The direct local delivery of short interfering RNA (siRNA) to tissues may present solutions to several complex medical conditions. In particular, chronic wound healing is a serious and painful complication of diabetes mellitus (DM) affecting as many as one in four patients with a three year recurrence rate of more than 50% and leaving over 70,000 patients in the United States alone facing amputation. Here we describe the use of siRNA delivered locally into the diabetic ulcer directly and in a sustained fashion to knockdown a chronically upregulated extracellular matrix protease, matrix metalloproteinase-9 (MMP-9), to improve wound healing.

There is a rapidly increasing interest in developing stimuli-responsive nanomaterials for treating a variety of diseases. By enabling the activation of function locally at the sites of interest, it is possible to increase therapeutic efficacy significantly while simultaneously reducing adverse side effects. While there are many sophisticated nanomaterials available, they are often highly complex and not easily transferrable to industrial scales and clinical settings. However, nanomaterials based on hyaluronic acid offer a compelling strategy for reducing their complexity while retaining several desirable benefits such as active targeting and stimuli-responsive degradation. Herein, the basic properties of hyaluronic acid, its binding partners, and natural routes for degradation by hyaluronidases-hyaluronic-aciddegrading enzymes-and oxidative stresses are discussed. Recent advances in designing hyaluronic acid-based, actively targeted, hyaluronidase-or reactive-oxygen-species-responsive nanomaterials for both diagnostic imaging and therapeutic delivery, which go beyond merely the classical targeting of CD44, are summarized.

Many biomaterials are designed to regulate the interactions between artificial and natural surfaces. However, when materials are inserted through the cell membrane itself the interface formed between the interior edge of the membrane and the material surface is not well understood and poorly controlled. Here we demonstrate that by replicating the nanometer-scale hydrophilichydrophobic-hydrophilic architecture of transmembrane proteins, artificial "stealth" probes spontaneously insert and anchor within the lipid bilayer core, forming a high-strength interface. These nanometer-scale hydrophobic bands are readily fabricated on metallic probes by functionalizing the exposed sidewall of an ultrathin evaporated Au metal layer rather than by lithography. Penetration and adhesion forces for butanethiol and dodecanethiol functionalized probes were directly measured using atomic force microscopy (AFM) on thick stacks of lipid bilayers to eliminate substrate effects. The penetration dynamics were starkly different for hydrophobic versus hydrophilic probes. Both 5-and 10 nm thick hydrophobically functionalized probes naturally resided within the lipid core, while hydrophilic probes remained in the aqueous region. Surprisingly, the barrier to probe penetration with short butanethiol chains (E o;5 nm ¼ 21.8k b T , E o;10 nm ¼ 15.3k b T ) was dramatically higher than longer dodecanethiol chains (E o;5 nm ¼ 14.0k b T , E o;10 nm ¼ 10.9k b T ), indicating that molecular mobility and orientation also play a role in addition to hydrophobicity in determining interface stability. These results highlight a new strategy for designing artificial cell interfaces that can nondestructively penetrate the lipid bilayer.atomic force microscopy | biophysics | membranes | proteins

Fluid lipid bilayers were deposited on alumina substrates with the use of bubble collapse deposition (BCD). Previous studies using vesicle rupture have required the use of charged lipids or surface functionalization to induce bilayer formation on alumina, but these modifications are not necessary with BCD. Photobleaching experiments reveal that the diffusion coefficient of POPC on alumina is 0.6 microm (2)/s, which is much lower than the 1.4-2.0 microm (2)/s reported on silica. Systematically accounting for roughness, immobile regions and membrane viscosity shows that pinning sites account for about half of this drop in diffusivity. The remainder of the difference is attributed to a more tightly bound water state on the alumina surface, which induces a larger drag on the bilayer.