Topical Application of Conditioned Medium from Hypoxically C… : Plastic and Reconstructive Surgery

We read, with great interest, the article by Takahashi et al.1 entitled “Topical Application of Conditioned Medium from Hypoxically Cultured Amnion-Derived Mesenchymal Stem Cells Promotes Wound Healing in Diabetic Mice.” We sincerely congratulate the authors for their attention to the area of diabetic ulcers. Their article is the first to report that topical application of amnion-derived mesenchymal stem cell–conditioned medium enhances the healing of diabetic wounds. Though the data presented by Takahashi and colleagues are encouraging, we still have some ideas and opinions that we would like to discuss with the authors.

So far, there indeed has been a lot of literature on mesenchymal stem cell media for wound repair, and the conclusions have been positive. The use of conditioned media rather than use of mesenchymal stem cells directly in the treatment of diabetic ulcers is similar to the recent popularity of extracellular vesicles.2,3 The conditioned media may contain extracellular vesicles. As with extracellular vesicles, the use of conditioned media avoids the immunogenicity associated with direct transplantation of stem cells and reduces rejection, but how applicable is this conditioned medium for clinical translational use? As a mixture, it contains a variety of paracrine cytokines. Which cytokines play a major role in wound repair? In addition, there is no consensus on the extraction process for conditioned medium, the number of cells needed to obtain the medium, and which generation of cells, with the highest activity, to harvest from the medium.

The authors used animal experiments to verify its therapeutic effect on diabetic ulcers, but they did not specify the dose of culture medium that was injected. The method of injection (intravenous or local? intradermal or subcutaneous?), the frequency of injection, whether the injection was given before or after the wound was established—all of these factors may affect the healing of the wound.

The authors verified the vascularization by detecting CD31 and vascular endothelial growth factor, and illustrated the epithelialization problem by detecting Ki67, which was far from sufficient. Through these experiments, it was rather far-fetched to conclude that conditioned media promoted the vascularization and epithelialization of the wound. If they had added some in vitro experiments to evaluate vascularization, such as a transwell migration assay, tube experiment, and Doppler flow imaging, their conclusions would be more convincing.

The repair of diabetic wounds has always been a difficult problem, and the authors’ work has shed light on future clinical application. It is possible that, via future technical means, cell-free media can be batch prepared into products for allogeneic use. We look forward to the authors’ follow-up work, so as to further explore the mechanism of hypoxic conditioned medium in the repair of diabetic ulcers.


The authors have no financial interest to declare in relation to the content of this communication.

Yiming Hu, M.D.
Quanding Yan, M.D.
Ziqi Tang, M.D.
Xiancheng Wang, M.D., Ph.D.
Department of Plastics and Aesthetic Surgery
The Second Xiangya Hospital of Central South University
Changsha, Hunan, People’s Republic of China


1. Takahashi H, Ohnishi S, Yamamoto Y, et al. Topical application of conditioned medium from hypoxically cultured amnion-derived mesenchymal stem cells promotes wound healing in diabetic mice. Plast Reconstr Surg. 2021;147:1342–1352.

2. Xiao S, Xiao C, Miao Y, et al. Human acellular amniotic membrane incorporating exosomes from adipose-derived mesenchymal stem cells promotes diabetic wound healing. Stem Cell Res Ther. 2021;12:255.

3. Shiekh PA, Singh A, Kumar A. Exosome laden oxygen releasing antioxidant and antibacterial cryogel wound dressing OxOBand alleviate diabetic and infectious wound healing. Biomaterials 2020;249:120020.


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