Heterogeneity is key to hydrogel-based cartilage tissue regeneration

Abstract

Degradable hydrogels have been developed to provide initial mechanical support to encapsulated cells while facilitating growth of neo-tissues. When cells are encapsulated within degradable hydrogels, the process of neo-tissue growth is complicated by the coupled phenomena of transport of large extracellular matrix macromolecules and the rate of hydrogel degradation. If hydrogel degradation is too slow, neo-tissue growth is hindered, whereas if it is too fast, complete loss of mechanical integrity can occur. Therefore, there is a need for effective modelling techniques to predict hydrogel designs based on the growth parameters of the neo-tissue. In this article, hydrolytically degradable hydrogels are investigated due to their promise in tissue engineering. A key output of the model focuses on the ability of the construct to maintain overall structural integrity as the construct transitions from pure hydrogel to an engineered neo-tissue. We show that heterogeneity in cross-link density and cell distribution are key elements for this successful transition and ultimately to achieve tissue growth. Specifically, we find that optimally large regions of weak cross-linking around cells in the hydrogel and well-connected and dense cell clusters create the optimum conditions needed for neo-tissue growth while maintaining structural integrity. Experimental observations using cartilage cells encapsulated in a hydrolytically degradable hydrogel are compared with model predictions to show the potential of the proposed model.

Mechanical instability and percolation of deformable particles through porous networks

“…Further research effort will, therefore, be necessary to fundamentally understand the motion of soft particles or macromolecules in porous media under the action of driving pressure, self-propulsion [64] and more. Applications in particle separation, filtration, sorting as well as our ability to control macromolecule transport in polymers for tissue engineering [65][66][67] will critically depend on this understanding.…”

Local Heterogeneities Improve Matrix Connectivity in Degradable and Photoclickable Poly(ethylene glycol) Hydrogels for Applications in Tissue Engineering

“…This phenomenon enables ECM elaboration and ECM connectivity between adjacent cells in the clusters while the background regions maintain a cross-linked hydrogel. 56 Thus, the transition from hydrogel to ECM depends on the number of cells, clusters, and cluster size. Indeed, our results show that in the low cell density condition, which has smaller cell clusters, the overall modulus drops by ~50% at 4 weeks.…”

Zr(IV)‐Crosslinked Polyacrylamide/Polyanionic Cellulose Composite Hydrogels with High Strength and Unique Acid Resistance

“…Further increasing the PAC dosage to 4.5 wt % generates more and smaller pores, and finally nanoscale pores emerge in the PAC6‐Zr0.1 gel. This heterogeneous porous structure is reported to be beneficial to the local transport and deposition of neotissue, such that the hydrogels studied herein may be useful in tissue engineering. In addition, inside the networks, tree‐like fibers with nanoscale thicknesses appear in the PAC4.5‐Zr0.1 and PAC6‐Zr0.1 gels, as shown in Figure (c,e).…”