Matthew Tirrell

The role of surface science in bioengineered materials

Abstract Materials employed in biomedical technology are increasingly being designed to have specific, desirable biological interactions with their surroundings, rather than the older common practice of trying to adapt traditional materials to biomedical applications. Moreover, materials scientists are also increasingly deriving new lessons from naturally occurring materials (from mollusk shells to soft animal tissue) about useful composition–structure property relationships that might be mimicked with synthetic materials. Together, these two areas of effort constitute what we may call bioengineered materials. It is possible to set down a reasonably thorough set of characteristics that bioengineered materials have in common. Among these characteristics we discuss the following: self-assembly, bioengineered materials often rely on information content built into structural molecules to determine the order and organization of the material; hierarchical structure, in most bioengineered materials several different length scales of structure are essential and are formed spontaneously and simultaneously via self-assembly; precision synthesis, fundamental to biological material structures is the idea of macromolecules constructed in a precise manner; templating, ordered structures in bioengineered materials are often propagated from one element or set of instructions, to another; specific and non-specific interactions, the forces involved in holding biomaterials structures together. In the future, a carefully selected combination of this set of characteristics will enable us to bioengineer surfaces that are capable to direct and control a desired biological response. Eventually, such bioengineered surfaces will become important tools to comprehend and analyze how materials interact in nature.

The healing process at polymer–polymer interfaces

When two pieces of the same amorphous polymer are brought into contact at a temperature above the glass transition, the junction surface gradually heals until, at very long contact times, it is indistinguishable from bulk polymer. We have developed an analysis of this welding process based on the reptation picture of polymer dynamics due to de Gennes. The theory predicts the number of bridges (pieces of polymer chain) per unit area spanning the original junction surface as a function of time. At fixed time the number of bridges (σ) also depends on the molecular weight (M) of the chains. If the initial contact is between surfaces which have been equilibrated against a gas phase, we find that σ∼t1/2M−3/2. Alternatively, if the contacting surfaces contain many chain ends, such as may be found at brittle fracture surfaces in glassy polymers, we find that σ∼t1/4M−1/4 at short times. The theory may be compared to available measurements on strength development in healing interfaces leading to the conclusion that...

Molecular dynamics of narrow, liquid‐filled pores

Molecular dynamics studies are reported for a 6‐12 Lennard–Jones liquid in pore channels ranging from about 2–12 molecules wide. The pore walls are modeled as flat surfaces interacting with the fluid molecules via a continuous potential varying only with perpendicular distance from the wall. Liquid density profiles, solvation forces, interfacial tensions, and self‐diffusion coefficients along the pore axis were computed. The density profiles indicate multilayer adsorption in the pore, whereas the locally defined diffusion coefficients do not vary significantly across the pore. The pore‐averaged diffusivity as well as the solvation force oscillate with varying pore width at constant chemical potential. For pore widths greater than ten molecular diameters, the average diffusion coefficient is almost equal to its bulk value, and the solvation force equals the bulk pressure. In the smaller pores the mean square displacement normal to the pore walls never achieves linearity in time, and thus does not reach a d...

Self-assembled peptide amphiphile micelles containing a cytotoxic T-cell epitope promote a protective immune response in vivo.

There is enormous potential in peptide-based immunotherapy to be effective for both prophylactic vaccines [ 1 , 2 ] and remedial treatments for cancer [ 3 ] and autoimmune diseases. [ 4 ] Peptides can be designed to contain the minimal amino acid sequences necessary to stimulate an adaptive immune response. However, peptides on their own tend to be weak immunogens and require strong, often toxic, adjuvants to be effective. [ 5 ] This limits their use in clinical applications. Effective peptide-based vaccines require peptide delivery systems that can boost peptidespecifi c immune responses without causing any undesirable side effects. [ 6 ] An effective delivery system should concentrate the antigen, protect the antigen from degradation, increase uptake and processing by dendritic cells (DCs), and induce the production of cytokines that create a robust immune response. [ 7 , 8 ] We propose that peptide amphiphiles (PAs), which self-assemble into nanometer-sized micelles, can meet these requirements for an effective antigen delivery system. PAs consist of a hydrophobic, lipid-like tail linked to a hydrophilic, biofunctional peptide headgroup. Under aqueous conditions, the PAs self-assemble into micelles in which the tails are buried in the core away from water, and the peptides are displayed on the outside. Micelles formed from PAs have

Laser-Activated Gene Silencing via Gold Nanoshell−siRNA Conjugates

The temporal and spatial control over the delivery of materials such as siRNA into cells remains a significant technical challenge. We demonstrate the pulsed near-infrared (NIR) laser-dependent release of siRNA from coated 40 nm gold nanoshells. Tat-lipid coating mediates the cellular uptake of the nanomaterial at picomolar concentration, while spatiotemporal silencing of a reporter gene (green fluorescence protein) was studied using photomasking. The NIR laser-induced release of siRNA from the nanoshells is found to be power- and time-dependent, through surface-linker bond cleavage, while the escape of the siRNA from endosomes occurs above a critical pulse energy attributed to local heating and cavitation. NIR laser-controlled drug release from functional nanomaterials should facilitate more sophisticated developmental biology and therapeutic studies.

Molecular dynamics of flow in micropores

The method of nonequilibrium molecular dynamics is used to study the viscosity and flow properties of strongly inhomogeneous liquids, a particular case of which is a liquid confined in a micropore only a few molecular diameters wide. Fluid inhomogeneity is introduced by imposing an external potential that in one case simulates flat solid walls and in the other case causes density peaks in the middle of a thin liquid film. For comparison a homogeneous fluid is also simulated. In both types of inhomogeneous fluid, the shear stress and effective viscosity are smaller than in the homogeneous fluid. The density profiles and the diffusivities in the micropore were found to be independent of flow, even at the extremely high rates, 1010–1011 s−1 of the simulation. The Green–Kubo relation is found to be valid for the diffusivity under the flow studied. We propose a local average density model (LADM) of viscosity and diffusivity, in which the local transport coefficients are those of homogeneous fluid at a mean den...

Targeting of albumin-embedded paclitaxel nanoparticles to tumors.

We have used tumor-homing peptides to target abraxane, a clinically approved paclitaxel-albumin nanoparticle, to tumors in mice. The targeting was accomplished with two peptides, CREKA and LyP-1 (CGNKRTRGC). Fluorescein (FAM)-labeled CREKA-abraxane, when injected intravenously into mice bearing MDA-MB-435 human cancer xenografts, accumulated in tumor blood vessels, forming aggregates that contained red blood cells and fibrin. FAM-LyP-1-abraxane co-localized with extravascular islands expressing its receptor, p32. Self-assembled mixed micelles carrying the homing peptide and the label on different subunits accumulated in the same areas of tumors as LyP-1-abraxane, showing that Lyp-1 can deliver intact nanoparticles into extravascular sites. Untargeted, FAM-abraxane was detected in the form of a faint meshwork in tumor interstitium. LyP-1-abraxane produced a statistically highly significant inhibition of tumor growth compared with untargeted abraxane. These results show that nanoparticles can be effectively targeted into extravascular tumor tissue and that targeting can enhance the activity of a therapeutic nanoparticle.

Targeting atherosclerosis by using modular, multifunctional micelles

Subtle clotting that occurs on the luminal surface of atherosclerotic plaques presents a novel target for nanoparticle-based diagnostics and therapeutics. We have developed modular multifunctional micelles that contain a targeting element, a fluorophore, and, when desired, a drug component in the same particle. Targeting atherosclerotic plaques in ApoE-null mice fed a high-fat diet was accomplished with the pentapeptide cysteine-arginine-glutamic acid-lysine-alanine, which binds to clotted plasma proteins. The fluorescent micelles bind to the entire surface of the plaque, and notably, concentrate at the shoulders of the plaque, a location that is prone to rupture. We also show that the targeted micelles deliver an increased concentration of the anticoagulant drug hirulog to the plaque compared with untargeted micelles.

Polymer Self-Diffusion in Entangled Systems

Abstract This article has focused on work in the last several years, a period during which theoretical insights and experimental techniques pertaining to polymer self-diffusion in entangled systems have advanced enormously. The point has been to lay out for the reader the means by which this information has been developed and to lay out the available information itself. The objective has been to facilitate comparisons regarding use and applicability of techniques, quality, and interpretations of data and the trends present in the various data. Presentation of the information in this style leads to a few definite conclusions and a larger number of problems which come more sharply than before into focus as ripe for continued study. Specific conclusions which seem reasonable at this point are: The molecular weight dependence of Ds is, in entangled systems, an inverse square law, consistent with the prediction of the reptation model. The self-diffusion coefficient becomes quite insensitive to the matrix molec...

A versatile approach to high-throughput microarrays using thiol-ene chemistry

Microarray technology has become extremely useful in expediting the investigation of large libraries of materials in a variety of biomedical applications, such as in DNA chips, protein and cellular microarrays. In the development of cellular microarrays, traditional high-throughput printing strategies on stiff, glass substrates and non-covalent attachment methods are limiting. We have developed a facile strategy to fabricate multifunctional high-throughput microarrays embedded at the surface of a hydrogel substrate using thiol-ene chemistry. This user-friendly method provides a platform for the immobilization of a combination of bioactive and diagnostic molecules, such as peptides and dyes, at the surface of poly(ethylene glycol)-based hydrogels. The robust and orthogonal nature of thiol-ene chemistry allows for a range of covalent attachment strategies in a fast and reliable manner, and two complementary strategies for the attachment of active molecules are demonstrated.