Biomimetic Gradient Scaffolds Containing Hyaluronic Acid and Sr/Zn Folates for Osteochondral Tissue Engineering

Abstract

Regenerative therapies based on tissue engineering are becoming the most promising alternative for the treatment of osteoarthritis and rheumatoid arthritis. However, regeneration of full-thickness articular osteochondral defects that reproduces the complexity of native cartilage and osteochondral interface still remains challenging. Hence, in this work, we present the fabrication, physic-chemical characterization, and in vitro and in vivo evaluation of biomimetic hierarchical scaffolds that mimic both the spatial organization and composition of cartilage and the osteochondral interface. The scaffold is composed of a composite porous support obtained by cryopolymerization of poly(ethylene glycol) dimethacrylate (PEGDMA) in the presence of biodegradable poly(D,L-lactide-co-glycolide) (PLGA), bioactive tricalcium phosphate β-TCP and the bone promoting strontium folate (SrFO), with a gradient biomimetic photo-polymerized methacrylated hyaluronic acid (HAMA) based hydrogel containing the bioactive zinc folic acid derivative (ZnFO). Microscopical analysis of hierarchical scaffolds showed an open interconnected porous open microstructure and the in vitro behaviour results indicated high swelling capacity with a sustained degradation rate. In vitro release studies during 3 weeks indicated the sustained leaching of bioactive compounds, i.e., Sr2+, Zn2+ and folic acid, within a biologically active range without negative effects on human osteoblast cells (hOBs) and human articular cartilage cells (hACs) cultures. In vitro co-cultures of hOBs and hACs revealed guided cell colonization and proliferation according to the matrix microstructure and composition. In vivo rabbit-condyle experiments in a critical-sized defect model showed the ability of the biomimetic scaffold to promote the regeneration of cartilage-like tissue over the scaffold and neoformation of osteochondral tissue.

Recent development in multizonal scaffolds for osteochondral regeneration

“…Its biodegradation rate is higher than that of PCL and can be easily tailored via various routes, such as by modulating the ratio of lactic acid to glycolic acid in the PLGA chain [ 203 ]. The good processing properties of PLGA make it an attractive candidate for 3D printing [ 204 ], or to be added to a polymeric matrix to control the biodegradation and biological performances of scaffolds [ 205 ]. Recently, PLGA has been used to fabricate the bone layer [ 23 , 64 , 104 ], the cartilage layer [ [82] , [83] , [84] ] or the entire MZS [ 63 , 73 , 77 , 78 , 86 , 205 ].…”

“…The good processing properties of PLGA make it an attractive candidate for 3D printing [ 204 ], or to be added to a polymeric matrix to control the biodegradation and biological performances of scaffolds [ 205 ]. Recently, PLGA has been used to fabricate the bone layer [ 23 , 64 , 104 ], the cartilage layer [ [82] , [83] , [84] ] or the entire MZS [ 63 , 73 , 77 , 78 , 86 , 205 ]. In these studies, PLGA supported cell attachment [ 206 ], high subchondral bone regeneration [ 23 , 78 , 104 ], and simultaneous chondrogenic and osteogenic differentiations [ 86 ].…”

Continuously released Zn2+ in 3D-printed PLGA/β-TCP/Zn scaffolds for bone defect repair by improving osteoinductive and anti-inflammatory properties

“…Ultimately, this long-term release of Zn 2+ made the scaffold had osteogenic and anti-inflammatory effects, suggesting that the scaffold is suitable for bone repair. Considering that the osteogenic and anti-inflammatory mechanisms of Zn-added polymers are currently unknown, there are no studies on the anti-inflammatory mechanisms of Zn-SPs-containing scaffolds [ 30 , 31 ]. We further explored the possible mechanisms by which Zn-SPs-containing PLGA/β-TCP scaffolds affect osteogenic differentiation and inflammatory responses by proteomic analysis.…”

A study on Sr/Zn phytate complexes: structural properties and antimicrobial synergistic effects against Streptococcus mutans

“…Thus, we propose the synthesis and evaluation of two metallic derivatives of PA bearing Zn 2+ and Sr 2+ (named as ZnPhy and SrPhy respectively). The selected cations have been applied on regenerative therapies exhibiting a significant promotion of bone and cartilage tissues formation in vivo 23 – 25 . Zn 2+ is a bioactive cation involved in several key metabolic processes and owns powerful antimicrobial, antioxidant and anti-inflammatory activities 26 , 27 .…”