Abstract
The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. We hypothesized that copper-based metal-organic framework nanoparticles (Cu-MOF NPs), referred to as HKUST-1, which are rapidly degraded in protein solutions, can be modified to slowly release Cu2+, resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic-acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addition, cytotoxicity and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu2+ release, thus enabling the direct application of Cu-MOF NPs to wounds.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1023-1032 |
| Number of pages | 10 |
| Journal | ACS nano |
| Volume | 12 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 27 2018 |
Funding
J.X. was funded in part by a grant from the American Heart Association (Grant #16POST27710031). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1324585 to S.H. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. O.K.F. gratefully acknowledges support from the Defense Threat Reduction Agency (HDTRA1-18-1-0003). The authors thank Dr. Bin Jiang (Dr. Ameer lab, Biomedical Engineering Department Northwestern University) for help with immunofluorescence data and suggestions and Chongwen Duan (Dr. Ameer lab, Biomedical Engineering Department, Northwestern University) for his assistance during the animal studies. This work made use of the J.B. Cohen X-ray Diffraction Facility supported by the MRSEC program of the National Science Foundation (DMR-1121262) at the Materials Research Center of Northwestern University. XPS and FT-IR measurements were performed in EPIC and Keck-II facilities of the NUANCE Center at Northwestern University, with the support from Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205); MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN. This work utilized the Northwestern University Micro/Nano Fabrication Facility (NUFAB), which is partially supported by SHyNE Resource (NSF ECCS-1542205) the Materials Research Science and Engineering Center (NSF DMR-1121262) the State of Illinois, and Northwestern University. J.X. was funded in part by a grant from the American Heart Association (Grant #16POST27710031). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1324585 to S.H. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. O.K.F. gratefully acknowledges support from the Defense Threat Reduction Agency (HDTRA1-18-1-0003). The authors thank Dr. Bin Jiang (Dr. Ameer lab, Biomedical Engineering Department, Northwestern University) for help with immunofluorescence data and suggestions and Chongwen Duan (Dr. Ameer lab, Biomedical Engineering Department, Northwestern University) for his assistance during the animal studies. This work made use of the J.B. Cohen X-ray Diffraction Facility supported by the MRSEC program of the National Science Foundation (DMR-1121262) at the Materials Research Center of Northwestern University. XPS and FT-IR measurements were performed in EPIC and Keck-II facilities of the NUANCE Center at Northwestern University, with the support from Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205); MRSEC program (NSF DMR-1121262) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN. This work utilized the Northwestern University Micro/Nano Fabrication Facility (NUFAB), which is partially supported by SHyNE Resource (NSF ECCS-1542205), the Materials Research Science and Engineering Center (NSF DMR-1121262), the State of Illinois, and Northwestern University.
Keywords
- copper
- diabetic ulcer
- folic acid
- metal-organic framework
- wound healing
ASJC Scopus subject areas
- General Engineering
- General Materials Science
- General Physics and Astronomy
