Click chemistry-based pre-targeting cell delivery for cartilage regeneration

Abstract

A fraction of the OA patient population is affected by post-traumatic osteoarthritis (PTOA) following acute joint injuries. Stopping or reversing the progression of PTOA following joint injury could improve long-term functional outcomes, reduced disability, and medical costs. To more effectively treat articular cartilage injury, we have developed a novel cell-based therapy that involves the pre-targeting of apoptotic chondrocytes and the delivery of healthy, metabolically active chondrocytes using click chemistry. Specifically, a pre-targeting agent was prepared via conjugating apoptotic binding peptide (ApoPep-1) and trans-cyclooctene (TCO) onto polyethylene glycol (PEG) polymer carrier. The pre-targeting agent would be introduced to injured areas of articular cartilage, leading to the accumulation of TCO groups on the injured areas from actively binding to apoptotic chondrocytes. Subsequently, methyltetrazine (Tz)-bearing chondrocytes would be immobilized on the surface of TCO-coated injured cartilage via Tz-TCO click chemistry reaction. Using an ex vivo human cartilage explant PTOA model, the effectiveness of this new approach was evaluated. Our studies show that this novel approach (Tz-TCO click chemistry) significantly enhanced the immobilization of healthy and metabolically active chondrocytes to the areas of apoptotic chondrocytes. Histological analyses demonstrated that this treatment regimen would significantly reduce the area of cartilage degeneration and enhance ECM regeneration. The results support that Tz-TCO click chemistry-mediated cell delivery approach has great potential in clinical applications for targeting and treatment of cartilage injury.

New Insights into Cartilage Tissue Engineering: Improvement of Tissue-Scaffold Integration to Enhance Cartilage Regeneration

“…Dual functionalization of PEG by transcyclooctene (TCO) and apoptotic binding peptide (ApoPep-1) led to the development of a crosslinker that binds to apoptotic chondrocytes of injured cartilage explant and methyltetrazine-bearing metabolically active chondrocytes through ApoPep-1 and TCO, respectively. This click chemistry-based pretargeting approach resulted in significant reduction of cartilage degeneration and increased ECM synthesis [ 72 ]. Since TCD is a developing approach for repairing cartilage defects, its integrative capacity is not well-studied yet, but is expected to be explored in early future.…”

Recent Biomimetic Approaches for Articular Cartilage Tissue Engineering and Their Clinical Applications: Narrative Review of the Literature

“…e results employing autogenic cartilage implanted in a pos-traumatic osteoarthritis defect indicated favorable results in cartilage damage specifically [31]. Furthermore, more advanced methods were used to improve articular cartilage regeneration using bioactive molecules.…”

Current Advances in the Regeneration of Degenerated Articular Cartilage: A Literature Review on Tissue Engineering and Its Recent Clinical Translation

“…Microfracture ± HA ± haMPCs [55] AD-MSCs ± allogeneic cartilage from fresh cadavers [56] Intra-articular injection of autologous SVF [57] Intra-articular injections of allogeneic haMPCs [58]…”

“…For this purpose, they developed a dual-acting system that first targets apoptotic chondrocytes by a PEG polymer carrier conjugated with apoptosis-targeting peptide-1 (ApoPep-1) and trans-cyclooctene (TCO) and, second, delivers metabolically active chondrocytes. The results of the in vitro assessments and ex vivo studies using human cartilage explant PTOA models showed promising outcomes in specifically targeting and treating cartilage injury [ 56 ]. Moreover, more complex technologies were applied to optimize articular cartilage regeneration via bioactive molecules.…”