Synergistic Effects of Bimetallic Biogenic Copper and Zinc ions Loaded Metal-Organic Frameworks Reinforced Bacterial Eradication and Wound Healing Enhancement in Diabetic Mice

Tarik Abdelkareem Mostafa Amera,†, Sathyadevi Palanisamyb,†, Pamela Berilyn Soc, Priya Vijayaraghavand, Shey-Cherng Tzoua, Tsai-Te Lub,*, Chia-Her Linc,*, and Yun-Ming Wanga,e, *

aDepartment of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan

bInstitute of Biomedical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan

cDepartment of Chemistry, National Taiwan Normal University, Taipei City 116059, Taiwan

dGraduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan 

eDepartment of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan 

The employment of metal-organic framework (MOF) based nanomaterials has been rapidly increasing in bio-applications owing to their biocompatibility, drug degradation, tunable porosity, and intrinsic biodegradability. This evidence suggests that the multifunctional bimetallic ions can behave as a remarkable candidate for infection control and wound healing. In this study, bimetallic MOFs (Zn-HKUST-1 and FolA-Zn-HKUST-1) embedded with and without folic acid were synthesized and used for tissue sealing and repairing incisional wound sites in mice models. For comparison, HKUST-1 and FolA-HKUST-1 were also synthesized. For topical application in wound healing, they display a wide range of healing characteristics including an antibacterial and sustained release with reduced toxicity and enhanced wound healing rates. In addition, in vitro cell migration and tubulogenic potentials were evaluated. The significant reduction in the wound gap and increased expression levels for CD31, eNOS, VEGF-A, and Ki67 are typical characteristics that were observed from immunohistological analyses to predict the angiogenesis behavior at the incision wound site. The wound healing rate was analyzed in the excisional dermal splinted wounds of diabetic mice model, in vivo. The co-delivery of copper (Cu2+) and zinc (Zn2+) ions from the folic acid-embedded MOFs significantly accelerated the wound repair process. On account of antibacterial potentials and tissue-repairing characteristics of Cu2+ and Zn2+ ions, designing an innovative mixed metal ion-based biomaterial has wide applicability and is expected to modulate the growth of various gradient tissues.

KEYWORDS: bimetallic, metal-organic frameworks, diabetic, wound healing, in vivo