Tissue engineering in diabetic wound healing



Diabetic patients need to constantly monitor their blood sugar levels to ensure that it remains in a safe range. Consequently, these patients often have to deal with constant finger punctures and expensive glucose monitoring systems. As an alternative to this situation, researchers have already developed wearable glucose biosensors printed through 3D printers, which can adhere to the patient's skin to monitor body fluids such as sweat. However, another problem that remains to be addressed is the significant number of patients suffering from non-healing wounds due to diabetes mellitus disease [1,2].


In diabetic wounds, collagen fibers are destroyed faster than their secretion, delaying the formation of adequate granulation tissue due to the high activity of matrix metalloproteinase enzymes in comparison to wounds in non-diabetic people [3]. Standard treatments for diabetic wounds, such as debridement of necrotic tissue, cannot guarantee satisfactory wound healing and can often lead to limb amputation [3,2]. The complete wound healing mechanisms generally involve four phases: hemostasis, inflammation, tissue proliferation, and remodeling. In a diabetic wound, insufficient blood supply at the wound site, venous drainage, and infections hamper efficient healing [4].


Figure 1: The wound healing phases (a) hemostasis; (b) inflammation; (c) proliferation; and (d) tissue remodeling [3].


Diabetic foot ulcers (DFU) are one of the most common and severe complications of diabetes mellitus; they dramatically influence patients’ quality of life, causing more pain, less vitality, and restriction of social functions. The higher glucose microenvironment in the DFUs acts as a significant barrier to wound healing at different stages. These high glucose levels in the microenvironment affect the physiological activities of different skin cells, such as keratinocytes, fibroblasts, macrophages, and endothelial cells, resulting in delayed or non-healing wounds [5].



Figure 2: Major factors that contribute to the pathophysiological status of diabetic foot ulcers [5].


In 2019, Wan et al. manufactured a bilayer skin substrate composed of a top layer made of gelatin cryogel loaded with silver and a bottom layer made of a 3D printed gelatin structure loaded with platelet-derived growth factor-BB (PDGF-BB) to heal diabetic wounds. In this study, silver nanoparticles significantly killed bacteria, including Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. In addition, the substrate was able to promote re-epithelialization, granulation tissue formation, collagen deposition, and angiogenesis in vivo indicating great potential for clinical applications for the treatment of diabetic wounds, consequently improving the quality of life of diabetic patients [6].



REFERENCES


1. WhatNext. 3D Printing in the fight against diabetes. https://www.whatnextglobal.com/post/3d-printing-in-the-fight-against-diabetes (2021).

2. Gadelkarim, M. et al. Adipose-derived stem cells: Effectiveness and advances in delivery in diabetic wound healing. Biomed. Pharmacother. 107, 625–633 (2018).

3. Lobmann, R. et al. Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 45, 1011–1016 (2002).

4. Masri, S. & Fauzi, M. B. Current Insight of Printability Quality Improvement Strategies in Natural-Based Bioinks for Skin Regeneration and Wound Healing. Polymers 13, (2021).

5. Tan, C. T., Liang, K., Ngo, Z. H., Dube, C. T. & Lim, C. Y. Application of 3D Bioprinting Technologies to the Management and Treatment of Diabetic Foot Ulcers. Biomedicines 8, (2020).

6.Wan, W., Cai, F., Huang, J., Chen, S. & Liao, Q. A skin-inspired 3D bilayer scaffold enhances granulation tissue formation and anti-infection for diabetic wound healing. J. Mater. Chem. B Mater. Biol. Med.7, 2954–2961 (2019).