Cell encapsulation in biodegradable hydrogels for tissue engineering applications

Abstract

Encapsulating cells in biodegradable hydrogels offers numerous attractive features for tissue engineering, including ease of handling, a highly hydrated tissue-like environment for cell and tissue growth, and the ability to form in vivo. Many properties important to the design of a hydrogel scaffold, such as swelling, mechanical properties, degradation, and diffusion, are closely linked to the crosslinked structure of the hydrogel, which is controlled through a variety of different processing conditions. Degradation may be tuned by incorporating hydrolytically or enzymatically labile segments into the hydrogel or by using natural biopolymers that are susceptible to enzymatic degradation. Because cells are present during the gelation process, the number of suitable chemistries and formulations are limited. In this review, we describe important considerations for designing biodegradable hydrogels for cell encapsulation and highlight recent advances in material design and their applications in tissue engineering.

FIG. 1.

Cell encapsulation strategies involve mixing cells with precursors in a liquid solution followed by gelation and encapsulation of cells. The crosslinked structure will largely dictate diffusion of newly synthesized ECM molecules, and therefore, degradation of the scaffold must closely follow ECM synthesis and macroscopic tissue development. The gel precursors, gelation mechanisms, and degradation products must be cytocompatible.

FIG. 2.

A typical plot of mass loss versus degradation time for a crosslinked hydrogel. A characteristic feature of the degradation profile is the point where there are fewer than two crosslinks per polymer chain and the highly branched polymer chains dissolve. This point is referred to as reverse gelation. A number of factors influence the degradation rate and profile, including the chemistry, as well as the number of degradable linkages present in the hydrogel and the crosslinking density of the hydrogel.

FIG. 3.

(A, B) Human mesenchymal stem cells (hMSCs) encapsulated in a photopolymerized hydrolytically biodegradable PEG hydrogel and cultured in osteogenic medium. After encapsulation and when limited degradation has occurred, hMSCs adopt a spherical morphology (A). With sufficient degradation, hMSCs are able to migrate and form cell–cell junctions and adopt a more osteogenic-like phenotype (B). Reproduced with permission from Cushing et al. (C, D) Engineered cartilage after 2 (C) and 6 (D) weeks in vitro culture (glycosaminoglycans stained red). Chondrocytes were encapsulated in a biodegradable PEG-co-PVA hydrogel exhibiting bimodal degradation. Reprinted with permission from Martens et al. (E, F) Fibroblasts encapsulated in an enzymatically degradable PEG hydrogel. When crosslinks are degraded, fluorescence is emitted at the degradation site enabling spatial visualization of the degrading gel. After 7 days postencapsulation, cell-mediated degradation was observed only in the direction of the extended process (E); however, when treated with an MMP inhibitor, no cell-mediated degradation was observed (F). Reproduced with permission from Lee et al. Color images available online at www.liebertpub.com/ten.