A novel full-reduced HMGB1 and kartogenin-containing bio-active scaffold for meniscus regeneration

Abstract

43 44 A novel bio-active scaffold for enhancing wounded meniscus healing has been developed by 45 combination of High mobility group box 1 protein (HMGB1) and kartogenin (KGN) with 46 alginate gel. The properties of the bio-active scaffold were also investigated using an in vitro cell 47 culture model and in vivo rat wounded meniscus healing model. This HMGB1-KGN-containing 48 bioactive scaffold released HMGB1 and KGN into wound area and kept high concentrations of 49 HMGB1 and KGN in the system for more than two weeks. This HMGB1-KGN-containing 50 bioactive scaffold also activated rat bone marrow stem cells (BMSCs) from G0 to GAlert stage and 51 promoted cell proliferation as evidenced by 5-bromo-2-deoxyuridine (BrdU) incorporation 52 testing. Our results also demonstrated that the HMGB1-KGN-containing bioactive scaffold 53 induced cell migration in vitro and recruited the cells to wound area to promote wounded rat 54 meniscus healing in vivo. 55 56 57 58 59 60 61 62 63 64 4 65 66 67The menisci are C-shaped fibrocartilage located between the femoral condyles and tibial plateau 68 to transmit the load across the joint space [1]. Menisci play an important role in joint 69 stabilization, proprioception, lubrication and protection of articular cartilage [2]. Such 70 environment and function lead to meniscus easily injury and damaged meniscus can cause the 71 progression of cartilage degeneration and result in osteoarthritis [3]. Clinical studies have found 72 that it is difficult to regenerate the meniscus due to the specific structural and functional 73 properties of the meniscus tissue [1]. 74 75Histology studies have shown that meniscus is a geometrically and biochemically complex tissue. 76Its outer 1/3 tissue is formed by collagen type I produced by fibroblast-like cells, while its inner 77 2/3 tissue is formed by collagen II and proteoglycan produced by chondrocyte-like cells [4]. 78 Vascularization in meniscus is of high relevance. The meniscus is fully vascularized during fetal 79 development though blood supply diminishes over time, receding to the peripheral 20-30% by 10 80 years of age [4], [1]. 81 82The injury in the avascular zone of the meniscus is generally more complex and broad, and is 83 often associated with a poor prognosis following repair [5]. Promoting the healing process in the 84 avascular zone of the meniscus is an ongoing challenge for both clinical medical doctors and 85 orthopedic researchers [6]. Recently, tissue engineering approaches that involve the use of adult 86 tissue-derived multi-potent stem cells and biomaterial scaffolds have gained increasing attention 87 5 for enhancing the wounded meniscus healing. However, the isolation and culture of stem cells 88 not only need the donor tissue obtained by additional surgical procedure but also take long time 89 and increase contamination risk. Therefore, recruiting stem cells to wound area to enhance 90 wound healing is still a new challenge for orthopedic researchers. 91 92 High mobility group box 1 protein (HMGB1) is a ubiquitously...