Page 235 - IJB-9-6

International Journal of Bioprinting Bioprinting in diabetic foot disease

due to excessive proliferation, impaired migration, Further research is needed to investigate the main
and imbalanced differentiation, resulting in impaired functional proteins of HE-Fibro, which is a seed cell, in
barrier function along with the excessive keratinization order to embed those proteins into bioinks.
of the epidermis . In addition, there are also functional
[71]
impairments in the communication between keratinocytes 3.1.3. ECM components
and immune cells, such as T cells, in chronic wounds . Chronic wounds exhibit ECM damage and dysfunction,
[72]
Histological studies have found that the disorder of especially the disordered expression of MMPs, MMP
keratinocytes in chronic wounds is related to the abnormal protease inhibitors, and tissue inhibitors of matrix
expression of cell cycle-related proteins such as myc metalloproteinases (TIMPs), which can lead to the
proto-oncogene protein (c-myc) . Upregulation of those degradation of the collagen matrix in ECM and play a key
[73]
cell cycle-related oncogenes, such as c-myc, and the Wnt role in normal wound healing [80-81] . Single-cell sequencing
pathway downregulated by myc gene family (including showed that the fibroblasts with high expression of CHI3L1
c-myc) may increase the risk of wound healing [73-74] . The on the DFU wound surface express a large amount of
[79]
cell cycle-related oncogenes dysregulated in DFU wound MMPs to promote ECM remodeling . In addition to
could be potential therapeutic targets in wound healing. MMP protease inhibitors, other protease inhibitors, such
For example, Su et al. found that using programmed as serine proteases, also degrade important components
[75]
death ligand 1 (PD-L1) embedded in hydrogel, which of ECM, such as fibronectin (FN) and important growth
[80]
can promote cell cycle progression and suppress factors and their receptors . The development of drugs
T-cell activation, to treat wounds in mice can reduce for targeting the dynamic transformation of the external
inflammation and improve re-epithelialization. However, matrix, protease inhibition, and activation pathways, such
there is currently a lack of further research on the use of as that of MMPs, can facilitate effective methods for DFU
[82]
bioinks with this type of potential therapeutic targets in chronic wound treatment .
bioprinting for DFU treatment.
3.1.4. Inflammation and angiogenesis
3.1.2. Fibroblasts It was found recently that the inflammatory response
As the main secretor of extracellular matrix, fibroblast of chronic wounds is characterized by a persistently
activation plays a crucial role in wound healing through low degree of inflammation, which impairs endothelial
immune cell recruitment, angiogenesis, and wound function in the long term and causes disorders, such as
contraction . Fibroblasts in the dermis have strong macrophage polarization disorders and neovascularization
[65]
heterogeneity in both acute and chronic wounds [63,76] . disorders, but is weaker than the inflammatory response
Phenotypic dysfunction and cellular aging are common of acute wounds [65,83] . Therefore, in chronic wounds, it is
characteristics of their inability to promote normal healing difficult to achieve high intense of short-term inflammation
processes in chronic wounds . Persistent hypoxia in the that is beneficial for acute wound healing . Usually, the
[83]
[63]
lower limbs of DFU patients is one of the causes of fibroblast persistent abnormal inflammatory state of DFU aggravates
aging and is accompanied by impaired maturation of the infiltration of fibroblasts on the wound surface, leading
collagen and production of hypoxia-inducible factor to endothelial dysfunction . Abnormal infiltration
[83]
(HIF), transforming growth factor (TGF), and epidermal of fibroblasts alters the normal ECM environment by
growth factor (EGF) receptor [77-78] . Another cause is the secreting proteins (mainly MMPs), thereby hindering
decreased level of growth factors secreted by fibroblasts, the generation of new blood vessels, and causing hypoxia
such as platelet-derived growth factor BB (PDGF-BB), in the wound [80-81] . The inflammatory state of DFU also
fibroblast growth factor (FGF), and EGF . Single-cell abnormally activates M1 type macrophages that promote
[78]
sequencing experiments have also facilitated the discovery inflammation, but the M1 type macrophages of DFU
of unique subsets of fibroblasts in DFU chronic wounds are unable to transform into anti-inflammatory M2 type
due to persistent inflammatory conditions, which are macrophages normally, resulting in persistent inflammation
also responsible for the inability of fibroblasts to heal state that cannot subside [65,72] . The mechanisms of DFU
properly [71,79] . The healing-enriched fibroblasts (HE-Fibro), causing the dysfunction of fibroblasts and macrophages
a unique population of fibroblasts identified by single- remain to be fully delineated. A further understanding of
cell sequencing in patients whose DFU has healed, may the changes in the cellular inflammatory environment and
promote wound repair by overexpressing proteins related their impact on wound healing can help improve clinical
to ECM remodeling (matrix metalloproteinase [MMP]-1, outcomes and wound treatment . In vivo and in vitro
[84]
MMP-3), as well as immune and inflammatory regulator experiments have confirmed that regulating inflammation
genes including tumor necrosis factor alpha induced can promote DFU healing [84-85] . Current research focuses
protein 6 (TNFαIP6) and chitinase 3-like 1 (CHI3L1) . on targeted supplementation of cytokines that are lacking
[79]

Volume 9 Issue 6 (2023) 227 https://doi.org/10.36922/ijb.0142