Dextran, a biocompatible, water-soluble polysaccharide, was modified at its hydroxyls with acetal moieties such that it became insoluble in water but freely soluble in common organic solvents enabling its use in the facile preparation of acid-sensitive microparticles. These particles degrade in a pH-dependent manner: FITC-dextran was released with a half-life at 37 ºC of 10 hours at pH 5.0 compared to a half-life of approximately 15 days at pH 7.4. Both hydrophobic and hydrophilic cargoes were successfully loaded into these particles using single and double emulsion techniques, respectively. When used in a model vaccine application, particles loaded with the protein ovalbumin (OVA) increased the presentation of OVA-derived peptides to CD8+ T-cells 16-fold relative to OVA alone. Additionally, this dextran derivative was found to be non-toxic in preliminary in vitro cytotoxicity assays. Due to its ease of preparation, processability, pH-sensitivity, and biocompatibility, this type of modified dextran should find use in numerous drug delivery applications.

Materials that combine facile synthesis, simple tuning of degradation rate, processability, and biocompatibility are in high demand for use in biomedical applications. We report on acetalated dextran, a biocompatible material that can be formed into microparticles with degradation rates that are tunable over 2 orders of magnitude depending on the degree and type of acetal modification. Varying the degradation rate produces particles that perform better than poly(lactic-co-glycolic acid) and iron oxide, two commonly studied materials used for particulate immunotherapy, in major histocompatibility complex class I (MHC I) and MHC II presentation assays. Modulating the material properties leads to antigen presentation on MHC I via pathways that are dependent or independent of the transporter associated with antigen processing. To the best of our knowledge, this is the only example of a material that can be tuned to operate on different immunological pathways while maximizing immunological presentation.acid-sensitive ͉ biocompatible ͉ encapsulation ͉ polymer ͉ vaccine

Dextran, a water-soluble, biocompatible polymer of glucose, was modified at its hydroxyls with arylboronic esters to make it soluble in common organic solvents, allowing for the facile preparation of oxidation-sensitive dextran (Oxi-DEX) carrier microparticles. These particles were found to release their payload with a half-life of 36 min at 1 mM H2O2, which can be compared with a half-life of greater than 1 week in the absence of H2O2. When used in a model vaccine application, Oxi-DEX particles loaded with ovalbumin (OVA) increased the presentation to CD8+ T-cells 27-fold relative to OVA encapsulated in a classical vehicle not sensitive to oxidation. No presentation was observed from cells incubated with unencapsulated OVA. Additionally, Oxi-DEX was found to be nontoxic in preliminary in vitro cytotoxicity assays. Because it is easy to prepare, sensitive to biological oxidation, and biocompatible, this material may represent an attractive new platform for selective delivery applications.

Cell adhesion organizes the structures of tissues and mediates their mechanical, chemical, and electrical integration with their surroundings. Here, we describe a strategy for chemically controlling cell adhesion using membrane anchored single-stranded DNA oligonucleotides. The reagents are pure chemical species prepared from phosphoramidites synthesized in a single chemical step from commercially available starting materials. The approach enables rapid, efficient, tunable cell adhesion, independent of proteins or glycans, by facilitating interactions with complementary labeled surfaces or other cells. We demonstrate the utility of this approach by imaging drug-induced changes in the membrane dynamics of non-adherent human cells while chemically immobilized on a passivated glass surface.

Developing tissues contain motile populations of cells that can selforganize into spatially ordered tissues based on differences in their interfacial surface energies. However, it is unclear how self-organization by this mechanism remains robust when interfacial energies become heterogeneous in either time or space. The ducts and acini of the human mammary gland are prototypical heterogeneous and dynamic tissues comprising two concentrically arranged cell types. To investigate the consequences of cellular heterogeneity and plasticity on cell positioning in the mammary gland, we reconstituted its selforganization from aggregates of primary cells in vitro. We find that self-organization is dominated by the interfacial energy of the tissue-ECM boundary, rather than by differential homo-and heterotypic energies of cell-cell interaction. Surprisingly, interactions with the tissue-ECM boundary are binary, in that only one cell type interacts appreciably with the boundary. Using mathematical modeling and cell-type-specific knockdown of key regulators of cell-cell cohesion, we show that this strategy of self-organization is robust to severe perturbations affecting cell-cell contact formation. We also find that this mechanism of self-organization is conserved in the human prostate. Therefore, a binary interfacial interaction with the tissue boundary provides a flexible and generalizable strategy for forming and maintaining the structure of two-component tissues that exhibit abundant heterogeneity and plasticity. Our model also predicts that mutations affecting binary cell-ECM interactions are catastrophic and could contribute to loss of tissue architecture in diseases such as breast cancer.heterogeneity | cell sorting | differential adhesion | mammary | prostate S elf-organization is a process that contributes to pattern formation and repair at all scales of biological complexity. At the tissue scale, defining robust strategies of self-organization is critical for engineering functional tissues, as well as for understanding development and the breakdown of tissue structure during diseases such as cancer (1). During development, two or more populations of motile cells can self-organize into spatially ordered tissues by a process referred to as cell sorting (2-4). The outcome of cell sorting can be rationalized using physical models that invoke cell-type-specific differences in interfacial energies. Interfacial energies arise through the action of a contractile cell cortex coupled to adhesion molecules (e.g., cadherins) that link the cortices of neighboring cells and signal to modulate cortical tension at specific cellular interfaces (5). In general, the organization of a tissue after cell sorting corresponds to a configuration that maximizes the formation of the most energetically favorable (hereafter referred to as most cell-cell cohesive) † cellular interfaces (6). For example, with an intermediate level of heterotypic cell-cell cohesion the most self-cohesive cell type is typically found in the tissue core, with the le...