Local delivery of HMGB1 in gelatin sponge scaffolds combined with mesenchymal stem cell sheets to accelerate fracture healing

// Deting Xue 1 , Wei Zhang 1 , Erman Chen 1 , Xiang Gao 1 , Ling Liu 2 , Chenyi Ye 1 , Yanbin Tan 1 , Zhijun Pan 1 and Hang Li 1 1 Department of Orthopaedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China 2 Department of Nephrology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou 310007, P.R. China Correspondence to: Zhijun Pan, email: zepzj001@163.com Hang Li, email: lihanghz001@163.com Keywords: cell sheets, HMGB1, fracture healing, gelatin sponge scaffold, tissue engineering Received: February 21, 2017      Accepted: March 28, 2017      Published: April 06, 2017 ABSTRACT Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention.