Articular cartilage is a load-bearing tissue that lines the surface of bones in diarthrodial joints. Unfortunately, this avascular tissue has a limited capacity for intrinsic repair. Treatment options for articular cartilage defects include microfracture and arthroplasty; however, these strategies fail to generate tissue that adequately restores damaged cartilage. Limitations of current treatments for cartilage defects have prompted the field of cartilage tissue engineering, which seeks to integrate engineering and biological principles to promote the growth of new cartilage to replace damaged tissue. To-date, a wide range of scaffolds and cell sources have emerged towards cartilage tissue engineering, with a focus on recapitulating microenvironments present during development or in adult tissue to induce the formation of cartilaginous constructs with biochemical and mechanical properties of native tissue. Hydrogels have emerged as a promising scaffold due to the wide range of properties that are possible and the ability to entrap cells within the material. Towards improving cartilage repair, hydrogel design has advanced in recent years to improve their utility. Some of these advances include the development of improved network crosslinking (e.g., double-networks), new techniques to process hydrogels (e.g., 3D printing), and the better incorporation of biological signals (e.g., controlled release). This review summarizes these innovative approaches to engineer hydrogels towards cartilage repair, with an eye towards eventual clinical translation.

3D microenvironmental parameters control cell behavior, but can be challenging to investigate over a wide range of conditions. Here, a combinatorial hydrogel platform is developed that uses light-mediated thiol-norbornene chemistry to encapsulate cells within hydrogels with biochemical gradients made by spatially varied light exposure. Specifically, mesenchymal stem cells are photoencapsulated in norbornene-modified hyaluronic acid hydrogels functionalized with gradients (0–5 mM) of peptides that mimic cell-cell or cell-matrix interactions, either as single or orthogonal gradients. Chondrogenesis varied spatially in these hydrogels based on the local biochemical formulation, as indicated by Sox9 and aggrecan expression levels. From 100 combinations investigated, discrete hydrogels are formulated and early gene expression and long-term cartilage-specific matrix production are assayed and found to be consistent with screening predictions. This platform is a scalable, high-throughput technique that enables the screening of the effects of multiple biochemical signals on 3D cell behavior.

3D bioprinting is a promising approach for the repair of cartilage tissue after damage due to injury or disease; however, the design of 3D printed scaffolds has been limited by the availability of bioinks with requisite printability, cytocompatibility, and bioactivity. To address this, we developed an approach termed in situ crosslinking that permits the printing of non-viscous, photocrosslinkable bioinks via the direct-curing of the bioink with light through a photopermeable capillary prior to deposition. Using a norbornene-modified hyaluronic acid (NorHA) macromer as a representative bioink and our understanding of thiol-ene curing kinetics with visible light, we varied the printing parameters (e.g., capillary length, flow rate, light intensity) to identify printing conditions that were optimal for the ink. The printing process was cytocompatible, with high cell viability and homogenous distribution of mesenchymal stromal cells (MSCs) observed throughout printed constructs. Over 56 days of culture in chondrogenic media, printed constructs increased in compressive moduli, biochemical content (i.e., sulfated glycosaminoglycans, collagen), and histological staining of matrix associated with cartilage tissue. This generalizable printing approach may be used towards the repair of focal defects in articular cartilage or broadly towards widespread biomedical applications across a range of photocrosslinkable bioinks that can now be printed.

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