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Review Article

Wound healing

Wang, Peng-Huia,b,c,d,*; Huang, Ben-Shiana,b,c; Horng, Huann-Chenga,b,e; Yeh, Chang-Chinga,b,c; Chen, Yi-Jena,b,c

Author Information
Journal of the Chinese Medical Association: February 2018 - Volume 81 - Issue 2 - p 94-101
doi: 10.1016/j.jcma.2017.11.002


    1. Introduction

    Wound healing is an important but complicated process in human or animal, containing a multifaceted process governed by sequential yet overlapping phases, including hemostasis/inflammation phase, proliferation phase, and remodeling phase.1 After an injury to skin, the exposed sub-endothelium, collagen and tissue factor will activate platelet aggregation, which results in degranulation and releasing chemotactic factors (chemokines) and growth factors (GFs) to form the clot, and all above-mentioned procedures will achieve successful hemostasis.2 Neutrophils, the first cells to appear at the injury site, cleanse debris and bacteria to provide a good environment for wound healing. In the following, macrophages accumulate and facilitate phagocytosis of bacteria and damage tissue.3 The hemostasis and inflammatory phase often takes 72 h to finish.

    The following proliferative phase is characterized with an accumulation of lots of cells and profuse connective tissue. The wound encompasses fibroblasts, keratinocytes, and endothelial cells. Extracellular matrix (ECM), including proteoglycans, hyaluronic acid, collagen, and elastin forms a granulation tissue to replace the original formation of clot.4 Many kinds of cytokines and GFs participate this phase, such as transforming growth factor-β family (TGF-β, including TGF-β1, TGF-β2, and TGF-β3), interleukin (IL) family and angiogenesis factors (i.e., vascular epidermal growth factor). This phase continues days and weeks.4

    The last step of wound healing is a remodeling phase, which needs a precise balance between apoptosis of existing cells and production of new cells. Gradual degradation of profuse ECM and the immature type III collagen and formation of mature type I collagen are critical in this phase, which continues a few months and years. Any aberration in this phase may lead to excessive wound healing or chronic wound.5,6

    Since a better understanding of the mechanism of wound healing can be presumed from the increased number of in vitro or in vivo experiments and a better treatment algorithm to maintain a regulated and orchestrated inflammatory response will be developed,7,8 the following is an update of wound healing.

    2. Wound healing in the fetus and adult

    It is evident that the ability to repair wounds without excessive wound healing is age-dependent.9 The more advanced age is and the higher possibility of excessive wound healing occurs. Fetal wound healing is characterized by regeneration of normal dermal architecture, which includes restoration of neurovasculature and dermal appendages.9 Wound healing in the fetal skin involves a distinct GF profile, a lower inflammatory response with an anti-inflammatory cytokine profile, lower biomechanical stress, an ECM rich in hyaluronic acid and type III collagen, and a potential role for stem cells.6,8–11 Compared with fetal skin, adult has a higher risk of scar formation.

    There are at least four mechanisms to show the difference of wound healing between fetal skin and adult's skin.10 The early stage of adult healing is characterized by an inflammatory reaction with migration of neutrophils and macrophages but inflammation is not apparent in fetus. Studies show that fewer of the inflammatory cells are found in the fetal wound than those in the adult wound.10

    Studies found that several cytokines, including IL-6 and IL-8, are elevated significantly in adult healing process compared with those in fetal healing process.8–11 By contrast, while IL-10 is higher in fetal healing than that in adult healing. TGF-β1 and TGF-β2 concentrations are higher in the adult wound, while TGF-β3 is lower in the adult wound.

    The content of ECM is significantly different between the fetal and adult wounds. Fibroblasts produce ECM at a higher rate in the fetal wound, and the ratio of type III to type I collagen is higher in the fetal wound. The amount of hyaluronic acid in the ECM is also high in the fetal wound but low in the adult wound.

    Myofibroblasts are only found in the adult wound. When mechanical tension of the adult wound increases, myofibroblasts become more apparent in the adult wound. By contrast, no or very few myofibroblasts can be found in the fetal wound.8 Therefore, further studies of the fundamental mechanisms of fetal wound healing will identify the potential remedies to minimize scar formation.

    3. Prostaglandins and their inhibitors on wound healing

    Prostaglandins (PGs) are lipid compounds that participate in a variety of physiologic and pathologic processes. Prostaglandin synthesis is dependent on three enzymatic conversions beginning with the conversion of membrane-derived phospholipids to arachidonic acid by phospholipase.4 Among them, PGE2 is a major mediator for inflammation,12 and also involves various kinds of diseases, such as rheumatoid arthritis and osteoarthritis. The cyclooxygenase (COX) pathway is essential for the conversion of arachidonic acid into PGH2, a precursor of various biologically active mediators including thromboxane A2, PGE2 and prostacyclin. Two types of COXs have been identified, including (i) COX-1 (house keeping gene) has been expressed constitutively in various tissues, including stomach, and (ii) COX-2 (induction gene) has been induced by cytokines, growth factors, tumor promoters, and other agents.4,13 COX-2-derived PGE2 and nitric oxide synthase (NOS)-derived NO is upregulated by pro-inflammatory mediators such as tumor necrosis factor (TNF)-α, lipopolysaccharide, and IL-1β. This induced inflammatory response triggers further damage to adjacent cells and tissues around the wound site, thus delaying the wound healing process. Prostaglandin E2 regulates fibroblasts in an autocrine pattern, including inhibition of fibroblast proliferation, migration, myofibroblast differentiation and collagen synthesis.4 As the aforementioned role of pro-fibrotic effect, overexpressed TGF-β1 is found in fibrotic tissues and widely involved in fibroblast functions. Nitric oxide is a highly reactive radical that is generated by the activation of iNOS and contributes to various biological processes including inflammation.14 Nitric oxide is thought to be a main disruptive factor in the wound healing process. Excessive generation of COX-2-derived PGE2 is a crucial physiological factor accelerating inflammation. Prostaglandin E2 is related to keratinocyte proliferation, angiogenesis and mediation of the inflammatory response. There are four receptors for PGE2, including EP1, EP2, EP3 and EP4. PGE2 through EP2 and EP4, known as coupling to G-proteins, increases intracellular cAMP formation.15,16

    Newly synthesized PGE2 simply diffused and actively extruded by the multidrug resistance 4 from the cells. Subsequently, EP receptor is activated followed by pericellular PGE2 is cleared via re-uptake of PGE2 by PG transporter and then rapidly metabolized by cytosolic enzyme named nicotinamide adenine dinucleotide (NAD)+-dependent 15-hydroxyprostaglandin dehydrogenase.17 This enzyme is expressed ubiquitously in mammalian tissues and responsible for biologic inactivation of PGE2 to 15-keto PGs.4

    Prostaglandin E2 has been also known as an important mediator for bone formation, gastric ulcer healing, and dermal wound healing. The level of PGE2 is positively correlated with wound healing rate. The release of PGE2 from skin tissue after toxic stimuli produces local edema and hyperalgesia. Prostaglandin E2 elevation using 15-hydroxy PGDH inhibitor would be valuable for the management disease that required elevated PGE2, like wound healing, contributing to the clinical use of PGE2 in the management of gastric ulcer in spite of high price and low efficacy.18

    Conventionally, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) or their selective COX-2 inhibitors, having been known as analgesic, antipyretic and anti-inflammatory effects, are reported to inhibit PGE2 production and act as effective pain-killers, and they are often prescribed and used postoperatively for pain control.19–23 However, the impact of aspirin and NSAIDs on wound healing is highly controversial, since the scientific literature suggests that inhibition of COX by aspirin or other NSAIDs, may be deleterious to normal wound repair processes and result in healing inhibition.24 Aspirin involves the first step of wound healing – hemostasis/inflammation phase directly.19 Aspirin can not only affect thrombotic activity of platelet activation (hemostasis) but also inhibit several potential pro-inflammatory effects (inflammation), which include platelet release of matrix metalloproteinases (MMPs), elastases, release of P selectin, and hence recruitment and activation of monocytes, monocyte and neutrophil adhesion to the endothelium, further release of chemoattractants for inflammatory cells such as monocyte chemoattractant protein 1, and release of pro-inflammatory cytokines, such as IL1 β, IL-6, and IL-8.19,25 Antagonizing EP2, not EP4, might abrogate the effect of PGE2 on TGF-β1-induced Smad pathway activation, unbalanced expression of MMPs/TIMP-1, and collagen synthesis.26 Zhao et al. demonstrated that TGF-β1 decreased the endogenous expression of COX-2 and PGE2 in dermal fibroblasts, and exogenous PGE2 could reverse TGF-β1-induced collagen over-expression mediated by cAMP.27

    The balance between these pro-inflammatory and inflammatory pathways is very important. The benefits of acute inflammatory response occur on early wound cellular functions, such as removing debris, and responding to pathogens in acute wound but chronic activation and prolonged production of these pro-inflammatory factors are likely to lead to continuous tissue destruction, inhibition of wound repair and pathological or excessive wound healing.

    4. The pathogenesis of excessive wound healing

    Excessive wound healing is caused by skin injury, which includes trauma, inset bite, burns, surgery, vaccinations, skin piercing, acne, and infections.2,3 After an injury to skin, the inflammatory process begins to initiate wound healing. Although the pathogenesis of excessive wound healing is not fully elucidated, clinical experience suggests that excessive wound healing is an aberrant form of wound healing, which may occur as a result of dysregulation in one of the three phases of wound healing, and is characterized by continuously localized inflammation.2,3 Excessive wound healing often involves an exaggerated function of fibroblasts and excess accumulation of ECM during wound healing.28 Two forms of excessive wound healing are reported, including keloid and hypertrophic scar. Dr. Ogawa defined “keloid” as strongly inflamed pathological process, and “hypertrophic scar” is a much more weakly inflamed pathological process, because both can be considered as successive stages of the same fibroproliferative skin disorders, with differing degrees of inflammation that might be affected by genetic predisposition (also shown below in Section 5 the epidemiology of excessive scarring).29,30 All excessive wound healings include initial purulent inflammatory process, upregulated fibroblast function, and excessive ECM deposition.31

    Hypertrophic scar does not overgrowing over the original wound boundaries and generally fades as well as flattens to the surrounding skin level, although it may be raised above the normal skin level, and contracture or more raised or larger than normal wound healing might occur. Hypertrophic scar is often self-limited and sometimes can regress with time.

    The histological features of keloid are whorls and nodules of thick, hyalinized collagen bundles, known as keloidal collagen, and tongue-like projections of scar tissue that advance underneath the surrounding normal epidermis.28 Representing an abnormally vigorous scarring formation extending beyond the edges of the original wound, and causing symptoms of pruritus and hyperesthesia, keloid scar is often more of a cosmetic concern than a health on.28 Keloid scar does not regress and tends to recur after excision.

    Keloid scar contains disorganized type I collagen and type III collagen. Hypertrophic scar consists of mainly type III collagen arranged parallel with skin surface.28 Elastic content was significantly different between normal and abnormal wound healings.31 Keloid scars contain more elastin content in deep dermal layer than hypertrophic scar and normal skin.31 In the superficial dermis, elastin content was 51% and 37% higher in normal skin compared to hypertrophic scars or keloids.31 Moreover, the significant decrease of fibrilin-1 is also noted throughout the dermis in both scar types, indicating the distortion of the composition of microfibrils.31

    Excessive collagen synthesis and abnormal collagen turnover, caused by dysregulation of matrix degrading enzymes contributes to excessive wound healing.32,33 Tissue inhibitors of metalloproteinases (TIMPs) can inhibit MMPs by either binding to the zinc-binding domain of active MMPs or by binding to the inactive proMMP zymogen, thereby slowing the process of activation.33 The MMP and TIMP proteins work in combination to regulate the synthesis and degradation of ECM at wound sites, and an imbalance of MMP and TIMP results in abnormal wound healing. These factors, including TGF-β and PG will be reviewed in the in vitro and in vivo models subsequently.

    5. The epidemiology of excessive wound healing

    Although excessive wound healing is seen in all ethnicities, the prevalence of keloid scars varies among different populations. Evidence shows the importance of genetic factors in excessive scarring and keloid scars are more common in African-Americans and Asians, especially in dark-skinned individuals.34 The familiar heritability and prevalence in twins also support the concept of the genetic predisposition to excessive scarring. Many local factors are believed to increase the chance of excessive scarring, including high skin tension, hypoxia, endocrine dysfunction, fatty acid, autoimmune, and genetic hypothesis.2,3 Cross-sectional analysis of BioBank Japan clinical data enrolling 200,000 patients with 47 common diseases found that individuals with a family history of keloid exhibited a higher odds ratio than those without a family history, highlighting the strong impact of host genetic factor on disease onset.35 Genome-wide association study suggested that some are an autosomal recessive inheritance pattern; some are an autosomal dominant inheritance mode with incomplete clinical penetrance and variable expression.36 Nakashima and colleagues found that significant associations of keloid with four single nucleotide polymorphism loci in three chromosomal regions: 1q41, 3q22.3–23 and 15q21.3 and among these, the most significance was observed at rs873549 (odds ratio [OR], 1.77) on chromosome 1.36 Association of rs8032158 located in neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) on chromosome 15 yielded OR of 1.51.36,37 The possible mechanism of NEDD4 involves keloid formation, including (i) NEDD4 affected subcellular localization and protein stability of p27 which was implied its critical role in contact inhibition; (ii) NEDD4 induced accumulation of β-catenin in the cytoplasm and activated the T-cell factor/β-catenin transcriptional activity; (iii) NEDD4 upregulated expressions of fibronectin and type 1 collagen and contributed to the excessive accumulation of extracellular matrix.37 One study focused on Chinese Han population and the results showed plasminogen activator inhibitor-1 promoter polymorphism -675 4G/5G and plasma plasminogen activator inhibitor levels are associated with keloid risk, supporting the importance of hereditary factor responsible for keloid formation.38 To date, there are several studies having reported polymorphisms that may be associated with keloids in many above-mentioned genes, such as TGF-β with known functions relevant to fibrosis; however, epigenetic modification (environmental factor) has been shown to be an important regulator during the dysfunction of wound repair process.39 Recent epidemiologic studies showed that some of medical illnesses, such as hypertension (endothelial cell dysfunction) are also associated with excessive scar formation, since many medical illnesses are also tendency to hereditary penetrance for the development of hypertrophic scar and keloid formation, supporting the evidence of important role of genetic and epigenetic characteristics on the scar formation.40 However, due to limitations of genetic studies on keloid scarring, there is still a long way to clarify the genetic role on the keloid formation.

    6. Thein vitroandin vivostudies for excessive wound healing

    In response to TGF-β1, fibroblasts differentiate into myofibroblasts to contract wound and help to remodel ECM.41,42 TGF-β1-induced myofibroblasts expression is mediated via Smad3 activation by the TGF-β1 receptor complex, resulting in Smad2/3 complex combination with Smad4 and translocation into the nucleus. Smad3 binding to Smad binding elements in the promoter region regulates α-smooth muscle actin (SMA) transcription to promote deposition of ECM proteins, such as collagen I and III.42

    There are different rolls for TGF-β1 and TGF-β3 on cell migration and progression in the in vitro medial edge epithelial (MEE) cell model.41 TGF-β1 induces cell cycle arrest in G1 phase in 98% of cultured cells, and TGF-β3 ceases progression in 79% of cells. But it is interesting, the two isoforms cause cell arrest commonly through the p15ink4b, a D-cyclin dependent kinase inhibitor.43 However, TGF-β1, instead of TGF-β3, plays a major role in activation of the p15ink4b gene to induce cell arrest via multiple Smad4 binding sites in the latter's promoter.43 In the same study, TGF-β3 was more effective in inducing MEE cell migration and this effect could be accentuated by adding p15ink4b to TGF-β3, but not to TGF-β1. Both TGF-β1 and TGF-β3 are capable to induce apoptosis, and augmented by adding p15ink4b. Finally, Iordanskaia and Nawshad suggested that early cell cycle arrest by TGF-β1 might be a condition for TGF-β3 mediated migration, but the overlapping roles of the two isoforms in abnormal wound healing demand further studies.43

    Downregulated TGF-β1, TGF-β1 type 1 receptor and TGF-β1 type 2 receptor expression inhibits fibroblast proliferation, contraction, and collagen production.4 The TGF-β1/Smad pathway is a promising target for the modulation of the scarring response.4 Persistent TGF-β1/Smad signaling caused proliferation of fibroblasts and excessive production of type I collagen and fibronectin, resulting in hypertrophic scarring, even when the wound has healed.41,42 Lin and colleagues have demonstrated that TGF-β1 increased the collagen content, procollagen I, and TIMP-1 production, but slightly decreased MMP-3 production of pulp cells through activin receptor-like kinase-5/Smad2/3 and MEK/ERK signaling.44 Aoki and colleagues using small interfering RNA (siRNA) to target TIMP1 also successfully increased degradation of collagen type I and further increased degradation of their thick collage bundles.45 Inhibition of TGF-β1 expression by siRNA and oxymatrine (Chinese herb extracts) resulted in an attenuation of TGF-β1 mediated phosphorylation of the kinase p38 and ERK1/2, and decreased phosphorylation of Smad2, Smad3, and Smad4 in keloid derived fibroblasts.46 Targeting fibroblast TGF-β type I receptor showed the decreased fibroblast production of ECM as well as scar tissue formation in rabbit model.46

    In recent studies, Smad7 expression was induced by asiaticoside and TNF-α-stimulated protein 6 (TSG-6) released from mesenchymal stem cells (MSCs), and the upregulated Smad7 altered hypertrophic scar fibroblast proliferation and collagen production, resulting in fibrosis inhibition.6,47 Venous ulcer keratinocytes possess under-phosphorylated Smad2 and this attenuation in Smad2 activation was not correlated with increased inhibitory signal of Smad7.48 MSCs might accelerate wound healing by reducing deleterious tissue inflammation, inducing angiogenesis in the wound bed, and reducing scarring following the repair process.49 MSC-released TSG-6 was identified to improve wound healing by limiting inflammation, fibrosis and macrophage activation.49 Reduced wound scarring was correlated with reduced TGF-β1/TGF-β3 ratio from wound lysates.1

    In the process of hypertrophic scar, keratinocytes are excessively differentiated and produce fibrotic factors to stimulate fibroblasts, such as vascular endothelial GF, epidermal GF, connective tissue GF and TGF-β.1–3 In recent studies, keratinocytes were excessively differentiated and produced TGF-β1, TGF-β2, insulin growth factor-1, epidermal GF, vascular endothelial GF and connective tissue GF, thus leading to fibroblast hyperproliferation and collagen production. Inhibiting keratinocyte function by Notch signaling blockade, for example, a γ-secretase inhibitor (DAPT) could inhibit fibroblast hyperproliferation.50

    In addition to the canonical TGF-β signaling pathway, TGF-β also activates several non-Smad signaling pathways, including members of the mitogen-activated protein kinase (MAPK) family, protein kinases A and C (PKA and PKC), or phosphatidylinositol-3 kinase (PI3K).51 Carthy and colleagues reported that tamoxifen inhibited TGF-β-mediated activation of cultured human primary fibroblasts via non-Smad signaling through ERK1/2 MAP-kinase and downstream AP-1 transcription factor FRA2.52 Interestingly, in the same study, tamoxifen exerted its effect in the fibroblasts independently of the estrogen receptor (ER).52 Furthermore, Kim et al. demonstrated that the effect of tamoxifen was dependent on its action as an ER-α agonist in renal fibroblasts. It is known that active ER can bind to Smad3 and inhibit its activity.53 Thus, the different tissue/organ distribution and function of tamoxifen in anti-fibrotic treatment demand further exploration, since using tamoxifen might prevent keloids or hypertrophic scar after burns or surgery.54,55

    MicroRNAs (miRNAs) act in post-transcriptional regulation of gene expression and involve in the regulation of skin fibrosis, including TGF-β signaling, fibroblast proliferation and differentiation, ECM deposition, and epithelial-to-mesenchymal transition (EMT).56–59 Growing evidences revealed different expression profiles of miRNAs between hyperplastic scar and normal skin and the altered miRNAs expression in abnormal scarring might be associated with TGF-β signaling.56 Li et al. reported that downregulated miR-200b was shown in hypertrophic scarring and miR-200b regulated cell proliferation and apoptosis of human hypertrophic scar fibroblasts by altering the TGF-β1/α-SMA signaling, fibronectin expression, and type I and III collagen synthesis.60 Further study revealed that decorin reduced fibrosis and induced regeneration in many tissues; decorin expression was significantly downregulated in hypertrophic scar and normal deep dermal fibroblasts.32 MicroRNA-181b involved in the different expression of decorin in skin and wound healing and TGF-β1 stimulation increased miR-181b level in hypertrophic scar and deep dermis.61 Blocking miR-181b reversed TGF-β1-induced decorin downregulation and myofibroblast differentiation in hypertrophic scar fibroblasts.61 The expression of miR-21 and miR-200b might participate in hypertrophic scar formation by TGF-β/miR-21/Smad7 and TGF-β/miR-200b/Zeb1 pathways.62 Studies also found that upregulation of miR-29b possessed anti-fibrotic effect in cardiac and renal fibroblasts via suppressing the activation of TGF-β/smad3 signaling pathway.63 Furthermore, overexpression of miR-29b decreased type I collagen expression in skin fibroblasts in vitro.64 Overexpression of miR-29b markedly reduced the expression levels of COL1A1 and α-SMA, and inhibited myofibroblast-like cell proliferation and induced apoptosis.65 Chau et al. have found that the miR-29 family involves in hypertrophic scar through regulating the translation of ECM mRNAs.66

    These data were further corroborated by a study using intravenous recombinant decorin, a natural inhibitor of TGF-β. Adult mice treated with recombinant decorin between days 3 and 14 post wounding showed 50% smaller scars.32 This reduction of scar volume (and length) was associated with decreased immunostaining for TGF-β1 and TGF-β2, but not TGF-β3.67 Together, these studies suggest that the development of a scar may be related to the relative expression and ratio of TGF-β3 to TGF-β1 and TGF-β2.

    7. Stem cell therapy

    Recently, stem cell-based therapies have been used for skin-regenerative and anti-fibrotic properties and have been shown to be efficacious in experimental and human disease.68–74 Human amniotic membrane (HAM) is the innermost layer of the fetal membrane and is derived from the epiblast as early as 8 days after fertilization and before gastrulation.69,75 HAM is a special tissue with anti-inflammatory and anti-fibrotic properties.76 Amniotic membrane can be collected during pregnancy and holds great potential for therapeutic use because it is an abundant source of progenitor cells from cells shed from the fetus.77 At least two kinds of stem cells can be isolated from the amniotic membrane: amniotic epithelial cells (AECs) and amniotic mesenchymal cells (AMCs).76–78 Both stem cell types are capable of self-renewal and differentiate into multiple cell lineages. Primary human AECs take the following advantages when they are considered most attractive for cellular therapies, including (i) AECs are plentiful and obtained without invasive and expensive procedures from term placenta, compared with adult tissue-derived stem cells; (ii) there are no tumor induction and ethical constraints of AECs, compared with embryonic stem cells; (iii) AECs still possess the ability to be differentiate toward the adipogenic, osteogenic, chondrogenic, skeletal myogenic, neurogenic lineage hepatic and pancreatic lineages. All support the use of AECs as a new anti-fibrotic treatment strategy, such as an attenuation of wound inflammation and a reprograming of resident cells to favor tissue regeneration and inhibit fibrosis. Paracrine signaling is considered one of the main underlying mechanisms behind the therapeutic effects of stem cells.78

    8. The prevention strategy

    The first step toward treatment of excessive wound healing is early recognition and institution of therapy after surgery or trauma. Meticulous tissue handling, suturing, and wound management with efforts to prevent infection are mandatory.79 Sun protection to reduce scar hyperpigmentation is essential. Patients who are at increased risk of excessive wound healing benefit from preventive techniques, which include silicone gel sheeting or ointments, hypoallergenic microporous tape, and concurrent intralesional steroid injection.80,81 Silicone gel sheeting is widely used for hypertrophic scar treatment and the only remedy with high evidence. Silicone gel sheeting has a 20-plus-year history with several randomized controlled trials that support its safe and effective use.82,83 Proposed mechanisms of action for scar reduction include improved hydration and occlusion, increased temperature and change in scar mechanical tension.

    In conclusion, most in vitro data derived from fibroblasts cultured from abnormal wound lesions only represent the terminal stage of this disease and in vivo animal models might not present a real condition in humans. The current review only provides a basic understanding of pathogenesis about the wound healing. More studies focusing on human wound healing are welcome.


    This work was supported by grants from the Ministry of Science and Technology (MOST 106–2314-B-075–061-MY3) and the Taipei Veterans General Hospital (Grant V106C-129 and V106D23–001-MY2–1), Taipei, Taiwan.


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