TYPE Review

PUBLISHED 23 September 2022

DOI 10.3389/fendo.2022.949535

Pathogenesis and treatment of

OPEN ACCESS wound healing in patients with
EDITED BY
Xingwu Ran,
Sichuan University, China
diabetes after tooth extraction
REVIEWED BY
Adem Kara, Shuting Yang, You Li, Chengcheng Liu, Yafei Wu,
Erzurum Technical University, Turkey
Guotian Luo, Zixin Wan and Daonan Shen*
Université de Paris,
France State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West
China Hospital of Stomatology, Sichuan University, Chengdu, China
*CORRESPONDENCE
Daonan Shen
[email protected]

SPECIALTY SECTION
Diabetes mellitus is a common systematic chronic disease amongst dental
This article was submitted to
Diabetes: Molecular Mechanisms, patients. The elevated glucose microenvironment can prolong the healing of
a section of the journal tooth extraction sockets. Therefore, the promotion of healing up tooth
Frontiers in Endocrinology
extraction sockets is of great clinical importance to the patients with
RECEIVED 21 May 2022 diabetes mellitus. The current evidence indicates the mechanism of the
ACCEPTED 31 August 2022
PUBLISHED 23 September 2022
recovery period of extraction sockets in hyperglycaemia conditions from
physiological, inflammation, immune, endocrine and neural aspects. New
CITATION
Yang S, Li Y, Liu C, Wu Y, Wan Z and advancements have been made in varied curative approaches and drugs in
Shen D (2022) Pathogenesis and the management of wound healing of tooth extraction sockets in diabetes.
treatment of wound healing in patients
However, most of the interventions are still in the stage of animal experiments,
with diabetes after tooth extraction.
Front. Endocrinol. 13:949535. and whether it can be put into clinical application still needs further
doi: 10.3389/fendo.2022.949535 explorations. Specifically, our work showed topical administration of plasma-
COPYRIGHT rich growth factor, advanced platelet-rich fibrin, leukocyte- and platelet-rich
© 2022 Yang, Li, Liu, Wu, Wan and
fibrin and hyaluronic acid as well as maxillary immediate complete denture is
Shen. This is an open-access article
distributed under the terms of the regarded as a promising approach for clinical management of diabetic patients
Creative Commons Attribution License requiring extractions. Overall, recent studies present a blueprint for new
(CC BY). The use, distribution or
reproduction in other forums is
advances in novel and effective approaches for this worldwide health ailment
permitted, provided the original and tooth extraction sockets healing.
author(s) and the copyright owner(s)
are credited and that the original
publication in this journal is cited, in KEYWORDS

accordance with accepted academic tooth extraction, diabetic, healing, dental extraction sockets, insulin-dependent diabetic
practice. No use, distribution or
reproduction is permitted which does
not comply with these terms.

Introduction
Diabetes mellitus (DM) is recognized as an enormous menace to the general
population globally, which affects 463 million adults (1). It is a systematic metabolic
disorder characterized by defective insulin secretion and impaired insulin, resulting in
microvascular complications and hyperglcemia (2). Diabetes is divided into diabetes
mellitus type 1 (T1DM) and diabetes mellitus type 2 (T2DM), with T2DM making up
90% of cases worldwide and thus more relevant research (3). Patients with DM are

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Yang et al. 10.3389/fendo.2022.949535

associated with a high risk of hyperlipidemia, obesity, and following trabecular bone formation occurs between 4 and 8
healing disorders. Considering that diabetes ranks 3th in the weeks after extraction (19, 20).
most prevalent chronic disease in the oral field (4), number of Delayed tooth extraction socket (TES) healing were often
diabetic patients experiencing oral manifestations exceeded 90% found in patients with poorly controlled or untreated DM (21).
(5). Diabetic patients have a prevalence of missing teeth, Tooth extraction healing is slower for diabetic than the group
prolonged wound healing, xerostomia, caries, burning mouth without diabetes, particularly on day 7 post-operatively (22).
disorder, lichen planus, and even bacterial osteomyelitis of the However, not all studies have reached the conclusion that
jaw, which could increase the treatment difficulty and diabetics have increased delayed healing (23). In the study by
compromise the treatment outcome of various oral diseases Goss et al. there was no statistically significant difference in
(6–13). A population-based cohort study proved that diabetic healing rate after tooth extraction in either T1DM or T2DM
patients have a higher risk of tooth extraction due to periodontal compared to non-diabetic patients, a result that supports the
disease than non-diabetic patients in South Korea (p <.01) (6). tendency for diabetic patients to recover well after tooth
The origin of the medication-related osteonecrosis of the jaws extraction when they are well controlled (24, 25). For instance
tends to be tooth extraction in elderly patients with uncontrolled it has been shown that the duration of bone healing is similar in
diabetes (P < 0.0125) (14). Case reports proved that bacteraemia diabetic and normal individuals (24). Still, due to the specificity
and fungal infection caused by diabetes-related tooth extraction of diabetes and the possibility of delayed-wound-healing risk
seem to be a triggering factor for osteomyelitis and after tooth extraction, it is of great value to understand the
mucormycosis, respectively (15, 16).Therefore, elucidating the mechanisms involved and the potential treatments.
mechanism and investigating the approaches to promoting the In recent years, the field of wound research has been
healing of tooth extraction sockets is of great clinical importance, broadened by an in-depth understanding of diabetes and its
especially for the patients with DM. In this review, we various aspects of physiological, inflammatory, immunological,
systematically searched and appraised the current literature to endocrine, neurological mechanisms and microRNAs (miRNAs)
summarize and discuss the mechanisms and managements of associated with the healing of extracted tooth sockets (26). Long-
delayed extraction sockets in patients with diabetes. standing wound healing in patients with diabetes is generally
attributed to the abnormal expression of all the cells involved as
well as the dysregulation of the expression of growth factors,
cytokines required to coordinate the normal healing process as
Mechanistic insight into delayed suggested by these research. Factors accounting for the healing
tooth extraction socket healing process of diabetic extraction sockets is presented in Figure 2.
among diabetic patients
The histological healing process in extraction-sockets is a Physiological mechanism
four-stage process involving the blood clot phase, the
inflammation phase of granulation tissue formation, the Healing of extraction sockets is a complex process involving
proliferation phase with woven bone formation and the the reconstruction of damaged soft and hard tissues. It embodies
modeling and remodeling phase, as shown below (Figure 1) the proliferation and differentiation of osteocytes, as well as the
(17, 18). Osteogenic tissue proliferates and bone maturity synthesis and mineralization of extracellular matrix, resulting in

FIGURE 1
Main processes of wound healing occurring in the socket after tooth extraction depicted as four time-related phases.

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FIGURE 2
Factors responsible for the healing process of diabetic extraction sockets. Diabetes inhibits mitotic growth factor expression through epigenetic
mechanisms; difficulty in wound healing after tooth extraction is associated with diminished osteogenic differentiation of mesenchymal stem
cells, activation of matrix metalloproteinase-9, persistent imbalance of RANKL/OPG ratio, and reduced expression of neuropeptides.
Hyperglycemia affects hormone receptor conversion as well as the formation of new blood vessels, and impaired angiogenesis not only hinders
bone formation but also affects the rate of wound healing. Diabetic wounds are characterized by chronic inflammation due to high levels of
reactive oxygen species, dysregulated M1/M2 macrophage polarization, and pro-inflammatory chemokines. High glucose levels have a negative
impact on macrophage function, mainly in the form of dysregulated levels of cytokine secretion such as TNF-a, IL-6 and IL-1b, in addition to
the inability of neutrophils to function in the inflammatory response phases of wound healing, migration, chemotaxis and adhesion. MicroRNAs
also influence the different phases of diabetic wound healing.

bone formation and remodelling. These activities are regulated the concentration alterations in tissue growth factors, such as
by various cytokines, comprising the transforming growth factor IGF-1, may be strongly correlated with wound healing of the
b (TGFΒ), the vascular endothelial growth factor (VEGF), the epithelium in rats (33). Noticeably, non-enzymatic glycosylation
insulin-like growth factor (IGF) and the bone morphogenetic of collagen in hyperglycaemic rats was found to impair the
protein (BMP) (27). The increased recovery rate was observed collagen metabolism, thus producing highly soluble and easily
through the local application of growth factors; however, the degradable collagen. In this case, the mechanical properties of
deficiency of growth factors in hyperglycaemia conditions the formed bone were weakened, and led to the delayed healing
caused a low level of wound healing in animal or clinical and increased alveolar destruction (34).
studies (28, 29). Decreased expression levels of these TGFΒ1-3, Interestingly, the gene expression profile of T2DM was
TGFbRII and TGFbRIII genes may be linked to impaired oral distinguishable from control subjects (35). According to Liang
mucosa healing in diabetic mice (30). Diabetes-induced et al. (36), 11 differentially expressed genes were substantially
detrimental effects on TES healing under the palatal plate may higher in the non-diabetic control group than in the T2DM
be mitigated due to the rise in salivary VEGF elicited by T2DM group, and among these genes, BMP-4, which is significantly
in clinical trials (31). However, the presence of VEGF would be under-expressed in T2DM blood, is the most important gene
insufficient to produce new bone under hyperglycemic regulating bone marrow mesenchymal stromal cells (MSCs)
conditions. The bone formation is disrupted due to osteogenic differentiation based on gene ontology annotation
crosslinking of advanced glycation end products (AGEs) and random forest analysis. Among BMP family, BMP-4 was
unfavorably, in spite of induction of VEGF-C and VEGF shown bone-forming potential in rat tooth sockets (37). BMP-4,
receptor-3 positivity in Akita mouse osteoblasts after associated with bone morphogenetic protein receptor 1,
extraction (19). IGF-1 could foster the osteogenic enhances the osteogenic differentiation of stem cells via
differentiation of apical papillae stem cells, which is likely to activation of Smad signaling (38). It is noteworthy that
be induced by c-Jun N-terminal kinase and p38 mitogen- recombinant BMP4/7 has a higher potential to induce MSC
activated protein kinase signaling pathways (32). In addition, differentiation than BMP4 (39). With high concentrations of

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glucose (25mmol/l), the levels of BMP-4, bone sialoprotein and Over and above that, hypoxia-inducible factor 1a may stimulate
osteopontin expression, expression of Shh and alkaline angiogenesis and enhance new bone formation as a transcription
phosphatase (ALP) were greatly reduced compared with low factor in vitro (58). During bone repair, its expression is
glucose (5.5mmol/l) (40). upregulated due to hypoxia, but its function of mediating
The nature of diabetic wounds that are resistant to healing is angiogenesis and osteogenesis is suppressed due to high
also connected to the involvement of matrix metalloproteinase glucose conditions in diabetic mice (59).
(MMP). The higher activity of MMP-2 and MMP-9 in diabetic
mice wounds is similar to that of hard-to-heal wounds caused by
ulcers or burns (41), and subsequently studies have identified Inflammation and immune mechanism
MMP-8 and MMP-9 from diabetic wounds and demonstrated
that MMP-8 inhibits apoptosis and favors wound healing, while Alterations in inflammation levels and reductions in new
conversely MMP-9 promotes apoptosis and renders wounds connective tissue and bone formation played an essential role in
unhealable in mice (42). Infection of wounds increases MMP-9 diabetic oral wound healing. Diabetes suppresses mitogenic
activity, facilitates macrophage infiltration and diminishes growth factor expression and increases pro-inflammatory
angiogenesis in animal and clinical experiments (43). Selective cytokine expression mediated by epigenetic mechanisms (60).
inhibition of MMP-9 together with locally applied active Chronic diabetic wounds are chronically inflamed due to a great
recombinant MMP-8 supports wound healing in diabetes in deal of reactive oxygen species (ROS), dysregulated M1
mice (44). Hyperglycaemia (25mmol/L) can affect the regulation macrophage polarization and pro-inflammatory chemokines in
of cellular Na+/K+ adenosine triphosphate enzyme activity, mice (61). TNF-a is acknowledged to stimulate inflammatory
increase protein kinase C activity, influence the conversion of response by increasing the number of blood vessels and vessel
hormone receptors and the formation of new blood vessels in vitro density and regulating M1/M2 macrophage polarization in in
(45, 46). This is corroborated by the fact that lower ATP vitro and animal studies (62–64). However, it is stated that
concentrations in plasma are coupled with lower blood flow in elevated TNF-a and promoting inflammatory cytokines in a
T2DM patients compared to healthy subjects (47). High blood hyperglycemic state (>16.7mmol/L) instead spur bone
glucose (>13.9mmol/L) can also contribute to the production of resorption on the one hand and restrain bone formation on
AGEs as well as receptor for AGEs (RAGE) under metabolic the other hand in rats (65). Runx2, important for the
disorders and inflammatory conditions in diabetic rats (48). In in differentiation of osteoblasts and maturation of chondrocytes,
vitro experiments, increased AGE levels elevate extracellular MMP is inhibited by pro-inflammatory cytokines in vitro (66, 67). A
inducer content and stimulate the secretion of MMP, reduction of Runx2 diminished MSC differentiation and the
accompanied by collagen degradation and a decrease in bone production of osteoblast cells (68). Besides, granulocytes were
strength (49). Large amount of aldoses of AGEs has been found to unable to function during the inflammatory response stage of
cause dysfunction of the endothelial cells and extracellular matrix the wound healing, migration, chemotaxis and the adhesion of
of the microvascular wall by covalently bounding to active amino neutrophil in T1DM patients (69). The impaired neutrophil
groups, and damage blood vessels by up-grading oxidative stress function, however, was found not related to the increased risk of
and inducing monocytes to produce platelet-derived growth short-term postoperative complications in T2DM (70). No
factors (50). Thus the blood vessels became pathologically correlation was found between extended wound
permeable and inelastic, and block the blood flow (51). epithelialization and reduced neutrophil function at three
Receptor activator of nuclear factor kappa B (RANK) and its weeks postoperatively (70).
ligand (RANKL), as well as the deceptive receptor Uncontrolled DM patients are regarded as immunosuppressed,
osteoprotegerin (OPG), are the three main proteins of the considering the negative impact of hyperglycaemia on the immune
RANKL/RANK/OPG signaling pathway encoded by system. It has been confirmed that high blood sugar (25mmol/L)
TNFRSF11B (52). RANKL-RANK interaction increases causes damage to the cellular immune response, inflammatory
osteoclast production, whereas OPG inhibits their binding. cytokines and microcirculation during the healing process (71,
This pathway is famed for its roles in bone remodeling and 72). The mechanism of impaired immune system is mainly
may have an impact on the pathogenesis of T2DM women (53). related to immune cells, such as macrophages and granulocytes.
For poorly controlled T2DM patients, a continual imbalance in High glucose levels (>16.7mmol/L) have a negative impact on the
RANKL/OPG ratio may be produced in periodontal tissues (54). function of macrophages, mainly in the form of dysregulated
Angiogenesis is described as new vessel formation out of secretion levels of cytokines such as TNF-a, IL-6 and IL-10, and
pre-existing ones and exerts its effects on wound healing (55). decreased metabolic activity in T1DM mice (73); in combination
The functional vascular supply is responsible for proper with enhanced pro-inflammatory macrophages was found in T1DM
ossification of newly deposited bone (56). Impaired mice in in vitro experiments, resulting in a higher risk of infection
angiogenesis in patients with hyperglycaemia affects the rate of (74). Defects in phagocytosis may interfere with the inflammatory
wound healing, in addition to impeding bone formation (57). response and microbial uptake, causing accumulated debris in the

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wound and preventing the formation of granulation tissues both in in rats (86). Diabetes can lead to autonomic and small sensory
vivo and in vitro (75). Notably, abnormal inflammatory responses nerve fiber neuropathy and dysregulation of inflammation, as
coordinated by M1 or M2 macrophages are also usually associated evidenced by reduced expression of neuropeptide and
with delayed healing. In a vitro co-culture model, M1 pro- imbalance in pro- and anti-inflammatory cytokine responses
inflammatory macrophages were found to act primarily by (87). It has been found that the exogenous SP improved wound
inhibiting capability of MSCs as well as the angiogenic ability of repair kinetics and suggested that the chronic trauma in DM
endothelial cells, while the opposite role was found for M2 anti- patients may be attributable to downgraded levels of
inflammatory macrophages (76). High glucose (25mmol/L) could neuropeptide nutrition (85).
drive M1 macrophage polarization via overproducing ROS under
inflammatory stimulation in T1DM rats (77). The polarization of
elevated M1 and reduced M2 macrophage may take responsibility The function of microRNAs in the
for slowed TES healing in subjects with T2DM through aberrant healing of diabetic wound
expression of tumor necrosis factor-a (TNF-a) and peroxisome
proliferator-activated receptor-g (21). MiRNAs, regulating expression of mRNA, are a kind of
short non-coding single-stranded RNA molecules (88). MiRNAs
influence several physiological and pathological processes, the
Endocrine mechanism and most notable being metabolism, proliferation, differentiation
neural mechanism and apoptosis. Therefore, they are being investigated as vital
markers at different stages of the wound healing process (89).
In diabetic patients, their hyperglycemic condition affects a There are several miRNAs involved in the regulation of
wide range of cell functions, for example, the regulation of bone- inflammatory phase of wound healing in a hyperglycemic
forming differentiation. Osteoblast proliferation and environment. For example, inflammation in unhealed wounds
differentiation can be inhibited by hyperglycemia (25mmol/L) of patients with T2DM affects plasma miRNA concentrations,
through caspase-1-mediated pyroptosis in vivo and in vitro (78). whereas miR-191 affects angiogenesis through its target zonula
It may cause osteoblast bone formation disorders and result in occludens-1 in order to slow down the tissue reparative process
pathological changes, such as diminished bone formation and (90). MiR-497, with its down-regulation activity for pro-
reduced alveolar bone height of tooth extraction wounds. It has inflammatory cytokines, to such factors as TNF-a, IL-1b, IL-6,
been suggested that the increased expression of glucose is considered as a promising curative factor for diabetic wound
transporter 1 might be part of the reasons for the inadequate healing in mice (91). MiR-129-2-3p at wound sites in type 2
mineralization of osteoblasts during hyperglycaemia in vitro diabetic mice may expedite wound healing by mediating the
( 7 9 ) . E x c e s s i v e p r o t e i n -l in k e d Β - a c e t y l g l u c o s a m i n e function of neutrophils (92).
glycosylation (-GlcNAcylation) induced by O-GlcNAc Other miRNAs participating in angiogenesis and
transferasewith high glucose (46,60 mmol/L), glucosamine remodeling stages consist of miR-15b, miR-20b, miR-21, etc.
(2.5-5mmol/L) or N-acetylglucosamine (5mmol/L) leads to a Both 15b and 200b can inflict impaired angiogenesis by
reduction in RUNX2 gene expression and thus has an inhibitory repressing the expression of VEGF in diabetic mice (93). In
effect on osteogenic differentiation in vitro (80). Furthermore, diabetic mice, knockdown of miR-20b-5p was found to
the weakening of MSC osteogenic differentiation might be an significantly potentiate wound repair and facilitate wound
essential factor responsible for TES healing for T2DM pig angiogenesis by regulating the Wnt9b/b-catenin signaling
models (81). Growth differentiation factor 11 was related to pathway (94). It has been shown that miR-21 expression is
the inhibited osteogenic differentiation of MSCs in TES in engaged in early healing of the incisor extraction sockets in mice
patients with T2DM (82). (95). Strauss et al. demonstrated that miR-21 knockout mice had
Sensory nerves contribute to inflammation and immune approximately 15% reduced bone formation in the mesial and
response, in particular, possess trophic-facilitating wound coronal portions of the extraction socket compared to wild-type
healing generally (83). Neuropeptides are neuromodulators controls (95). MiR-27b was revealed to prompt wound healing
involved in a variety of processes, diabetic wound healing by rescuing damaged angiogenic cells in T2DM mice (96). For
released by sensory nerves included (84). Insufficiency of pigs and mice, anti-angiogenic MiR-92a, its inhibitor, possesses
neurogenic mediators such as substance P (SP), secreted the ability to accelerate wound healing (97). In in vitro
from sensory neurons, may participate in wound experiments, upregulated MiR-140-3p exosomes promoted the
epithelization in mutant diabetic mice with delayed healing differentiation of MSCs into osteoblasts (98).
(85). Moreover, SP stimulates bone formation in osteoblasts by Nevertheless, the study of miRNAs and diabetic TES healing
neurokinin-1 receptors at advanced stages of bone formation paves the way for miRNA-based dental regeneration strategies.

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Potential interventions in the diabetic patients (99). Another animal research study assessed
the effect of topical application of autologous platelet-rich
management of extraction sockets plasma on extraction wound and found that it prevents the
healing in patients with diabetes medication-related osteonecrosis of the jaws (108). Activated
platelet lysates induce OPG expression and stimulate soft tissue
Ideal interventions used in oral surgery should facilitate the healing and osteoblast differentiation in rats (109). IGF-I was
repair of extraction sockets, and reduce the postoperative found to increase the volume of neoformed bone after tooth
infection, pain and complications. Plenty of investigations extraction in diabetic rats by regulating glucose transporter 1
have explored pathways to acceleration of TESs healing under expression, as well as increases osteoblast mineralization during
high-glucose conditions based on molecular regulators of their extraction wound healing (79, 110). For those patients with
activity, either directly or indirectly. It is encouraging to see that insulin resistance, IGF-I treatment can be considered, but the
a considerable number of results have entered clinical trials, as effectiveness and safety of IGF-I for long-term use in the
shown in the table below (Table 1). Directly interacting targets management of diabetes and complications involved need
include growth factors, BMPs, parathyroid Hormone (PTH), further studies (111). Hence, locally delivered growth factors
and stem cells. A variety of drugs may act indirectly on to promote healing may be a potential therapy for the treatment
molecular targets by up- or down-regulating the expression of of diabetic osteopathy.
growth factors, MMP, collagen synthesis/degradation, pro- and Local hemostatics are beneficial in reducing underlying
anti-inflammatory cytokines, and pro-angiogenic factors. Drugs postsurgical bleeding and to pace healing (112). Leukocyte-
or natural products or formations of molecular targets that are and platelet-rich fibrin (L-PRF) enhanced bone density and
involved on a direct or indirect basis in a proposed treatment reduced inflammation, used as a graft to fill the TES and
will be described below. stabilize the blood clot in patients (100). L-PRF alone or in
combination with hyaluronic acid (HA) was effective in
improving mucosal healing and preventing alveolar osteitis
Molecular targets and infection following mandibular third molars extraction
(101). However, it has also been the finding that L-PRF adds
Local delivery of growth factors, as for instance by the to the growth factors concentration in the TES but has no
delivery of platelet-derived growth factor (99), IGF (79), positive outcome on bone healing (113). Additionally, the
fibroblastic growth factor (105), has been verified to favor finding demonstrated the potential of advanced platelet-rich
wound healing in poorly controlled diabetes. Systematic fibrin (A-PRF) as a therapeutic biomaterial for bone
reviews and meta-analyses have found the efficacy of platelet regeneration after surgical extractions of third molars in
derivatives to improve the wound healing and bone density, clinical trials, but further studies with larger sample sizes and
thereby stimulating the soft tissues and bone regeneration (106, more systematic and reliable e valuat ion tools are
107). Platelet-rich plasma is dependent on platelets to exert great necessary (102).
influence on healing. In a split-mouth study recruiting 34 Treating the diabetic sockets with BMP may be useful to TES
patients with T1DM, the application of plasma-rich growth healing. Controlled local release of recombinant human BMP-2
factor after extraction yielded remarkably diminished residual dramatically promoted bone production in diabetic mice to near
TES volumes and improved Healing Indices by accelerating the normality and potentiates bone rejuvenation in normal mice
socket closure (epithelialization) and tissue maturation in (114). BMP-6 can facilitate the osteoblast differentiation from

TABLE 1 List of clinical trials studies on extraction sockets healing in patients with diabetes.

Intervention Year Study design Results Reference

PRGF 2014 Retrospective, split-mouth study PRGF reduced residual socket volumes and improved Healing Indices (99)
L-PRF 2019 Prospective, double-blind, split-mouth study L-PRF enhanced bone density (p=0.007) (100)
2019 Prospective, randomized, double-blind, L-PRF and HA mucosa improved healing scores within 3 weeks (101)
controlled study
A-PRF 2019 Randomized, split-mouth, double-blind A-PRF slightly affected PD positively (102)
Study
HA 2020 Randomized controlled split-mouth study The sockets healing was better in the HA group, especially on day 10 (p=0.006) (103)
and day 15 (p=0.021)
MICD 2016 Prospective study MICD reduced SOD significantly and improved chewing ability within 3 weeks (104)

L-PRF leukocyte- and platelet-rich fibrin, A-PRF advanced platelet-rich fibrin, HA hyaluronic acid, PD pocket depth, MICD maxillary immediate complete denture, SOD socket
opening diameters

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MSCs and the chondrocyte maturation by signalling through and apoptosis, but also increased osteoblast differentiation at
type I and type II BMP receptors (115). The extra-alveolar tissue varied glucose levels (0.99, 1.98, 3.96, and 7.92 g/L), which may
of diabetic rats showed a subcellular periosteal reaction by day 3, be related to the promotion of Runx2 and IGF-1 expression in
and a large amount of cartilage had been formed by day 7 vitro (122). Noticeably, osteogenic differentiation potential of
following the application of BMP-6 (116). It has been reported MSCs could be enhanced by metformin in T2DM patients
that down-regulated BMP-6 in certain tissues such as through the BMP-4/Smad/Runx2 signaling pathway (36).
myofibroblast progenitor cells in diabetic patients thereby Goto-Kakizaki rats with T2DM showed improved blood
inhibited the cartilage formation delaying the healing (117). glucose and bone volume percentage, the number of
Therefore, the topical application of BMP-6 is promising to trabecular, as well as bone density after using metformin (124).
reverse the healing inhibition of diabetes. Moreover, the level of
expressed BMP-4, bone sialoprotein and osteopontin, ALP
activity and the increased number of matrix mineralized Natural product-based treatment
nodules in MSCs correlated with the Lenti – Shh activated Shh
signaling pathway; in vivo experiments revealed that Lenti – Shh Natural ingredients, namely obtained from natural sources,
invoked additional osteogenesis (40). The intraoral injection of often stand for the topic of further research and have been
the inhibitor of growth differentiation factor 11 has been found exploited as an alternative therapy like spirulina, chitosan,
to promote the bone healing in the post-extraction site as well as flavonoids and many more. Chitosan is a deacetylated
the osteogenic differentiation of porcine MSCs (82). polysaccharide from chitin, which can accelerate new bone
Furthermore, activating macrophages by mannose receptor formation and enhance neovascularization in vivo (125).
clustering and enhancing M2 macrophage polarization were Besides chitosan, spirulina, a microalgae containing
found to contribute to accelerated wound healing, increase the kaempferol, also has antioxidant and anti-inflammatory
collagen expression and reduce the infection in hyperglycemic effects (126). Due to the fact that the addition of 12%
conditions in mice (118). Sustained Interleukin-4 released spirulina and 20% chitosan to the dental socket of mice
markedly enhanced osteogenic and angiogenic gene expression yielded an alkaline pH that was suited to ALP activity, the
with improved socket healing in T2DM mice by inducing bone remodeling process can be completed by promoting an
macrophage transformation towards M2 polarization (21). increase in osteoblast cells and a decrease in osteoclasts (127).
PTH is an important hormone to regulate the bone Ellagic acid is a natural component that effectively prevents
metabolism. PTH has been shown to reduce the alveolar bone bone loss induced by tooth removal in diabetic rats; diabetic
loss in the intermittent and systemic administrations by rats treated with ellagic acid express a stronger
decreasing the RANKL/OPG ratio in diabetic rats (119). immunohistochemical response to fibroblastic growth factor-
However, some studies found that PTH did not improve the 2 and ALP than non-treated diabetic rats (105).
post-extraction wound healing or stimulate the osseointegration Flavonoids are known as a natural component that can
in hyperglycemic rats, regardless of administration of PTH inhibit inflammation whilst speeding up wound healing.
(intermittent versus continuous) (120). This can be explained Morin, as a pleiotropic dietary flavonoid, may prevent bone
by the overall inhibitory effect of high levels of AGEs and histomorphological alterations in diabetic rats through a
collagen cross-linking on bone formation under diabetic potential mechanism of the insulin/IGF-1 pathway (128).
metabolism (121). The anabolic role of PTH in the repair after Extract of okra fruit containing flavonoid, possesses strong
DM extraction needs to be confirmed by further studies. antioxidant and anti-inflammatory properties. Okra fruit
extract (250 mg/kg) increased TGFΒ1 levels in post-
extraction wounds of diabetic Wistar rats (129). Treatment
Synthetic drugs of hyperglycemic diabetic rats with a new chemically
modified curcumin 2.24 contributed to the alleviation of
The acceleration of TES recovery with insulin or metformin local and systemic inflammation and reduced bone loss,
has already been reported in previous research (34, 122). Insulin, plus inhibition of collagenolytic MMPs as well as pro-
a first-line drug in the clinical therapy of DM, can directly hasten inflammatory cytokines (130). A modified curcumin was
TES healing by raising TGFb-3 expression and lowering IGF-1R found to accelerate skin wound healing in hyperglycemic
expression in diabetic rabbits (27). Moreover, the consequences rats induced by streptozotocin (131). Probiotics serve as a
of high blood glucose and metformin on peri-implant healing potential strategy to augment insulin sensitivity and
should be attached importance to. Metformin is the most minimize autoimmune responses by modifying intestinal
commonly employed oral hypoglycemic agents; its benefit flora and reducing inflammatory responses and oxidative
attributed to its preferential influence on endothelial cells, as stress (132). It is showed that exogenous SP favourably
well as its antioxidant and anti-inflammatory properties (123). promotes wound healing kinetics in Mutant diabetic mice
Metformin not only remarkably reduced both intracellular ROS ( 8 5 ) . F u r t h e r , n e w b o n e fo r m a t i on w a s e n h a n c e d

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histomorphometrically when using deproteinized bovine Conclusions

bone mineral containing 10% collagen with hypoxia-
inducible factor 1a in dogs (133). These materials provide a This review investigated the mechanism and treatment of
clue for latent auxiliary therapies in the management of post- the extraction sockets healing process in diabetic patients.
extraction wound in patients with DM. Approaches involving the growth factor, growth factors, BMP,
PTH, stem cells, synthetic drugs, natural product, HA, Low-level
laser therapy have been evaluated with limited achievement.
Other approaches Various clinical trials have been explored to enhance the healing
process of post-extraction sockets under hyperglycemic
HA could be a reliable approach to wound closure. One conditions, including plasma-rich growth factor, L-PRF, A-
study investigated the underlying role of HA, a component of PRF, HA, maxillary immediate complete denture. However,
extracellular matrix, in promoting TES healing in diabetic most of these interventions are mostly still in the stage of
patients. In a randomized controlled split-mouth study animal experiments, and further studies are still needed before
including 30 patients with poorly controlled T2DM who they can be applied in clinical practices. In the light of these facts,
required tooth extraction, 0.8% HA placed in post-extraction they present a hope that new approaches development will
socket improved the wound healing, in particular on the first further supervene for this worldwide health ailment and
days after applying (103). In addition, sodium hyaluronate (HY) healing of tooth extraction sockets.
is the product of the neutralization of the carboxyl groups of HA,
which has been proved to enhance the healing process in the
extraction sockets of rats (134). Diabetic rats gained greater Author contributions
percentage of newly formed trabeculae in the post-extraction
wound treated with HY or carbon nanotubes functionalized with SY: researched data, wrote, reviewed, and edited the
HY (135). manuscript. YL: commentary. YW, ZW and CL: revised the
Low-level laser therapy offered a good treatment option for manuscript. DS: critical review, funding acquisition. All authors
TES healing in T2DM patients (136). Rat sockets irradiated by contributed to the article and approved the submitted version.
808 nm or 660 nm laser had less inflammatory cell infiltration
and more angiogenesis than unirradiated sockets apparently
(137). Low-level laser therapy at 808 nm was able to
considerably improve osteoid regeneration, while no
Funding
substantial difference was observed in the amount of bone
This study was supported by the National Natural Science
formation with 660 nm (137). Park et al. agreed that 980-nm
Foundation (82170970).
laser irradiation in diabetic and normal rats for 1 minute per day
contributed to early TES healing and further calcification with a
high expression of Runx2 and collagen type I mRNA (138).
Maxillary immediate complete denture has been considered as a Conflict of interest
feasible treatment for TES healing in T2DM patients with lower
reduction of socket opening diameters, as it offers an The authors declare that the research was conducted in the
opportunity to train chewing ability, and thus maintaining absence of any commercial or financial relationships that could
good nutrition in post-extraction period (104). be construed as a potential conflict of interest.
To date, the clinically safe and effective therapy to facilitate
the healing of TESs in patients with DM is still lacking. Many
clinical trials and animal experiments have explored the Publisher’s note
interventions for facilitating the healing of extraction sockets
and improving clinical symptoms (24, 105). However, the All claims expressed in this article are solely those of the
efficacy of these methods is not satisfactory because of the authors and do not necessarily represent those of their affiliated
complicated nature of diabetes, the fragility of the oral organizations, or those of the publisher, the editors and the
environment and short-term assessment. Well-designed large- reviewers. Any product that may be evaluated in this article, or
scale multi-centre clinical trials are still required for the claim that may be made by its manufacturer, is not guaranteed
investigation of interventional wound healing diabetics. or endorsed by the publisher.

Frontiers in Endocrinology 08 frontiersin.org

Yang et al. 10.3389/fendo.2022.949535

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