Bioresorbable Polymeric Scaffold Research Articles

Bismuth-infused perivascular wrap facilitates delivery of mesenchymal stem cells and attenuation of neointimal hyperplasia in rat arteriovenous fistulas

BackgroundMesenchymal stem cells (MSCs) have emerged as novel therapies for supporting arteriovenous fistula (AVF) maturation, and bioresorbable polymeric scaffolds have enabled sustained MSC delivery into maturing AVFs. However, the radiolucency of biopolymeric wraps prevents in vivo monitoring of their integrity and location, hindering long-term preclinical investigations. MethodsWe infused bismuth nanoparticles (BiNPs) into polycaprolactone (PCL) to fabricate an electrospun perivascular wrap capable of MSC delivery and conducive to longitudinal monitoring using conventional imaging. We tested the wraps' effects on the attenuation of markers of neointimal hyperplasia (i.e., endothelial dysfunction, hypoxia, and inflammation), the leading cause of AVF failure, in rats with induced chronic kidney disease (n = 3 per time point) for the following groups: control (no wrap), PCL wrap, PCL with MSCs, PCL-Bi (BiNP-infused wrap), and PCL-Bi with MSCs. ResultsPhysicochemical characterization and in vitro biocompatibility tests revealed that BiNP infusion did not alter the wrap's non-cytotoxicity toward vascular cells, hemocompatibility, and capacity for MSC loading but facilitated long-term monitoring via micro-computed tomography. After 8 weeks, all treatment groups demonstrated significant improvement in wall-to-lumen ratio on ultrasonography (P < 0.001), neointima-to-lumen ratio on histomorphometry (P < 0.001), and attenuation of neointimal hypoxia on immunohistochemistry (P < 0.05). Compared to non-MSC wraps, MSC-loaded wraps not only attenuated endothelial dysfunction and neointimal inflammation but also reduced hypoxia and inflammation across all vascular layers. ConclusionThese results demonstrate that MSC delivery through a radiopaque polymeric wrap could enhance AVF patency outcomes through the inhibition of multiple pathways inducing AVF failure.

Solid-Phase Orientation (Die Drawing) of Polymer Tubes to Enhance Mechanical Properties of Bioresorbable Vascular Scaffolds

Die-drawing, also known as solid phase orientation, is a technique used to enhance the mechanical properties of polymers for non-medical applications [1]. Arterius has adapted and optimised this technology to manufacture state-of-the-art bioresorbable polymeric scaffolds (stents) based on polylactic acid (PLA) for vascular and non-vascular applications. The mechanical properties of the polymer are improved by orientating the polymer chains and introducing crystallinity to the polymer. As the PLA polymer is drawn over a mandrel and through a die, close to the glass transition temperature (Tg &gt; 55 °C), the polymer chains align, gradually increasing orientation with the bi-axial draw, thus promoting significantly improved mechanical properties. In-house testing of the die-drawn tubing compared to the extruded tubing showed an increase in tensile modulus up to 79.7%, yield strength increases of up to 121.5%, ultimate tensile strength increases of up to 267.9% and elongation at break increase of up to 1,022.8%. The die-drawing process also introduces crystallinity into the PLLA tubing, initially the amorphous extruded tube has a crystallinity of around 1.3% which increased to around 40% crystallinity after the die-drawn process. Another attribute of the orientated polymer tubing is the radial strength it provides to the scaffold once it has been laser cut into an innovative closed-cell design, which is comparable to market-leading metallic stents.

An integrated mechanical degradation model to explore the mechanical response of a bioresorbable polymeric scaffold

Simulation of bioresorbable medical devices is hindered by the limitations of current material models. Useful simulations require that both the short- and long-term response must be considered; existing models are not physically-based and provide limited insight to guide performance improvements. This study presents an integrated degradation framework which couples a physically-based degradation model, which predicts changes in both crystallinity (Xc) and molecular weight (Mn), with the results of a micromechanical model, which predicts the effective properties of the semicrystalline polymer. This degradation framework is used to simulate the deployment of a bioresorbable PLLA (Poly (L-lactide) stent into a mock vessel and the subsequent mechanical response during degradation under different diffusion boundary conditions representing neointimal growth. A workflow is established in a commercial finite element code that couples both the immediate and long-term responses. Clinically relevant lumen loss is reported and used to compare different responses and the effect of neo-intimal tissue regrowth post-implantation on degradation and on the mechanical response is assessed. In addition, the effects of possible changes in Xc, which could occur during processing and stent deployment, are explored.

Solvent/non-solvent treatment as a method for surface coating of poly(ε-caprolactone) 3D-printed scaffolds with hydroxyapatite

Introduction Over the last decades numerous new materials and techniques for bone tissue engineering have been developed. The use of bioresorbable polymeric scaffolds is one of the most promising techniques for surgical management of bone defects. However, the lack of bioactive properties of biodegradable polymers restricts the area of their application for bone tissue engineering.The aim of study was to apply solvent/non-solvent treatment to coat the surface of 3D-printed bioresorbable poly(ε-caprolactone) scaffolds with bioactive hydroxyapatite particles and report on the physicochemical properties of the resulting materials.Material and Methods In the present study, biomimetic poly(ε-caprolactone) scaffolds were 3D-printed via fused deposition modeling technology and their surface was treated with the solvent/non-solvent method for coating with bioactive particles of hydroxyapatite.Results It has been found that treatment in the mixture of toluene and ethanol is suitable for the coating of poly(ε-caprolactone) scaffolds with hydroxyapatite. The scaffolds maintain porous structure after treatment while hydroxyapatite particles form homogeneous coating. The amount of hydroxyapatite on the treated scaffolds was 5.7 ± 0.8 wt. %.Discussion The proposed method ensures a homogeneous coating of outer and inner surfaces of the poly(ε-caprolactone) scaffolds with hydroxyapatite without a significant impact on the structure of a scaffold. Fourier-transform infrared spectroscopy confirmed that the solvent/non-solvent treatment has no effect on the chemical structure of PCL scaffolds.Conclusion Coating of biomimetic 3D-printed PCL scaffolds with bioactive hydroxyapatite by the solvent/non-solvent treatment has been successfully carried out. Upon coating, scaffolds retained their shape and interconnected porous structure and adsorbed hydroxyapatite particles that were uniformly distributed on the surface of the scaffold.

430 CT Imaging Of Gadolinium And Iodine Doped Bioresorbable Vascular Scaffolds

Introduction: Radiographic visualization of vascular scaffolds provides potential advantages during initial deployment and follow-up assessments. However, bioresorbable scaffolds are typically not constructed from radiopaque materials and image interpretation is often complicated by adjacent vascular calcifications and iodinated intravascular contrast. One strategy to achieve fluoroscopic and CT-based visualization of bioresorbable polymeric scaffolds is to dope them with radiopaque additives. Gadolinium (Gd) and iodine (I) are potentially useful radiopaque dopants for polymeric bioresorbable scaffolds due to their established biocompatibility.

Bioresorbable Polymeric Scaffold in Cardiovascular Applications.

Advances in material science and innovative medical technologies have allowed the development of less invasive interventional procedures for deploying implant devices, including scaffolds for cardiac tissue engineering. Biodegradable materials (e.g., resorbable polymers) are employed in devices that are only needed for a transient period. In the case of coronary stents, the device is only required for 6–8 months before positive remodelling takes place. Hence, biodegradable polymeric stents have been considered to promote this positive remodelling and eliminate the issue of permanent caging of the vessel. In tissue engineering, the role of the scaffold is to support favourable cell-scaffold interaction to stimulate formation of functional tissue. The ideal outcome is for the cells to produce their own extracellular matrix over time and eventually replace the implanted scaffold or tissue engineered construct. Synthetic biodegradable polymers are the favoured candidates as scaffolds, because their degradation rates can be manipulated over a broad time scale, and they may be functionalised easily. This review presents an overview of coronary heart disease, the limitations of current interventions and how biomaterials can be used to potentially circumvent these shortcomings in bioresorbable stents, vascular grafts and cardiac patches. The material specifications, type of polymers used, current progress and future challenges for each application will be discussed in this manuscript.

Laser Surface Microstructuring of a Bio-Resorbable Polymer to Anchor Stem Cells, Control Adipocyte Morphology, and Promote Osteogenesis.

New strategies in regenerative medicine include the implantation of stem cells cultured in bio-resorbable polymeric scaffolds to restore the tissue function and be absorbed by the body after wound healing. This requires the development of appropriate micro-technologies for manufacturing of functional scaffolds with controlled surface properties to induce a specific cell behavior. The present report focuses on the effect of substrate topography on the behavior of human mesenchymal stem cells (MSCs) before and after co-differentiation into adipocytes and osteoblasts. Picosecond laser micromachining technology (PLM) was applied on poly (L-lactide) (PLLA), to generate different microstructures (microgrooves and microcavities) for investigating cell shape, orientation, and MSCs co-differentiation. Under certain surface topographical conditions, MSCs modify their shape to anchor at specific groove locations. Upon MSCs differentiation, adipocytes respond to changes in substrate height and depth by adapting the intracellular distribution of their lipid vacuoles to the imposed physical constraints. In addition, topography alone seems to produce a modest, but significant, increase of stem cell differentiation to osteoblasts. These findings show that PLM can be applied as a high-efficient technology to directly and precisely manufacture 3D microstructures that guide cell shape, control adipocyte morphology, and induce osteogenesis without the need of specific biochemical functionalization.

3D printing of PLGA scaffolds for tissue engineering.

We proposed a novel method of generation of bioresorbable polymeric scaffolds with specified architectonics for tissue engineering using extrusion three-dimensional (3D) printing with solutions of polylactoglycolide in tetraglycol with their subsequent solidifying in aqueous medium. On the basis of 3D computer models, we obtained the matrix structures with interconnected system of pores ranging in size from 0.5 to 500 µm. The results of in vitro studies using cultures of line NIH 3Т3 mouse fibroblasts, floating islet cultures of newborn rabbit pancreas, and mesenchymal stem cells of human adipose tissue demonstrated the absence of cytotoxicity and good adhesive properties of scaffolds in regard to the cell cultures chosen. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 104-109, 2017.

Computational analysis of mechanical stress–strain interaction of a bioresorbable scaffold with blood vessel

Crimping and deployment of bioresorbable polymeric scaffold, Absorb, were modelled using a finite element method, in direct comparison with Co–Cr alloy drug eluting stent, Xience V. Absorb scaffold has an expansion rate lower than Xience V stent, with a less outer diameter achieved after balloon deflation. Due to the difference in design and material properties, Absorb also shows a higher recoiling than Xience V, which suggests that additional post-dilatation is required to achieve effective treatment for patients with calcified plaques and stiff vessels. However, Absorb scaffold induces significantly lower stresses on the artery–plaque system, which can be clinically beneficial. Eccentric plaque causes complications to stent deployment, especially non-uniform vessel expansion. Also the stress levels in the media and adventitia layers are considerably higher for the plaque with high eccentricity, for which the choice of stents, in terms of materials and designs, will be of paramount importance. Our results imply that the benefits of Absorb scaffolds are amplified in these cases.

Biocorrodible metals for coronary revascularization: Lessons from PROGRESS-AMS, BIOSOLVE-I, and BIOSOLVE-II.

The impetus for developing drug-eluting bioresorbable scaffolds (BRS) has been driven by the need for elastic and transient platforms instead of stiff and permanent metallic implants in diseased coronary anatomies. This endeavor would prevent acute recoil or occlusion, allow sealing of post-procedural dissections following acute barotrauma, provide inhibition of in-segment restenosis through efficient drug-elution and would further prepare the vessel to enter a reparative phase following scaffold resorption. Biocorrodible metallic platforms have been introduced as alternatives to bioresorbable polymeric scaffolds for the treatment of significant atherosclerosis and in view of the body of evidence derived from recent clinical trials we elaborate on the clinical safety and efficacy of these devices in interventional cardiology.

Bioresorbable polymeric scaffolds for coronary revascularization: Lessons learnt from ABSORB III, ABSORB China, and ABSORB Japan.

Bioresorbable polymers and biocorrodible metals are the latest developments in biodegradable materials used in interventional cardiology for the mechanical treatment of coronary atherosclerosis. Poly-L-lactic acid is the most frequently used bioresorbable polymer and initial evidence of feasibility, efficacy and clinical safety following deployment of polymer-based platforms was gained after completion of the first-in-man longitudinal ABSORB registries, Cohorts A and B and ABSORB Extend.In these studies, the biologic interaction of the first-generation Absorb Bioresorbable Vascular Scaffold (BVS) (Abbott Vascular, SC, Calif., US) with the underlying vascular tissue was evaluated in vivo with multiple imaging modalities such as intravascular ultrasound (IVUS), virtual histology-IVUS, IVUS-palpography, optical coherence tomography as well as ex vivo with coronary computed tomography. Efficacy measures following this in vivo multi-imaging assessment as well as clinical safety were comparable with current generation drug-eluting stents (DES) (Abbott Vascular, SC, Calif., US) in non-complex lesions over a 3-year follow-up. Furthermore, novel properties of functional and anatomic restoration of the vessel wall during the late phases of resorption and vascular healing were observed transforming the field of mechanical treatment of atherosclerosis from delivering only acute revascularization to additionally enable late repair and subsequent restoration of a more physiologic underlying vascular tissue.Despite the sufficient evidence and the subsequent Conformité Européenne mark approval of the first fully biodegradable scaffold (Absorb BVS) in 2012 for revascularizing non-complex lesions, the paucity of randomized comparisons of fully bioresorbable scaffolds (BRS) with metallic DES in a “real-world” clinical setting raised controversies among the interventional community for the merit of these technologies. Only recently, results from international large-scale randomized trials from the United States (U.S.), China and Japan were revealed.Herein we provide a comprehensive overview of the ABSORB III, ABSORB China and ABSORB Japan studies demonstrating the consistent non-inferiority in clinical safety and efficacy measures of the Absorb BVS vs. current generation DES.

TCT-617 Short- and long-term safety evaluation of a novel bioresorbable scaffold in a miniature swine coronary artery model

Current bioresorbable scaffold technology has shown promising results in small-sized clinical studies. However, preclinical data addressing long-term vascular reactions remain limited. The aim of this study was to investigate vascular responses of a novel bioresorbable polymeric scaffold (BRS) (PLA

Temporal evolution of strut light intensity after implantation of bioresorbable polymeric intracoronary scaffolds in the ABSORB cohort B trial-an application of a new quantitative method based on optical coherence tomography.

Quantitative light intensity analysis of the strut core by optical coherence tomography (OCT) may enable assessment of changes in the light reflectivity of the bioresorbable polymeric scaffold from polymer to provisional matrix and connective tissues, with full disappearance and integration of the scaffold into the vessel wall. The aim of this report was to describe the methodology and to apply it to serial human OCT images post procedure and at 6, 12, 24 and 36 months in the ABSORB cohort B trial. In serial frequency-domain OCT pullbacks, corresponding struts at different time points were identified by 3-dimensional foldout view. The peak and median values of light intensity were measured in the strut core by dedicated software. A total of 303 corresponding struts were serially analyzed at 3 time points. In the sequential analysis, peak light intensity increased gradually in the first 24 months after implantation and reached a plateau (relative difference with respect to baseline [%Dif]: 61.4% at 12 months, 115.0% at 24 months, 110.7% at 36 months), while the median intensity kept increasing at 36 months (%Dif: 14.3% at 12 months, 75.0% at 24 months, 93.1% at 36 months). Quantitative light intensity analysis by OCT was capable of detecting subtle changes in the bioresorbable strut appearance over time, and could be used to monitor the bioresorption and integration process of polylactide struts.

Evaluation of electrospun bioresorbable scaffolds for tissue-engineered urinary bladder augmentation

Tissue engineering represents a potential and valuable approach for the treatment of urologic pathologies. Bioresorbable polymeric scaffolds can be regarded as effective platforms to surgically treat bladder diseases and subsequently guide the formation of novel tissue after implantation. To this aim, the evaluation of electrospun scaffolds made up of poly(ε-caprolactone) blended with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) is presented here. Firstly, the microstructure and the viscoelastic/mechanical properties of the electrospun fabrics were investigated. Then, the in vivo response was assessed by performing a urinary bladder augmentation using female Wistar rats as an animal model. 15 days after the surgical procedure, the scaffolds were covered by regenerative urothelium up to 50%, which increased to 50–100% after 30 days. These encouraging results, collected in the 90-day follow-up, clearly showed the potential applications of tissue engineering in the urologic field. A longer in vivo evaluation is currently underway.

TCT-449: Pre-clinical Evaluation of a Myolimus-Eluting Bioresorbable Polymeric Scaffold in the Porcine Coronary Artery Model

TCT-449: Pre-clinical Evaluation of a Myolimus-Eluting Bioresorbable Polymeric Scaffold in the Porcine Coronary Artery Model

In vivo mesenchymal cell recruitment by a scaffold loaded with transforming growth factor beta1 and the potential for in situ chondrogenesis.

The objectives of this study were (1) to develop a biphasic implant made of a bioresorbable polymeric scaffold in combination with TGF-beta1-loaded fibrin glue for tissue-engineering applications, and (2) to determine whether the implant made of a polycaprolactone (PCL) scaffold and TGF-beta1-loaded fibrin glue could recruit mesenchymal cells and induce the process of cartilage formation when implanted in ectopic sites. Twenty-four 6-month-old New Zealand White rabbits were used. Scaffolds loaded with various doses of TGF-beta1 in fibrin glue were implanted subcutaneously, intramuscularly, and subperiosteally. The rabbits were killed and implants were removed at 2, 4, and 6 weeks postoperatively. The specimens were subjected to various staining techniques for histological analysis. Light microscopic examination of all specimens revealed that the entire pore space of the scaffolds was filled with various tissues in each group. The entire volume of the scaffolds in the groups loaded with TGF-beta1 and implanted intramuscularly and subcutaneously was populated with mesenchymal cells surrounded with an abundant extracellular matrix and blood vessels. The scaffold loaded with TGF-beta1 and implanted subperiosteally was found to be richly populated with chondrocytes at 2 and 4 weeks and immature bone formation was identified at 6 weeks. We conclude that scaffolds loaded with TGF-beta1 can successfully recruit mesenchymal cells and that chondrogenesis occurred when this construct was implanted subperiosteally.

A method for tissue engineering of cartilage by cell seeding on bioresorbable scaffolds.

This chapter describes a method for the in vitro generation of a 3-dimensional cartilage matrix from articular chondrocytes seeded onto a bioresorbable polymeric scaffold. This particular growth system was chosen for the subject of this chapter owing to the relative simplicity of the methods required and the ease with which the necessary materials can be obtained. The tissue produced using this protocol is a cellular, metabolically active hyaline-like matrix, containing the major cartilage constituents: sulfated proteoglycan, collagen type II, and water. It serves as a useful in vitro tool for studying the influence of various mechanical and chemical factors on cartilage metabolism, as well as providing an implantable material for in vivo cartilage repair studies.