Synergistic enhancement of tendon-to-bone healing via anti-inflammatory and pro-differentiation effects caused by sustained release of Mg²⁺/curcumin from injectable self-healing hydrogels

Abstract

Poor healing response after rotator cuff reconstruction is multifactorial, with the inflammatory microenvironment and deficiency of stem cell differentiation factors at the lesion site being most relevant. However, there is a lack of effective tissue engineering strategies that can simultaneously exert anti-inflammatory and pro-differentiation effects to promote rotator cuff healing. Methods: In this study, we synthesized and characterized a novel active drug delivery vector that successfully overcame the challenge of simultaneous high-efficiency loading and controlled release of Mg 2+ and curcumin. The anti-inflammatory and pro-differentiation effects of the composite hydrogel were evaluated in vitro and in vivo . Moreover, healing of the rotator cuff tendon-to-bone interface was studied by histology, immunofluorescence, and biomechanical tests. Results: The composite hydrogel exhibited excellent biocompatibility and injectability, good adhesiveness, and rapid self-healing. The released curcumin showed obvious anti-inflammatory and antioxidation effects, which protected stem cells and tendon matrix. Furthermore, released Mg 2+ promoted stem cell aggregation and chondrogenesis. Moreover, biomechanical tests and histological results of a rat rotator cuff tear model at 8 weeks after surgery indicated that the composite hydrogel significantly enhanced tendon-to-bone healing. Conclusions: The composite hydrogel mediated sustained in situ release of curcumin and Mg 2+ to effectively promote rotator cuff tendon-to-bone healing via anti-inflammatory and pro-differentiation effects. Therefore, this composite hydrogel offers significant promise for rotator cuff repair.

Bioactive Herbal Extracts of Traditional Chinese Medicine Applied with the Biomaterials: For the Current Applications and Advances in the Musculoskeletal System

“…Interestingly, in another study, liposomal curcumin released from the three-dimensional printed scaffold showed significant cytotoxicity toward in vitro osteosarcoma cells, whereas it promoted osteoblast cell viability, and proliferation (Sarkar and Bose, 2019). Moreover, the composite hydrogel loading with Mg 2+ and curcumin could simultaneously exert anti-inflammatory and pro-differentiation effects to accelerate rotator cuff healing (Chen et al, 2021).…”

Hydrogel adhesives for generalized wound treatment: Design and applications

“…The biomechanical test and histological results of the rat rotator cuff tear model at 8 weeks after surgery showed that the hydrogel adhesive significantly enhanced the healing of the rotator cuff tendon‐bone interface. [ 120 ] Moreover, another study found that injection of ECM hydrogel into the achilles tendon defect in rats can promote the healing of the Achilles tendon. [ 118 ]…”

“…[ 145 ] Second, in addition to loading autologous chondrocytes, hydrogel adhesives can also promote cartilage repair by loading other biologically active ingredients (such as drugs, cytokines, and metal ions, etc.). [ 119,120,145 ] For instance, researchers loaded kartogenin (KGN; can induce BMSCs into chondrocytes) into the acrylated hyaluronic acid (m‐HA) hydrogel adhesive (Figure 10C), and in vitro study showed that KGN had a chondrogenesis effect on SMSCs, and in vivo studies showed its potential role for cell homing, especially for recruiting the host's endogenous cells (SMSCs and BMSCs), and promote the production of the tissue similar to cartilage. [ 145 ] In summary, because the mechanical strength and abrasion resistance of existing hydrogel adhesives are difficult to meet the needs of maintaining the normal function of cartilage.…”

Self-Healing Hydrogels: Preparation, Mechanism and Advancement in Biomedical Applications

“…Very recently, injectable and self-healing hydrogel comprising Mg 2+ /curcumin was used to treat rotator cuff injury [213]. Starting materials were quaternized chitosan (QCS) and Pluronic ® F127 (PF127-CHO).…”