Therapeutic application of 3B-PEG injectable hydrogel/Nell-1 composite system to temporomandibular joint osteoarthritis

Abstract

This study aims to construct a composite system of the tri-block polyethylene glycol injectable hydrogel (3B-PEG IH) and neural epithelial growth factor-like protein 1 (Nell-1), and to analyze its therapeutic effect on temporomandibular joint osteoarthritis (TMJOA). Sol-gel transition temperature was measured via inverting test. The viscoelastic modulus curves was measured by rheometer. Degradation and controlled release profiles of 3B-PEG IH were drawn in vitro. In vivo gel retention and biocompatibility were completed subcutaneously on the back of rats. After primary chondrocytes were extracted and identified, the cell viability in 3B-PEG IH was measured. Evaluation of gene expression in hydrogel was performed by real-time polymerase chain reaction. TMJOA rabbits were established by intra-articular injection of type II collagenase. Six weeks after composite systems being injected, gross morphological score, micro-CT, histological staining and grading were evaluated. The rusults showed that different types of 3B-PEG IH all reached a stable gel state at 37 °C and could support the three-dimensional growth of chondrocytes, but poly(lactide-co-caprolactone)-block-poly(ethyleneglycol)-block-poly(lactide-co-caprolactone) (PLCL-PEG-PLCL) hydrogel had a wider gelation temperature range and better hydrolytic stability for about 4 weeks. Its controlled release curve is closest to the zero-order release kinetics. In vitro, PLCL-PEG-PLCL/Nell-1 could promote the chondrogenic expression and reduce the inflammatory expression. In vivo, TMJOA rabbits were mainly characterized by the disorder of cartilage structure and the destruction of subchondral bone. However, PLCL-PEG-PLCL/Nell-1 could reverse the destruction of the subchondral trabecula, restore the fibrous and proliferative layers of the surface, and reduce the irregular hyperplasia of fibrocartilage layer. In conclusion, by comparing the properties of different 3B-PEG IH, 20 wt% PLCL-PEG-PLCL hydrogel was selected as the most appropriate material. PLCL-PEG-PLCL/Nell-1 composite could reverse osteochondral damage caused by TMJOA, Nfatc1-Runx3 signaling pathway may play a role in it. This study may provide a novel, minimally-invasive therapeutic strategy for the clinical treatment of TMJOA.

Role of hydrogels in osteoarthritis: A comprehensive review

“…Mandibular condylar chondrocytes (MCSs) cultured with tri‐block polyethylene glycol hydrogel with neural epithelial growth factor‐like protein 1 (3B‐PEG IH/Nell‐1) showed increased chondrogenic expression of SOX9 and aggrecan. When IL‐1β treated OA rabbit MCSs, there were increased levels of MMP‐3, MMP‐13, and ADAMTS5, but the addition of 3B‐PEG IH/Nell‐1hydrogel downregulated the inflammatory proteins and RUNX3 23 . Together, polyethylene glycol‐based hydrogels may inhibit pro‐inflammatory component production.…”

“…23 After injection of 3B-PEG IH/Nell-1 hydrogel, it restored surface fibrous and proliferative layers, reduced irregular hyperplasia of the fibrocartilage layer, improved cartilage matrix expression, and downregulated levels of nuclear factor of activated T-cells 1 (NFATc1) and RUNX3. 23 This was consistent with another growth factor-related hydrogel, where microfracture surgery-induced OA minipigs injected with insulin-like growth factor I (IGF-I) overexpressed recombinant adeno-associated virus (rAAV) hydrogel for a year. Total histological scores were improved, and there was much deposition of ECM components in the repair tissue of defects and reduced expression of IL-1β and TNFα in the repair tissue of defects.…”

“…ACLT surgery‐induced OA rats injected with self‐assembling peptide hydrogel‐based agomir‐29b‐5p (SKP@miR) showed no joint effusion, periarticular osteophyte formation, stable subchondral bone, lower synovitis scores in knees, relieved thickening of the synovial lining layer, lower OARSI score, and higher expression of collagen IIɑ1, decreased levels of MMP‐13 37 . In temporomandibular joint OA rabbits injected with collagenase II, there were decreased bone volume fraction (BVF), bone mineral density (BMD), increased bone surface (BS)/bone volume (BV)/trabecular separation (Tb.Sp), and a thinner surface fibrous layer of condylar cartilage 23 . After injection of 3B‐PEG IH/Nell‐1 hydrogel, it restored surface fibrous and proliferative layers, reduced irregular hyperplasia of the fibrocartilage layer, improved cartilage matrix expression, and downregulated levels of nuclear factor of activated T‐cells 1 (NFATc1) and RUNX3 23 .…”

“…In temporomandibular joint OA rabbits injected with collagenase II, there were decreased bone volume fraction (BVF), bone mineral density (BMD), increased bone surface (BS)/bone volume (BV)/trabecular separation (Tb.Sp), and a thinner surface fibrous layer of condylar cartilage 23 . After injection of 3B‐PEG IH/Nell‐1 hydrogel, it restored surface fibrous and proliferative layers, reduced irregular hyperplasia of the fibrocartilage layer, improved cartilage matrix expression, and downregulated levels of nuclear factor of activated T‐cells 1 (NFATc1) and RUNX3 23 . This was consistent with another growth factor‐related hydrogel, where microfracture surgery‐induced OA minipigs injected with insulin‐like growth factor I (IGF‐I) overexpressed recombinant adeno‐associated virus (rAAV) hydrogel for a year.…”

Advanced injectable hydrogels for cartilage tissue engineering

“…Hydrogel development is the most promising method for treating cartilage defects and cartilage regeneration ( Wei et al, 2021 ; Huang et al, 2022 ). Injectable hydrogels have attracted the attention of biomaterial scientists in cartilage tissue engineering ( Schaeffer et al, 2020 ; Wang et al, 2021a ) ( Figure 1 ). Because it can replace open implants with minimally invasive injections, it has the advantages of being less invasive, fewer complications, shorter hospital stays, and forming any desired shape in situ to match irregular defects ( Liu et al, 2017a ; Pascual-Garrido et al, 2018 ; Lin et al, 2021a ).…”