ABSTRACT
The demand for body fat reduction is increasing. However, conventional lipolytic approaches fail to control adipose tissue reduction and cause severe side effects in adjacent nonadipose tissues. A strategy to specifically reduce subcutaneous fat using adipocytolytic polymer nanoparticles in a minimally invasive manner is reported here. The polymer nanoparticles are designed to generate carbon dioxide gas when selectively absorbed by adipocytes. The carbon dioxide gas generated within late endosomes/lysosomes induces adipocytolysis, thereby reducing the number of cells. Localized injection of the adipocytolytic nanoparticles substantially reduces subcutaneous fat in a high-fat diet-induced obese mouse model, without significant changes in hematological or serum biochemical parameters. The adipocytolytic efficacy of the nanoparticles is also evaluated in a porcine model. This strategy addresses the need to develop safe and effective adipocytolytic agents using functional polymer nanoparticles.
Subject(s)
Carbon Dioxide , Nanoparticles , Mice , Swine , Animals , Carbon Dioxide/pharmacology , Obesity , Adipose Tissue , AdipocytesABSTRACT
Modulation of the viscoelastic properties of hydrogels is critical in tissue engineering applications. In the present study, a hyaluronate-alginate hybrid (HAH) was synthesized by introducing alginate to the hyaluronate backbone with varying molecular weights (700-2500 kDa), and HAH hydrogels were prepared in the presence of calcium ions at the same cross-linking density. The storage shear moduli of the HAH hydrogels increased with the concomitant increase in the molecular weight of hyaluronate in the HAH polymer. The HAH hydrogels were also modified with arginine-glycine-aspartic acid (RGD) and histidine-alanine-valine (HAV) peptides to enhance cell-matrix and cell-cell interactions, respectively. The chondrogenic differentiation of ATDC5 cells encapsulated within the HAH hydrogels was enhanced with the increase in the storage shear moduli of the gels in vitro as well as in vivo. This approach of regulating the viscoelastic properties of hydrogels using polymers of varying molecular weights at the same cross-linking density may prove to be useful in various tissue engineering applications including cartilage regeneration.
ABSTRACT
Tissue engineering typically requires a use of scaffolds when delivering tissue-specific cells to be engineered. Hydrogels are frequently used as scaffolds, because their composition, structure, and function resemble the natural tissue extracellular matrix. In this study, hyaluronate-alginate hybrid (HAH) was synthesized by conjugating alginate (ALG) with the hyaluronate (HA) backbone using various types of linkers. HAH hydrogel was prepared by physically cross-linking the HAH polymer in the presence of calcium ions without chemical cross-linkers. The mechanical stiffness of HAH hydrogel was significantly affected by changing the type of a linker between HA and ALG. The mechanical stiffness increased with increasing linker length, likely due to enhanced intermolecular reactions between HA and ALG. This enables controlling the mechanical properties of HAH hydrogels. The types of linkers used to synthesize HAHs also influenced the chondrogenic differentiation of ATDC5 cells cultured in HAH hydrogel in vitro. This hybrid system that can change the mechanical stiffness by varying the linker type while maintaining the cross-linking density may be useful to design and fabricate scaffolds for tissue engineering applications, including cartilage regeneration.
ABSTRACT
Hyaluronate-based hydrogels have been widely exploited as synthetic extracellular matrices in many tissue engineering applications, including cartilage tissue engineering. Hyaluronate-based hydrogels are typically prepared by chemical cross-linking reactions, in which chemical reagents may induce side effects, unless they are completely removed after the cross-linking reaction. We thus suggest the utilization of hybrid materials composed of hyaluronate as a main chain and alginate for physical cross-linking to simply form hydrogels in the presence of calcium ions under physiological conditions. In this study, we hypothesized that the introduction of biomimetic peptides to hyaluronate-alginate hybrid (HAH) hydrogels could be useful to regulate the chondrocyte phenotype, including chondrogenic differentiation. HAH was modified with the arginine-glycine-aspartate (RGD) peptide as a cell-matrix interaction motif and/or histidine-alanine-valine (HAV) as a cell-cell interaction motif. The HAV peptide is known to bind to cadherin, which is a key factor involved in homophilic cell-cell interactions as well as chondrogenesis. The viability and growth of mouse chondrocytes (ATDC5 cells) increased significantly when cultured on RGD-modified HAH hydrogels. Cell aggregates formed on HAV-modified HAH hydrogels, resulting in enhanced chondrogenic differentiation via enhanced cell-cell interactions by HAV modification. Interestingly, a synergistic effect of HAV and RGD peptides within HAH hydrogels on chondrogenesis was found in 3-D experiments in vitro. This approach to utilizing physically cross-linkable hyaluronate-based hydrogels presenting biomimetic peptides has potential applications in tissue engineering, including cartilage regeneration.
