Recent advances in hydrogels for cartilage tissue engineering

Abstract

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 with a focus on recapitulating the microenvironments present during development or in adult tissue, in order 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 possible properties 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 better incorporation of biological signals (e.g. controlled release). This review summarises these innovative approaches to engineer hydrogels towards cartilage repair, with an eye towards eventual clinical translation.

Fig. 1

Schematic depicting different designs utilized in hydrogels, from (a) traditional single polymer networks to those that include (b,c) multiple networks and (d-f) mixtures of polymers. Double networks may be linked together, but this is not a requirement. Generally, the network design controls properties such as mechanics and degradation.

Fig. 2

(a) SEM micrograph of a fibrinogen hydrogel with (bottom) and without (top) interpenetrating methacrylated HA network (Snyder et al., 2014). (b) MSCs encapsulated in gelatin methacrylamide hydrogels exhibit more aggrecan (green) with increasing concentrations of methacrylated HA, which acts as a dual network (Levett et al., 2014). (c) Hydrogel molecular structures and crosslinking schemes can become quite complex, as seen by this schematic depicting supramolecular hydrogels prepared with CB[6]-HA, DAH-HA, and drug conjugated Dexa-CB[6] (Jung et al., 2014).

Fig. 3

Overview of different macroporous scaffold structures used for cartilage tissue engineering. To create hydrogel fibers, 3D printing and spinning techniques have been employed (blue box). In contrast, porous hydrogels and complementary microsphere hydrogels can also be fabricated (red box). To recapitulate native cartilage structures (e.g., different regions of cartilage, the osteochondral interface), multi-layer hydrogels incorporating several fabrication techniques can also be utilized (bottom).

Fig. 4

SEM micrographs of PBLG microsphere hydrogels fabricated at a gelatin concentration of (a,b) 1.9 % and (c,d) 3.25 % (Fang et al., 2015). 3D printing was used to print (e) a human ear and (f,g) sheep meniscus, as seen from different angles with Ink8020 after crosslinking (Muller et al., 2015).

Fig. 5

Overview of controlled presentation of biochemical factors. These include cell-cell and cell-matrix interactions, as well as growth factors and other molecules that can be either tethered to the hydrogels via affinity or heparin binding, or encapsulated in MPs and NPs for controlled release.

Fig. 6

Human MSCs were (a) photoencapsulated in hydrogels containing either N-cadherin mimics or scrambled sequence controls. (b) After 4 weeks of in vitro culture, N-cadherin mimics enhanced chondroitin sulfate (CS) and type II collagen (COL2) by human MSCs, as seen by immunohistochemical staining (Bian et al., 2013). (c-d) Single cell analysis of MSCs in these hydrogel environments showed an increase in N-cadherin mediated β-catenin signaling after 3 days in culture. (c) Cross-sectional images of MSCs stained for β-catenin (green) show that N-cadherin mimics recruit β-catenin to the cell membrane. Additionally, N-cadherin mimics induced an increase in nuclear β-catenin, as confirmed by (d) representative maximum (top) and average (bottom) projections of single MSCs stained for actin (red), nucleus (blue) and β-catenin (green) (Vega et al., 2016). Scale bars: b = 50 μm; c,d = 25 μm.