challenging to treat due to a heterogeneous combination of causative factors, creating a creating causative factors, of combination due aheterogeneous to treat to challenging wounds extremely These are simply oldage. or paralysis, suchasdiabetes, conditions with individuals disproportionally affect problem that adevastating wounds are dermal Chronic Abstract chronic wound, diabetic ulcer, wound biomaterials, Key tissue repair healing, Words: None Declarations: [email protected] Email: D Almquist Benjamin Author: Corresponding This article isprotected Allrights bycopyright. reserved. doi: 10.1111/exd.13290 Accepted thisversionandthe between lead todifferences been through the copyediting, typesetting, and proofreading which may pagination process, forpublicati accepted This articlehasbeen ArticleMara APop A pathway chronicBiomaterials: healing potential to wounds? Article type : Viewpoint 28-Dec-2016 : Date Accepted :17-Nov-2016 Date Revised :25-Feb-2016 Date Received DR. BENJAMIN DAVID ALMQUIST (Orcid ID : 0000-0001-9718-777X) 1. Department of Bioengineering, Imperial College London, London SW7 College 2AZ,Imperial UK of Bioengineering, Department 1.

1 and Benjamin DAlmquist andBenjamin 1

on and undergone full peer review buthasnot review undergone fullpeer on and Version of Record. PleaseVersion cite thisarticle as increased risk of amputation, anxiety, amputation, anddepression of risk increased to contributing and deprivation, mobility, sleep lossof to leading life, of quality individual's DFUs by 85%of amputations preceded upto compared non-diabetics, with to ulceration following individuals diabetic (DFU), increase possessa23-fold inthe ulcers ofrate amputation population over 65 population UK the andashigh5%of population, UKadult anestimated the total 1%of they affect This article isprotected Allrights bycopyright. reserved. world the around countries developing developed and inboth onsocieties impact ulcers ulcerations or suchasvenous, decubitus, have diabetic skin alarge Chronic skin Chronic arewounds a major burden on and individuals society successful healing. pathway apromising driving and providing innovative inturn for to newhealing, technologies wound simultaneously allowing of barriers numerous to them repair, to address ‘conductor’ encourage that positions biomaterials the asapotential matrices This growth of tissue. degradation, and sensitive provide biologics protect supportive from therapeutics, multiple delivery of temporal coordinate now ability to are enablethe dressings beingdeveloped that wounds; thesewound advanced devastating healing comprehensive to approaches possess occurwithin wounds. Biomaterials that an the ability provide new enticing to biological options the lack changes effectively underlying of treating astartling currently for is there large impact, their Despite systems onhealthcare worldwide. burden substantial cancer have or beas amputations been ofto than and breast high those found higher prostate treatment. innovations for without any further rise only expected to are values these population, Accepted Article

s6 s7 . Moreover, the 5-year mortality rates associated with DFUs or DFU-related DFU-related or DFUs with associated rates mortality 5-year Moreover, the . . With an increasing frequency of diabetes and obesity, along with an aging with anaging along diabetes andobesity, anincreasing of frequency . With s1 . . woundsThese devastating have anenormous negative on an impact s2–s6 . Looking solely at diabetic foot foot solely diabetic at Looking . 1 . In the UK the matrix within the wound bed within the matrix the of native the modulation of ECM multiple features andallow mimic that scaffolds polymeric anddegradable constructs, skin living such replacements, matrices, asdecellularised skin out the process the of tissueout repair properlycells within skinto carry ability of the affect the that changes biological underlying may stem Manyto of number thisresistance treatment individuals. from times significant extracellular matrix (ECM) they deposit matrix extracellular growth factors to response intheir differences RNA moleculessuch as microRNAs This article isprotected Allrights bycopyright. reserved. successful wound inmanyto patients closure negative suchasdebridement, canleadstrategies pressure andoffloading orthotics therapy, conventional While lab. the insights from recent of take advantage that them treating enable novelBiomaterials therapeutic approaches repair mechanisms repair andmechanisms, canact as bioactive reservoirs to stimulate innate that retain tissue agents have and controllable degradation metabolites, nutrients of allow cells, diffusion of andadhesion infiltration the support to sites with cell-binding tagged microstructures porous Acceptedsuccess translational active achieving towards role andimportant amore has slowly played andbiomaterials engineering tissue the of prospects, field of future interms dire may seem this failures. While of a splendidgraveyard decadeshasbeen two past bedside over the pharmaceutical-based the of translation approaches Unfortunately, benchfrom the to has beenactively as a strategy explored newkey developing options. therapeutic for Article Despite the large impact of these wounds, there are surprisingly few options available for wounds, for available these surprisingly impact options of are there few large the Despite The ability to correct these biological abnormalities within the wound microenvironment wound within microenvironment the abnormalities these biological correct ability to The 2,s16–s24 . Significant emphasis hasbeen bioengineered onthe developmentput of Significant . 2,s24,s29 2,s24,s29 (Figure 1). 1). wayIn this asathey act (Figure support nativetowound the s9 s25–s28 ; cells isolated from DFUshave beenshown display cellsisolated from ; to s15 . . Such scaffolds, whether natural or synthetic, have synthetic, whether or natural Suchscaffolds, . s12 , levels of proteases produced of levels , s10 s8 , proliferation rates proliferation , , these treatments are ineffective for a for are ineffective treatments these , s11 s13,s14 , composition of the of composition , , and regulatory andregulatory , wound model burn mouse regenerative inathird-degree promote are healing able to polymers diacrylate glycol andpolyethylene dextran-allyl isocyanate-ethylamine UV-crosslinked of consisting wound compared to healing lacking scaffolds micropores or sham wounds. wounds, skin 70:30 rat thickness these stimulated scaffolds more andeffectivecol/PCL rapid into full- implanted When matrix. dermal normal the mimic to scaffold the remodelling while also andfibronectin, ascollagen such molecules, native andsecrete ECM scaffolds the into migrate neonatal foreskin isolated from fibroblasts human primary that demonstrated andproliferation attachment, infiltration, that mesh fosters fibroblast anoptimal creates architecture This scaffold. of the thickness the mechanically throughout These microporous scaffolds are electrospun from collagen I (col) and I poly scaffolds collagen (col) electrospun These microporous from are ( (PCL) in a 70:30 ratio, with pores of 160 of pores with ratio, ina70:30 (PCL) This article isprotected Allrights bycopyright. reserved. Accepted dressings control wound the tissue, compared rich of area and enhanced re-epithelialisation togranulation ECM- neovascularisation, promoted of through tissueformation hydrogel regeneration fast weeksthree post wounding. recently burn wound inaporcine tested When the model, same neovascularisation at significant byregeneration skin by 7, promoting day followed complete inturn of degradation the hydrogel, leadsto rapid by cellsthat inflammatory early infiltration Article scaffoldsone study have ECM-mimicking cell beendeveloped encourage migration to scaffold. in instance, the For of onthe depending functionality required from pick available to wound closure. efficient for crucial are cuesthat instructive wound, providing the cellswithin of differentiation and migration, proliferation, suchasthe cellbehaviour, regulate to microenvironment

In other work, other In researchers demonstrated adextran-based that hydrogel scaffold When aiming are aiming synthesise When scaffolds, to there many biomaterial avenues are that 4 . This hydrogel, with no additional growth factors, cytokines, or cells, facilitates cytokines, cells, withfacilitates growth hydrogel, or noadditional factors, This . s30 . Other work by the group has given rise to a hypoxia-inducible hydrogel has ahypoxia-inducible by hydrogel to work given rise the . group Other μ m diameter subsequently introduced being diameter m in vitro ε -caprolactone) -caprolactone) . The authors The . 3 . gradients generated within hydrogel the generated gradients display such heterogeneous changes using a display suchheterogeneous Assuming action. wounds of overcome, of challenge hurdles treating are thatsite the these appropriate the at localisedtherapy efficient and dosage, facilitate relevant physiologically anextended present release to control of rate therapeutic the woundhostile environment, protect degradation them bythat inthe mechanisms complexfrom delivery enzymes require agents 2). observedbiological These wounds (Figure inchronic deficiencies biological the to address nucleicacids, fully or suchas growth factors sensitive biologics, deliver it cells, may be also necessary to infiltrating andwound providefor ascaffold environment wound resolution. promoting approach for interesting and apotentially diabetic venous are ischaemic ulcers within concentration localoxygen canmanipulate that wounds,chronic biomaterials This article isprotected Allrights bycopyright. reserved. vascular morphogenesis guides that Acceptedwounds many when that presentscompliance chronic asignificant challenge times treating serious may that leadto side-effects, deliveries bolus releases andhigh-dosage initial inlarge resulting pattern, delivery spatiotemporal ability easily the does enablethe to methods tune these not Using strategy. this fully exploit necessary to control are provide the to Heberprot-P) unlikely and (e.g. injections trafermin), on the of impact preceding onesand synergisefurther with eachother efficacy.improved for canbuild eachtherapeutic so, doing In wound bed. the into therapeutics multiple delivery of advanced wound wounds cancoordinate temporal that dressings the require These likely Article local manipulate the that matrices creating for provide options examples these While

However, traditional delivery platforms such as creams (e.g. becaplermin), sprays (e.g. sprays (e.g. becaplermin), suchas (e.g. creams delivery platforms traditional However, s31,s32 . in vitro 5 . Although not currently used for the treatment of treatment the currently usedfor not Although . and single while also requiring a high-level of patient ahigh-level of while alsorequiring in vivo therapeutic is still a daunting prospect. isstill adaunting therapeutic by establishing precise oxygen precise oxygen establishing by lower than previously than FDAapprovedlower the for used becaplermin gel dose a using factor of growth an accomplished total 300 amount 150ng, approximately times and theangiogenesis of with granulation tissue dressings. the wasformation This localised release of siRNA targeting MMP-9 (siMMP-9) indb/db mice MMP-9 (siMMP-9) of siRNA targeting localised release wound create facilitate that isableto the dressings that LbL technique demonstrated by-Layer (LbL) onto VEGF-165 wovenincorporated and PDGF-BB wound nylonusing the Layer- dressings This article isprotected Allrights bycopyright. reserved. ROS-degradable via PHD2knockdown that group hasdemonstrated same the Recently, to leading a VEGF day in vessel andFGF-2, at 33. inturn 280% increase genes area inHIF1 increase inasignificant resulted This PHD2. 2, enzyme the prolyl of hydroxylase knockdown andcontrolled sustained through wound model mouse angiogenesis balb/c promoted ina delivery platform the study, this In milieu. extracellular being inthe instead of released endosome (pH 5.8), acidifying by degradation nucleasesfrom enters an onceit andensure thesiRNAisdelivered individual kinetics release their of modulation independent while allowing enablesactive woundfor of sustainedmultiple that coating growth release factors dressings Accepted injectable scaffolds polyurethane in biodegradable composed whichnanoparticles 2-dimethylaminoethyl methacrylate, of incorporated are then polymer pH-responsive within siRNAmolecules packaging woundsis possibleby skin to siRNAdelivery sustained hasdemonstrated research recent that instance, For biologics. delivery of enableefficient have to beendeveloped that manystrategies other are and re-epithelialization. tissue formation of granulation rate improvements inthe indramatic resulting respectively, Article 75%and55%, over weeks of two after MMP-9expression andactivity in a reduction To overcome someTo of we barriers havethese developed recently aself-assembled While these two examples demonstrate the flexibility of a technique such there atechnique asLbL, the these of twoflexibility demonstrate examples While s33 process. Experiments in db/db mice demonstrated increased levels of both both increased indb/db demonstrated levelsmice Experiments of process. α –mediated transcription of thepro-angiogenic of transcription –mediated 8 . The nanoparticles protect the siRNA the protect nanoparticles The . 7 s34 . This strategy leads to . Further. to thiswe 6 . In this work, we expression, and rate of wound healing of andrate expression, PKC of with knockdown wounds, siRNA chronic wounds displaying upregulation woundsstrong chronic displaying during junctions cell-cell epithelial regulating in Ephrin-B1 of role have animportant elucidated Recent findings area. inthis made of context chronic as in the new exciting wound are developments constantly healing, being The pathway forward changes biological inchronic wounds.target efficiently to potential have anenormous platforms biomaterial-based designed how carefully This article isprotected Allrights bycopyright. reserved. mice alsoimproves indiabetic woundscaffolds healing persistent PKC persistent DFUs innon-healing of maturation enhance andepithelial tissue granulation formation significantly hasbeenshown anantioxidant to hydrogel thermoresponsive from (SDF-1) derived factor-1 patient populations into treatable cohorts. populations For into treatable based stratification patient patient instance, on Accepted various withcan biomarkers that bepaired of thedevelopment stratify need to effectively wound the microenvironment. strategiesThese chronicfor woundstreating will likely then for matrix andprovide extracellular supportive schedules, dosing a optimise extracellular), (intracellular, eachtherapeutic for delivery needs differential address simultaneously can that technology picture the asanenabling enter iswhere biomaterials This drive healing. to wound environment local the synergistically rewire to manner concerted in cellsand of nucleicacids, scaffolds act a proteins, polymeric together that combination a require likely will unknown; suchastrategy isstill findings prior builds onextensive Article There are many interesting biological targets that need further exploration and validation andvalidation thatexploration need targets biological further are many interesting There How these new insights can be integrated into into a that Howcan beintegrated strategy comprehensive newinsights therapeutic these s37 . δ expression inhibits insulin signalling in fibroblasts 1diabetic from Type infibroblasts insulinsignalling expression inhibits in vivo in δ resulting in increased levels of p-AKT, VEGF p-AKT, of levels inincreased resulting s35 s36 re-epithelialization, with clinical non-healing clinicalnon-healing with re-epithelialization, . In other . ithasresearch, beenshown that . Finally, sustained release of stromal cell stromal of release sustained Finally, . 9 . These examples together illustrate illustrate examples together . These the devastatingthe chronic wounds impact have onsociety. onreducing impact ameaningful make can that soonbedeveloped will new interventions that we cancers, some optimistic are than worse rates survival with condition amedical for help regulatory of combination easeadvancement promising from With therapies bodiesto way. bi-directional ina over time biology with interact that materials design to ability on our inflammatory response overinflammatory time the raise have surrounding the localacidity ability of and to apronouncedtissue the trigger ester-based Suchproductsmechanisms). degradation carboxylicderived from acidproducts (e.g. products degradation toxic can form gels as these repair, tissue for hydrogels of withthese hostmaterials the Care betissue. must taken when degradable designing with complexity materials asthe levelof the the along toxicity increases, andbiocompatibility of includethe manufacturability beaddressed still needto hurdlesthat applications, healing successadvanced therapies. the of maximising crucial for are strategies treatment certain from likely benefit to most are wounds that identify This article isprotected Allrights bycopyright. reserved. expression gene macrophage Accepted continuallywounds being uncovered are around the world andchronic woundhealing of biology the into new discoveries insightful growing, is interplay immunogenicity. minimal andtriggering integration tissue whilequality promoting degradation products detrimental Article

However, despite these stimulating advances in the field of biomaterials for wound of theseadvances biomaterials despite inthe However, stimulating field for Nevertheless, we are excited by the fact that our understanding of tissue-biomaterial of tissue-biomaterial understanding our that fact the by we excited Nevertheless, are s38 or potentially by using non-invasive imaging of wounds of imaging non-invasive using by potentially or s40 ; ideally, biodegradable hydrogels will create nowill hydrogels create biodegradable ideally, ; s41–s51 , and progress isbeing andprogress , made s39 to This article isprotected Allrights bycopyright. reserved. KM, S.Hypoxia-inducible hydrogels. Gerecht Park 5. SunG, Shen Zhang X, Y-I 4. L, Ragnarson-Tennvall G AJM, Boulton Vileikyte 1. References contributed toAll authors the conception andwriting of this article. Author Contributions organizations. views funding of the represent not anddo the authors, of those views are (A1071). within The contained Trust and Rosetrees Society (RG140614); Royal (109838/Z/15/Z); Trust by BDAissupported Wellcome lab of Research inthe EPSRC PhDscholarship for MAPfunding. acknowledges (EP/L504786/1) Acknowledgements Accepted Schultz MJ, Mitchell PP, EH Bonvallet 3. Evans Stevens PlaceES, ND, MM 2. Article doi:10.1038/ncomms5075 doi:10.1038/ncomms5075 Natl AcadSci. Natl responses andpromote burn wound during skin complete regeneration healing. 2434–2445. disease. foot Scaffolds Promote Accelerated Skin Regeneration. Regeneration. Skin Accelerated Promote Scaffolds engineering. Nat Mater. Nat Lancet. 2011; 2005; 108 2009; 2009; : 20976–20981.: et al. et 366 8 : 1719–1724.: : 457–470.: Dextran hydrogel enhance scaffolds angiogenic et al. et et al. et Complexity in biomaterials for tissue Complexity inbiomaterials for Microporous Dermal-Like Electrospun et al. et Nat Commun. Nat Tissue A. EngPart The global burden of diabetic burden of global The 2014; 2014; 5 : 4075 20 : Proc Proc Figure 1. 1. Figure LegendsFigure delivery. intracellular efficient and wound thefacilitate hostile environment, sensitive from biologics for provide protection therapeutics, synergistic multiple of coordination enabletemporal wound They local sites. 2. Figure the localmicroenvironment. manipulating and properties, regulatory mechanisms, for mechanisms mechanical degradation celladhesionsites, of incorporation controllable biomaterials for allows of structure the Manipulating molecular (b) and deposition. matrix subsequent cellinfiltration rapid 9. Martin JR, Nelson CE, Gupta MK Nelson CE,Gupta JR, Martin 9. 8. Nelson CE, Kim AJ,AdolphEJ NelsonCE, 8. 7. Castleberry SA, Almquist BD, Li W Li BD, SA,Almquist Castleberry W 7. This article isprotected Allrights bycopyright. reserved. Accepted Article SunJB BD,Castleberry SA, Almquist 6. doi:10.1002/adhm.201600820 doi:10.1002/adhm.201600820 Diabetic Scaffolds to Degradable Promote Healing. Wound Scaffold Promote Angiogenesis Into Vivo. Scaffold 1817. MMP-9 and Improve Diabetic MMP-9 andImprove Healingin Vivo. Wound Vivo. Vivo. In Healing Dressings Improves Ulcer Assembled Diabetic Electrostatically Wound Biomaterials present a flexible approach to controlled delivery of to therapeutics of delivery controlled to a present approach Biomaterials flexible (a) The texture, topology, and porosity of biomaterials can be used to facilitate facilitate canbeusedto biomaterials andporosity of topology, The texture, (a) Adv HealthcMater. 2015; et al. et 4 : 2090–2099. et al. et et al. et Tunable Delivery of siRNA from a Biodegradable Delivery siRNA of Tunable from et al. et Local Delivery of PHD2 siRNA from ROS- PHD2 LocalDeliverysiRNA of from Self-Assembled Dressings Silence Wound Adv Mater. Combination Factor Growth Therapy via 2014; Adv Mater. Adv Healthc Mater. 26 : 607–614.: 2016; 28 : 1809– : 2016; This article isprotected Allrights bycopyright. reserved. Accepted Article