Advanced Drug Delivery Reviews 192 (2023) 114671

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/adr

Role of wound microbiome, strategies of microbiota delivery system and

clinical management
Qinghan Tang a,1, Nannan Xue a,b,1, Xiaofeng Ding c,d, Kevin H.-Y. Tsai e, Jonathan J. Hew f, Ruihan Jiang a,
Rizhong Huang a, Xuxi Cheng a, Xiaotong Ding a, Yuen Yee Cheng g, Jun Chen a,b,⇑, Yiwei Wang a,b,e,⇑
a
Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
b
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
c
Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine,
Nanjing 210023, PR China
d
Department of Plastic Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, PR China
e
Burns and Reconstructive Surgery Group, ANZAC Research Institute, Concord Hospital, The University of Sydney, Concord West, NSW 2137, Australia
f
General Surgery, Lesimore Hospital, NSW 2480, Australia
g
Institute for Biomedical Materials and Devices, School of Mathematical and Physical Sciences, University of Technology Sydney, NSW 2007 Australia

a r t i c l e i n f o a b s t r a c t

Article history: Delayed wound healing is one of the most global public health threats affecting nearly 100 million people
Received 27 September 2022 each year, particularly the chronic wounds. Many confounding factors such as aging, diabetic disease,
Revised 23 November 2022 medication, peripheral neuropathy, immunocompromises or arterial and venous insufficiency hypergly-
Accepted 14 December 2022
caemia are considered to inhibit wound healing. Therapeutic approaches for slow wound healing include
Available online 17 December 2022
anti-infection, debridement and the use of various wound dressings. However, the current clinical out-
comes are still unsatisfied. In this review, we discuss the role of skin and wound commensal microbiota
Keywords:
in the different healing stages, including inflammation, cell proliferation, re-epithelialization and remod-
Wound healing
Skin microbiome
elling phase, followed by multiple immune cell responses to commensal microbiota. Current clinical
Inflammation management in treating surgical wounds and chronic wounds was also reviewed together with potential
Clinical wound care controlled delivery systems which may be utilized in the future for the topical administration of probi-
Cell response to microbiome otics and microbiomes. This review aims to introduce advances, novel strategies, and pioneer ideas in
Probiotic delivery regulating the wound microbiome and the design of controlled delivery systems.
Ó 2022 Elsevier B.V. All rights reserved.

Abbreviations: 16S-rDNA, 16S ribosomal DNA identification; b2-AR, b2-adrenergic receptor; ADAM10, A disintegrin and metalloprotease 10; AHR, aryl hydrocarbon
receptor; AMP, adenosine monophosphate; B. subtilis, Bacillus subtilis; C. albicans, Candida albicans; CSF, colony-stimulating factor; CXCL2, chemokine (C-X-C motif) ligand 2;
CXCL10, chemokine (C-X-C motif) ligand 10; CXCL12, chemokine (C-X-C motif) ligand 12; DFU, diabetic foot ulcer; ECM, extracellular matrix; E. coli, Escherichia coli; EPB,
epidermal permeability barrier; EVs, extracellular vesicles; FDA, Food and Drug Administration; hBD, human b-defensin; HF, Hair follicle; HMP, Human Microbiome Project;
IL-1, interleukin-1; IL-1R, interleukin-1R; IL-1b, interleukin-1b; IL-6, interleukin-6; IL-23, interleukin-23; K. pneumoniae, Klebsiella pneumoniae; L. acidophilus, Lactobacillus
acidophilus; L. lactis, Lactococcus lactis; L. plantarum, Lactobacillus plantarum; L. reuteri, Lactobacillus reuteri; L. rhamnosus, Lactobacillus rhamnosus; M CSF, macrophage colony-
stimulating factor; MHCII, major histocompatibility complex II; MMP-9, matrix metalloproteinase-9; MRSA, methicillin-resistant Staphylococcus aureus; MYD88, myeloid
differentiation factor 88; NETs, neutrophil extracellular traps; NIH, National Institutes of Health; NPWT, negative pressure wound therapy; P. aeruginosa, Pseudomonas
aeruginosa; pDCs, plasmacytoid dendritic cells; PEO, polyethylene oxide; PLA, polylactic acid; ROS, reactive oxygen species; PRP, Plat-rich plasma; PVA, polyvinyl alcohol; PVP,
polyvinyl pyrrolidone; SadA, serum adenosine deaminase; S. aureus, Staphylococcus aureus; Sbi, staphylococcal immunoglobulin-binding protein; SCMC, sodium
carboxymethylcellulose; S. epidermidis, Staphylococcus epidermidis; SLO, streptolysin O; SpA, Staphylococcal protein A; SPF, specific pathogen-free; SSWI, surgical site wound
infection; TAs, trace amines; Tc17, cytotoxic T cells 17; TGF-b1, transforming growth factor-b1; TNF-a, tumor necrosis factor-a; VEGF, vascular endothelial growth factor;
WHO, World Health Organisation.
⇑ Corresponding authors at: Jiangsu Provincial Engineering Research Center of TCM External Medication Development and Application, Nanjing University of Chinese
Medicine, 138 Xianlin Avenue, Nanjing 210023, PR China.
E-mail addresses: chenjun75@163.com, chenjun75@njucm.edu.cn (J. Chen), yiweiwang@njucm.edu.cn (Y. Wang).
1
These authors contributed equally to these work.

https://doi.org/10.1016/j.addr.2022.114671
0169-409X/Ó 2022 Elsevier B.V. All rights reserved.
Q. Tang, N. Xue, X. Ding et al. Advanced Drug Delivery Reviews 192 (2023) 114671

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Skin microbiome and wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Skin microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.2. Wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.3. Role of wound microbiome on the inflammation stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.4. Effect of wound microbiome on cell proliferation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.5. Effect of wound microbiome on re-epithelialization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.6. Wound microbiome and remodelling phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3. Immune cell response to bacterial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.1. Neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.2. Monocytes and macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.3. Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4. Clinical management in regulating wound microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.1. Role of commensal microbiota on surgical wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.2. Clinical management in treating chronic wounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5. Strategies in controlled delivery of probiotics and microbiome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.1. Microencapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5.2. Electrospun scaffolds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.3. Hydrogels and 3D bioprinting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.4. Microneedles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1. Introduction
Delayed wound healing has become a global public health prob-
lem, particularly in chronic wounds. According to the World Health
Organisation (WHO), over 6 million people are affected by delayed
wound repair every year in the United States with a cost of $25 bil-
lion (USD) in the health system [1]. About 100 million people need
wound care every year, and about 30 million people with complex
and refractory chronic skin wounds require further intervention
[2]. All types of wounds or injuries initiate the healing process,
which consists of several highly integrated and overlapping
phases: inflammation, cell recruitment, matrix deposition, epithe-
lialization and tissue remodelling. Due to confounding factors such
as aging, stage of diabetic disease, medication (or treatment),
peripheral neuropathy, immunocompromised status and/or arte-
rial and venous insufficiency hyperglycaemia, chronic wounds
are at high risk of delayed healing [3]. At present, the therapeutic
approach for the treatment of delayed wound healing is anti-
infection and debridement or the use of various wound dressing
and dermal templates, but the clinical outcomes are unsatisfactory.
Therefore, advanced approaches are urgently required by clini-
cians. Recent studies demonstrated that regulation of the wound
microbiome can promote diabetic wound healing. Few pioneer
studies reported that increased diversity of wound microbiome
and suppression of Staphylococcus aureus (S. aureus) can signifi-
cantly promote the wound repair [4]. In the present article, we dis-
cuss the skin microbiome, the effect of the microbiome on different
stages of the healing process, immune cell responses to the wound
microbiome and clinical treatment with a focus on advances and
novel strategies in the future design of a controlled delivery system
for probiotics and microbiomes.
2. Skin microbiome and wound healing
2.1. Skin microbiome
Human skin is exposed to maternal and environmental bacteria
and other microbes (e.g. viruses, fungi and protozoa) immediately
after born [5]. Approximately 1,000 species of known bacteria and
about 100 billion microbiomes are detectable on a person’s skin
[6]. Bacteria (2 million/cm2) on human skin [5] can be divided into
four phyla: Actinobacteria (51.8 %), Firmicutes (24.4 %), Proteobac-
teria (16.5 %), and Bacteroidetes (6.3 %), including three most com-
mon genera: Corynebacterium, Propionibacterium, and
Staphylococcus [7]. This data suggests that bacterial colonies are
more abundant on the surface of the skin compared to any other
epithelium [8]. Human skin can be seen as a culture medium,
and its composition is greatly influenced by genetics, diet, lifestyle
and the living environment [6]. Therefore, each site of human skin
is unique in terms of the composition of the microbes, while resi-
dent microbes in specific areas on the skin are also known to be
identical at the genus level [9–10]. The composition and abun-
dance of different microbes vary widely across individuals and
over time, forming a dynamic and highly variable microbiome
[5]. A Human Microbiome Project (HMP), led by the National Insti-
tutes of Health (NIH), was conducted to characterize microbial
populations in five major body sites, including the oral cavity, skin,
nasal cavity, gastrointestinal tract, and genitourinary tract [11].
Data from this project showed that microbiomes are able to control
signalling pathways related to body metabolism, especially those
with diseases in different body sites. In addition, thousands of
microbiomes (bacteria, viruses, fungi) were identified living on
the skin surface, which has tremendous positive effects on human
survival [11].
Skin is the first barrier of the human body while the formation
of a wound provides an opportunity for commensal microbiota on
the skin surface to migrate to the underlying tissue with coloniza-
tion and growth [12–13]. During the healing process, cell interac-
tion with the wound microbiome is hypothesized to be beneficial
in regulating the innate immune response [13]. In contrast, patho-
genic microbiota is known to play a negative role in mediating the
wound healing process [14–15]. According to statistics, wound
contains diverse microbiota, the main components of which are
Staphylococcus, Pseudomonas, Corynebacterium, Streptococcus,
Anaerobic Coccus, and Enterococcus, as well as other genera with
lower abundance [3]. Chronic wounds generally contain more

2
Q. Tang, N. Xue, X. Ding et al.
microbes than acute wounds [3]. Over 2900 samples collected from
various wounds were subjected to multiple microbiological analy-
ses, while Staphylococcus and Pseudomonas were found to be the
most common species, accounting for 63 % and 25 %, respectively
[16]. Moreover, a study proved that there is an association between
microbiota composition and clinical factors [17]. Higher microbial
diversity was observed in deeper ulcers and ulcers of longer dura-
tion, as well as increased anaerobic and the relative abundance of
Gram-negative Proteobacteria [18]. In contrast, many Staphylococci,
mainly S. aureus, were found in superficial and short-term ulcers,
suggesting that bacterial species are correlated with the host
pathophysiology. Notably, commensal bacteria, including
Corynebacterium and Propionibacterium, as well as anaerobes were
prevalent in chronic wounds [19]. Taken together, a stable equilib-
rium between wound microbiotas and the host is believed to play
an important role in wound repair and the healing process.
Although the role of the skin microbiota on wound healing has
been comprehensively investigated [20], conclusions remain con-
troversial. Few pioneer studies found that the wound microbiota
may contribute to the composition and overall toxicity of the
wound microbiome through forming biofilms in chronic wounds.
Changes in force may lead to infection or hinder wound healing
[21]. In the past, scientists and clinicians all agreed that S. epider-
midis positively affects healing, but S. aureus seems to be a villain
[6]. Multiple studies have shown that modulating wound microbes
can improve wound healing, with significant positive implications
for human survival [20]. These new findings open a new avenue to
explore microbes’ role and underlying mechanisms in the wound
healing process.
2.2. Wound healing
Wound healing is a dynamic and highly coordinated process,
mainly including the haemostatic phase, inflammatory phase, cell
proliferation phase (formation of granulation tissue vasculariza-
tion and wound closure) and tissue remodelling phase [22–23]. A
variety of inflammatory cells, cell cytokines, inflammatory media-
tors and extracellular matrix are involved in the healing process
[24–25]. Normally, wound healing can be divided into acute or
chronic wound healing [26]. The primary difference between acute
and chronic wounds is the length required for healing [27], in
which acute wounds can heal in 4 weeks, but chronic wounds have
significantly delayed healing over months or even years [28].
The healing rate is highly related to injury types, severity, size of
the wounds aging, co-morbidities as well as post-injury care [3].
Acute trauma has different wound microbiota composition. Studies
found that the most common pathogens in the acute phase post-
burns are S. aureus, followed by Escherichia coli (E. coli), Pseu-
domonas aeruginosa (P. aeruginosa), and coagulase-negative Staphy-
lococci, etc [29–30]. Over surgery, microbiomes on sutures or
prostheses can induce wound infection and cause acute surgical
site wound infections (SSWIs). The most common pathogenic
microbiotas involved in SSWIs are S. epidermidis and S. aureus,
but E. coli, Clostridium difficile, and coagulase-negative Staphylococci
also occur to a lesser extent [31].
Wounds that do not heal after 1 month of treatment are gener-
ally considered chronic wounds. Chronic wound formation is com-
plex and more likely to occur in the elderly patients with vascular
disease, diabetes, or a combination of these factors compared to
acute wounds [13]. With the increased elderly population, chronic
wounds have become a major burden on healthcare worldwide
[32]. The main cause of chronic wound infections and non-
curative wounds is that the wound surface is colonized by polymi-
crobial communities, leading to the formation of biofilms [17].
Generally, Gram-negative bacteria compose common colonizing
microbiotas around the chronic wound area, accounting for 61 %
3
Advanced Drug Delivery Reviews 192 (2023) 114671
of all microbial isolates. S. aureus is the most commonly found
pathogen among them, followed by P. aeruginosa [3]. Wound bac-
teria, such as S. aureus, P. aeruginosa, Corynebacterium striatum, and
Alcaligenes faecalis were detected in patients with diabetic foot
ulcers [33]. In a study of 145 patients with pressure ulcers, S. aur-
eus and Gram-negative bacilli were detected in 112 wounds [34].
2.3. Role of wound microbiome on the inflammation stage
Immediately after injury, the wound initiates an inflammatory
response that mediates pathogen clearance and stimulates restora-
tion of the skin barrier integrity [35]. However, in a chronic wound,
these inflammatory responses are either absent or hyperactive and
in a state of dysregulated inflammation, resulting in abnormal tis-
sue formation and long-term defects in the epidermal barrier [14].
Despite the robust diversity of the skin microbiome, understanding
how skin microbiota regulates the inflammatory response over the
inflammation stage has important implications for the develop-
ment of therapeutic and preventive strategies (Fig. 1).
In 2020, a study reported for the first time the beneficial role of
the symbiotic skin microbiota and its correlation with the inflam-
matory response [36]. When the skin is injured, researchers found
that skin microbiota, consisting of commensal Staphylococci and
Micrococci, migrated from the epidermis to the dermis of the
injured skin, triggering the activation of neutrophils with the
expression of CXC chemokine ligand-10 (CXCL10) (Fig. 1). There-
after, CXCL10 activates plasmacytoid dendritic cells (pDC) by form-
ing complexes with bacterial DNA, while activated pDC produce
large amounts of type I interferon, which accelerate wound closure
via triggering inflammation and early T cell-independent
responses, mediated by macrophages and fibroblasts that produce
major growth factors required for healing. In addition, the pro-
duced interferon induces early wound repair responses and accel-
erates wound healing by stimulating the growth of fibroblasts [36].
A recent study further revealed that the A20 clade of the skin com-
mensal S. epidermidis could induce adaptive immunity with both
anti-infection and tissue repair functions [37]. S. epidermidis was
capable of stimulating the recruitment of a special CD8+ T cell
(Fig. 1), directly killing pathogens together with enhanced re-
epithelialization and keratinocyte migration. The immune
response elicited by S. epidermidis is found via the non-specific
CD8 + MHCIb pathway, but not the CD4 + MHCII pathway [37]
(Table 1).
By now, only a few specific microbiotas have been investigated
in immunology or inflammatory processes [20]. In addition to Sta-
phylococcus, Corynebacterium, a commensal of mouse and human
skin microbiota, was reported to activate the skin immune system
in an IL-23-dependent manner [38]. Such a system depends on the
expression of mycolic acid, a significant component of the coryne-
form cell wall. The inflammatory effect of microbiomes also
depends on the physiological state of the host, and the skin micro-
biota is triggered by the host’s dietary changes, obesity, or meta-
bolic state to stimulate inflammation or immune responses [38].
Although S. aureus is the most prominent cause SSWIs worldwide,
studies have shown that S. aureus surface proteins A (SpA) and
staphylococcal immunoglobulin-binding protein (Sbi) induce IL-
1b and IL-6 at the initial stage of S. aureus infection and promote
the expression of TNF-a and CXCL-1. Expression of IL-10 in wounds
induced by SpA and Sbi not only contributes to the recruitment of
neutrophils but also extends the time of immune cells such as neu-
trophils and macrophages recruited to the site of infection (Fig. 2).
SpA is also known to aid the bacterial clearance by neutrophil
extracellular traps (NET) (Table 1), thereby contributing to proper
abscess formation and inflammatory responses [39].
Q. Tang, N. Xue, X. Ding et al.
Fig. 1. Microbiota regulates the inflammatory response and the related signalling pathways.
2.4. Effect of wound microbiome on cell proliferation
The inflammatory phase is followed by a cell proliferation
phase, in which fibroblasts, keratinocytes, and endothelial cells
migrate and proliferate, promoting angiogenesis and synthesis of
new extracellular matrix (ECM) [40]. The transition from the
inflammatory phase to the proliferative phase is a critical step in
the healing process. Thus, the poor transition is associated with
impaired wound repair.
S. epidermidis is closely associated with keratinocytes as an
antibacterial defender with increased wound healing rate [41]. S.
epidermidis was reported to recruit IL-17A+ CD8+ T (Tc17) cells
infiltrating into the epidermis with enhanced innate barrier immu-
nity via upregulating toll-like receptors and limiting the pathogen
invasion [41]. Upregulated TNF-a gene expression promotes rapid
cell proliferation of keratinocytes, thereby accelerating the healing
rate (Table 1). Interestingly, S. epidermidis-induced Tc17 cells
highly expressed a series of key factors involved in angiogenesis,
extracellular matrix production, and tissue remodelling [37]
(Fig. 2). Recent studies have shown that skin microbes can also
act as a facilitator by activating biosensors on the skin, such as
the aryl hydrocarbon receptor (AHR) in keratinocytes to upregulate
gene expressions that are involved in cell proliferation, differenti-
ation, and inflammation [42–43]. AHR plays a crucial role in skin
homeostasis and the skin development, function, and integrity of
the epidermal permeability barrier. A comprehensive study
showed that commensal flora is required for the formation of the
skin barrier and that skin epithelial cell development and differen-
tiation are impaired in germ-free mice [43]. When microbiota,
including S. epidermidis, Staphylococcus warneri, Staphylococcus
hemolyticus, Micrococcus luteus and Corynebacterium aurimucosum,
isolated from normal human skin were transplanted into germ-
free mouse skin, engraftment of commensal microbiota regulated
4
Advanced Drug Delivery Reviews 192 (2023) 114671
epithelial cell differentiation via AHR and promoted the restoration
of skin barrier function compared with mice not colonized or trea-
ted with antibiotics (Table 1).
2.5. Effect of wound microbiome on re-epithelialization
Re-epithelialization is the process of re-build/reformation of
the external surface of wound epithelium via keratinocyte migra-
tion from the wound edge to the centre area. Re-epithelialization
mainly relies on keratinocyte migration, in which keratinocytes
are the most predominant cell type in the epidermis. Many bac-
teria on human skin can convert aromatic amino acids into so-
called trace amines (TAs) [44] (Fig. 2). When the wound occurs,
in response to stress, the damaged epithelial cells release epi-
nephrine while b2-adrenergic receptor (b2-AR) in keratinocytes
is activated to hinder the migration of keratinocytes and reduce
collagen production [45]. TAs are known as b2-AR antagonists
that can attenuate the effects of epinephrine, resulting in acceler-
ated wound healing [44]. The serum adenosine deaminase (SadA)
gene encodes an aromatic amino acid decarboxylase that converts
aromatic amino acids into TAs, such as tryptamine, phenethy-
lamine, and tyramine [46]. Additionally, SadA homologs were
found in at least 7 phyla in the human skin microbiota, including
Firmicutes, Actinobacteria, Proteobacteria, Bacteroides Acidobac-
teria, Chloroflexi and Cyanobacteria [47]. Taking S. epidermidis
with SadA gene as an example, it can increase the migration rate
of keratinocytes and ultimately accelerate wound healing
(Table 1).
The skin microbiome also plays a role in strengthening the
physical barrier to skin integrity. Keratinocytes and the micro-
biome produce sphingomyelinase, which processes lamellar lipids
into ceramides, which are important molecules in maintaining skin
structure and function [48]. Using a mouse model of impaired skin
Q. Tang, N. Xue, X. Ding et al. Advanced Drug Delivery Reviews 192 (2023) 114671

Table 1
Summary of wound microbiome effects in wound healing phases.

Wound healing phase Strains/proteins Wound model Mechanism References

Inflammatory Commensal Staphylococci and
Micrococci (S. epidermidis, S.
xylosus, S. saprophiticus and
M. luteus,)
S. epidermidis
Tape stripping wound Activates neutrophils, produce type I interferons, and [36]
and full-thickness stimulates the growth of fibroblasts and macrophages.
wound of C57BL/6 mice
Punch biopsy wound in Stimulate recruitment of CD8+ T cells and Up-regulated the [37]
the ear pinnae and back expression levels of various immune and tissue repair-
skin of C57BL/6 mice related genes.

Staphylococcal surface proteins
(SpA) and the Staphylococcal
immunoglobulin binding protein
(Sbi)
BALB/c mice skin  Promotes the secretion of IL-1b, IL-6, TNF-a and CXCL-1, [39,52]
infected with and IL-10 in skin-infected tissues;
Staphylococci  Contributes to the recruitment of neutrophils, extends the
time of neutrophils and macrophages recruiting to the site
of infection;
 Aid the clearance of bacterial contamination by NETs.

Cell proliferation
Re-epithelialization
Tissue remodelling
S. epidermidis
S. epidermidis, S. warneri, S.
hemolyticus, M. luteus and C.
aurimucosum
Firmicutes, Actinobacteria,
Proteobacteria, Bacteroides,
Acidobacteria, Chloroflexi and
Cyanobacteria
A. faecalis and C. striatum
Haemolytic exotoxin produced by
Streptococcus
S. epidermidis and low abundance
of S. aureus
S. aureus
Ear pinnae of BALB/c  Recruit IL-17A+ CD8+ T cells and express key factors [41]
mice involved in angiogenesis, extracellular matrix production
and tissue remodelling, by upregulating toll-like
receptors；
 Up-regulated TNF-a gene promotes rapid cell
proliferation of keratinocytes.
Tape stripping wound of Activates aryl hydrocarbon receptors, promotes epithelial [42–43]
germ-free C57BL6/J cell differentiation.
mice;
Epidermal keratinocytes
exposed to high calcium
media
Full-thickness wounds Produces trace amines, antagonizes b2-adrenergic [44,46–47]
of DDY mice receptors, increases keratinocyte migration.
Full-thickness Promote epithelial regeneration. [15]
excisional wounds of
db/db mice
Human skin organ  Stimulates keratinocyte migration; [49]
culture wound  Activate CD44 expression in keratinocytes in vitro and
promote the assembly of hyaluronan-rich ECMs.
Keratinocytes exposed Trigger keratinocytes to produce b-defensin and CAP18 [50,53]
to S. aureus against Staphylococcus aureus.
Full thickness excisional Activates the IL-1b-IL-1R-MYD88 signalling pathway to [4]
wounds of C57BL/6 trigger hair follicle regeneration.
mice

barrier function, Staphylococcus colonization on the surface of
mouse skin was reported to have less transdermal water loss com-
pared to the animals not treated with S. epidermidis [15,48]. This
finding provides new insights into the underlying mechanisms of
how the skin microbiome interacts with the host skin.
In addition to the direct beneficial effects of wound microbiotas
on wound healing, the bacterial toxins secreted also play a specific
role [49] (Table 1). Streptococcus pyogenes is known for causing
superficial infections and invasive diseases, and streptolysin O
(SLO) is a hallmark toxin secreted by Streptococcus pyogenes at
low concentrations (0.02–0.2 U /mL). SLO promotes wound healing
in vitro by stimulating the migration of keratinocytes. Such a cellu-
lar mechanism via SLO may be explained via maintaining the
expression of the hyaluronic acid receptor, CD44, in keratinocytes,
which benefits the composition of the hyaluronic acid-rich ECM
through the formation of CD44-hyaluronic acid complexes wound
healing process [49]. Both S. epidermidis and typical low abundance
S. aureus can stimulate human keratinocytes to express antimicro-
bial peptide (AMPs), protecting skin against the invasion of patho-
genic microbiotas [50] (Fig. 2). Human b-defensin (hBD) is a small
molecule cationic antimicrobial peptide, which is expressed and
uniformly distributed in all human epithelial cells, supporting ker-
atinocyte differentiation together with recognition of microbiotas,
AMP has thus emerged as a new target for accelerating wound
healing.
2.6. Wound microbiome and remodelling phase
When the wound is completely closed, remodelling occurs
when the newly formed epithelial cells constantly divide, thicken-
ing the epidermis. There is no direct evidence showing that the
microbiome in wound healing regulates collagen deposition. How-
ever, skin bacteria were recently reported to have a direct correla-
tion with the hair follicle (HF) neogenesis [4] (Fig. 2). Scientists
found that germ-free mice have less ability to regenerate hair fol-
licles. In contrast, mice with skin commensal microbiota can trig-
ger the regeneration of hair follicles via activation of the
interleukin-1 receptor (IL-1R) - MYD88 signalling pathway [4,51].
Furthermore, recent data showed that the transmembrane
endopeptidase ADAM10-Notch signalling pathway in HF is an
essential regulator of the microbiota in the hair follicle opening
region. Disruption of the DAM10-Notch signalling pathway leads
to upregulation of inflammation-related genes’ expressions, and
inflammatory alopecia, resulting in dysbiosis of the Corynebac-
terium-dominated flora, causing hair follicle cell death and irre-
versible hair loss. ADAM10-Notch signalling can enhance innate
epithelial immunity by promoting type I interferon responses
downstream of b-defensin-6. Therefore, the host-microbe symbio-
sis balance mediated by the ADAM10-Notch signalling axis pro-
tects HF from inflammatory destruction and has clinical
implications for maintaining the tissue integrity [4] (Table 1).

5
Q. Tang, N. Xue, X. Ding et al.
Fig. 2. A summary of key bacteria and factors involved in different stages of the wound healing process.
3. Immune cell response to bacterial
Multiple immune cells are required to achieve tissue regenera-
tion and homeostasis post-injury, including innate and adaptive
immune cells [54]. These cells are significantly heterogeneous,
plastic, and can have different functions in response to different
environmental stimuli [55]. Wound microbes can also interact
dynamically with various types of cells to regulate wound repair
and regeneration (Fig. 3).
3.1. Neutrophils
Following injuries, neutrophils, circulating inflammatory cells,
are the first responders recruited from the blood strain to the
wound site [56]. Neutrophils accumulate abundantly at the would
site, releasing chemokines and inflammatory cytokines that further
recruit more neutrophils and other immune cells [57]. Neutrophils
also act as host defence by engulfing pathogens, secreting granules
filled with cytotoxic enzymes, or expelling neutrophil extracellular
traps (NETs) to trap and kill pathogens (a process is known as
NETosis) [58]. NETs are a DNA network structure formed by neu-
trophils activated by various stimuli and released to the outside
of the cell [59]. With DNA as the backbone, the network structure
is inlaid with a variety of proteins, including histones, matrix met-
alloproteinase 9 (MMP-9), neutrophil elastase, myeloperoxidase,
protease 3, etc., aiming to kill pathogens or increase their perme-
ability [60]. Currently, S. aureus, Streptococcus pneumoniae, E. coli,
Helicobacter pylori, Pseudomonas aeruginosa, Candida albicans (C.
albicans) and fungi were found to stimulate neutrophils to produce
NETs [61] (Fig. 3).
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Advanced Drug Delivery Reviews 192 (2023) 114671
In-depth studies have found that the ability of bacteria to
induce NETs varies by bacterial species, while the most potent
inducer of NETs is S. aureus [62–63]. However, S. aureus has mul-
tiple evasion strategies against the human immune system, such
as the production of immunomodulators and secretion of nucle-
ases. It can also target neutrophils by blocking neutrophils roll-
ing on activated endothelial cells antibodies and opsonin
necessary for pathogen recognition by cells to escape phagocytic
neutrophils, allowing them to escape NETs [39]. Among the var-
ious virulence factors secreted by S. aureus, leukotoxins and
leukocidins can promote the production of NETs through a
non-ROS-dependent pathway [64]. In addition, the expression
of S. aureus protein SPA in subcutaneous skin infection can also
assist neutrophils recruitment, and clearance of bacteria through
the NET capture [39,52].
In contrast, few studies have proved that NETs are a ‘‘double-
edged sword”. NETs can eliminate pathogens and reduce inflam-
mation, while they can reprogram macrophages to reach M2
Phenotypic regulation for a faster wound healing [65]. However,
over-promoted neutrophils by pathogens in the wound area stim-
ulate severe expression of inflammatory mediators (such as IL-1,
TNF-a) and proteolytic enzymes, resulting in excessive and persis-
tent inflammation that exacerbates tissue damage or even damage
surrounding healthy tissue [55]. For example, over-expressed NETs
were found in diabetic foot wounds, leading to further tissue dam-
age and delayed wound healing. In an animal model of diabetic
mice, inhibiting the formation of NETs or the cleavage of NETs
can significantly reduce inflammation and improve the wound
healing [66]. The presence and activity of neutrophils mediated
Q. Tang, N. Xue, X. Ding et al.
Fig. 3. Response of immune cells, including neutrophils, macrophages, and T cells to wound microbiome.
by microbiomes is therefore a challenge in wound care which
request close monitoring of inflammation or infection [66].
3.2. Monocytes and macrophages
Over the inflammatory phase of wound healing, neutrophils are
cleared by macrophages [67], further removing pathogens and cel-
lular debris directly or indirectly via secreting transforming growth
factor-b (TGF-b1) and vascular endothelial growth factor (VEGF)
[68–69]. Macrophages include tissue-resident macrophages
located in the skin and monocytes recruited from bone marrow
through blood circulation. Macrophages are the key orchestrators
of the wound healing process against infection [70], while pro-
inflammatory macrophages are often described as M1 macro-
phages, and anti-inflammatory and repairing macrophages are
M2 macrophages [71]. M1 macrophages are usually detected early
in the repair process, secreting cytokines such as IL-6, TNF-a and
nitric oxide synthase that regulate the early stages of healing
[72]. Approximately 80–85 % of the M1 pro-inflammatory pheno-
type are converted to anti-inflammatory M2 macrophages on days
5–7 of acute wounding [73]. M2 macrophages normally lead to
increased secretion of anti-inflammatory cytokines (e.g., IL-10,
Arginase-1) that suppress inflammation and increase growth fac-
tors required for proliferation, migration, and repair processes
[71]. In diabetic patients, M1 macrophages drive the elevated
and prolonged non-resolving inflammation seen in diabetic foot
ulcers (DFU) [74] with around 80 % of macrophages at the edge
of chronic wounds being the pro-inflammatory M1 phenotype,
and the transition to an M2 phenotype is a hindrance. Therefore,
the polarization of macrophages is crucial for faster wound healing.
7
Advanced Drug Delivery Reviews 192 (2023) 114671
To date, the effect of probiotics on macrophage polarization has
become a new research trend. The lactic acid secreted by Lactococ-
cus lactis (L. lactis) was proved to reverse the inflammatory and
proteolytic characteristics of diabetic wounds via the M2 polariza-
tion [75–76]. Scientists also attempted to programme L. lactis by
transforming a plasmid encoding VEGF, to maximize VEGF produc-
tion, and reduce intrinsic deactivation of the VEGF [77]. The genet-
ically engineered L. lactis can continuously secrete VEGF and
lactate, with enhanced angiogenesis and induction of M2 polariza-
tion [77]. Such pioneer ideas are based on live engineered bacteria,
which can promote wound healing by exogenous supplementation
of probiotics in the future.
Similar to mammalian cells, gram-negative and gram-positive
bacteria constitutively release lipid bilayer-enclosed, nanosized
extracellular vehicles (EVs) or membrane vesicles [78]. As EVs con-
tain bioactive molecules, including nucleic acids, proteins, lipids,
toxins and various virulence factors, they were reported to have
diverse functions in cell-to-cell communication between bacteria
[79]. Bacterial EVs are proven more effective compared to bacterial
extracts or purified toxins in evoking cellular responses in the
recipient cells [56]. A pioneer study proved that EVs derived from
Lactobacillus plantarum (L. plantarum), LEV, could successfully
induce monocyte differentiation into M2 macrophages in human
THP1 cells, with increased secretion of the anti-inflammatory cyto-
kine IL-10, along with immunomodulatory cytokines IL-1b, GM-
CSF and a higher population of M2b macrophages [60]. Such
promising results showed that LEVs can be used as anti-
inflammatory and immunomodulatory substances by regulating
the conversion of M1 and M2 macrophages, thereby improving
hyperinflammatory skin conditions and the phenotypes of inflam-
matory skin disorders. Therefore, determining which uptake path-
Q. Tang, N. Xue, X. Ding et al.
ways and signalling molecules are involved in LEV-evoked cellular
responses may further assist in interpreting bacterial EV-mediated
phenomena in human cells and designing alternative methods
using bacterial EVs as immunomodulatory materials.
3.3. Lymphocytes
Lymphocytes are immune cells that are recruited to the wound
at a late stage aiming for fibrous tissue regeneration [80]. B lym-
phocytes are relatively rare in the skin at a steady state. Elevation
of B lymphocytes can be observed in the skin disease, such as
human atopic eczema, cutaneous leishmaniasis, and skin sclerosis
[81]. Recent studies have found that B cells can act as a regulator of
the tissue regeneration [82]. ECM component can induce CD19-
dependent Toll-like receptor (TLR) signalling in wound B cells,
thereby inducing the production of cytokines, IL-10 and TGF-b,
directly reducing the inflammatory response [83]. When mature
B cells were applied locally to acute or chronic wounds, increased
fibroblast proliferation is noted with a reduced level of apoptosis
and an accelerated healing rate [84]. However, to our knowledge,
no data or report was seen on the role of wound microbiome-
mediated B cells.
T lymphocytes are mainly categorized into ab T cells and cd T
cells according to their composition [85]. cd T cells have a high pro-
portion in the mouse skin tissue, accounting for more than 90 % of
T cells in the epidermis as a skin immune defensor [86–87]. Human
skin contains ab T cells and cd T cells with an expression ratio of
approximately 5:1, distributed in both the epidermis and dermis
[88–89]. cd T cells are highly involved in psoriasis [90], tumours
[91–92], viral infection [93] and wound healing [94]. Burn injury
has been found to activate cdT cells to produce a large amount of
insulin-like growth factor 1 (IGF-1) (Fig. 3). However, the presence
of P. aeruginosa in burn wounds was reported to reduce the synthe-
sis of IGF-1 in burn patients with peripheral blood cdT cells,
adversely affecting wound repair [95]. When cd T cells are acti-
vated by an infection, a large amount of IL-17 can be produced to
resist infection [55] Hence, IL-17 also plays a crucial role in the
immune response to pathogens, including Klebsiella pneumoniae
(K. pneumoniae), Citrobacter rodentium, C. albicans [96–97]. In addi-
tion, cd T can also regulate and control ab T cell-mediated inflam-
mation, to reduce the activity of lymphocytes and the production
of IFN-c in delayed hypersensitivity reactions [98].
4. Clinical management in regulating wound microbiome
4.1. Role of commensal microbiota on surgical wounds
Surgical incisions breach the skin barrier, disrupting the com-
mensal resident microbiota, triggering a host immune response
and wound healing processes [99]. All surgical wounds are re-
colonised by a patient’s resident microbiome and environmental
organisms. Some wounds become infected when organisms invade
tissue or cause cellular injury. Depletion of the resident skin micro-
biome in favour of opportunistic pathological organisms capable of
invasion results in SSWIs [100]. SSWIs impose a significant burden
on the health care system and are a leading cause of morbidity
after surgery occurring in up to 5 % of patients post-operatively
[101]. This accounts for approximately 20 % of all healthcare-
associated infections and costs $5000-$13,000 per incident [102].
Methods for the prevention of wound infection are largely
instrumental in the management of surgical patients. These inter-
ventions support the return of a commensal wound neomicrobiota
and suppress domination by opportunistic pathogens. The neomi-
crobiome describes the process of re-colonisation of the wound
after surgery with resident and transmitted non-resident organ-
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Advanced Drug Delivery Reviews 192 (2023) 114671
isms, including bacteria, fungi and viruses [99]. Reservoirs of resi-
dent organisms, which form the neomicrobiome, are found on the
surrounding superficial skin, in deeper skin layers and the pilose-
baceous unit [12]. Other organisms may enter the wound from
environmental contamination before an operation at the time of
wounding, or during the operation e.g. respiratory, alimentary,
genital or urinary tract organisms or after in the hospital or home
environment [103].
Repopulating the wound neomicrobiome is a dynamic process
and changes with time. Immediately after wounding, there is a
gram-negative shift with resident commensals such as Proteobacte-
ria and Bacteroidetes and gram-negative environmental contami-
nants such as Pseudomonas colonising wounds [104–105]. Gram-
positive bacteria are still present but with a reduced number, such
as the facultative anaerobe Propionibacterium [12]. This is in-part
due to the suppression of gram-positive Staphylococcus and Strep-
tococcus populations with the SSWI antibiotic prophylaxis [105].
With wound healing, reservoirs of resident commensal organisms
repopulate the wound area while a gram-positive shift occurs with
a return to the normal skin flora [12,104]. Total microbial load is
also variable but critical to wound healing and infection. Overpop-
ulation of commensal organisms or environmental pathogens is
causative of SSWI and delays wound healing. Once bacterial levels
reach a threshold of > 105 colony-forming units, tissue invasion
and wound infection are common [100,106]. The dynamic process
of the surgical wound microbiome is a novel area of research. At
this point, analysis has focused on the bacterial neomicrobiome
[107].
Repopulation of the wound with resident commensal organ-
isms accelerates wound healing and prevents wound infection by
opportunist pathogens with evidence suggesting that this process
occurs over a period of 2–6 weeks [4,12,108]. Commensal micro-
biota is beneficial through indirect competition, occupying the skin
niche and utilising available nutrients [109]. The diversity of the
resident commensal microbes prevents domination by a single
pathogen. Evidence of this has been demonstrated in numerous sit-
uations. For example, low levels of commensal Pseudomonas accel-
erate wound healing. However, overpopulation results in tissue
invasion and SSWI’s [100,110]. Resident microbes also directly
support wound healing by producing anti-microbial molecules,
metabolites and immune-enhancing actions [36,109,111–112].
Surgical wound management, therefore, aims to encourage the
repopulation of a neomicrobiome with the diverse commensal res-
ident flora restoring skin homeostasis and preventing wound infec-
tion. Various surgical techniques are directed at controlling the
number of microbes and resorting balance to the neomicrobiome
[13,113]. This includes surgical techniques to aid wound closure,
control of contamination, antiseptic and antibiotics.
Surgical wounds may be closed primarily where healing occurs
from approximation of tissue using sutures, staples or glue.
Wounds heal by primary intention, minimising exposure to
endogenous and exogenous contaminants [114]. Healing by sec-
ondary intention is the process of an open wound healing through
granulation, contracture and epithelialisation. An open wound is
exposed to environmental contaminants, and healing occurs in
the presence of a complex relationship between microbial coloni-
sation and the immune system [115–116]. The success and failure
of tertiary healing largely depend on the wound bioburden with
graft or primary closure failure, highly likely with an elevated bac-
terial load [100,117].
The degree of wound contamination influences the inoculum of
a wound with foreign microbes and depends on pre- and intra-
operative events determining whether a wound is clean, clean-
contaminated, contaminated, or dirty. In clean wounds, the respi-
ratory, alimentary, genital or urinary tract is not entered. Clean
contaminated wounds reflect a controlled entry into the respira-
Q. Tang, N. Xue, X. Ding et al.
tory, alimentary, genital or urinary tract. Contaminated wounds
are open, fresh, accidental wounds or occur in operations with
major breaks in sterile technique, gross spillage of the gastroin-
testinal tract or acute non-purulent inflammation encountered.
In both clean-contaminated and contaminated wounds, the neomi-
crobiome is exposed to foreign microbes e.g., gastrointestinal bac-
teria. Dirty-infected wounds include old traumatic wounds and
wounds with existing infection. Contamination of a wound during
or before an operation inoculates the wound with potential patho-
gens which may dominate the neomicrobiome [106]. This is sup-
ported by evidence which shows the SSWI rates following clean,
clean-contaminated, contaminated, and dirty procedures are
1.76 %, 3.94 %, 4.75 %, and 5.16 %, respectively [101].
In treating acute wounds, ethanol, povidone-iodine and/or
chlorhexidine are widely applied clinically as the pre-operative
topical antiseptics. The latest report showed that exposure to
antiseptic treatments can elicit rapid but temporary depletion of
microbial community diversity and membership [118], while the
wound microbiome was found highly dependant on personalized
and body site-specific colonization signature. Moreover, another
clinical study compared the efficacy of povidone-iodine-alcohol
and chlorhexidine-alcohol for surgical wounds, showing skin
microflora was more affected by povidone-iodine in short time
but not in prolonged contact times over 3 h [119]. These studies
confirmed the short-time stability and resilience of the skin micro-
biome to antiseptic and its effect on the incidence of SSWI
remained unknown.
The use of antibiotics before, during and after surgery alters the
structure and function of wound microbial communities. Systemic
and topical antibiotics suppress common pathogens, and lower
wound tissue inoculum from intra-operative contamination but
also eliminate commensal resident bacteria [120–121]. It has been
proven definitively that systemic antibiotics given at the time of
induction reduce SSWI for wound healing by primary and sec-
ondary intention [122]. Topical antibiotics after primary closure
also reduce SSWI [101]. It is unclear whether the antibiotics’ mech-
anism of SSWI reduction after surgery is from eliminating environ-
mental pathogens or through suppressing the overgrowth of a
commensal opportunist, it is likely a combination of both [103].
Overall healing of surgical wounds is intrinsically linked to the
health of the wound neomicrobiome. A complex interplay exists
between the neomicrobiome composed of commensal residential
and environmental organisms, wound healing processes, the
wound environment and the immune system. Surgical techniques
are aimed at preventing wound infection and restoring the resi-
dential wound microbiome.
4.2. Clinical management in treating chronic wounds
Chronic wounds are different from surgical wounds. Studies
have found that chronic wounds are colonized by bacteria living
in biofilms, and are more likely to be home to bacterial infection
[32]. Colonization of skin bacteria is now considered a major cause
of delayed healing and ineffective treatment response [123]. Gram-
positive (GP) bacteria were sensitive to linezolid, vancomycin and
teicoplanin [124–125]. However, over 50 % of Gram-negative (GN)
bacteria were resistant to third-generation cephalosporins, while
the resistance rates of piperacillin/tazobactam, amikacin, merope-
nem and imipenem were low [126]. A study found that the most
common pathogens in 216 diabetic foot patients were: S. aureus
(28 %), E. coli (19 %), and S. epidermidis (14 %) [127]. Antibiotics
were therefore prescribed from ceftriaxone (49.4 %), metronidazole
(21 %) to ciprofloxacin (7.5 %) for skin and soft tissue infections.
Currently, therapeutic interventions for chronic wound man-
agement are aiming to prevent the infection or chronicity. The
standard protocols include debridement of necrotic tissue, ade-
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Advanced Drug Delivery Reviews 192 (2023) 114671
quate glycemic control, decompression, wound coverage with
appropriate dressings, revascularization performed if necessary
and appropriate antimicrobial therapy for clinically infected
[128–129]. A recent clinical study showed that when wounds have
no infection and no antibiotic treatment, debridement can signifi-
cantly reduce the pathogenic anaerobes, such as Anaerococcus lac-
tolyticus, Porphyromonas Somerae, Prevotella melaninogenica, and
Veillonella dispar. However, debridement was found to have no
effect on the commensal wound microbiota [15,130]. Under antibi-
otic treatment, effects of debridement on the diversity of micro-
biomes seem to be overcome by antibacterial therapy, resulting
in no changes in the wound microbiota [131]. These data suggest
that debridement may be beneficial for controlling wound infec-
tion without antibiotic treatment, but its role in mediating wound
microbiome is limited [131].
Antibiotic treatment is well known for treating chronic wound
infection, and it also leads to major changes in the composition
of the wound commensal microbiota [18]. A clinical study on DFUs
revealed that at 0, 4 and 8 weeks post-debridement and antibiotic
treatment, patients with healed wounds had a larger abundance of
Actinomycetales and Staphylococcaceae [132]. However, in the same
study, another 12 unhealed patients were detectable with Bac-
teroidales and Streptococcaceae, suggesting the presence of Actino-
mycetales and Staphylococcaceae is a good prognostic indicator
but appears that Bacteroides and Streptococcaceae seem to have a
poor outcome [132]. Moreover, an increase in the Bacteroides fam-
ily may be a sign of changing antibacterial or requiring additional
debridement. Another study further showed that antibiotics could
result in a significantly decreased diversity of microbiota in
3 weeks, following an unexpected increase thereafter [133]. Swab
samples taken before debridement showed greater changes in bac-
terial composition associated with antibiotics (doxycycline) [134],
while samples taken from wound centres had higher bacterial
loads compared to the wound edges [135]. To date, Imipenem
was found to be the most efficient antibiotic against Gram-
positive and Gram-negative bacteria for patients with chronic
wounds [136–137].
Negative pressure wound therapy (NPWT) is also commonly
used in treating chronic wounds [138]. A study found that addi-
tional oxygen supply to diabetic wounds could promote wound
repair, while wound microbiota shifted to a diverse bacteria dom-
inated by aerobic bacteria and facultative anaerobes [139].
Platelet-rich plasma (PRP), as an additional therapeutic option for
infected wounds, was reported to significantly inhibit the growth
of methicillin-resistant S. aureus (MRSA), K. pneumoniae and P.
aeruginosa [140]. It is important to emphasize that few chronic
wounds do not heal despite various treatments. Therefore, clinical
management aims to create a balanced microbiome environment
to achieve normal wound healing.
5. Strategies in controlled delivery of probiotics and
microbiome
Although topical antibiotics for wound sterilization are still
widely used clinically, studies have pointed out that local antimi-
crobial therapy is difficult to achieve effective antibacterial concen-
trations and is prone to antibiotic abuse and to cause bacterial
resistance [141]. In addition, removal of beneficial microbiota from
wounds via topical administration of antibiotics can further result
in an imbalance of the wound microbiota [4,142]. As discussed
above, more recent studies confirmed that microbiomes are closely
related to wound healing [143]. However, to our knowledge, there
is no report of using microbiomes in the treatment of wound heal-
ing, but probiotics are widely developed, aiming to achieve optimal
wound microbiome and promote wound healing [144–147]. Such a
Q. Tang, N. Xue, X. Ding et al.
delivery system may also be utilized in the future for the topical
administration of microbiomes.
Two strategies are currently utilized in probiotic development.
The first is to directly use natural probiotic strains or engineered
probiotics in wound healing. The second strategy is to use a probi-
otic strain loaded in a delivery carrier with controlled delivery
capacity to enhance wound healing. The topical application of L.
plantarum showed great potential in a mouse model for the treat-
ment of burn wound sepsis infected by P. aeruginosa [124]. Topical
use of Kefirs gel (a mixture containing Lactobacillus and Yeast) on
the burn injury wound was further confirmed with the faster
regeneration of epidermis and more collagen deposition, promot-
ing wound healing rate [148]. Genetically engineered bacteria,
AUP-16, is the first-in-class that has entered the clinical stage for
the treatment of diabetic foot ulcers, venous ulcers of the lower
extremities, and pressure ulcers [149]. AUP-16 is a genetically
engineered Lactococcus lactate, a non-pathogenic probiotic that
carries genes encoding multiple regenerative factors, including
human basic fibroblast growth factors (FGF2, bFGF), interleukin 4
(IL-4) and macrophage colony-stimulating factor (CSF1, mCSF)
[149]. AUP-16 can continuously secrete lactic acid, reverse the
alkaline environment of the wound and induce M2 macrophage
polarization to promote angiogenesis and granulation tissue for-
mation with rapid wound healing [149]. Furthermore, studies have
shown that the chemokine CXCL12 can increase the density of
macrophages and TGF-b expressing macrophages in the dermis
and epidermis at the wound edge. Lactobacillus Reuteri were trans-
fected with a plasmid encoding the chemokines CXCL12 and deliv-
ered directly to the damaged skin of mice, which were proved to
release large amounts of CXCL12. The lactate production can fur-
ther reduce the local wound pH, improve the bioavailability of
CXCL12, and strongly promote wound healing [150]. Thereafter,
varying drug delivery system was developed and investigated for
the controlled release of probiotics which may be an alternative
used for delivering microbiome in the future study (Table 2).
5.1. Microencapsulation
Microencapsulation is a widely used technology for probiotics
delivery [156–157]. According to biomedical applications with
desired outcomes, materials utilised to encapsulate probiotics
should meet the following characteristics, such as non-toxicity,
the viability of probiotics, bioactivity maintenance, fine biocom-
patibility and biodegradability, permselectivity, protection of pro-
biotics from harsh environments, controlled/delayed release,
good formability, low cost and easy accessibility [156]. In recent
decades, varying polysaccharides (biomaterials), such as alginate,
carrageenan, gums, and chitosan, have been utilised for probiotics
delivery aiming to maintain the viability and stability of probiotics
viability over drug delivery [158].
Table 2
Overview of different probiotic strains, methods of delivery, materials used for skin-related application.
Strain Method
L. reuteri; Microencapsulation
Lactobacillus fermentum;
Bacillus subtilis sp. natto
Hydrogel fabrication
L. rhamnosus
Enterococcus mundtii Electrospinning
Lactobacillus acidophilus; Microencapsulation
Lactobacillus casei;
L. rhamnosus
L. plantarum Microencapsulation
Bacillus coagulans Microencapsulation
Advanced Drug Delivery Reviews 192 (2023) 114671
Chitosan which is produced by N-deacetylation of the polysac-
charide chitin demonstrates non-toxicity and satisfying biocom-
patibility and biodegradability in the food and pharmaceutical
field [159]. These unique biological properties have enabled chi-
tosan to develop into a variety of wound dressings, which have
antimicrobial, biologically adhesive and hemostatic effects, and
provide an ideal moist wound environment, infection control and
removal of the wound exudate [160–162]. Moreover, positively
charged chitosan has strong adhesive properties with negatively
charged polymers [163]. Thus, recent studies showed that chitosan
can act as a coating material for microcapsules of probiotics to pre-
vent direct contact between probiotics microcapsules and harsh
environments, providing protective effects [164]. As a coating
material, chitosan has been found to increase probiotics survival
rate and probiotics stability during cold storage [165–166]. How-
ever, the solublity of chitosan is pH-dependent. Chitosan has poor
solubility when the pH value exceeds 5.4 [167]. In general, healthy
skin has a pH value ranging from 4.5 to 6.5. A wound pH value can
increase to a range of 7.4 to 9 due to the by-products of proliferat-
ing bacterial colonies [3]. Thus, the application of chitosan as a
delivery system of probiotics on wounds might be limited. Chem-
ical modification of chitosan through derivatization by acylation,
alkylation and quaternization reactions has been proven to signif-
icantly increase the water solubility of chitosan, further improving
its drug delivery application on skin and wounds [168]. Alginate,
extracted from seaweeds, is another common anionic biomaterial
for probiotics encapsulation [156,163]. Alginate demonstrates
extraordinary physicochemical and mechanical properties, favour-
able hydrogel formability, great hydrophilicity and excellent cell
adhesion compatibility [169]. Alginate-formulated microcapsules
have a highly porous structure [170]. Therefore, most studies used
a composite of alginate with other materials to facilitate its encap-
sulation effects. For instance, the composite of sodium alginate and
calcium chloride can form probiotics capsules having better per-
meability, which is favourable for air and nutrient exchange, and
metabolite release [171–173]. Alginate has also been broadly
employed as a wound dressing for specifically exuding wounds
by generating a slightly wet wound healing environment [174].
Some alginate-based dressings have been demonstrated to stimu-
late human macrophage activities in chronic wound beds to gener-
ate a pro-inflammatory signal and initiate a resolving
inflammation characteristic of healing wounds [175]. Carrageenan
extracted from red seaweeds, known as Irish moss, is natural linear
sulphated polysaccharides [176]. It is a hydrophilic biopolymer and
has been widely used in the food industry and recently drew a lot
of attention to its uses in tissue engineering, wound coverage and
drug delivery [177]. Carrageenan involves 15–40 % ester-sulphate
content, making them anionic polysaccharides. They can be classi-
fied into three different types according to their sulphate content,
including kappa-carrageenan (one sulphate group per disaccha-
Material Application Reference
Chitosan Wound healing [151]
Hyaluronate-dipic dihydrazide/ Superbacteria-induced skin [147]
Pluronic F127/ Fucoidan wound infections
PVA/PVP/Glycerol Infection control [152]
Dermal burn healing
Alginate Wound infection [153]
Sodium alginate /Calcium chloride Atopic dermatitis [154]
Gelatin emulgel Wound healing [155]
10
Q. Tang, N. Xue, X. Ding et al.
ride), iota-carrageenan (two sulphate groups), and lambda-
carrageenan (three sulphate group), whereas only kappa- and
iota-carrageenan have gelling ability [178]. Kappa-carrageenan is
thermal-responsive and is able to undergo reversible volume tran-
sitions in response to thermal environments [163] with the capa-
bility to be used for delivery systems based on the thermal
control [179]. Kappa-carrageenan encapsulating probiotics have
shown great acid and bile tolerance. Carrageenan blended with
other materials has also been used to improve encapsulation
effects [180]. Carrageen-based hydrogels can create a damp envi-
ronment to accelerate the wound healing [181]. It has been
reported composite cyclic glucan/carrageenan hydrogels could
induce fibroblast cell migration, facilitating wound healing attrib-
uted to their immunomodulatory properties [181]. Xanthan gum
is a polysaccharide, produced from simple sugars by Xanthomonas
campestris fermentation [182]. In tissue engineering, xanthan gum
has exhibited superb biocompatibility, gelation ability and stability
in a wide range of pH, temperature, and ionic strength, remaining
activity/effectivity in acid and heat conditions [183]. Xanthan gum
was also combined with alginate to encapsulate probiotics, which
has shown improved encapsulation efficiency, survival rate under
simulated gastric conditions, heat resistance, storage stability and
target release to the intestine [184].
5.2. Electrospun scaffolds
Electrospun scaffolds with micro- or nano-fibres, can be ulized
to encapsulate probiotics bacterial for a controlled delivery [185].
Polymers, such as polyethylene oxide (PEO), polyvinyl alcohol
(PVA), copolymers, polyvinyl pyrrolidone (PVP), polylactic acid
(PLA), and PluronicÒ F127 were genuinely favoured and safe mate-
rials for entrapping probiotics and wound healing [156,186–188].
PEO is a non-immunogenic, non-toxic and hydrophilic polymer
[189]. PEO has excellent biocompatibility and mucoadhesive activ-
ity and it appears not to impact the bioactivity of delivered sub-
stances. A number of studies have reported the addition of
lyoprotectants into PEO can significantly enhance the viability of
probiotics during the drying process [190]. PVA is also a widely
accepted synthetic polymer for probiotics delivery. It is generated
from polyvinyl acetate and possesses numerous hydroxyl groups.
PVA has shown good stability in a wide range of pH from 1 to
13, and the great gelling ability by chemical or physical crosslink-
ing. It has been reported that the combination of PVA and
fructooligo-saccharides considerably improved the thermal stabil-
ity and viability of entrapped probiotics [191]. PVA-based hydro-
gels have also been used as wound dressings to enhance chronic
wound healing attributed to their outstanding biological properties
and drug delivery capability [192–193]. The in-vitro cell study con-
firmed that PVA-based dressings have either low or no cytotoxicity
to human dermal fibroblasts, human epidermal keratinocytes and
mouse fibroblast cells [194–195]. PVP has long been used in tissue
engineering, drug delivery or probiotics delivery via electrospin-
ning. The previous study designed the composite PVP/PCL nanofi-
bers loaded with a bioactive agent, pioglitazone, with non-
toxicity and sustained drug release for treating diabetic wounds
[196].
Nanofibers of PVP have been evidenced to ameliorate the meta-
bolic activity of probiotics, L. acidophilus [197]. The other study
exhibited that the viability of various lactobacilli species entrapped
in electrospun fibres varied depending on the ratio of PVP incorpo-
ration during delivery [198]. PLA is a polymer of organic acid and
can be produced by polycondensation of lactic acid and/or ring-
opening polymerization of lactide [199]. PLA has long been
approved by The US Food and Drug Administration (FDA) due to
its attractive biocompatibility and biodegradability. In humans,
PLA is metabolised into harmless products, CO2 and H2O, which
11
Advanced Drug Delivery Reviews 192 (2023) 114671
can be released through the kidneys [200]. PLA can be fabricated
as a variety of biodegradable devices, such as absorbable surgical
sutures, injection capsules, orthopedic fixation materials, micro-
spheres for drug release, and tissue-engineered stents. In a recent
study, coaxial electrospun PLA nanofibers have been proved to
increase probiotics viability through encapsulation [200]. Pluro-
nicÒ F127 is a copolymer synthesized using dicyclohexylcarbodi-
imide and dimethylaminopyridine. PluronicÒ F127 has also been
widely used as it has decent cytocompatibility and temperature-
sensitive sol gel properties. However, its incompetent mechani-
cal strength and stability have minimised its medical application
[147]. Therefore, the composites of PluronicÒ F127 with other bio-
materials, such as chitosan, collagen, and hyaluronic acid, have
been employed to improve the aforesaid weakness [147].
Whilst these synthetic polymers have favourable characteristics
as materials of electrospun fibres for probiotics delivery purposes,
a couple of challenges such as poor cell affinity and adverse foreign
body response still limited the clinical application. Therefore, most
studies investigated to use the synthetic polymers combined with
biopolymers, such as chitosan, alginate, and cellulose to improve
biodegradability, bioactivity, and biocompatibility.
5.3. Hydrogels and 3D bioprinting
Hydrogel, within hydrophilic 3D network structures, can mimic
the extracellular matrix and support cell growth [201–202]. The
therapeutic potential of hydrogel-encapsulated bacteria has been
validated in many studies [203], as hydrogel can protect bacteria
from environmental damage over recycling together via providing
ingredients for bacterial growth. Bacillus subtilis was encapsulated
in a thermosensitive hydrogel, and the formed hydrogel not only
effectively accumulate in the epidermis, but serve as a small fac-
tory for the efficient the production of antifungal ingredients (e.g.
surfactin), showing a promising antifungal effect in the skin model
of C. albicans infection [204]. A heparin-poloxamer heat-responsive
hydrogel was investigated in loading Lactobacillus to treat diabetic
wounds. The results showed that when the thermosensitive hydro-
gel is applied to wounds, it can rapidly form a gel to limit the
spread of bacteria, while maintaining bacterial activity and pro-
longing its residential time on the wound area [77]. The use of pro-
biotics in hydrogels for open wounds can partially reduce the
occurrence of local inflammation, and the strong lactic acid pro-
duction capacity of Lactobacillus can promote the transformation
of macrophages to M2 phenotype, improve tissue regeneration
and recovery potential, and promote rapid healing of the wound
environment [149]. The hydrogel system confines bacterial popu-
lations within the wound, thereby minimizing the risk of systemic
toxicity [77]. However, the composition of the hydrogel may influ-
ence the viability and function of the loaded bacteria [205], so it
needs to be further investigated for safety prior to clinical
application.
3D bioprinting is considered as a powerful and advanced
biomanufacturing technique in skin tissue engineering [206–
207], due to its precisely controlled distribution of a bioink consist-
ing of biomaterials, bioactive factors and incorporated living cells
via the computer-aided design [208]. Currently, embryonic stem
cells, and mesenchymal stem cells can be successfully bio-
printed as the artificial skin [209], suggesting the possibility of
using bioprinting technology and bioink for delivering probiotics
and microbiota in the future. However, there is no study on the
delivery system of probiotics prepared by 3D bioprinting which
may be explained by the low viability of probiotics post-
fabrication and the complexity of commensal microbiota on the
wound area. As discussed above, the environmental factors should
not be overlooked when scientists attempt to design 3D printing
Q. Tang, N. Xue, X. Ding et al.
materials for probiotics delivery together with internal structure
and varying fabrication approaches.
5.4. Microneedles
Microneedle is a non-invasive or minimally invasive route
developed for transdermal drug delivery. Microneedle drug deliv-
ery can penetrate the stratum corneum of the skin and release
the drug directly into the subcutaneous space without irritating
nerves and causing pain [210], and additionally microneedles can
also be utilized in the treatment of chronic wounds [211–212]. Dis-
solvable microneedles filled with cell-laden GelMA cores were
investigated for the delivery of mesenchymal stem cells with the
intention to modulate the wound microenvironment via secreting
growth factors, exosomes, and cytokines to enhance angiogenesis
and tissue remodelling [213]. Bioactive probiotics Lactobacillus
was loaded into soluble sodium carboxymethylcellulose (SCMC)
microneedle arrays and successfully released into the dermis
[214]. Transdermal administration of Lactobacillus was further
proved to enhance skin conditioning and immunity [214]. Soluble
microneedles can be used as a painless release tool for probiotics
and achieve highly stable encapsulation of probiotics after skin
penetration and their rapid release without causing any adverse
skin irritation.
Emerging antimicrobial transdermal and ocular microneedle
patches have become promising medical devices for the delivery
of antibacterial, antifungal, and antiviral therapeutics, including
nano-silver, nanoparticles, gentamicin and zinc oxide [215–216]
to treat bacterial biofilms [217–218]. Scientists developed a flexi-
ble polymer composite microneedle array that can overcome the
bacterial biofilm present in chronic wounds, and co-deliver oxygen
and bactericidal agents [217]. Such microneedles effectively ele-
vated the oxygen level from 8 to 12 ppm over 2 h and also provided
strong anti-bactericidal effects on both liquid and biofilm bacteria
found in dermal wounds. Self-dissolvable microneedles and needle
tips loaded with chloramphenicol and gelatinase-sensitive
nanoparticles were further fabricated and proved to simultane-
ously penetrate the biofilm matrix with controlled delivery of chlo-
ramphenicol into the active regions of the biofilm [218]. More
recently, novel ice microneedles made from versatile soft materials
were successfully developed aiming to carry and deliver small
molecules and biosafe Bacillus subtilis (B. subtilis) in the treatment
of fungal infection in the wound area [219]. Results from this study
showed live B. subtilis can be incorporated in the microneedles
with remaining high viability over 12 h and continue to divide
and proliferate, significantly inhibiting fungal infection in a mouse
model [219–220]. While there are many advantages over tradi-
tional delivery systems, microbiome-based therapies face various
challenges. Understanding the microbiome and its functions may
help prevent or treat personalized medicine in the setting. At pre-
sent, the specific mechanism of action of scavenging microbial
components on wound healing is not yet known, but there is a
deep connection between the two. Targeting or repairing the
microbiota may be an effective therapeutic strategy in the future.
6. Conclusion
Pioneer investigations have been made in studying the role of
wound microbiome in various wound healing, including
microbiome-regulated inflammatory, proliferation and remod-
elling together with the skin appendage regeneration, immune cell
response and enhanced systemic drug delivery for wound infec-
tion. As a result, mediation of wound microbiome is expected to
be a new target for finding novel pharmacological interventions
or therapeutical approaches in the treatment of wound repair.
12
Advanced Drug Delivery Reviews 192 (2023) 114671
However, our knowledge about wound microbiota remains lim-
ited, and further research is needed. In particular, investigation
on how to control wound microbiome with essential inflammatory
response, development of a controlled delivery system for sus-
tained releasing of beneficial microbiome and design of monitoring
system for health diversity of wound microbiome, should be prior-
itized. Further research will continue to extend our understanding
of microbiomes on skin and identify novel targets in wound care to
ultimately enhance the clinical outcome for patients.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgment
This study was supported by National Science Foundation of
China (82172217), Fundamental Science (Natural Science)
Research Project of the Jiangsu Higher Education Institutions of
China (No. 21KJB360016) and Natural Science Foundation of Nan-
jing University of Chinese Medicine (No. XZR2020069). Professor
Yiwei Wang was supported by Jiangsu Distinguish Professor fel-
lowship, Nanjing University of Chinese Medicine.
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