Curbing Inflammation in Skin Wound Healing a Review

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Review Article | July 01 2021

Wound dressings: curbing inflammation in chronic wound healing

Davide Vincenzo Verdolino;

Davide Vincenzo Verdolino

1Section of Materials, School of Natural Sciences, Faculty of Science and Engineering and The Henry Royce Institute, Royce Hub Building, The University of Manchester, Manchester, U.Thousand.

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Helen A. Thomason;

ii3M, Medical Solutions Division, Knutsford, U.One thousand.

iiiSchoolhouse of Wellness Sciences, Kinesthesia of Biological science, Medicine and Health, The University of Manchester, Manchester, U.One thousand.

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Andrea Fotticchia;

23M, Medical Solutions Division, Knutsford, U.K.

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Sarah Cartmell

1Section of Materials, School of Natural Sciences, Kinesthesia of Science and Engineering and The Henry Royce Found, Royce Hub Building, The University of Manchester, Manchester, U.K.

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Emerg Superlative Life Sci (2021) 5 (4): 523–537.

Chronic wounds stand for an economic burden to healthcare systems worldwide and a societal brunt to patients, deeply impacting their quality of life. The incidence of recalcitrant wounds has been steadily increasing since the population more than susceptible, the elderly and diabetic, are rapidly growing. Chronic wounds are characterised by a delayed wound healing process that takes longer to heal under standard of care than acute (i.e. healthy) wounds. Two of the nigh common issues associated with chronic wounds are inflammation and infection, with the latter usually exacerbating the erstwhile. With this in listen, researchers and wound care companies accept developed and marketed a wide diverseness of wound dressings presenting dissimilar compositions simply all aimed at promoting healing. This makes it harder for physicians to choose the right therapy, peculiarly given a lack of public quantitative data to support the manufacturers' claims. This review aims at giving a cursory introduction to the clinical need for chronic wound dressings, focusing on inflammation and evaluating how bio-derived and synthetic dressings may control backlog inflammation and promote healing.

Introduction

Wound healing is a complex procedure that involves numerous cell types, cytokines, chemokines, growth factors and extracellular matrix (ECM) components, which work synergistically to achieve healing [1,2]. It consists of four overlapping stages: haemostasis, inflammation, proliferation and remodelling, each with its own part and role valuable for the side by side phase to occur smoothly and with no delay [one,2]. In a healthy wound (i.due east. acute wound), these stages unremarkably occur with no obstacle, resulting in a completely healed wound with minimal scar tissue, admitting with slightly reduced mechanical properties (∼80%), when compared with the skin before injury [3].

A chronic wound is defined every bit a wound that has failed to proceed through the wound healing process readily, and it does non heal within iii months under standard of care [2,4]. It ordinarily results when patients present comorbidities such as diabetes, obesity, immune system deficiencies, peripheral vascular disease and cardiopulmonary disease [1,2,5]. These wounds often stall in the inflammatory stage, whereby excess and persistent inflammation creates a hostile wound surroundings. A wound that is ho-hum or fails to heal is at greater risk of infection. If infection does occur, the heightened inflammation is further exacerbated [1,2]. Chronic wounds include diabetic foot ulcers (DFUs), pressure ulcers (PUs) and leg ulcers (LUs), which include venous leg ulcers, arterial leg ulcers and ulcers of mixed aetiology [4].

Wound care and chronic wounds, in particular, represent a health economic burden worldwide, bookkeeping for an NHS almanac expenditure in the management of chronic wounds of £five.3billion with a hateful toll of £3700 per unhealed wound [6,7]. With such a demand, the global advanced wound dressings marketplace targeting chronic and surgical wounds is expected to exceed ∼£16.5 billion past 2024 [5]. Furthermore, as population and life expectancy increases, the outcome of wound management and chronic wounds on global wellness services will increase further, calling for the development of therapies that can relieve both patients and healthcare systems of this economic and societal burden [8,9].

Two main factors that are usually addressed as common underlying bug in non-healing wounds are inflammation and infection [ii]. Infection occurs when immune cells fail to readily eliminate harmful microorganisms infiltrating the wound [10]. Dissimilar grades of infection require different therapies and present unlike degrees of severity: local infection (when infection is contained only at the wound site, normally easy to address); spreading infection (signs and symptoms of infection outside wound border in neighbouring tissues); systemic infection (affects the whole body and may nowadays a severe upshot for the health of the patient) [ii]. Infection is a major contributing factor to the failure of a wound to heal [two].

Inflammation represents the body'south allowed organisation response to foreign agents such as microorganisms or damaged host tissue; therefore, information technology is necessary and essential to achieving healing [11]. Inflammation occurs in two stages: early and tardily inflammation [1,two]. During early inflammation, the innate immune organization is activated, and neutrophils are recruited in the wound to remove microorganisms, cellular debris and not-functional tissue [i,9,11]. Neutrophils are followed by infiltrating monocytes that differentiate into 'M1' pro-inflammatory macrophages every bit a response to pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), IL-ii, IFN-γ and TNF-α [9,12,13]. 'M1' macrophages present a high phagocytic capability, and their primary role is to remove any harmful agents. They also secrete pro-inflammatory cytokines such equally IL-one, TNF-α, IL-6, IL-12, reactive oxygen species (ROS) and matrix metalloproteinase (MMPs) [9,12,13]. ROS are produced equally a mechanism of killing microorganisms, merely in excess, when inflammation is out of control, they crusade direct tissue damage to the ECM and result in premature prison cell senescence [xiv]. MMPs dethrone the damaged ECM to allow infiltration of pro-healing cells and factors [nine,13]. It is idea that elevated levels of MMPs participate in stalling and delaying the wound healing procedure in chronic wounds [9,13]. This is because there is a delicate balance betwixt MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPS) [ix,xiii]. When this balance is tipped in favour of MMPs, degradation of healthy tissue and subsequent persistent inflammation creates a negative feedback loop that contributes to delayed healing [9,13]. In an acute wound, once inflammation is resolved and the wound is cleared of contamination, healing progresses into the proliferative phase, where granulation tissue is formed. Keratinocytes start to proliferate and migrate across the wound bed to re-epithelialise the wound [ix,thirteen]. More macrophages switch from the pro-inflammatory 'M1' phenotype to the pro-healing 'M2' phenotype, becoming the most mutual leukocyte in the wound [nine,12,thirteen]. At this signal, a chronic wound tends to stall since 'M1' macrophages persist without switching to the 'M2' phenotype, resulting in elevated levels of pro-inflammatory cytokines produced by 'M1' macrophages and by the delayed removal of expended neutrophils [9,xi–thirteen]. Information technology is worth noting that macrophages do non present a binary nomenclature of phenotype, only rather a spectrum, as shown in Figure 1; however, in this review, 'M1' and 'M2' terminology volition be used for simplicity [11,xiii]. A prolonged and heightened state of inflammation, no thing the cause, results in delayed healing. Various means have been proved to curb inflammation in wound healing [15,sixteen]; in this paper, nosotros review how wound dressings reduce backlog inflammation assuasive chronic wounds to heal more readily.

Schematic of the wound healing stages focusing on macrophage phenotypes classification in vivo and in vitro with their corresponding functions.

Figure 1.

Adapted with permission from [13]. Created with BioRender.com.

Schematic of the wound healing stages focusing on macrophage phenotypes classification in vivo and in vitro with their respective functions.

Adapted with permission from [xiii]. Created with BioRender.com.

Wound dressings: an introduction

The increasing prevalence of chronic wounds highlights the importance of developing innovative products to promote healing [two,17]. In a clinical setting, when a patient presents a wound, clinicians utilise a set of principles that aids them to understand the wound aetiology and subsequent wound bed training [17,xviii]. These principles are represented past the acronym Time, which is defined as Tissue cess and direction, Infection/Inflammation management, Moisture imbalance/management and Edge of wound observation and management [17,eighteen]. Even when Fourth dimension management is followed, some wounds fail to heal and require more advanced interventions to restart the healing process [17,18].

Over time, wound management has evolved drastically, from assuming that a dry out wound environment would assist healing to prioritise moisture retention when developing new wound dressings [19]. This shift in knowledge was mirrored in the shift in the type of wound dressings used. The more than traditional wound dressings (e.g. gauze, lint and cotton fiber wool), which aimed at only covering the wound, have now been replaced by sophisticated materials (due east.m. hydrogels, hydrocolloids, foams, films, etc.) that aim to [19–21]:

Provide or maintain a moist environment;
Heighten cellular migration;
Promote angiogenesis and new tissue synthesis;
Allow gas exchange from/to wound;
Maintain appropriate tissue temperature;
Protect confronting bacterial infection;
Exist easily removed after healing or between dressing changes;
Promote autolytic debridement;
Exist sterile, non-toxic and hypoallergenic.

One of the more contempo advantages introduced into wound dressing formulations, and an indirect way to reduce inflammation by resolving bioburden, is the addition of antimicrobial agents such as antiseptics, antibiotics and natural products [22]. Several reviews provide additional information for a more detailed assay of the different types of antimicrobial agents and dressings [23–25].

There are thousands of wound dressings on today'due south market, some claiming the aforementioned benefits but presenting unlike compositions [ii,21]. This large number of options makes choosing an appropriate dressing an ever so complicated chore for physicians [ii,21,26]. Choosing an advisable dressing is essential to attain faster healing and depends on many factors, including the type and location of the wound, the level of exudate, the integrity of the surrounding skin, and whether the wound is infected or stalled in the inflammatory phase of healing [21,23,24,27]. A summary of different types of wound dressings is given in Tabular array 1.

Table 1.

Summary of different types of dressing with the corresponding description

Blazon of dressings	Description	Ref
Gauze	Drying Cheap May produce painful removal	[19–21]
Foams	Soft and conformable Loftier porosity, moderately absorbent Thermal insulating Wounds may dry out if little or no exudate	[23,24]
Films	Occlusive, retains moisture No absorptive properties Protects against infection Can cause fluid collection	[19,20,102,103]
Hydrogels	Maintain moist environment Aid in autolytic debridement Rehydrates dry wound Easy removal Not suitable for heavily exuding wounds May crave secondary dressing	[20,103–105]
Hydrocolloids	Occlusive Highly absorbent May cause peri-wound maceration May adhere to the wound and damage frail tissue	[23,24,103,106]
Alginates	Moderate-highly absorbent Haemostatic Maintain moist surround Not suitable for dry out wounds May crave secondary dressing	[20,103,107,108]
Gelling Fibres	Moderate-highly absorbent Maintain moist environs Forms gel when in contact with exudate Easy to remove Not suitable for dry wounds	[109,110]
Superabsorbent dressings	Highly absorptive Conformable Prevents maceration Non suitable for dry wounds	[111–114]

Type of dressings	Clarification	Ref
Gauze	Drying Inexpensive May produce painful removal	[19–21]
Foams	Soft and conformable Loftier porosity, moderately absorbent Thermal insulating Wounds may dry out if little or no exudate	[23,24]
Films	Occlusive, retains wet No absorbent properties Protects confronting infection Can crusade fluid drove	[nineteen,20,102,103]
Hydrogels	Maintain moist surroundings Aid in autolytic debridement Rehydrates dry wound Like shooting fish in a barrel removal Not suitable for heavily exuding wounds May require secondary dressing	[20,103–105]
Hydrocolloids	Occlusive Highly absorbent May crusade peri-wound maceration May adhere to the wound and damage fragile tissue	[23,24,103,106]
Alginates	Moderate-highly absorptive Haemostatic Maintain moist environment Not suitable for dry wounds May require secondary dressing	[xx,103,107,108]
Gelling Fibres	Moderate-highly absorbent Maintain moist environs Forms gel when in contact with exudate Piece of cake to remove Not suitable for dry out wounds	[109,110]
Superabsorbent dressings	Highly absorbent Conformable Prevents maceration Non suitable for dry wounds	[111–114]

As described earlier, pathologically extensive inflammation plays an essential part in the delayed wound healing process of chronic ulcers [28]. This is usually acquired by multifactorial stimuli that create a hostile microenvironment (east.g. excess levels of inflammatory cells) in which the balance between pro-inflammatory mediators (due east.chiliad. chemokines, cytokines, proteases) and their inhibitors is disrupted [28]. The large number of biological entities involved in the inflammatory process makes anti-inflammatory wound dressings varied in their mechanisms of activity. For example, some only address locking in exudate away from the wound bed forth with the inflammatory components present in wound exudate [29,30]. Others instead focus on regulating pro- and anti-inflammatory cytokines either directly or via macrophage phenotype regulation [31–35]. Nonetheless, the ultimate aim of anti-inflammatory wound dressings is to remove the perpetuating cause and provide a healthy wound microenvironment to promote granulation tissue formation and to promote the healing processes [28].

Bio-derived wound dressings to regulate inflammation

In the terminal decade, more researchers investigated bio-derived materials as building blocks for new wound dressings [36,37]. These aim to mimic the skin'due south ECM to provide the chronic wound with a substrate that tin function as a healthy ECM or equally a sacrificial scaffold for proteases degradation, thereby protecting the native ECM and rebalancing the wound microenvironment allowing for faster healing. The ECM is more than a passive concrete substrate for cells; information technology actively participates in prison cell–cell communications via prison cell–matrix interactions, every bit a result of and resulting in the activation of biochemical mediators, cytokines and growth factors, which play a pregnant office in wound physiology [38–40]. Although bio-derived materials can provide a high caste of biomimicry, they can be limited by their reproducibility during manufacturing, given past variance between batches [37,41]. The utilisation of animal sources raises business organization as well from the manual of pathogens standpoint [42].

The skin ECM comprises the epidermal ECM (i.due east. a basement membrane, which separates the epidermis from the dermis) and the dermal ECM. The latter is composed of fibroblasts embedded in connective tissue fibres, interstitial fluid, cell adhesion proteins (eastward.grand. laminin, vitronectin, fibronectin), glycosaminoglycans (GAGs) and proteoglycans [43]. Collagen is the major component of dermal ECM, bookkeeping for ∼seventy% of peel (dry weight) [44]. It presents 28 genetically different variants, with blazon I and Three variants being the almost abundant in the skin [44–46].

Refer to Tabular array 2 for a summary of currently commercially available dressings or in the research stage of development.

Table 2.

Non-exhaustive summary of wound dressings with anti-inflammatory effects currently on the market (M) or in the research (R) stage, showing their composition and reported anti-inflammatory power

Dressing	Composition	Anti-inflammatory effects	Market place (jurisdiction) or research	Ref.
Bio-derived Dressings
Endoform® Antimicrobial Dermal Template	Decellularised ovine forestomach matrix with 0.3%due west/due west silver chloride	Broad-spectrum of MMPs inactivation capability Retention of structural molecules and growth factors	M(US)	[32,57,61]
Puracol® Ultra Matrix	Decellularised porcine mesothelium matric	Memory of growth factors (FGF-basic, VEGF, and TGF-β1) MMPs inactivation adequacy	1000(US)	[58]
Integra® Dermal Regeneration Template	Cross-linked bovine tendon collagen type I, shark chondroitin-6-sulfate GAG, silicon membrane	Chondroitin-vi-sulfate GAG has anti-inflammatory properties Allows quick permeation of cells	1000(United states & European union)	[49–53]
OASIS® Ultra Tri-Layer Matrix	Decellularised porcine small intestinal submucosa	Retention of structural molecules and growth factors	K(United states)	[54,115–117]
Apligraf®	Bovine type I collagen seeded with human neonatal fibroblasts and keratinocytes	↑ VEGF, IL-6, IL-viii ↓ fibrotic TGF-β1 Restore fibroblasts function	Thou(US)	[118–123]
Q-peptide	Chitosan-collagen hydrogel functionalised with QHREDGS peptide	Provide resistance to oxidative stress Induce shift in macrophage polarisation	R	[33,86–88]
Co-modified CBD-VEGF-SDF-1α collagen scaffold	Collagen scaffold modified with CBD-VEGF-SDF-1α	↓ Infiltration of 'M1' macrophages ↓ IL-1β and TNF-α	R	[34]
NAg-CSS	Chitosan-collagen loaded with silver nanoparticles	Attune macrophage polarisation ↓ IL-6, TNF-α and TGF-β ↑ IL-10 and IFN-γ	R	[35]
Promogran™ Matrix	Freeze-dried matrix composed of 55% bovine blazon I collagen with 45% ORC	Demark and inactivate proteases by means of ORC Bind and protect naturally occurring growth factors Demonstrate costless radical scavenging properties and anti-inflammatory activeness in vitro	Grand(United states & EU)	[viii,82–85,124]
Promogran Prisma™ Matrix	Freeze-dried matrix composed of 55% bovine type I collagen with 44% ORC and 1% silver-ORC	Same benefits as Promogran™ Matrix Silver provides both antimicrobial and anti-inflammatory properties.	M(US & European union)	[8,82–85,124]
ColActive® PLUS	Porcine collagen, sodium alginate, CMC, EDTA and silver chloride	EDTA and collagen target and deactivate elevated MMP Activity	Yard(Usa & EU)	[125–127]
Suprasorb® Ten + PHMB	Biocellulose dressing made up of small-pored HydroBalance fibres that are produced using Acetobacter xylinium	Exudate control	M(US & EU)	[128–132]
BIOSTEP™ Collagen Matrix	Porcine gelatin and blazon I collagen matrix, EDTA, CMC and alginate	EDTA and collagen target and conciliate elevated MMPs activeness	Grand(US)	[74,75]
Cutimed® Epiona	Fenestrated substrate fabricated of xc% native bovine-derived collagen and 10% alginate	MMPs sequestered past the substrate due to collagen-binding properties.	M(US & Eu)	[76,77]
Grafix®	Cryopreserved placental membrane, comprised of native viable cells, GFs and ECM	Retentivity of epithelial cells, fibroblasts and mesenchymal stem cells ↓ TNF-α and IL-1α ↑ IL-10	Chiliad(US)	[133–136]
Constructed Dressings
UrgoStart®	Soft-adherent foam dressing with TLC and NOSF	Neutralisation of excess proteases	M(European union)	[95–101]
PVA Sponge + MCG	Polyvinyl alcohol sponge impregnated with modified collagen gel	Promote shift of macrophage phenotype from 'M1' to 'M2' ↑ IL-10, IL-4 and VEGF	R	[31]
Drawtex®	Hydroconductive dressing obtained using LevaFibre™ technology, made of two absorbent, cross-activeness structures of viscose (63.ii%) and polyester (26.viii%)	Locks exudate and components away from the wound through capillary action ↓ MMPs levels	M(United states of america & Eu)	[29,thirty,137]
Biatain® Ag	Polyurethane cream with semi-permeable, bacteria- and top waterproof picture show	Exudate control Minimise take chances of maceration and leakage	M(European union)	[138–141]
Dermagraft®	Polyglactin mesh with neonatal foreskin fibroblasts	Stimulate granulation tissue formation Stimulate secretion of cytokines and growth factors	M(US)	[142–146]

Dressing	Composition	Anti-inflammatory furnishings	Market (jurisdiction) or research	Ref.
Bio-derived Dressings
Endoform® Antimicrobial Dermal Template	Decellularised ovine forestomach matrix with 0.3%w/w silver chloride	Broad-spectrum of MMPs inactivation adequacy Retention of structural molecules and growth factors	M(The states)	[32,57,61]
Puracol® Ultra Matrix	Decellularised porcine mesothelium matric	Retention of growth factors (FGF-basic, VEGF, and TGF-β1) MMPs inactivation capability	M(United states)	[58]
Integra® Dermal Regeneration Template	Cross-linked bovine tendon collagen type I, shark chondroitin-6-sulfate GAG, silicon membrane	Chondroitin-half dozen-sulfate GAG has anti-inflammatory properties Allows quick permeation of cells	M(U.s. & EU)	[49–53]
Oasis® Ultra Tri-Layer Matrix	Decellularised porcine pocket-size intestinal submucosa	Retention of structural molecules and growth factors	M(The states)	[54,115–117]
Apligraf®	Bovine type I collagen seeded with human neonatal fibroblasts and keratinocytes	↑ VEGF, IL-half-dozen, IL-eight ↓ fibrotic TGF-β1 Restore fibroblasts role	M(The states)	[118–123]
Q-peptide	Chitosan-collagen hydrogel functionalised with QHREDGS peptide	Provide resistance to oxidative stress Induce shift in macrophage polarisation	R	[33,86–88]
Co-modified CBD-VEGF-SDF-1α collagen scaffold	Collagen scaffold modified with CBD-VEGF-SDF-1α	↓ Infiltration of 'M1' macrophages ↓ IL-1β and TNF-α	R	[34]
NAg-CSS	Chitosan-collagen loaded with silvery nanoparticles	Modulate macrophage polarisation ↓ IL-vi, TNF-α and TGF-β ↑ IL-ten and IFN-γ	R	[35]
Promogran™ Matrix	Freeze-dried matrix equanimous of 55% bovine type I collagen with 45% ORC	Bind and inactivate proteases by means of ORC Demark and protect naturally occurring growth factors Demonstrate free radical scavenging backdrop and anti-inflammatory action in vitro	M(US & EU)	[8,82–85,124]
Promogran Prisma™ Matrix	Freeze-dried matrix equanimous of 55% bovine type I collagen with 44% ORC and 1% silverish-ORC	Aforementioned benefits as Promogran™ Matrix Silverish provides both antimicrobial and anti-inflammatory properties.	M(US & Eu)	[8,82–85,124]
ColActive® PLUS	Porcine collagen, sodium alginate, CMC, EDTA and silver chloride	EDTA and collagen target and deactivate elevated MMP Activity	G(United states & EU)	[125–127]
Suprasorb® X + PHMB	Biocellulose dressing made upward of small-pored HydroBalance fibres that are produced using Acetobacter xylinium	Exudate control	M(US & Eu)	[128–132]
BIOSTEP™ Collagen Matrix	Porcine gelatin and type I collagen matrix, EDTA, CMC and alginate	EDTA and collagen target and deactivate elevated MMPs activeness	M(U.s.a.)	[74,75]
Cutimed® Epiona	Fenestrated substrate made of 90% native bovine-derived collagen and 10% alginate	MMPs sequestered by the substrate due to collagen-bounden properties.	Thou(US & EU)	[76,77]
Grafix®	Cryopreserved placental membrane, comprised of native viable cells, GFs and ECM	Retention of epithelial cells, fibroblasts and mesenchymal stem cells ↓ TNF-α and IL-1α ↑ IL-10	M(United states of america)	[133–136]
Synthetic Dressings
UrgoStart®	Soft-adherent foam dressing with TLC and NOSF	Neutralisation of backlog proteases	M(European union)	[95–101]
PVA Sponge + MCG	Polyvinyl alcohol sponge impregnated with modified collagen gel	Promote shift of macrophage phenotype from 'M1' to 'M2' ↑ IL-10, IL-4 and VEGF	R	[31]
Drawtex®	Hydroconductive dressing obtained using LevaFibre™ applied science, made of two absorbent, cross-activeness structures of viscose (63.2%) and polyester (26.8%)	Locks exudate and components away from the wound through capillary action ↓ MMPs levels	K(US & European union)	[29,30,137]
Biatain® Ag	Polyurethane foam with semi-permeable, bacteria- and top waterproof film	Exudate command Minimise risk of maceration and leakage	M(European union)	[138–141]
Dermagraft®	Polyglactin mesh with neonatal foreskin fibroblasts	Stimulate granulation tissue formation Stimulate secretion of cytokines and growth factors	M(United states)	[142–146]

Legend: ↑: up-regulate; ↓: down-regulate, (US): canonical to market in the United States; (Eu): canonical to market in the European union; (US & Eu): approved to market in both US and EU.

Skin substitutes

Skin substitutes are bioengineered dressings made of natural or synthetic polymers gear up to mimic the physiological geometry and function of native skin [47]. Skin substitutes for recalcitrant wounds are usually either acellular or cellular dermal components or dermo-epidermal components obtained through chemical synthesis of biological components or decellularisation of native ECM [48].

Integra® Dermal Regeneration Template (Integra Life Sciences Corporation, Plainsboro, New Bailiwick of jersey, U.s.a.) was the first dermal skin substitute product approved past the Us Food and Drug Administration (FDA). It consists of a porous matrix of cross-linked bovine tendon collagen type I, shark chondroitin-6-sulfate GAG and covered past a semi-permeable silicone membrane [47,49–53]. Chondroitin-half-dozen-sulfate GAG has been shown to have anti-inflammatory result on macrophages; however, when the effects of Integra® on macrophage phenotype was analysed, a temporal down-regulation of 'M2a' macrophages (ECM deposition macrophages) was observed [54,55]. This is assumed to be due to the presence of glutaraldehyde every bit cantankerous-linking agent in Integra® [54]. Yet, clinical data show that Integra® induces deposition of collagen, histologically indistinguishable from native dermal collagen, achieving practiced quality tissue with no hypertrophic or keloid scar formation [54,56].

Decellularised xenografts have shown promising results in wound healing direction, as they retain the native construction of the ECM, which comprises not only collagen but too structural, adhesion and signalling molecules (east.m. laminin, GAGs, elastin, fibronectin) [57,58]. Endoform® Antimicrobial Dermal Template (Aroa Biosurgery Ltd., Auckland, NZ) presents a matrix of ovine forestomach (OFM) with 0.3% w/w silver chloride [59,60]. Its master component, OFM, has been shown to promote wound healing in recalcitrant wounds (wound closure achieved within iv–24 weeks) with no reports of adverse reactions when used every bit Endoform® Dermal Template [61–63]. OFM/silver has been demonstrated to be effective at inhibiting a broad spectrum of MMPs and exhibits depression cytotoxicity in vitro [32,57,64]. This large MMP-spectrum is causeless to be due to the retained native ECM structure [32,57,64]. A preliminary in vivo study showed positive results on wounds characterised past dissimilar aetiologies [65].Puracol® Ultra ECM (Puracol® Ultra ECM, Medline Industries Inc., Northfield, IL) is a decellularised porcine mesothelium matrix that has also been shown to have a loftier retention of growth factors (FGF-basic, VEGF, and TGF-β1) later on the decellularisation process, high angiogenetic potential in vitro and similar MMPs-inhibition abilities to OFM/silver [58]. Although more research is needed on skin substitutes' total effects in curbing inflammation, they correspond an attractive, admitting expensive, fashion of modulating inflammation and promoting healing [66].

Collagen dressings

Collagen plays many roles in wound direction, including chemotaxis of fibroblasts, wound contraction, induction of growth factors and cytokines, activation and inhibition of MMPs [67,68]. Together with its biocompatibility, biodegradable, and non-toxic attributes, these advantages make collagen an attractive candidate material for treating recalcitrant wounds. Numerous clinical studies highlight the benefit of collagen-based dressings for treating chronic wounds, showing faster healing rates or shorter healing times, inactivation of proteases and maintenance of moist wound environment [69–72].

There are many commercially available collagen-based wound dressings, all with different limerick but similar claims. They are made of collagen or a combination of collagen and other ECM components, such equally elastin, hyaluronic acid and chitosan or in conjunction with other biologically derived materials like alginate and cellulose [73]. BIOSTEP™ Collagen Matrix dressing (Smith & Nephew, London, U.G.) is a matrix presenting both type I and denatured (gelatin) porcine collagen with the addition of EDTA, CMC and alginate [74]. The collagen acts equally a sacrificial layer for excess MMPs, while EDTA binds and permanently inactivate them [74,75]. The presence of both collagen and gelatin is claimed to concenter both collagenase (MMP-ane) and gelatinase (MMP-2, MMP-9) [74]. Cutimed® Epiona (Essity Medical Solutions, Stockholm, Sweden) is a fenestrated substrate fabricated of xc% native bovine-derived collagen and 10% alginate [76,77]. The dressing structure is claimed to be nearly identical to homo dermis, which allows for MMP bounden and reduction in inflammation [76,77]. Despite the common employ of collagen-based wound dressings in wound care, more than enquiry is needed to understand their mechanisms of action. Many dressings lack satisfactory show-based data due to poorly-designed studies that, in many cases, are manufacture-funded or nowadays traditional dressing (i.east. saline moistened gauze) as control [69,70].

Cellulose

Cellulose is a naturally occurring polymer used in biomedical applications for its biocompatibility, biodegradability, low-toxicity and good assimilation backdrop [78,79]. In that location are different cellulose sources and derivatives. An instance is given by oxidised regenerated cellulose (ORC), a chemically modified form of cellulose with haemostatic abilities [80,81]. The Promogran™ Matrix family (3M, Saint Paul, MN, Usa) of wound dressings are collagen-based dressings containing ORC (3M™ Promogran™ Protease Modulating Matrix) or ORC and argent-ORC (3M™ Promogran Prisma™ Wound Balancing Matrix). Promogran™ Matrix is composed of a freeze-dried matrix made of 55% type I bovine collagen and 45% oxidised regenerated cellulose (ORC), whereas Promogran Prisma™ Matrix replaces 1% of ORC with silvery-ORC to provide the dressing with antimicrobial properties. The combination of collagen and ORC presents a series of anti-inflammatory benefits. Firstly, ORC has been shown to passively affect protease levels through its negative accuse that attracts positively charged metal ions which are essential for the activation of MMPs and thereby reduces MMPs activity [82]. ORC has the additional benefit of reducing elastase activity, an enzyme that breaks down elastin fibres within the ECM and contributes to not-healing wounds' chronicity. Studies have shown that collagen/ORC dressings reduce elastase activity and inhibit MMP-2 and MMP-9 activity in chronic wound exudate, resulting in increased healing rates [83,84]. Additionally, collagen/ORC binds platelet-derived growth factor (PDGF) and shields it from deposition inside the wound and γ-irradiation when loaded into the dressing during the manufacturing process, opening a series of opportunities to locally deliver exogenous growth factors and protection of endogenous growth factors inside the wound [82,83]. These benefits have also been analysed and recognised by many clinical reviews [8,85].

Functionalised collagen dressings

Numerous studies showed functionalisation of collagen-based dressings incorporating growth gene or peptides to provide a more instructive wound microenvironment to help cellular behaviour and tissue regeneration [86]. An instance is given past a chitosan-collagen hydrogel which incorporates an angiopoietin-i (Ang1) mimetic peptide, QHREDGS (glutamine-histidine-arginine-glutamic acid-aspartic acrid-glycine-serine) [33,86–88]. Ang1 has been widely recognised to positively participate in several cellular processes such as vascular protection, wound healing and inflammation, providing skin cells protection from oxidative stress [87]. This product is in development as an injectable gel and a pre-gelled patch and presents the QHREDGS peptide conjugated to the dressing's chitosan component to avert systemic circulation of the peptide and to promote a more localised activity [88]. The QHREDGS-functionalised hydrogel has been shown to ameliorate in vitro keratinocytes resistance to oxidative stress caused by elevated ROS levels, which is common in diabetic chronic wounds [87]. In improver, when co-cultured with macrophages, the Q-peptide hydrogel induces a shift in macrophages polarisation, resulting in the expression of both pro-inflammatory and anti-inflammatory cytokines; information technology, therefore, offers the potential to modulate the stalled inflammatory process in chronic wounds [33].

Growth factors accept also shown promising results when included in a scaffold as topical therapies [34,89,xc]. Long et al. [34] produced a collagen scaffold co-modified with VEGF and SDF-1α. These were loaded onto the scaffold later separately beingness fused with a collagen-bounden domain (CBD); this allows for a more controlled release of the growth factors once implanted [34]. This co-modified CBD-VEGF-SDF-1α collagen scaffold showed reduced infiltration of 'M1' macrophages together with reduced expression of IL-1β and TNF-α, 2 pro-inflammatory cytokines constitute at high levels in chronic wounds [34]. Furthermore, the synergic activeness of VEGF and SDF-1α promotes claret vessel germination, which is thought to reduce hypoxia at the wound site [34].

Silver

Ionic silver (Ag+) has been shown to provide anti-inflammatory properties in addition to its antimicrobial activity, although the mechanism of action is non well understood [15,91]. A argent nanoparticle loaded collagen/chitosan scaffold (NAg-CSS) claimed to modulate fibroblast migration and macrophage activation to promote healing has been devised past You and colleagues [35]. Compared with non-loaded collagen/chitosan scaffold, NAg-CSS significantly decreased the expression of CD68 (a macrophage marker), farther proven by the inhibition of pro-inflammatory cytokines IL-vi, TNF-α and TGF-β while upwardly-regulating the anti-inflammatory cytokines, IL-10 and IFN-γ [35]. Fifty-fifty though argent nanoparticles' verbal anti-inflammatory mechanism is not still fully understood, the dissimilar NAg-CSS components' combinations could offering a synergic effect. Chitosan has been shown to stabilise collagen scaffolds' mechanical backdrop while too providing practical benefits such as antioxidant and antimicrobial properties [92].

Synthetic wound dressings to regulate inflammation

Synthetic wound dressings are considered not equally competitive as bio-derived every bit they do not mimic the native EMC in a like mode to bio-derived dressings [nineteen]. The most common types of polymers used in wound dressings include polyurethane, polyester, poly(glycolic acid), poly-50-lactide and poly(lactic-co-glycolic acrid) [93,94]. Compared with bio-derived dressings, constructed dressings present advantages in terms of reproducibility and tailoring every bit their synthesis is more easily controlled. Yet, they tend to be more inert, not provide a physiological microenvironment to promote healing, and consideration needs to be given to degradation components left in the host tissue [37,41].

Refer to Table 2 for a summary of dressings currently available or in the inquiry stage.

Technology lipido colloid (TLC)

The synthetic dressing UrgoStart® (Urgo Medical, Chenôve, France) presents a polyester mesh saturated with a sucrose octasulfate potassium salt (Nano Oligo Carbohydrate Factor, NOSF) embedded lipido-colloid matrix (Engineering Lipido-Colloid, TLC). NOSF and TLC composition are protected under the manufacturer'due south patent. UrgoStart (TLC-NOSF) turns into a colloidal solution, allowing for conformability to the wound bed [95]. Oligosaccharides (NOSF) take been shown to reduce MMPs level and restore growth factors biological functions, while the TLC matrix creates a moist wound surroundings [96]. Furthermore, in vitro data report decreased levels of gelatinases and an initial decrease of collagenases (MMP-ane and MMP-8) [97]. Multiple clinical studies study its effectiveness in DUs, VUs and PUs; however, there is a lack of data regarding its mechanism of action [96,98–101].

Polyvinyl alcohol (PVA) sponge

An exciting example of a collagen-functionalised synthetic dressing is presented by Das and co-workers [31]. The authors saturated a polyvinyl booze (PVA) sponge with a modified collagen gel (MCG), implanted it subcutaneously in a mouse model and assessed the effects on inflammation after 3 and vii days [31]. They constitute MCG increased macrophage recruitment in situ, decreased pro-inflammatory 'M1' phenotype and promoted an 'M2' phenotype [31]. This was further proved past the increased levels of anti-inflammatory IL-10 and IL-four and pro-angiogenic VEGF production [31]. Furthermore, they showed MCG induces IL-10 product via the miR-21-JNK pathway; however, the lack of testing in a wound model calls for further inquiry [31].

Summary

Wound treatment represents one of the most expensive burdens on healthcare systems worldwide.
Many chronic wounds become stuck in the inflammatory phase, which prevents healing from progressing.
A vast market of wound dressings presents different composition but similar claims, making it difficult for healthcare practitioners to decide the appropriate treatment.
Collagen is one of the virtually used materials in wound dressings since it helps mimic the native wound microenvironment.
Boosted research is needed to fully understand the mechanisms of action of collagen-based wound dressings to adjourn inflammation, and a improve clinical study design needs to be implemented so that the results obtained are truly valuable.

Competing Interests

H.A.T. and A.F. are employees of 3M, and S.C. and D.V.Five. received funding from 3M.

Writer Contributions

D.V.Five. wrote the newspaper with input from all authors.

Funding

The authors would like to thank the EPSRC grant reference EP/S022201/1 for funding this work.

Abbreviations

Ang1
CBD
CMC
DAMPs

danger-associated molecular patterns
DFUs
ECM
EDTA

ethylenediaminetetraacetic acid
FDA

Us Food and Drug Administration
GAGs
IFN-γ
IL-ten

interleukin-x (e.chiliad. IL-6, IL-10, IL-4, etc.)
LUs
MCG
MMPs

matrix metalloproteinases
NHS

Great britain National Health Services
OFM
ORC

oxidised regenerated cellulose
PAMPs

pathogen-associated molecular patterns
PDGF

platelet-derived growth gene
PHMB

polyhexamethylene biguanide
Pus
QHREDGS

glutamine–histidine–arginine–glutamic acid–aspartic acid–glycine–serine
ROS
SDF-1α

stromal prison cell-derived cistron-1α
TGF-β
TIMPs

tissue inhibitors of metalloproteinases
TNF-α
VEGF

vascular endothelial growth cistron

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jonessatereat.blogspot.com

Source: https://portlandpress.com/emergtoplifesci/article/5/4/523/229143/Wound-dressings-curbing-inflammation-in-chronic

Jones Satereat

Curbing Inflammation in Skin Wound Healing a Review

Wound dressings: curbing inflammation in chronic wound healing

Introduction

Schematic of the wound healing stages focusing on macrophage phenotypes classification in vivo and in vitro with their corresponding functions.

Wound dressings: an introduction

Bio-derived wound dressings to regulate inflammation

Skin substitutes

Collagen dressings

Cellulose

Functionalised collagen dressings

Silver

Synthetic wound dressings to regulate inflammation

Technology lipido colloid (TLC)

Polyvinyl alcohol (PVA) sponge

Summary

Competing Interests

Writer Contributions

Funding

Abbreviations

References

Post a Comment for "Curbing Inflammation in Skin Wound Healing a Review"

Curbing Inflammation in Skin Wound Healing a Review

Comprehend Epitome

Wound dressings: curbing inflammation in chronic wound healing

Introduction

Schematic of the wound healing stages focusing on macrophage phenotypes classification in vivo and in vitro with their corresponding functions.

Wound dressings: an introduction

Bio-derived wound dressings to regulate inflammation

Skin substitutes

Collagen dressings

Cellulose

Functionalised collagen dressings

Silver

Synthetic wound dressings to regulate inflammation

Technology lipido colloid (TLC)

Polyvinyl alcohol (PVA) sponge

Summary

Competing Interests

Writer Contributions

Funding

Abbreviations

References

Post a Comment for "Curbing Inflammation in Skin Wound Healing a Review"