the current biodegradable stents being evaluated for congenital heart disease applications.

Bacterial sensitivity assessment of multifunctional polymeric coatings for airway stents.

Current interventional technology for pediatric airway obstruction consists of cardiovascular stents and silicon tubes. These devices are composed of permanent materials that have limitations in biocompatibility and mechanical properties that make them controversial for used in pediatrics. Bioresorbable stents offer a temporary intervention that dissolves in the body over time and can serve as a platform for local drug delivery. Here we investigate a novel approach to use an antibiotic, ciprofloxacin, as a polymerization initiator to synthesize poly(ciprofloxacin fumaric acid) (PCFA) and then a second polymer using gadodiamide as an initiator to synthesize poly(gadodiamide ciprofloxacin fumaric acid) (PGCFA). Polymer structure, degradation, thermal properties, and rheological behavior were analyzed. Ciprofloxacin released was determined and polymer degradation extracts were used in bacterial sensitivity assessments with four common airway pathogens. PCFA and PGCFA polymers and drug release properties were compared to our previously published polymer poly(fumaric acid) (PFA). These novel polymers enable new possibilities as coatings for bioresorbable biomedical applications that require antibiotic resistance and imaging capabilities. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2153-2161, 2017.

Mechanical Interaction of an Expanding Coiled Stent with a Plaque-Containing Arterial Wall: A Finite Element Analysis.

Wall injury is observed during stent expansion within atherosclerotic arteries, related in part to stimulation of the inflammatory process. Wall stress and strain induced by stent expansion can be closely examined by finite element analysis (FEA), thus shedding light on procedure-induced sources of inflammation. The purpose of this work was to use FEA to examine the interaction of a coiled polymer stent with a plaque-containing arterial wall during stent expansion. An asymmetric fibrotic plaque-containing arterial wall model was created from intravascular ultrasound (IVUS) images of a diseased artery. A 3D model for a coil stent at unexpanded state was generated in SolidWorks. They were imported into ANSYS for FEA of combined stent expansion and fibrotic plaque-distortion. We simulated the stent expansion in the plaqued lumen by increasing balloon pressure from 0 to 12 atm in 1 atm step. At increasing pressure, we examined how the expanding stent exerts forces on the fibrotic plaque and vascular wall components, and how the latter collectively resist and balance the expansive forces from the stent. Results show the expanding coiled stent creates high stresses within the plaque and the surrounding fibrotic capsule. Lower stresses were observed in adjacent medial and adventitial layers. High principal strains were observed in plaque and fibrotic capsule. The results suggest fibrotic capsule rupture might occur at localized regions. The FEA/IVUS method can be adapted for routine examination of the effects of the expansion of selected furled stents against IVUS-reconstructed diseased vessels, to improve stent deployment practices.

Thermally processed polymeric microparticles for year-long delivery of dexamethasone.

Dexamethasone-releasing poly(lactic-co-glycolic acid) (PLGA) microparticles were formulated using a solvent displacement technique with the addition of distillation aiming to increase drug delivery lifetime. Two PLGA copolymer ratios (50:50 and 75:25) were used to determine the influence of lactic acid and glycolic acid ratio on microparticle characteristics. The addition of distillation significantly slows the release of dexamethasone compared to traditional solvent removal via evaporation while still maintaining a therapeutic dosage. Microparticles formulated with PLGA 50:50 controllably release dexamethasone up to one year and 75:25 release up to two years in-vitro. The ratio of lactic acid to glycolic acid plays a significant role in microparticle stability, drug loading efficiency, and thermal properties. In all, this formulation technique offers new prospects for inflammation suppression in pediatric vascular and airway diseases.

Poly(gadodiamide fumaric acid): A Bioresorbable, Radiopaque, and MRI-Visible Polymer for Biomedical Applications.

Bioresorbable medical devices once implanted into the body are "invisible" to imaging techniques such as X-ray/fluoroscopy and magnetic resonance imagining (MRI). Prior attempts to produce radiopaque polymers have limited success due to their inability to generate homogeneous mixtures of polymer and contrast agent without subsequent alterations in polymer structure. Here we investigate a novel approach in which a MRI contrast medium, gadodiamide, can be used as a polymerization initiator in poly(propylene fumarate) (PPF) synthesis to achieve a radiopaque and MRI-visible polymer poly(gadodiamide fumaric acid) (PGFA). With this method polymer structure, thermal properties, and rheological behavior are conserved with no prior manipulation to monomer units necessary. This unique polymer in combination with poly(lactic-co-glycolic acid) (PLGA) can be formulated into MRI-visible nanoparticles with drug delivery potential. This novel polymer in both liquid and nanoparticle form enables new possibilities in medical device and drug delivery design.

Novel bioresorbable stent coating for drug release in congenital heart disease applications.

A novel double opposed helical poly-l-lactic acid (PLLA) bioresorbable stent has been designed for use in pediatrics. The aim was to test the PLLA stent biocompatibility. The PLLA stent was immersed into whole pig's blood in a closed loop circuit then fibrin and platelet association was assessed via enzyme-linked immunosorbent assay. D-Dimer was valued at 0.2 ± 0.002 ng/mL and P-selectin 0.43 ± 00.01 ng/mL indicating limited association of fibrin and platelets on the stent. To improve biocompatibility by targeting inflammatory cells, dexamethasone was incorporated on PLLA fibers with two coating methods. Both coatings were poly(l-lactide-co-glycolide) acid (PLGA) but one was made porous with sucrose while the other remained nonporous. There was no change in mechanical properties of the fiber with either coating of PLGA polymer. The total amount of dexamethasone released was then determined for each coating. The cumulative drug release for the porous fiber was significantly higher (∼100%) over 8 weeks than the nonporous fiber (40%). Surface examination of the fiber with scanning electron microscopy showed more surface microfracturing in coatings that contain pores. The biocompatibility of this novel stent was demonstrated. Mechanical properties of the fiber were not altered by coating with PLGA polymer. Anti-inflammatory drug release was optimized using a porous PLGA polymer.

The influence of thermal treatment on the mechanical characteristics of a PLLA coiled stent.

We studied the effects of thermal treatment on the expansive characteristics of a coil-within-coil Poly(L-lactic acid) (PLLA) fiber stent developed at our institution to improve its mechanical performance and reproducibility. Following fabrication, furled stents were thermally treated at 62 degrees C for 25 min. The mechanical characteristics were measured compared with those of untreated stents when both were expanded via sequential balloon catheter pressure loading up to 12 atm. Treated stents reached full diameter at 3 atm and maintained that diameter despite further pressure increases. Using measurements of pressure, diameter, and axial length, we calculated the sequential mechanical work required to unfurl the stent. The mechanical work for complete unfurling of treated stents was significantly less than that required for untreated controls. Little axial dimensional change was observed for treated stents. Treated stents exhibited higher stiffness than controls at all pressure levels and also demonstrated higher resistance to external pressure-induced collapse, as measured in a special apparatus developed in our laboratory. Differential scanning calorimetry measurements indicated higher crystallinity values for fibers used in treated stents compared with controls. SEM examination of striations revealed that treated stents underwent less twist than controls following balloon-induced unfurling. The results indicate that, thermal treatment improves the reorientation and realignment of fiber crystalline structure, and favorably influences on the fiber stress-strain behavior and the expansive mechanical characteristics of the PLLA fiber stents.