Combining decellularized adipose tissue with decellularized adventitia extravascular matrix or small intestinal submucosa matrix for the construction of vascularized tissue-engineered adipose

Lu Cui; Yujia Zhao; Yuxuan Zhong; Lanlan Zhang; Xinnan Zhang; Zhenglong Guo; Fanglin Wang; Xin Chen; Hao Tong; Jun Fan

doi:10.1016/j.actbio.2023.08.060

Combining decellularized adipose tissue with decellularized adventitia extravascular matrix or small intestinal submucosa matrix for the construction of vascularized tissue-engineered adipose

Acta Biomater. 2023 Oct 15:170:567-579. doi: 10.1016/j.actbio.2023.08.060. Epub 2023 Sep 7.

Authors

Lu Cui¹, Yujia Zhao¹, Yuxuan Zhong¹, Lanlan Zhang¹, Xinnan Zhang¹, Zhenglong Guo², Fanglin Wang¹, Xin Chen¹, Hao Tong¹, Jun Fan³

Affiliations

¹ Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, PR China.
² Second Clinical Medical College, Shengjing Hospital, China Medical University, No.36 Sanhao Road, Heping District, Shenyang, Liaoning Province 110004, PR China.
³ Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, PR China. Electronic address: jfan@cmu.edu.cn.

PMID: 37683968
DOI: 10.1016/j.actbio.2023.08.060

Abstract

Adipose tissue is an endocrine organ. It serves many important functions, such as energy storage, hormones secretion, and providing insulation, cushioning and aesthetics to the body etc. Adipose tissue engineering offers a promising treatment for soft tissue defects. Early adipose tissue production and long-term survival are closely associated with angiogenesis. Decellularized matrix has a natural ECM (extracellular matrix) component, good biocompatibility, and low immunogenicity. Therefore, in this study, the injectable composite hydrogels were developed to construct vascularized tissue-engineered adipose by using the pro-angiogenic effects of aortic adventitia extravascular matrix (Adv) or small intestinal submucosa (SIS), and the pro-adipogenic effects of decellularized adipose tissue (DAT). The composite hydrogels were cross-linked by genipin. The adipogenic and angiogenic abilities of composite hydrogels were investigated in vitro, and in a rat dorsal subcutaneous implant model. The results showed that DAT and SIS or Adv 1:1 composite hydrogel promoted the migration and tube formation of endothelial cells. Furthermore, DAT and SIS or Adv 1:1 composite hydrogel enhanced adipogenic differentiation of adipose-derived mesenchymal stem cells (ASCs) through activation of PPARγ and C/EBPα. The in vivo studies further demonstrated that DAT with SIS or Adv in a 1:1 ratio also significantly promoted adipogenesis and angiogenesis. In addition, DAT with SIS or Adv in a 1:1 ratio hydrogel recruited macrophage population with enhanced M2-type macrophage polarization, suggesting a positive effect of inflammatory response on angiogenesis. In conclusion, these data suggest that the composite hydrogels of DAT with SIS or Adv in 1:1 ratio have apparent pro-adiogenic and angiogenic abilities, thus providing a promising cell-free tissue engineering biomaterial with broad clinical applications. STATEMENT OF SIGNIFICANCE: Decellularized adipose tissue (DAT) has emerged as an important biomaterial in adipose tissue regeneration. Early adipose tissue production and long-term survival is tightly related to the angiogenesis. The revascularization of the DAT is a key issue that needs to be solved in adipose regeneration. In this study, the injectable composite hydrogels were developed by using DAT with Adv (aortic adventitia extravascular matrix) or SIS (small intestinal submucosa) in different ratio. We demonstrated that the combination of DAT with SIS or Adv in 1:1 ratio effectively improved the proliferation of adipose stem cells and endothelial cells, and promoted greater adipose regeneration and tissue vascularization as compared to the DAT scaffold. This study provides the potential biomaterial for clinical soft tissue regeneration.

Keywords: Adipose regeneration; Angiogenesis; Decellularized adipose tissue; Extravascular matrix; Hydrogels; Small intestinal submucosa; Tissue engineering.