Harnessing cell-material interactions to control stem cell secretion for osteoarthritis treatment.

Osteoarthritis (OA) is the most common debilitating joint disease, yet there is no curative treatment for OA to date. Delivering mesenchymal stromal cells (MSCs) as therapeutic cells to mitigate the inflammatory symptoms associated with OA is attracting increasing attention. In principle, MSCs could respond to the pro-inflammatory microenvironment of an OA joint by the secretion of anti-inflammatory, anti-apoptotic, immunomodulatory and pro-regenerative factors, therefore limiting pain, as well as the disease development. However, the microenvironment of MSCs is known to greatly affect their survival and bioactivity, and using tailored biomaterial scaffolds could be key to the success of intra-articular MSC-based therapies. The aim of this review is to identify and discuss essential characteristics of biomaterial scaffolds to best promote MSC secretory functions in the context of OA. First, a brief introduction to the OA physiopathology is provided, followed by an overview of the MSC secretory functions, as well as the current limitations of MSC-based therapy. Then, we review the current knowledge on the effects of cell-material interactions on MSC secretion. These considerations allow us to define rational guidelines for next-generation biomaterial design to improve the MSC-based therapy of OA.

Click and bioorthogonal hyaluronic acid hydrogels as an ultra-tunable platform for the investigation of cell-material interactions.

The cellular microenvironment plays a major role in the biological functions of cells. Thus, biomaterials, especially hydrogels, which can be design to mimic the cellular microenvironment, are being increasingly used for cell encapsulation, delivery, and 3D culture, with the hope of controlling cell functions. Yet, much remains to be understood about the effects of cell-material interactions, and advanced synthetic strategies need to be developed to independently control the mechanical and biochemical properties of hydrogels. To address this challenge, we designed a new hyaluronic acid (HA)-based hydrogel platform using a click and bioorthogonal strain-promoted azide-alkyne cycloaddition (SPAAC) reaction. This approach facilitates the synthesis of hydrogels that are easy to synthesize and sterilize, have minimal swelling, are stable long term, and are cytocompatible. It provides bioorthogonal HA gels over an uncommonly large range of stiffness (0.5-45 kPa), all forming within 1-15 min. More importantly, our approach offers a versatile one-pot procedure to independently tune the hydrogel composition (e.g., polymer and adhesive peptides). Using this platform, we investigate the independent effects of polymer type, stiffness, and adhesion on the secretory properties of human adipose-derived stromal cells (hASCs) and demonstrate that HA can enhance the secretion of immunomodulatory factors by hASCs.

Clickable Dynamic Bioinks Enable Post-Printing Modifications of Construct Composition and Mechanical Properties Controlled over Time and Space.

Bioprinting is a booming technology, with numerous applications in tissue engineering and regenerative medicine. However, most biomaterials designed for bioprinting depend on the use of sacrificial baths and/or non-physiological stimuli. Printable biomaterials also often lack tunability in terms of their composition and mechanical properties. To address these challenges, the authors introduce a new biomaterial concept that they have termed "clickable dynamic bioinks". These bioinks use dynamic hydrogels that can be printed, as well as chemically modified via click reactions to fine-tune the physical and biochemical properties of printed objects after printing. Specifically, using hyaluronic acid (HA) as a polymer of interest, the authors investigate the use of a boronate ester-based crosslinking reaction to produce dynamic hydrogels that are printable and cytocompatible, allowing for bioprinting. The resulting dynamic bioinks are chemically modified with bioorthogonal click moieties to allow for a variety of post-printing modifications with molecules carrying the complementary click function. As proofs of concept, the authors perform various post-printing modifications, including adjusting polymer composition (e.g., HA, chondroitin sulfate, and gelatin) and stiffness, and promoting cell adhesion via adhesive peptide immobilization (i.e., RGD peptide). The results also demonstrate that these modifications can be controlled over time and space, paving the way for 4D bioprinting applications.