Engineering homologous platelet-rich plasma, platelet-rich plasma-derived exosomes, and mesenchymal stem cell-derived exosomes-based dual-crosslinked hydrogels as bioactive diabetic wound dressings

Bianza Moise Bakadia; Abeer Ahmed Qaed Ahmed; Lallepak Lamboni; Zhijun Shi; Biampata Mutu Mukole; Ruizhu Zheng; Mazono Pierre Mbang; Bi Zhang; Mario Gauthier; Guang Yang

doi:10.1016/j.bioactmat.2023.05.002

Engineering homologous platelet-rich plasma, platelet-rich plasma-derived exosomes, and mesenchymal stem cell-derived exosomes-based dual-crosslinked hydrogels as bioactive diabetic wound dressings

Bioact Mater. 2023 May 17:28:74-94. doi: 10.1016/j.bioactmat.2023.05.002. eCollection 2023 Oct.

Authors

Affiliations

¹ Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
² Institut Supérieur des Techniques Médicales de Lubumbashi, Lubumbashi, Congo.
³ Department of Molecular Medicine, Biochemistry Unit, University of Pavia, 27100, Pavia, Italy.
⁴ Institut National de Recherche Biomédicale, Ministère de la Santé, Congo.
⁵ College of Life Science and Technology, Key Laboratory of Molecular Biophysics of MOE, Huazhong University of Science and Technology, Wuhan, China.
⁶ Department of Chemistry, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada.

Abstract

The management of diabetic wounds remains a critical therapeutic challenge. Platelet-rich plasma (PRP) gel, PRP-derived exosomes (PRP-Exos), and mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated therapeutic potential in wound treatment. Unfortunately, their poor mechanical properties, the short half-lives of growth factors (GFs), and the burst release of GFs and exosomes have limited their clinical applications. Furthermore, proteases in diabetic wounds degrade GFs, which hampers wound repair. Silk fibroin is an enzyme-immobilization biomaterial that could protect GFs from proteases. Herein, we developed novel dual-crosslinked hydrogels based on silk protein (SP) (sericin and fibroin), including SP@PRP, SP@MSC-Exos, and SP@PRP-Exos, to promote diabetic wound healing synergistically. SP@PRP was prepared from PRP and SP using calcium gluconate/thrombin as agonist, while SP@PRP-Exos and SP@MSC-Exos were derived from exosomes and SP with genipin as crosslinker. SP provided improved mechanical properties and enabled the sustained release of GFs and exosomes, thereby overcoming the limitations of PRP and exosomes in wound healing. The dual-crosslinked hydrogels displayed shear-induced thinning, self-healing, and eradication of microbial biofilms in a bone-mimicking environment. In vivo, the dual-crosslinked hydrogels contributed to faster diabetic wound healing than PRP and SP by upregulating GFs expression, down-regulating matrix metalloproteinase-9 expression, and by promoting an anti-NETotic effect, angiogenesis, and re-epithelialization. Hence, these dual-crosslinked hydrogels have the potential to be translated into a new generation of diabetic wound dressings.

Keywords: Diabetic wound; Dual-crosslinked hydrogel; Exosomes (Exos); Platelet-rich plasma (PRP); Silk protein.