Iodinated Polyesters with Enhanced X-ray Contrast Properties for Biomedical Imaging.

Synthetic materials exhibiting contrast imaging properties have become vital to the field of biomedical imaging. However, polymeric biomaterials are lacking imaging contrast properties for deep tissue imaging. This report details the synthesis and characterization of a suite of aryl-iodo monomers, which were used to prepare iodinated polyesters using a pre-functionalization approach. Commercially available 4-iodo-phenylalanine or 4-iodobenzyl bromide served as the starting materials for the synthesis of three iodinated monomeric moieties (a modified lactide, morpholine-2,5-dione, and caprolactone), which under a tin-mediated ring-opening polymerization (ROP), generated their respective polyesters (PE) or poly(ester amides) (PEA). An increase in X-ray intensity of all synthesized iodine-containing polymers, in comparison to non-iodinated poly(lactic acid) (PLA), validated their functionality as radio-opaque materials. The iodinated-poly(lactic acid) (iPLA) material was visualized through varying thicknesses of chicken tissue, thus demonstrating its potenial as a radio-opaque biomaterial.

Recent Advances in Polyesters for Biomedical Imaging.

Several synthetic materials exhibiting contrast imaging properties have become vital to the field of biomedical imaging. Polymeric biomaterials and metals are commonly used imaging agents and can assist in the monitoring of therapy response, migration, degradation, changes in morphology, defects, and image-guided surgery. In comparison to metals, most bio and synthetic polymers lack inherent imaging properties. Polymeric biomaterials, specifically polyesters, have gained a considerable amount of attention due to their unique properties including biocompatibility, biodegradation, facile synthesis, and modification capability. Polyester implants and nanomaterials are available on the market or are in clinical trials for many applications including: dental implants, cranio-maxilofacial implants, soft tissue sutures and staples, abdominal wall repair, tendon and ligament reconstruction, fracture fixation devices, and coronary drug eluting stents. This review aims to provide a summary of the recent developments of polyesters with bioimaging contrast properties. The three main approaches to prepare bioimaging polyesters (coating, encapsulation, and functionalization) are discussed in depth. Furthermore, commonly used imaging modalities including X-ray computed tomography, magnetic resonance imaging, ultrasound, fluorescence, and radionucleotide polyester contrast agents are highlighted. In each section, examples of impactful bioimaging polyesters in the five major imaging modalities are evaluated.

Non-invasive deep tissue imaging of iodine modified poly(caprolactone-co-1-4-oxepan-1,5-dione) using X-ray.

When biodegradable polyester devices, like sutures and screws, are implanted into the body, it is very challenging to image them in deep tissue, monitor their degradation, and detect defects. We report our recent findings on non-invasive deep tissue imaging of polyester degradation, stability and integrity using an iodinated-polycaprolactone (i-P(CLcoOPD)) X-ray imaging contrast agent. The results of experiments performed with i-P(CLcoOPD) demonstrate the feasibility to quantify in-situ polyester degradation in vitro and in vivo using rats. We also demonstrate that X-ray imaging could be used to identify and quantify physical defects, such as cracks, in polymeric implants using rabbit animal models. This approach enables non-invasive monitoring of polyester materials and is expected to become an important technology for improving the imaging of polymers at clinically relevant depths.

Self-assembled multilayers of nanocomponents.

We show it is possible to assemble nanoparticle-polymer layers in a controllable manner dictated by the difference in nano-object morphology and dielectric properties. A thin (10-100 nm) layer of the two components is spin coated onto a solid substrate and the system thermally aged to activate a cross-linking process between polymer molecules. The nanoparticles segregate to the solid substrate prior to complete cross-linking if entropic forces are dominant or to the air interface if dielectric (surface energy) forces are properly tuned. Subsequent layers are then spin coated onto the layer below, and the process is repeated to create layered structures with nanometer accuracy useful for tandem solar cells, sensors, optical coatings, etc. Unlike other self-assembly techniques the layer thicknesses are dictated by the spin coating conditions and relative concentration of the two components.

Cross-linked and functionalized polyester materials constructed using ketoxime ether linkages.

A modular and simple approach to the graft functionalization and cross-linking of ketone-containing poly(ε-caprolactone)s has been investigated for the preparation of novel gel and nanoparticulate materials. Poly(ε-caprolactone--2-oxepane-1,5-dione) (P(CL--OPD)), was grafted by reaction with 1-aminooxydodecane and cross-linked by reaction with 1,6-bis(aminooxy)hexane, each at room temperature in tetrahydrofuran at 1 and 10 wt% polymer in the absence of an acid catalyst, and at 1, 5 and 10 wt% polymer in the presence of -toluenesulfonic acid. The grafting process served as a model system for the cross-linking reactions, affording products that were fully characterizable and retained the physical properties of (P(CL--OPD)), with a slight increase in measured molecular weight and characteristic spectroscopic signatures for the dodecyl chains and the newly introduced ketoxime functionalities. Early stages of the intermolecular cross-linking were followed by gel permeation chromatography and atomic force microscopy. Ultimately, insoluble, but tetrahydrofuran-swollen gelled products were obtained, which were characterized by infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. These materials exhibited interesting melting transition profiles, undergoing melting at lower temperatures and broader temperature ranges than observed for their polymer precursors. This study represents an advance in the development of rapid and efficient chemistry for the preparation of functional and robust hydrolytically-degradable polymer materials with degradable linkages.

General strategies for nanoparticle dispersion.

Traditionally the dispersion of particles in polymeric materials has proven difficult and frequently results in phase separation and agglomeration. We show that thermodynamically stable dispersion of nanoparticles into a polymeric liquid is enhanced for systems where the radius of gyration of the linear polymer is greater than the radius of the nanoparticle. Dispersed nanoparticles swell the linear polymer chains, resulting in a polymer radius of gyration that grows with the nanoparticle volume fraction. It is proposed that this entropically unfavorable process is offset by an enthalpy gain due to an increase in molecular contacts at dispersed nanoparticle surfaces as compared with the surfaces of phase-separated nanoparticles. Even when the dispersed state is thermodynamically stable, it may be inaccessible unless the correct processing strategy is adopted, which is particularly important for the case of fullerene dispersion into linear polymers.

Conformation of intramolecularly cross-linked polymer nanoparticles on solid substrates.

The conformation of cross-linked, monomolecular, polystyrene nanoparticles on a solid substrate is considered as a function of cross-linking degree and substrate surface free energy. It is found that an extreme amount of cross-linking is necessary for the ca. 5-10 nm diameter nanoparticles to retain their original spherical shape, regardless of surface free energy. A lesser amount of cross-linking produces a nanoparticle that collapses to a pancake-like conformation on a high-energy substrate yet remains spherical on a low-energy surface. A simple model is developed to reveal the relationship between nanoparticle modulus and surface free energy to define the nanoparticle conformation.

Nanoscale effects leading to non-Einstein-like decrease in viscosity.

Nanoparticles have been shown to influence mechanical properties; however, transport properties such as viscosity have not been adequately studied. This might be due to the common observation that particle addition to liquids produces an increase in viscosity, even in polymeric liquids, as predicted by Einstein nearly a century ago. But confinement and surface effects provided by nanoparticles have been shown to produce conformational changes to polymer molecules, so it is expected that nanoparticles will affect the macroscopic viscosity. To minimize extraneous enthalpic or other effects, we blended organic nanoparticles, synthesized by intramolecular crosslinking of single polystyrene chains, with linear polystyrene macromolecules. Remarkably, the blend viscosity was found to decrease and scale with the change in free volume introduced by the nanoparticles and not with the decrease in entanglement. Indeed, the entanglements did not seem to be affected at all, suggesting unusual polymer dynamics.

A facile approach to architecturally defined nanoparticles via intramolecular chain collapse.

A novel approach is presented for the controlled intramolecular collapse of linear polymer chains to give well-defined single-molecule nanoparticles whose structure is directly related to the original linear polymer. By employing a combination of living free radical polymerization and benzocyclobutene (BCB) chemistry, nanoparticles can be routinely prepared in multigram quantities with the size being accurately controlled by either the initial degree of polymerization of the linear chain or the level of incorporation of the BCB coupling groups. The latter also allows the cross-link density of the final nanoparticles to be manipulated. In analogy with dendritic macromolecules, a significant reduction of up to 75% in the hydrodynamic volume is observed on going from the starting random coil linear chains to the corresponding nanoparticles. The facile nature of the living free radical process also permits wide variation in monomer selection and functional group incorporation and allows novel macromolecular architectures to be prepared. Furthermore, the use of block copolymers functionalized with benzocyclobutene groups in only one of the blocks gives, after intramolecular collapse, a hybrid architecture in which a single linear polymer chain is attached to the globular nanoparticle.