Crimping-induced structural gradients explain the lasting strength of poly l-lactide bioresorbable vascular scaffolds during hydrolysis.

Biodegradable polymers open the way to treatment of heart disease using transient implants (bioresorbable vascular scaffolds, BVSs) that overcome the most serious complication associated with permanent metal stents-late stent thrombosis. Here, we address the long-standing paradox that the clinically approved BVS maintains its radial strength even after 9 mo of hydrolysis, which induces a ∼40% decrease in the poly l-lactide molecular weight (Mn). X-ray microdiffraction evidence of nonuniform hydrolysis in the scaffold reveals that regions subjected to tensile stress during crimping develop a microstructure that provides strength and resists hydrolysis. These beneficial morphological changes occur where they are needed most-where stress is localized when a radial load is placed on the scaffold. We hypothesize that the observed decrease in Mn reflects the majority of the material, which is undeformed during crimping. Thus, the global measures of degradation may be decoupled from the localized, degradation-resistant regions that confer the ability to support the artery for the first several months after implantation.

Multiplicity of morphologies in poly (l-lactide) bioresorbable vascular scaffolds.

Poly(l-lactide) (PLLA) is the structural material of the first clinically approved bioresorbable vascular scaffold (BVS), a promising alternative to permanent metal stents for treatment of coronary heart disease. BVSs are transient implants that support the occluded artery for 6 mo and are completely resorbed in 2 y. Clinical trials of BVSs report restoration of arterial vasomotion and elimination of serious complications such as late stent thrombosis. It is remarkable that a scaffold made from PLLA, known as a brittle polymer, does not fracture when crimped onto a balloon catheter or during deployment in the artery. We used X-ray microdiffraction to discover how PLLA acquired ductile character and found that the crimping process creates localized regions of extreme anisotropy; PLLA chains in the scaffold change orientation from the hoop direction to the radial direction on micrometer-scale distances. This multiplicity of morphologies in the crimped scaffold works in tandem to enable a low-stress response during deployment, which avoids fracture of the PLLA hoops and leaves them with the strength needed to support the artery. Thus, the transformations of the semicrystalline PLLA microstructure during crimping explain the unexpected strength and ductility of the current BVS and point the way to thinner resorbable scaffolds in the future.

Tungsten disulfide nanotubes enhance flow-induced crystallization and radio-opacity of polylactide without adversely affecting in vitro toxicity.

Treatment of vascular disease, from peripheral ischemia to coronary heart disease (CHD), is poised for transformation with the introduction of transient implants designed to "scaffold" regeneration of blood vessels and ultimately leave nothing behind. Improved materials could expand the use of these devices. Here, we examine one of the leading polymers for bioresorbable scaffolds (BRS), polylactide (PLA), as the matrix of nanocomposites with tungsten disulfide (WS2) nanotubes (WSNT), which may provide mechanical reinforcement and enhance radio-opacity. We evaluate in vitro cytotoxicity using vascular cells, flow-induced crystallization and radio-opacity of PLA-WSNT nanocomposites at low WSNT concentration. A small amount of WSNT (0.1 wt%) can effectively promote oriented crystallization of PLA without compromising molecular weight. And radio-opacity improves significantly: as little as 0.5 to 1 wt% WSNT doubles the radio-opacity of PLA-WSNT relative to PLA at 17 keV. The results suggest that a single component, WSNT, has the potential to increase the strength of BRS to enable thinner devices and increase radio-opacity to improve intraoperative visualization. The in vitro toxicity results indicate that PLA-WSNT nanocomposites are worthy of investigation in vivo. Although substantial further preclinical studies are needed, PLA-WSNT nanocomposites may provide a complement of material properties that may improve BRS and expand the range of lesions that can be treated using transient implants. STATEMENT OF SIGNIFICANCE: Bioresorbable Scaffolds (BRSs) support regeneration of arteries without permanent mechanical constraint. Poly-L-lactide (PLLA) is the structural material of the first approved BRS for coronary heart disease (ABSORB BVS), withdrawn due to adverse events in years 1-3. Here, we examine tungsten disulfide (WS2) nanotubes (WSNT) in PLA to address two contributors to early complications: (1) reinforce PLLA (enable thinner BRS), and (2) increase radiopacity (provide intraoperative visibility). For BRS, it is significant that WSNT disperse, remain dispersed, reduce friction and improve mechanical properties without additional chemicals or surface modifications. Like WS2 nanospheres, bare WSNT and PLA-WSNT nanocomposites show low cytotoxicity in vitro. PLA-WSNT show enhanced flow-induced crystallization relative to PLA, motivating future study of the processing behavior and strength of these materials.

Cyclic ruthenium-alkylidene catalysts for ring-expansion metathesis polymerization.

A series of cyclic Ru-alkylidene catalysts have been prepared and evaluated for their efficiency in ring-expansion metathesis polymerization (REMP). The catalyst structures feature chelating tethers extending from one N-atom of an N-heterocyclic carbene (NHC) ligand to the Ru metal center. The catalyst design is modular in nature, which provided access to Ru complexes having varying tether lengths, as well as electronically different NHC ligands. Structural impacts of the tether length were unveiled through (1)H NMR spectroscopy as well as single-crystal X-ray analyses. Catalyst activities were evaluated via polymerization of cyclooctene, and key data are provided regarding propagation rates, intramolecular chain transfer, and catalyst stabilities, three areas necessary for the efficient synthesis of cyclic poly(olefin)s via REMP. From these studies, it was determined that while increasing the tether length of the catalyst leads to enhanced rates of polymerization, shorter tethers were found to facilitate intramolecular chain transfer and release of catalyst from the polymer. Electronic modification of the NHC via backbone saturation was found to enhance polymerization rates to a greater extent than did homologation of the tether. Overall, cyclic Ru complexes bearing 5- or 6-carbon tethers and saturated NHC ligands were found to be readily synthesized, bench-stable, and highly active catalysts for REMP.

Sustained release of human growth hormone from in situ forming hydrogels using self-assembly of fluoroalkyl-ended poly(ethylene glycol).

Poly(ethylene glycol)s modified with fluorocarbon end groups are capable of in situ transition from an injectable liquid to a viscoelastic hydrogel by hydrophobic interaction of the end groups; this class of materials is useful for a variety of biomedical applications, including sustained protein release. The hydrogel state can be transformed into an injectable state by the addition of a toxicologically acceptable organic solvent, such as N-methyl pyrrolidone; after injection, this solution quickly returns to a gel state by diffusion of the water-miscible organic solvent into the surrounding environment. In vitro characterization of sustained release of human growth hormone (hGH) using this injectable depot shows that hGH remains stable inside the hydrogel formed, and demonstrates more than 2 weeks of prolonged release of hGH complexed with Zn(2+) ions without protein aggregation or initial burst.

Measuring shear strength of soft-tissue adhesives.

A method for evaluating strength of adhesives for hydrogels and soft tissues is presented. Quantitative measurements of shear strength for applications in tissue engineering and biomedicine are performed in torsion using a rheometer. Small, disk shaped specimens of soft biological tissues and/or hydrogels (8 mm diameter, 1-2 mm thick) are mounted onto rheometer tools and then bonded together using the adhesive to be tested. The torsional loading geometry imposes simple shear without deforming the planar adhesive bond, in contrast to the lap-shear test. It retains the advantages of the napkin ring test while reducing artifacts due to cutting and handling soft specimens. The method is demonstrated by measuring the shear strength of two types of biomedical adhesives (cyanoacrylate and polyethylene glycol-based) between model hydrogels (gelatin) and tissues (corneal stroma and skin).

Model of drug-loaded fluorocarbon-based micelles studied by electron-spin induced (19)f relaxation NMR and molecular dynamics simulation.

Rf-IPDU-PEGs belong to a class of fluoroalkyl-ended poly(ethylene glycol) polymers (Rf-PEGs), where the IPDU (isophorone diurethane) functions as a linker to connect each end of the PEG chain to a fluoroalkyl group. The Rf-IPDU-PEGs form hydrogels in water with favorable sol-gel coexistence properties. Thus, they are promising for use as drug delivery agents. In this study, we introduce an electron-spin induced 19F relaxation NMR technique to probe the location and drug-loading capacity for an electron-spin labeled hydrophobic drug, CT (chlorambucil-tempol adduct), enclosed in the Rf-IPDU-PEG micelle. With the assistance of molecular dynamics simulations, a clear idea regarding the structures of the Rf-IPDU-PEG micelle and its CT-loaded micelle was revealed. The significance of this research lies in the finding that the hydrophobic drug molecules were loaded within the intermediate IPDU shells of the Rf-IPDU-PEG micelles. The molecular structures of IPDU and that of CT are favorably comparable. Consequently, it appears that this study opens a window to modify the linker between the Rf group and the PEG chain for achieving customized structure-based drug-loading capabilities for these hydrogels, while the advantage of the strong affinity among the Rf groups to hold individual micelles together and to interconnect the micellar network is still retained in hopes of maintaining the sol-gel coexistence of the Rf-PEGs.

Tuning the erosion rate of artificial protein hydrogels through control of network topology.

Erosion behaviour governs the use of physical hydrogels in biomedical applications ranging from controlled release to cell encapsulation. Genetically engineered protein hydrogels offer unique means of controlling the erosion rate by engineering their amino acid sequences and network topology. Here, we show that the erosion rate of such materials can be tuned by harnessing selective molecular recognition, discrete aggregation number and orientational discrimination of coiled-coil protein domains. Hydrogels formed from a triblock artificial protein bearing dissimilar helical coiled-coil end domains (P and A) erode more than one hundredfold slower than hydrogels formed from those bearing the same end domains (either P or A). The reduced erosion rate is a consequence of the fact that looped chains are suppressed because P and A tend not to associate with each other. Thus, the erosion rate can be tuned over several orders of magnitude in artificial protein hydrogels, opening the door to diverse biomedical applications.

Self-assembled liquid-crystalline gels designed from the bottom up.

Liquid crystals are often combined with polymers to influence the liquid crystals' orientation and mechanical properties, but at the expense of reorientation speed or uniformity of alignment. We introduce a new method to create self-assembled nematic liquid-crystal gels using an ABA triblock copolymer with a side-group liquid-crystalline midblock and liquid-crystal-phobic endblocks. In contrast to in situ polymerized networks, these physical gels are homogeneous systems with a solubilized polymer network giving them exceptional optical uniformity and well-defined crosslink density. Furthermore, the unusually high-molecular-weight polymers used allow gels to form at lower concentrations than previously accessible. This enables these gels to be aligned by surface anchoring, shear, or magnetic fields. The high content of small-molecule liquid crystal (>/=95%) allows access to a regime of fast reorientation dynamics.