Application of Alginate Hydrogels for Next-Generation Articular Cartilage Regeneration

Abstract

The articular cartilage has insufficient intrinsic healing abilities, and articular cartilage injuries often progress to osteoarthritis. Alginate-based scaffolds are attractive biomaterials for cartilage repair and regeneration, allowing for the delivery of cells and therapeutic drugs and gene sequences. In light of the heterogeneity of findings reporting the benefits of using alginate for cartilage regeneration, a better understanding of alginate-based systems is needed in order to improve the approaches aiming to enhance cartilage regeneration with this compound. This review provides an in-depth evaluation of the literature, focusing on the manipulation of alginate as a tool to support the processes involved in cartilage healing in order to demonstrate how such a material, used as a direct compound or combined with cell and gene therapy and with scaffold-guided gene transfer procedures, may assist cartilage regeneration in an optimal manner for future applications in patients.

Keywords: alginate; cartilage regeneration; cell therapy; gene therapy; hydrogel; scaffold-guided gene transfer.

Figure 1

Research progress on alginate for cartilage regeneration (created with Prism).

Figure 2

Structure of 1,4-linked β-D-mannuronic acid and 1,4 linked α-L-guluronic acid. The two-dimensional structures of (a) 1,4-linked β-D-mannuronic acid (CID: 439630) and (b) 1,4 linked α-L-guluronic acid (CID: 446401) were obtained from PubChem and their three-dimensional structures were drawn with LiteMol Viewer (1.6.5).

Figure 3

Fabrication of a cell–alginate hydrogel. (a–c) Cell encapsulation, (d,e) cell adhesion, (a,b,d,e) cation diffusion, and (c) cation dissociation (created with BioRender.com).

Figure 4

Relationship between the cell redifferentiation abilities. (a) Modification of cell expression associated with the relative/absolute relationship between dedifferentiation and redifferentiation (duration of passage: 7.4 ds, according to [21,34,79,93,151,167,196,206,207,208]). (b) Ratio (dedifferentiation/redifferentiation) for collagen expression (* indicates statistically significant differences between groups). (c) Relationship between chondrogenic expression (PGs, type-II/-I/-X/-III collagen) and culture period (dots represent independent publications matching the parameters of duration of chondrocyte redifferentiation versus differentiation) (created with Prism (a,b) and Past (c)).

Figure 5

Use of alginate for chondrocyte redifferentiation versus other materials. Biomaterials used for chondrocyte redifferentiation in total (a) and annual (b) publications. PGA, poly(glycolic acid); GelMA, gelatin methacryloyl; HA, hyaluronic acid; PCL, poly(ε-caprolactone); PEG, polyethylene glycol; PEGT-PBT, polyethylene glycol terephthalate/polybutylene terephthalate; PMMA, poly(methyl methacrylate); Poly(N-D), poly(NaAMPS-co-DMAAm); PolyHEMA, poly-(2-hydroxyethyl methacrylate); created with Prism (a) and Morpheus (b).

Figure 6

Strategies using gene therapy combined with alginate for articular cartilage regeneration. The approaches include (a–c) the indirect, cell-associated encapsulation of genetically modified cells in alginate and (d) the direct, cell-free formulation of gene transfer vectors in alginate, both as potential implantable platforms in articular cartilage defects. (a) Genetic modification before alginate encapsulation [68]. (b) Genetic modification after alginate encapsulation [343]. (c) Genetic modification with alginate encapsulation (gene-activated matrix) [344,345]. (d) Gene vectors with alginate encapsulation [342]. Created with BioRender.com.

Figure 7

Enhanced cell adhesion with alginate incorporation and alginate modification (yearly distribution of the number of publications); created with Morpheus.

Figure 8

Co-culture systems and 3D printing techniques. (a) Co-culture systems using alginate. The orange part presents cells mixed, encapsulated in alginate, and then maintained in culture. The blue part presents cells encapsulated in alginate, mixed, and then maintained in culture. The deep cords show combinations of chondrocytes and progenitor cells (A) in alginate, (M) in monolayer, (C) in collagen, (B) in bioglass, and (D) in direct contact (ACs, articular chondrocytes; AM-, amniotic membrane; B-, bovine; BM-, bone marrow; bMSCs, bone marrow mesenchymal stromal cells; Cartilage, zonal cartilage tissue; De-ACs, dedifferentiated articular chondrocytes; H-, human; MSCs, mesenchymal stromal cells; OACs, osteoarthritic articular chondrocytes; OASF, osteoarthritic synovial fibroblasts; P-, porcine; Ra-, rat; Rb-, rabbit; S-, synovium; SCOB, subchondral osteoblasts). (b) Use of alginate as a bioink in 3D printing (ADA, alginate-di-aldehyde; AG, agarose; Alginate SNC, alginate sulfate nano-cellulose; ASCs, adipose-derived stromal cells (progenitors); CMSUP, calcium-magnesium silicate ultrafine particles; CNC, cellulose nanocrystals; Col-I, type-I collagen; CS, chondroitin sulfate; CS-AEMA, chondroitin sulfate amino ethyl methacrylate; ECM, extracellular matrix; F127, Pluronic F127; GelMA, gelatin methacrylamide; GO, graphene oxide; HA, hyaluronate; HACA, catechol modified hyaluronic acid; HAMA, hyaluronic acid methacrylate; HNT, halloysite nanotube; MC, methyl cellulose; MSCs, mesenchymal stromal cells; NFC, nanofibrillated cellulose; NPs, nanoparticles; OxA, oxidized alginate; PCL, polycaprolactone; PEG, poly(ethylene glycol); PEOXA, poly(2-ethyl-2-oxazoline); PLA, polylactic acid; PVDF, polyvinylidene fluoride; RGD-gamma-alginate, gamma-irradiated alginate with RGD peptides); created with Flourish.