Benjamin Nottelet

Degradation and Healing Characteristics of Small-Diameter Poly(ε-Caprolactone) Vascular Grafts in the Rat Systemic Arterial Circulation

Background— Long-term patency of conventional synthetic grafts is unsatisfactory below a 6-mm internal diameter. Poly(&egr;-caprolactone) (PCL) is a promising biodegradable polymer with a longer degradation time. We aimed to evaluate in vivo healing and degradation characteristics of small-diameter vascular grafts made of PCL nanofibers compared with expanded polytetrafluoroethylene (ePTFE) grafts. Methods and Results— We prepared 2-mm–internal diameter grafts by electrospinning using PCL (Mn=80 000 g/mol). Either PCL (n=15) or ePTFE (n=15) grafts were implanted into 30 rats. Rats were followed up for 24 weeks. At the conclusion of the follow-up period, patency and structural integrity were evaluated by digital subtraction angiography. The abdominal aorta, including the graft, was harvested and investigated under light microscopy. Endothelial coverage, neointima formation, and transmural cellular ingrowth were measured by computed histomorphometry. All animals survived until the end of follow-up, and all grafts were patent in both groups. Digital subtraction angiography revealed no stenosis in the PCL group but stenotic lesions in 1 graft at 18 weeks (40%) and in another graft at 24 weeks (50%) in the ePTFE group. None of the grafts showed aneurysmal dilatation. Endothelial coverage was significantly better in the PCL group. Neointimal formation was comparable between the 2 groups. Macrophage and fibroblast ingrowth with extracellular matrix formation and neoangiogenesis were better in the PCL group. After 12 weeks, foci of chondroid metaplasia located in the neointima of PCL grafts were observed in all samples. Conclusions— Small-diameter PCL grafts represent a promising alternative for the future because of their better healing characteristics compared with ePTFE grafts. Faster endothelialization and extracellular matrix formation, accompanied by degradation of graft fibers, seem to be the major advantages. Further evaluation of degradation and graft healing characteristics may potentially lead to the clinical use of such grafts for revascularization procedures.

Factorial design optimization and in vivo feasibility of poly(epsilon-caprolactone)-micro- and nanofiber-based small diameter vascular grafts

Because of the severe increase of mortality by cardiovascular diseases, there has been rising interest among the tissue-engineering community for small-sized blood vessel substitutes. Here we present small diameter vascular grafts made of slow degradable poly(epsilon-caprolactone) nanofibers obtained by electrospinning. The process was optimized by a factorial design approach that led to reproducible grafts with inner diameters of 2 and 4 mm, respectively. Fiber sizes, graft morphology, and the resulting tensile stress and tensile strain values were studied as a function of various parameters in order to obtain optimal vascular grafts for implantation after gamma-sterilization. The influence of polymer concentration, solvent, needle-collector distance, applied voltage, flow rate, and spinning time has been studied. Consequently, an optimized vascular graft was implanted as an abdominal aortic substitute in nine rats for a feasibility study. Results are given following up a 12-week implantation period showing good patency, endothelization, and cell ingrowth.

Degradation and healing characteristics of small-diameter poly(epsilon-caprolactone) vascular grafts in the rat systemic arterial circulation.

Background— Long-term patency of conventional synthetic grafts is unsatisfactory below a 6-mm internal diameter. Poly(&egr;-caprolactone) (PCL) is a promising biodegradable polymer with a longer degradation time. We aimed to evaluate in vivo healing and degradation characteristics of small-diameter vascular grafts made of PCL nanofibers compared with expanded polytetrafluoroethylene (ePTFE) grafts. Methods and Results— We prepared 2-mm–internal diameter grafts by electrospinning using PCL (Mn=80 000 g/mol). Either PCL (n=15) or ePTFE (n=15) grafts were implanted into 30 rats. Rats were followed up for 24 weeks. At the conclusion of the follow-up period, patency and structural integrity were evaluated by digital subtraction angiography. The abdominal aorta, including the graft, was harvested and investigated under light microscopy. Endothelial coverage, neointima formation, and transmural cellular ingrowth were measured by computed histomorphometry. All animals survived until the end of follow-up, and all grafts were patent in both groups. Digital subtraction angiography revealed no stenosis in the PCL group but stenotic lesions in 1 graft at 18 weeks (40%) and in another graft at 24 weeks (50%) in the ePTFE group. None of the grafts showed aneurysmal dilatation. Endothelial coverage was significantly better in the PCL group. Neointimal formation was comparable between the 2 groups. Macrophage and fibroblast ingrowth with extracellular matrix formation and neoangiogenesis were better in the PCL group. After 12 weeks, foci of chondroid metaplasia located in the neointima of PCL grafts were observed in all samples. Conclusions— Small-diameter PCL grafts represent a promising alternative for the future because of their better healing characteristics compared with ePTFE grafts. Faster endothelialization and extracellular matrix formation, accompanied by degradation of graft fibers, seem to be the major advantages. Further evaluation of degradation and graft healing characteristics may potentially lead to the clinical use of such grafts for revascularization procedures.

Well-defined PCL-graft-PDMAEMA prepared by ring-opening polymerisation and click chemistry

Amphiphilic and cationic PCL-based degradable polyester was synthesized by copper-catalyzed azide-alkyne cycloaddition (CuAAC).

Paclitaxel-eluting biodegradable synthetic vascular prostheses: a step towards reduction of neointima formation?

Background— Clinical small-caliber vascular prostheses are unsatisfactory. Reasons for failure are early thrombosis and late intimal hyperplasia. We thus prepared biodegradable small-caliber vascular prostheses using electrospun polycaprolactone (PCL) with slow-releasing paclitaxel (PTX), an antiproliferative drug. Methods and Results— PCL solutions containing PTX were used to prepare nonwoven nanofibre-based 2-mm ID prostheses. Mechanical morphological properties and drug loading, distribution, and release were studied in vitro. Infrarenal abdominal aortic replacement was carried out with nondrug-loaded and drug-loaded prostheses in 18 rats and followed for 6 months. Patency, stenosis, tissue reaction, and drug effect on endothelialization, vascular remodeling, and neointima formation were studied in vivo. In vitro prostheses showed controlled morphology mimicking extracellular matrix with mechanical properties similar to those of native vessels. PTX-loaded grafts with suitable mechanical properties and controlled drug-release were obtained by factorial design. In vivo, both groups showed 100% patency, no stenosis, and no aneurysmal dilatation. Endothelial coverage and cell ingrowth were significantly reduced at 3 weeks and delayed at 12 and 24 weeks in PTX grafts, but as envisioned, neointima formation was significantly reduced in these grafts at 12 weeks and delayed at 6 months. Conclusions— Biodegradable, electrospun, nanofibre, polycaprolactone prostheses are promising because in vitro they maintain their mechanical properties (regardless of PTX loading), and in vivo show good patency, reendothelialize, and remodel with autologous cells. PTX loading delays endothelialization and cellular ingrowth. Conversely, it reduces neointima formation until the end point of our study and thus may be an interesting option for small caliber vascular grafts.

New antibiotic-eluting mesh used for soft tissue reinforcement.

The surgical implantation of prostheses for soft tissue repair may be followed by post-operative mesh-related infection, a significant and dramatic complication, that is treated by mesh removal. A new antibiotic-eluting mesh has been manufactured on pre-existing polypropylene prostheses using an airbrush spraying technology. Among the degradable polymers tested as coating agents and drug reservoirs, poly(ε-caprolactone) (PCL), which is deposited after heating, provides a homogeneous, regular and smooth shell around the polypropylene filaments of the mesh without dramatically altering the biomechanical properties of the new modified mesh. An anti-infective drug (e.g. ofloxacin) is incorporated into this polymeric coating giving a limited burst effect followed by sustained drug diffusion for several days. An ofloxacin-eluting mesh has demonstrated excellent antibacterial activity in vitro on Escherichia coli adherence, biofilm formation and inhibitory diameter, even with low drug loads. Although further in vivo investigations are required to draw conclusions on the anti-infective effectiveness of the coated mesh, the airbrush coating of ofloxacin-PCL on existing prostheses is already potentially appealing in an effort to decrease post-operative infection.

PLA-based biodegradable and tunable soft elastomers for biomedical applications

Although desirable for biomedical applications, soft degradable elastomers having balanced amphiphilic behaviour are rarely described in the literature. Indeed, mainly highly hydrophobic elastomers or very hydrophilic elastomers with hydrogel behaviours are found. In this work, we developed thermoset degradable elastomers based on the photo-cross-linking of poly(lactide)-poly(ethylene glycol)-poly(lactide) (PLA-PEG-PLA) triblock prepolymers. The originality of the proposed elastomers comes from the careful choice of the prepolymer amphiphilicity and from the possible modulation of their mechanical properties and degradation rates provided by cross-linkers of different nature. This is illustrated with the hydrophobic and rigid 2,4,6-triallyloxy-1,3,5-triazine compared to the hydrophilic and soft pentaerythritol triallyl ether. Thermal properties, mechanical properties, swelling behaviours, degradation rates and cytocompatibility have been evaluated. Results show that it is possible to generate a family of degradable elastomers covering a broad range of properties from a single biocompatible and biodegradable prepolymer.

Aliphatic polyesters for medical imaging and theranostic applications

Medical imaging is a cornerstone of modern medicine. In that context the development of innovative imaging systems combining biomaterials and contrast agents (CAs)/imaging probes (IPs) for improved diagnostic and theranostic applications focuses intense research efforts. In particular, the classical aliphatic (co)polyesters poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA) and poly(ɛ-caprolactone) (PCL), attract much attention due to their long track record in the medical field. This review aims therefore at providing a state-of-the-art of polyester-based imaging systems. In a first section a rapid description of the various imaging modalities, including magnetic resonance imaging (MRI), optical imaging, computed tomography (CT), ultrasound (US) and radionuclide imaging (SPECT, PET) will be given. Then, the two main strategies used to combine the CAs/IPs and the polyesters will be discussed. In more detail we will first present the strategies relying on CAs/IPs encapsulation in nanoparticles, micelles, dendrimers or capsules. We will then present chemical modifications of polyesters backbones and/or polyester surfaces to yield macromolecular imaging agents. Finally, opportunities offered by these innovative systems will be illustrated with some recent examples in the fields of cell labeling, diagnostic or theranostic applications and medical devices.

Redox and thiol–ene cross-linking of mercapto poly(ε-caprolactone) for the preparation of reversible degradable elastomeric materials

A novel thiol-functionalized PCL (PCL-HDT) was synthesized following a convenient two-step procedure. Taking advantage of the pendant thiol group, degradable elastomeric materials have been prepared from PCL-HDT by redox or thiol–ene reaction. Elastomers were characterized by HRMAS NMR spectroscopy to confirm the formation of disulfide or thioether cross-links. The thermal and mechanical properties of elastomers have been assessed by DSC, DMA and tensile tests. Disulfide containing elastomers (EMSS) and thioether containing elastomers (EMTE) exhibited improved mechanical properties with ultimate strains up to 220%. The stability of the mechanical properties at temperatures close to body temperature was confirmed by DMA with G′ ≈ 200 MPa and G′′ ≈ 15 MPa. Finally, the reversibility of the disulfide formation and breaking has been evaluated, and confirmed the potential of these degradable elastomers as biomaterials.

Functionalized PCL/HA nanocomposites as microporous membranes for bone regeneration

In the present work, microporous membranes based on poly(ε-caprolactone) (PCL) and PCL functionalized with amine (PCL-DMAEA) or anhydride groups (PCL-MAGMA) were realized by solvent-non solvent phase inversion and proposed for use in Guided Tissue Regeneration (GTR). Nanowhiskers of hydroxyapatite (HA) were also incorporated in the polymer matrix to realize nanocomposite membranes. Scanning Electron Microscopy (SEM) showed improved interfacial adhesion with HA for functionalized polymers, and highlighted substantial differences in the porosity. A relationship between the developed porous structure of the membrane and the chemical nature of grafted groups was proposed. Compared to virgin PCL, hydrophilicity increases for functionalized PCL, while the addition of HA influences significantly the hydrophilic characteristics only in the case of virgin polymer. A significant increase of in vitro degradation rate was found for PCL-MAGMA based membranes, and at lower extent of PCL-DMAEA membranes. The novel materials were investigated regarding their potential as support for cell growth in bone repair using multipotent mesenchymal stromal cells (MSC) as a model. MSC plated onto the various membranes were analyzed in terms of adhesion, proliferation and osteogenic capacity that resulted to be related to chemical as well as porous structure. In particular, PCL-DMAEA and the relative nanocomposite membranes are the most promising in terms of cell-biomaterial interactions.