Drug delivery to solid tumors is hindered by hydrostatic and physical barriers that limit the penetration of nanocarriers into tumor tissue. When exploiting the enhanced permeability and retention (EPR) effect for passive targeting of nanocarriers, the increased interstitial fluid pressure and dense extracellular matrix in tumors limits the distribution of the nanocarriers to perivascular regions. Previous strategies have shown that magnetophoresis enhances accumulation and penetration of nanoparticles into solid tumors. However, because magnetic fields fall off rapidly with distance from the magnet, these methods have been limited to use in superficial tumors. To overcome this problem, we have developed a system comprising two oppositely-polarized magnets that enables the penetration of magnetic nanocarriers into more deeply-seeded tumors. Using this method, we demonstrate a 5-fold increase in the penetration and a 3-fold increase in the accumulation of magnetic nanoparticles within solid tumors compared to EPR.

The ability to direct cell behavior has been central to the success of numerous therapeutics to regenerate tissue or facilitate device integration. Biomaterial scientists are challenged to understand and modulate the interactions of biomaterials with biological systems in order to achieve effective tissue repair. One key area of research investigates the use of extracellular matrix-derived ligands to target specific integrin interactions and induce cellular responses, such as increased cell migration, proliferation, and differentiation of mesenchymal stem cells. These integrin-targeting proteins and peptides have been implemented in a variety of different polymeric scaffolds and devices to enhance tissue regeneration and integration. This review first presents an overview of integrin-mediated cellular processes that have been identified in angiogenesis, wound healing, and bone regeneration. Then, research utilizing biomaterials are highlighted with integrin-targeting motifs as a means to direct these cellular processes to enhance tissue regeneration. In addition to providing improved materials for tissue repair and device integration, these innovative biomaterials provide new tools to probe the complex processes of tissue remodeling in order to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies.

The immune microenvironment induced by biomaterials played vital roles in bone regeneration. Hydroxyapatite (HA) and its ion-substituted derivates represent a large class of core inorganic materials for bone tissue engineering. Although ion substitution was proved to be a potent way to grant HA more biological functions, few studies focused on the immunomodulatory properties of ion-doped HA. Herein, to explore the potential osteoimmunomodulatory effects of ion-doped HA, zinc and strontium co-assembled into HA through a collagen template biomimetic way (ZnSr-Col-HA) was successfully achieved. It was found that ZnSr-Col-HA could induce a favorable osteo-immune microenvironment by stimulating macrophages. Furthermore, ZnSr-Col-HA demonstrated a procedural promoting effect on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro . Specifically, the osteo-immune microenvironment acted as a dominant factor in promoting osteogenic gene expressions at the early stage through OSM signal pathway. Whereas the direct stimulating effects on BMSCs by Zn 2+ /Sr 2+ were more effectively at the later stage with Nfatc1/Maf and Wnt signals activated. In vivo study confirmed strong promoting effects of ZnSr-Col-HA on critical-sized cranial defect repair. The current study indicated that such a combined biomaterial design philosophy of dual ion-doping and biomimetic molecular co-assembly to endow HA applicable osteoimmunomodulatory characteristics might bring up a new cutting-edge concept for bone regeneration study.

A new methodology is presented for generating hydrocolloid inks, emulsions of hydrogel precursor solutions with mineral oil, for solid freeform fabrication of porous hydrogel scaffolds. These hydrocolloid inks exhibit viscoplastic behavior and rapid photopolymerization that permit high fidelity printing of complex geometries. Hydrocolloid inks based on poly(ethylene glycol) diacrylate are utilized to fabricate custom scaffolds using open source 3D printing software and customized paste extruder with cure‐on‐dispense capabilities. Scaffolds exhibit a hierarchical porosity from the microscale emulsion templated pores to the macroscale lattice structure and geometry programmed into the printing process. The extensibility of this system is also demonstrated by creating hydrocolloid inks from a range of natural hydrogel solutions including cellulose, gelatin, alginate, and hyaluronic acid. Unlike other methods of modulating hydrogel rheology to increase printability, these versatile hydrocolloid inks enable high fidelity printing of hydrogels without relying on high polymer concentrations or complex polymerization mechanisms.

Chronic wounds are projected to reach epidemic proportions worldwide because of the aging population and the increasing incidence of diabetes. Despite extensive research, infection remains one of the leading sources of complications in chronic wounds, resulting in improper healing, biofilm formation, and lower extremity amputation. To address the limitations of standard treatments, we have developed a hydrogel wound dressing with self-tuning moisture control that incorporates a novel antimicrobial agent to eliminate and prevent infection. 3D-printing of a hydrogel dressing with dual porosity resulted in a new dressing with greater flexibility, increased water uptake, and more rapid swelling than bulk hydrogel dressings. Additionally, gallium maltolate (GaM) was incorporated into the dressing to investigate the efficacy of this antimicrobial agent. Loading profiles, release kinetics, and the bactericidal activity against Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus ) of GaM were investigated in vitro to identify target profiles that supported infection control. Finally, GaM-loaded hydrogel dressings were evaluated in vivo , utilizing a murine splinted-wound model that was inoculated with S. aureus . In comparison to an untreated control, GaM dressings markedly reduced the wound bacterial load without compromising wound closure rates. Overall, this work demonstrates the utility of a 3D-printed hydrogel dressing as an antimicrobial dressing to control infection in chronic wounds.

Biofilm infections can consist of bacterial aggregates that are an order of magnitude larger than neutrophils, phagocytic immune cells that densely surround aggregates but do not enter them. Because a neutrophil is too small to engulf the entire aggregate, it must be able to detach and engulf a few bacteria at a time if it is to use phagocytosis to clear the infection. Current research techniques do not provide a method for determining how the success of phagocytosis, here defined as the complete engulfment of a piece of foreign material, depends on the mechanical properties of a larger object from which the piece must be removed before being engulfed. This article presents a step toward such a method. By varying polymer concentration or cross-linking density, the elastic moduli of centimeter-sized gels are varied over the range that was previously measured for Pseudomonas aeruginosa biofilms grown from clinical bacterial isolates. Human neutrophils are isolated from blood freshly drawn from healthy adult volunteers, exposed to gel containing embedded beads for 1 h, and removed from the gel. The percentage of collected neutrophils that contain beads that had previously been within the gels is used to measure successful phagocytic engulfment. Both increased polymer concentration in agarose gels and increased cross-linking density in alginate gels are associated with a decreased success of phagocytic engulfment. Upon plotting the percentage of neutrophils showing successful engulfment as a function of the elastic modulus of the gel to which they were applied, it is found that data from both alginate and agarose gels collapse onto the same curve. This suggests that gel mechanics may be impacting the success of phagocytosis and demonstrates that this experiment is a step toward realizing methods for measuring how the mechanics of a large target, or a large structure in which smaller targets are embedded, impact the success of phagocytic engulfment.

No abstract

In this study, a new platform based on electric cell-substrate impedance sensing (ECIS) was constructed for the dynamic monitoring of changes in cells during and after hyperthermia treatments. ECIS profiling was compared with traditional methods for monitoring the status of A549 cells under three typical treatment conditions, i.e., 30 min of hyperthermia at 41, 43, and 45 C. The impedance value rapidly changed, and severe morphological changes were observed during and after the hyperthermia. The impedance curves revealed that different hyperthermia conditions differentially affected the cells: the 41 C treatment caused a minor decrease in impedance that almost completely recovered in 1-2 h; the 43 C treatment led to a greater decrease in impedance, which also recovered over several hours before slowly decreasing again, possibly indicating apoptosis; the 45 C treatment resulted in the greatest decrease in impedance, which never recovered, possibly indicating rapid necrosis. Further, these three hyperthermia treatment regimens were applied to four additional cell lines. By comparing the impedance curves of different cell lines, we found that cancer cells (HepG2) may be more sensitive to hyperthermia than normal cells (LO2). Moreover, different cancer cell lines (HeLa, MCF-7, A549, and HepG2) exhibited different thermal sensitivities. These results fit previous theories on hyperthermia, demonstrating that the platform established in this study is a useful analytical tool for the in vitro research of thermal therapy, and the dynamic data generated will enable us to examine phenomena and theories.