Antibiotic-Loaded Polymethyl Methacrylate Cement Drives Fibroblast-Mediated Angiogenesis via LOXL2 to Accelerate Diabetic Foot Ulcer Healing

  • FASEB J. 2026 Jun 15;40(11):e71881. doi: 10.1096/fj.202600478R.
Yueheng Zhang  1  2  3  4 ,  Ding Luo  3 ,  Ronghua Li  1 ,  Fengwei Lv  1 ,  Mulan Qahar  3 ,  Chenglan Yang  1 ,  Fang Qi  1  2  3  4 ,  Shaoying Gao  1 ,  Zairong Wei  1  2  3  4
Affiliations
  • 1. Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
  • 2. The 2011 Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
  • 3. The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi, Guizhou, China.
  • 4. Guizhou Biofabrication Laboratory, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
PMID: 42213591 DOI: 10.1096/fj.202600478R
Abstract

Antibiotic-loaded polymethylmethacrylate (PMMA) cement (APC) improves healing in diabetic foot ulcers (DFUs), yet the cellular mechanisms underlying its pro-angiogenic effects remain unclear. This study aimed to identify key cell populations and molecular pathways by integrating scRNA-seq and proteomic profiling. DFU wound tissues, treated with APC or controls, were analyzed for differentially expressed proteins (DEPs) using label-free quantitative proteomics. Paired scRNA-seq identified APC-responsive cell populations, and pseudotime and BEAM analyses, integrated with proteomic data, pinpointed key regulatory genes. The analysis revealed that APC treatment specifically upregulated 63 DEPs. scRNA-seq of 20 245 cells identified six major cell types, with fibroblasts showing significant expansion and transcriptional changes. Further analysis identified LOXL2 as a central regulator of fibroblast remodeling. LOXL2high fibroblasts were enriched in healed wounds and promoted angiogenesis through ANGPTL2-ITGA5-mediated endothelial interactions. In vivo, LOXL2 facilitated wound closure and Collagen deposition. Our findings suggest that LOXL2 emerges as a core molecular target for APC therapy in diabetic foot ulcers by reshaping fibroblast heterogeneity and enhancing fibroblast-endothelial cell communication.

Keywords
angiogenesis; antibiotic‐loaded polymethyl methacrylate cement; diabetic foot ulcer; proteomics; single cell RNA sequencing.
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