Glycosaminoglycans (GAGs) and glycoproteins are vital components of the extracellular matrix, directing cell proliferation, differentiation, and migration and tissue homeostasis. Here, we demonstrate supramolecular GAG-like glycopeptide nanofibers mimicking bioactive functions of natural hyaluronic acid molecules. Self-assembly of the glycopeptide amphiphile molecules enable organization of glucose residues in close proximity on a nanoscale structure forming a supramolecular GAG-like system. Our in vitro culture results indicated that the glycopeptide nanofibers are recognized through CD44 receptors, and promote chondrogenic differentiation of mesenchymal stem cells. We analyzed the bioactivity of GAG-like glycopeptide nanofibers in chondrogenic differentiation and injury models because hyaluronic acid is a major component of articular cartilage. Capacity of glycopeptide nanofibers on in vivo cartilage regeneration was demonstrated in microfracture treated osteochondral defect healing. The glycopeptide nanofibers act as a cell-instructive synthetic counterpart of hyaluronic acid, and they can be used in stem cell-based cartilage regeneration therapies.

Glycosaminoglycans (GAGs) are important extracellular matrix components of cartilage tissue and provide biological signals to stem cells and chondrocytes for development and functional regeneration of cartilage. Among their many functions, particularly sulfated glycosaminoglycans bind to growth factors and enhance their functionality through enabling growth factor−receptor interactions. Growth factor binding ability of the native sulfated glycosaminoglycans can be incorporated into the synthetic scaffold matrix through functionalization with specific chemical moieties. In this study, we used peptide amphiphile nanofibers functionalized with the chemical groups of native glycosaminoglycan molecules such as sulfonate, carboxylate and hydroxyl to induce the chondrogenic differentiation of rat mesenchymal stem cells (MSCs). The MSCs cultured on GAG-mimetic peptide nanofibers formed cartilage-like nodules and deposited cartilage-specific matrix components by day 7, suggesting that the GAG-mimetic peptide nanofibers effectively facilitated their commitment into the chondrogenic lineage. Interestingly, the chondrogenic differentiation degree was manipulated with the sulfonation degree of the nanofiber system. The GAG-mimetic peptide nanofibers network presented here serve as a tailorable bioactive and bioinductive platform for stem-cell-based cartilage regeneration studies.

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Ranibizumab is a recombinant VEGF-A antibody used to treat the wet form of age-related macular degeneration. It is intravitreally administered to ocular compartments, and the treatment requires frequent injections, which may cause complications and patient discomfort. To reduce the number of injections, alternative treatment strategies based on relatively non-invasive ranibizumab delivery are desired for more effective and sustained release in the eye vitreous than the current clinical practice. Here, we present self-assembled hydrogels composed of peptide amphiphile molecules for the sustained release of ranibizumab, enabling local high-dose treatment. Peptide amphiphile molecules self-assemble into biodegradable supramolecular filaments in the presence of electrolytes without the need for a curing agent and enable ease of use due to their injectable nature—a feature provided by shear thinning properties. In this study, the release profile of ranibizumab was evaluated by using different peptide-based hydrogels at varying concentrations for improved treatment of the wet form of age-related macular degeneration. We observed that the slow release of ranibizumab from the hydrogel system follows extended- and sustainable release patterns without any dose dumping. Moreover, the released drug was biologically functional and effective in blocking the angiogenesis of human endothelial cells in a dose-dependent manner. In addition, an in vivo study shows that the drug released from the hydrogel nanofiber system can stay in the rabbit eye’s posterior chamber for longer than a control group that received only a drug injection. The tunable physiochemical characteristics, injectable nature, and biodegradable and biocompatible features of the peptide-based hydrogel nanofiber show that this delivery system has promising potential for intravitreal anti-VEGF drug delivery in clinics to treat the wet form age-related macular degeneration.

Articular cartilage, which is exposed to continuous repetitive compressive stress, has limited self-healing capacity in the case of trauma. Thus, it is crucial to develop new treatment options for the effective regeneration of the cartilage tissue. Current cellular therapy treatment options are microfracture and autologous chondrocyte implantation; however, these treatments induce the formation of fibrous cartilage, which degenerates over time, rather than functional hyaline cartilage tissue. Tissue engineering studies using biodegradable scaffolds and autologous cells are vital for developing an effective long-term treatment option. Three-dimensional scaffolds composed of glycosaminoglycan-like peptide nanofibers are synthetic, bioactive, biocompatible, and biodegradable and trigger cell-cell interactions that enhance chondrogenic differentiation of cells without using any growth factors. We showed differentiation of mesenchymal stem cells into chondrocytes in both 2-dimensional and 3-dimensional culture, which produce a functional cartilage extracellular matrix, employing bioactive cues integrated into the peptide nanofiber scaffold without adding exogenous growth factors.