Multilayer Injectable Hydrogel System Sequentially Delivers Bioactive Substances for Each Wound Healing Stage

Zhijie Ma; Wei Song; Yaohua He; Haiyan Li

doi:10.1021/acsami.0c06360

Multilayer Injectable Hydrogel System Sequentially Delivers Bioactive Substances for Each Wound Healing Stage

ACS Appl Mater Interfaces. 2020 Jul 1;12(26):29787-29806. doi: 10.1021/acsami.0c06360. Epub 2020 Jun 18.

Authors

Zhijie Ma^{1

2}, Wei Song^{3

4}, Yaohua He^{3

4}, Haiyan Li^{1

2}

Affiliations

¹ Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China.
² School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China.
³ Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
⁴ Department of Orthopedics, Shanghai Sixth People's Hospital, Jinshan Branch, 147 Jiankang Road, Shanghai 201599, China.

PMID: 32515577
DOI: 10.1021/acsami.0c06360

Abstract

Wound healing is a dynamic and complex process that contains several sequential phases. However, most of the current drug delivery systems were designed to treat only one certain phase of wound repair, ignoring the fact that every stage plays critical roles in the wound healing process and those critical stages coordinately work to ensure optimal tissue regeneration. Therefore, a delivery system that can precisely meet the requirements of each wound healing stage is desired to enhance tissue regeneration. In this study, an injectable sodium alginate/bioglass (SA/BG) composite hydrogel was used to carry SA microparticles containing a conditioned medium (CM) of cells (SA_CM). Inside the SA_CM microparticles, poly(lactic-co-glycolic acid) (PLGA) microspheres containing pirfenidone (PFD) were encapsulated (PLGA_PFD). This multilayer injectable hydrogel system (SA/BG-SA_CM-PLGA_PFD) was designed to sequentially deliver bioactive molecules for meeting the bioactivity requirement and timeline of each wound healing stage. First, SA/BG hydrogels could rapidly release BG ionic products in the first 1-3 days to regulate the inflammatory response of the host and initiate the subsequent tissue regeneration. Then, SA_CM hydrogel microparticles could release CM of RAW 264.7 cells stimulated with BG ionic products in 2-7 days to facilitate the formation of the vascularized granulation tissue. Finally, PLGA_PFD microspheres released PFD in 8-20 days to prevent the fibrosis and scar formation in the regenerated skin. Thus, this SA/BG-SA_CM-PLGA_PFD delivery system could restrain host inflammation, accelerate wound healing, and inhibit the fibrosis formation in a diabetic mouse skin damage model, enhancing skin regeneration. As the bioactive components in each layer of the system can be adjusted according to the requirements of different tissue regeneration, this three-layered injectable biomaterial system has a wide application potential in the regenerative medicine field.

Keywords: co-culture; injectable hydrogel; sequential delivery system; tissue regeneration; wound healing.

MeSH terms

Animals
Culture Media, Conditioned / chemistry
Hydrogels / chemistry*
Mice
Microspheres
Polylactic Acid-Polyglycolic Acid Copolymer / chemistry
Pyridones / chemistry
Pyridones / pharmacology
RAW 264.7 Cells
Regeneration / physiology
Regenerative Medicine / methods*
Skin / cytology
Wound Healing / drug effects

Substances

Culture Media, Conditioned
Hydrogels
Pyridones
Polylactic Acid-Polyglycolic Acid Copolymer
pirfenidone