Perspective on Plasma Polymers for Applied Biomaterials Nanoengineering and the Recent Rise of Oxazolines

materials

Review Perspective on Plasma Polymers for Applied Biomaterials Nanoengineering and the Recent Rise of Oxazolines

Melanie Macgregor 1,2 and Krasimir Vasilev 1,2,*

1 School of Engineering, University of South Australia, Adelaide, SA 5000, Australia; [email protected] 2 Future Industries Institute, University of South Australia, Adelaide, SA 5000, Australia * Correspondence: [email protected]; Tel.: +61-8-8302-5697

Received: 3 December 2018; Accepted: 2 January 2019; Published: 8 January 2019

Abstract: Plasma polymers are unconventional organic thin films which only partially share the properties traditionally attributed to polymeric materials. For instance, they do not consist of repeating monomer units but rather present a highly crosslinked structure resembling the chemistry of the precursor used for deposition. Due to the complex nature of the deposition process, plasma polymers have historically been produced with little control over the chemistry of the plasma phase which is still poorly understood. Yet, plasma polymer research is thriving, in par with the commercialisation of innumerable products using this technology, in fields ranging from biomedical to green energy industries. Here, we briefly summarise the principles at the basis of plasma deposition and highlight recent progress made in understanding the unique chemistry and reactivity of these films. We then demonstrate how carefully designed plasma polymer films can serve the purpose of fundamental research and biomedical applications. We finish the review with a focus on a relatively new class of plasma polymers which are derived from oxazoline-based precursors. This type of coating has attracted significant attention recently due to its unique properties.

Keywords: plasma polymers; oxazoline; biomaterials; medical devices; implants; coatings

1. Introduction Plasma in its natural state can be seen as the polar lights and lightning. Far from being rare, this high energy ionised gas phase, referred to as the fourth state of matter, represents more than 99% of the visible universe. Humans artificially induce plasmas using a variety of energy sources including strong magnetic fields, lasers, radiofrequency, electric fields and microwaves. Man-made plasmas are nowadays seen everywhere from commodities such as TV screens, toys and low energy lighting to nuclear reactors and aircraft propulsion turbines. What may be less obvious for some are all industrial uses of plasmas, not as a finished product, but as a manufacturing tool for material surface modification [1]. Plasmas are constituted of highly energetic molecules, molecular fragments, ions, radicals and free electrons. As a result, when plasmas come in contact with solid surfaces, may it be metal, plastic or any other material, they cause important changes to the material surface properties. In this way, it is possible to use plasma-assisted processes to modify a material surface energy, wettability, chemistry and even topography to suits a variety of applications with the added advantage that the properties of the bulk materials are preserved. Plasma-assisted surface modifications encompass a range of techniques which Chu et al. described in quite some detail for the specific case of biomaterials surface modification [2]. Yet, plasma-induced surface treatments processes are used to create novel materials with unique electronic, optical, mechanical and biological

Materials 2019, 12, 191; doi:10.3390/ma12010191 www.mdpi.com/journal/materials Materials 2019, 12, 191 2 of 18 properties for many different ﬁelds of applications. When the excited species present in the plasma generated from inert (Ar, Ne, He ... ) or reactive (O2,N2, NH3, CO2 ... ) gases collide with the solid, Materials 2018, 11, x FOR PEER REVIEW 2 of 18 enough energy may be acquired by the atoms on the surface layer of the solid for them to detach from the surface.generated When from inert the physical(Ar, Ne, He degradation …) or reactive of the(O2,bulk N2, NH material3, CO2 …) is limitedgases collide to the with outermost the solid, layer, the plasmaenough processenergy may is called be acquired sputtering, by the atoms Figure on1 athe [ 3 surface]. This layer is the of processthe solid usedfor them in plasmato detach cleaners from to removethe surface. impurities When from the physical contaminated degradation surfaces. of theIf bu furtherlk material deeper is limited loss of to the the exposed outermost material layer, the occurs, however,plasma the process process is iscalled referred sputtering, to as plasma Figure etching,1a [3]. This Figure is the1b. process Plasma used etching in plasma is a process cleaners in to which the adsorptionremove impurities of energetic from contaminat species ised followed surfaces. by If further product deeper formation, loss of the prior exposed to product material desorption occurs, [4]. Combinationhowever, processesthe process have is referred also been to as reported plasma etching, where anisotropicFigure 1b. Plasma chemical etching etching is a process is accelerated in which by ion the adsorption of energetic species is followed by product formation, prior to product desorption [4]. sputtering [5]. In biomaterials engineering, plasma is generally used for surface cleaning and sterilisation Combination processes have also been reported where anisotropic chemical etching is accelerated by but at its extreme, plasma etching can also be used for surface roughening and nanopatterning, and ion sputtering [5]. In biomaterials engineering, plasma is generally used for surface cleaning and evensterilisation generating but novel at nanostructuresits extreme, plasma [6–9]. etching It is also can possible also be for used excited for speciessurface presentroughening in the and plasma phasenanopatterning, to directly react and with even the generating substrate novel and nanostructur induce surfacees [6–9]. modification It is also possible including for excited the grafting species of new chemicalpresent functions, in the plasma such asphase amine to ordirectly hydroxyl react groupswith the [10 substrate]. This process and induce is often surface referred modification to as plasma ion implantation.including the grafting The downside of new chemical of modifying functions, a surface such as via amine plasma or hydroxyl sputtering groups or implantation [10]. This process is that the modificationis often referred is short to lived as plasma because ion reorientation implantation. of The the surfacedownside functional of modifying group a occurssurfaceovertime via plasma [11 –14]. Surfacessputtering with lasting or implantation properties is that the completely modification differ is fromshort thoselived because of the bulk reorientation materials of can the besurface generated via plasmafunctional polymer group occurs deposition. overtime It [11–14]. differs fromSurfaces the with other lasting plasma-assisted properties that surface completely modification differ from in the those of the bulk materials can be generated via plasma polymer deposition. It differs from the other fact that a thin organic coating is formed over the surface of the original material (Figure1d). Figure1 plasma-assisted surface modification in the fact that a thin organic coating is formed over the surface provides an simplified visual representation of the main class of plasma surface modification processes, of the original material (Figure 1d). Figure 1 provides an simplified visual representation of the main in whichclass theof plasma effect of surface plasma-wall modification interaction processes, and particlein which distribution the effect of in plasma-wall the sheathregion interaction have and not been represented.particle distribution Important in phenomena the sheath region occurring have innot this been region represented. are still Important under fervent phenomena investigation occurring [15 ,16]. The figurein this alsoregion does are not still represent under fervent the influence investigation of reactor [15,16]. geometry The figure on also the plasmadoes not deposition represent the process. The interestedinfluence of reader reactor can geometry refer to on an the article plasma by Whittledepositio etn al.process. where The an interested international reader consortium can refer to compares an coatingsarticle produced by Whittle in et 14 al. different where an plasma international reactors cons [17ortium]. compares coatings produced in 14 different plasma reactors [17].

FigureFigure 1. Plasma-assisted 1. Plasma-assisted surface surface modiﬁcation modification processes (a ()a sputtering) sputtering (b) (etchingb) etching (c) implantation (c) implantation and (andd) polymer (d) polymer deposition. deposition.

Materials 2019, 12, 191 3 of 18

In this review, we highlight the versatile nature of organic thin films deposited from plasma. We then provide specific examples where carefully designed plasma polymers are used to generate model substrates with controlled surface properties to elucidate fundamental research questions from nanowetting mechanisms to protein adsorption. We illustrate the most recent advances in plasma polymer applications to novel technologies ranging from the development of prosthetic materials, diagnostic devices and even hydrocarbon recovery technologies. Finally, we discuss a new class of plasma polymers that are based on oxazoline precursors pioneered recently by our team. We should stress that this review is not intended to cite all papers published in this exciting field. It is rather intended to summarise recent advances while referring the reader to reviews published by others where a particular aspect of the field is described.

2. Plasma Polymers Plasma-assisted deposition is a coating technique used to form thin polymer-like films on surfaces. Plasma-enhanced chemical vapour deposition (PECVD) is one of the most common plasma polymerization techniques. It uses plasmas of volatile organic precursors to create polymeric films at low or atmospheric pressure [18]. While plasma polymerization can be performed by a variety of others means such as magnetron sputtering, liquid-assisted deposition, plasma-assisted thermal evaporation, etc., the focus is here given to low pressure PECVD. One intrinsic advantage of PECVD is that it is a dry technique which only uses a minimal amount of precursors and does not produce liquid organic waste. As such, the method is cost effective and environmentally friendly [19–21]. The great advantage of plasma polymer deposition compared to conventional techniques for thin film deposition is the capacity to deposit the same surface chemistry with the same conditions on practically any type of substrate material [22–25]. This is because after the initial deposition of a few angstroms of material, the film growth becomes substrate independent [22,23]. In contrast, techniques for surface modification such as layer-by-layer (L-b-L) and Self Assembled Monolayers (SAMs) require substrates with highly specific properties, which narrows opportunities for applications [26]. The films generated are commonly referred to as plasma polymers although they do not formally classify as polymers because they do not consist of repeating monomer units. Instead, they are formed of a variety of precursor fragments and recombination products, and are generally highly crosslinked. Historically, such films have been produced with little control over the chemistry of the plasma phase. Despite the use of advanced techniques directly in the plasma phase such as Mass Spectroscopy, Langmuir probes and Optical Emission Spectroscopy, the mechanisms of plasma polymerization remain poorly understood [27–30]. However, advances in surface characterization techniques and the pull for applications have fueled much progress in this area, and it is now possible to control deposition conditions in many ways so that chemistry and functionality of the resulting coating can be finely tailored to suit specific applications ranging from wearable electronics [31] and solar cells [32] all the way to water treatment [33]. It is also possible to deposit plasma polymers onto micro and nanomaterials as well as powders. This approach has been used to create adsorbents for water treatment purposes. Silica or magnetic nanoparticles can be coated with a hydrophobic plasma polymer layer to remove hydrocarbon residue from waste water [33,34]. Thiophene-coated particles are able to isolate heavy metals [35], and allylamine-coated powders successfully remove dyes from waters which is relevant for the leather, textile, paper, pharmaceuticals, paper and food industries [36]. Plasma polymers coatedmagnetic nanoparticles were even recently used to remove haze proteins from wines [37,38]. The first degree of freedom when designing a plasma polymer is the monomer choice amongst a wealth of precursors [39]. Plasma polymers can be deposited from practically any compound volatile enough to be introduced into the reaction chamber. Table1 provide examples of organic precursors commonly used to produce thin polymeric films from their plasma phase. This list includes monomers like ethanol which are difficult to polymerise via conventional means but can be deposited into a polymeric film using plasma processes [29,40]. It also includes examples of precursors containing sulfur Materials 2018, 11, x FOR PEER REVIEW 4 of 18

Materials 2018, 11, x FOR PEER REVIEW 4 of 18 chemistry routes, oxaolines are polymerized via ring opening polymerization which results in a linear Materials 2018, 11, x FOR PEER REVIEW 4 of 18 chemistrypolymer with routes, amide oxaolines repeating are polymerized units. Several via works ring opening have demonstrated polymerization that which the plasma results deposition in a linear ofMaterials oxazolines 2018, 11 generates, x FOR PEER surface REVIEW chemistries that are not achievable via conventional means, including4 of 18 polymerMaterialschemistry 2018 with routes,, 11 ,amide x FOR oxaolines PEER repeating REVIEW are polymerizedunits. Several via works ring openinghave demonstrated polymerization that whichthe plasma results deposition in a linear4 of 18 the formation of isocyanate and nitrile groups but also the retention of the oxazoline ring itself. The ofchemistrypolymerMaterials oxazolines 2018 with routes,, 11 generates , amidex FOR oxaolines PEER repeating surface REVIEW are chemistries polymerizedunits. Several that via works are ring not openinghave achievable demonstrated polymerization via conventional that which the plasma means, results deposition includingin a linear4 of 18 presence of intact oxazoline rings provides unique opportunities to conduct binding reactions of thechemistrypolymerofMaterials oxazolines formation 2018 with routes,, 11 generates of, amidex FORisocyanate oxaolines PEER repeating surface REVIEW areand polymerizedchemistries units.nitrile Several groups that via worksbut arering al not so openinghave achievablethe demonstratedretention polymerization via of conventional the that oxazoline which the plasma means,results ring depositionitself. inincluding a linear4 The of 18 biomolecules,polymer with nanoparticlesamide repeating and units. various Several ligands works that have carry demonstrated carboxyl acid that groups the plasmain their depositionstructures presenceofthechemistryMaterials oxazolines formation 2018 of routes,, 11intact generates , ofx FOR isocyanate oxaolinesoxazoline PEER surface REVIEW areand rings polymerizedchemistries nitrile provides groups that viaunique but arering alnot openingsoopportunities achievablethe retention polymerization via to of conventionalconduct the oxazoline which binding means,results ring reactions itself.inincluding a linear4 Theof of 18 [41,42]. Other groups have investigated the plasma deposition of other ring-containing monomers biomolecules,ofthepresencepolymerchemistry oxazolines formation withof routes, intact generates nanoparticlesofamide isocyanate oxaolines oxazoline repeating surface areand rings polymerizedchemistriesunits. nitrilevarious provides Several groups ligands that via unique works but arering that alnot openingsohave opportunitiescarry achievablethe demonstrated retentioncarboxyl polymerization via to ofacid conventional conduct the thatgroups oxazoline which the binding inplasma means, results their ring reactions deposition structures itself.includingin a linear The of withMaterials heteroatoms 2018, 11, x FOR including PEER REVIEW pyrrole [43], furfuryl [44], thiophene [45], aniline [46] and even essential4 of 18 [41,42].thepresencebiomolecules,ofchemistrypolymer oxazolines formationMaterials Other withof routes, intact generates2019 groupsofnanoparticlesamide isocyanate ,oxaolines 12oxazoline, 191 repeatinghave surface investigatedare and andrings polymerized chemistriesunits. nitrile various provides Several groups the ligands that via plasmaunique works but arering that alnot openingdepositionsohaveopportunities carry achievablethe demonstratedretention carboxyl polymerization of viaother to of acidconventional conduct the ring-containingthat groups oxazoline which the binding plasmain means,results their ring reactionsmonomers deposition structuresitself.inincluding a linear The of 4 of 18 withoilspresencetheof oxazolines formation [47–49].heteroatoms of intactPlasma generates of isocyanate including oxazoline polymers surface pyrroleand rings preparedchemistries nitrile provides[43], groups furfurylfrom that unique non-syntheticbut are [4 al4],not soopportunities thiophene achievablethe retention monomers [45], via to of anilineconventional conduct the are oxazoline a[46] particularly binding and means, ringeven reactions itself. includinghotessential topic The of biomolecules,[41,42].polymerchemistry Other with routes, nanoparticlesgroupsamide oxaolines repeating have areinvestigated and polymerizedunits. various Several theligands viaplasma works ring that openingdepositionhave carry demonstrated carboxyl polymerization of other acid ring-containingthat groups which the plasmain results their monomers deposition structuresin a linear oilsbecausebiomolecules,presencethe [47–49].formation theyof Plasmaintact nanoparticlesofcombine isocyanate oxazoline polymers desirable andand rings prepared nitrilevarious providesoptical groups from ligands andunique non-synthetic but thatphys al soopportunities carry icalthe retention carboxylpropertiesmonomers to ofacid conduct thewithare groups oxazolinea particularlybiocompatibility binding in their ring reactions structuresitself.hot topic andThe of [41,42].withofpolymer oxazolines heteroatomsand Other with fluoro generates groupsamide heteroatoms including repeating have surface investigatedpyrrole which chemistriesunits. [43], can Several provide thefurfuryl that plasma works are very [4 not4], depositionhave interesting thiopheneachievable demonstrated of reactivity[45], via other conventional aniline ring-containingthat and [46]the wetting plasmaand means, even properties. monomersdeposition including essential Another becauseenvironmental[41,42].biomolecules,presence Other theyof intact groupsnanoparticles combinesustainability oxazoline have desirable investigated and [50,51].rings various providesoptical However, theligands and plasmaunique as that physthe depositionopportunities complexitycarryical propertiescarboxyl of of other tothe acid conduct withmonomer ring-containing groups biocompatibility binding inincreases, their reactions monomers structures so doesand of withoilstheof oxazolines formation[47–49]. heteroatomsinteresting Plasma generates of isocyanate exampleincluding polymers surface is andpyrrole that preparedchemistries nitrile of [43], oxazolines. groups fromfurfuryl that non-syntheticbut are Following [4 alnot4],so thiophene achievablethe retention classic monomers [45], via organic of conventionalaniline the are chemistryoxazoline a [46] particularly and means, routes,ring even itself.including hotessential oxaolines topic The are environmentalthewith[41,42].biomolecules, importance heteroatoms Other groupsnanoparticlessustainability of including carefully have investigated pyrroleand[50,51]. tuning various [43],However, the thefurfurylligands plasma plasma as [4thatthe 4],deposition depositioncomplexity carrythiophene carboxyl conditionof [45],of other the acid aniline monomer ring-containing groupsto [46]tailor andincreases,in thetheir even amountmonomers structures essential so does of oilsbecausepresencethe formation[47–49].polymerized theyof intactPlasma ofcombine isocyanate oxazoline via polymers ring desirable openingand rings prepared nitrile provides polymerizationoptical groups from andunique non-syntheticbut phys al which soopportunities icalthe resultsretentionproperties monomers in to aof linear conduct the withare oxazoline polymer a biocompatibilityparticularly binding withring reactions amideitself.hot topic andThe repeating of thefunctionalityoilswith[41,42]. importance[47–49]. heteroatoms Other Plasma retention groups of including carefullypolymers have to suit investigatedpyrrole tuning anyprepared specific [43], the fromthefurfuryl plasmaapplication plasma non-synthetic [4 deposition4], deposition thiophene[52,53] monomers andcondition of [45], ensureother aniline are ring-containing thatto a tailor[46] particularlyfilm and reactivitythe even amount monomers hotessential can topic ofbe becauseenvironmentalbiomolecules,presenceunits. theyof Severalintact nanoparticles sustainabilitycombine oxazoline works desirable have and[50,51].rings demonstratedvarious providesoptical However, ligands andunique thatas that physthe the opportunities complexitycarryical plasma propertiescarboxyl deposition of to the acid conduct withmonomer groups of oxazolinesbiocompatibility binding inincreases, their reactions generates structures so doesand of surface functionalitymaintainedbecauseoilswith [47–49]. heteroatoms they for Plasmaretention relevantcombine including polymers to aging suitdesirable pyrrole any timeprepared specific [54]. optical[43], fromfurfuryl application and non-synthetic [4phys4], [52,53]thiopheneical properties monomersand [45], ensure aniline with are that a [46]biocompatibilityfilmparticularly and reactivity even hot essential can topicand be environmentalthe[41,42].biomolecules, importancechemistries Other nanoparticlesgroups sustainability of that carefully arehave not investigated and [50,51]. achievabletuning various However, the viatheligands plasma conventionalplasma as that the deposition deposition complexitycarry means, carboxyl conditionof includingof other the acid monomer ring-containing groupsto the tailor formation inincreases, thetheir amount ofmonomers structures isocyanate so does of and maintainedenvironmentalbecausewithoils [47–49]. heteroatoms they for Plasma relevantsustainabilitycombine including polymers aging desirable pyrrole [50,51].time prepared [54]. [43],optical However, fromfurfuryl and non-synthetic as [4physthe4], complexity thiopheneical properties monomers [45],of the aniline withmonomer are a [46] biocompatibilityparticularly andincreases, even hotessential so topicdoesand thefunctionality[41,42]. importanceTablenitrile Other 1. groups retentionExamples groups of butcarefully have toof also suitcommon investigated the anytuning retention specificorganic the the of precursorsapplicationplasma theplasma oxazoline deposition depositionused [52,53] ringto prepare and itself. conditionof ensureother Theplasma-deposited ring-containing presence thatto tailor film of reactivitythe intact film amountmonomers with oxazoline can beof rings theenvironmentaloilsbecause [47–49].importance they Plasma sustainabilitycombine of carefullypolymers desirable [50,51]. tuningprepared optical However, the from plasma and non-synthetic as physthe deposition complexityical properties monomers condition of the withmonomerare to a tailorbiocompatibilityparticularly increases, the amount hot so topicdoesand of functionalitymaintainedwith differentheteroatomsprovides for surfaceretention uniquerelevant including chemistry. opportunitiesto aging suit pyrrole anytime specific [54]. [43], to conduct furfuryl application binding [44], thiophene[52,53] reactions and of[45], ensure biomolecules, aniline that [46] film nanoparticles and reactivity even essential can and be various functionalitytheenvironmental Tableimportance 1. Examplesretention sustainability of carefully ofto commonsuit [50,51]. anytuning organicspecific However, the precursorsapplicationplasma as the deposition used complexity [52,53] to prepare and condition of ensure theplasma-deposited monomer thatto tailor film increases, reactivitythe film amount with so can does beof maintainedbecauseoils [47–49].ligands they for Plasma that relevantcombine carry polymers aging carboxyldesirable timeprepared acid [54].optical groups from and non-synthetic in theirphys structuresical properties monomers [41,42 ]. withare Other a biocompatibilityparticularly groups have hot investigated topicand maintainedfunctionalitythe differentimportance for surface retention relevant of chemistry.carefully to aging suit timeanytuning specific [54]. the applicationplasma deposition [52,53] and condition ensure thatto tailor film reactivitythe amount can beof environmentalbecauseTablethe they plasma1. Examples sustainabilitycombine deposition of desirablecommon of[50,51]. other organicoptical However, ring-containing precursors and as physthe used complexity monomersical toproperties prepare withof the Surfaceplasma-deposited heteroatoms withmonomer biocompatibility increases, including film with so pyrrole doesand [43], maintainedthefunctionality importanceTabledifferent 1. for surfaceExamplesretention Precursorrelevant of chemistry.carefully ofto aging suitcommon timeanytuning specificorganic[54]. the Chemical precursorsapplicationplasma Formuladeposition used [52,53] to prepare and condition ensure plasma-deposited thatto tailor film reactivitythe Ref.film amount with can beof environmentalfurfuryl [sustainability44], thiophene [50,51]. [45], aniline However, [46] andas the even complexity essential Functionalityof oils Surfacethe [47 monomer–49 ]. Plasma increases, polymers so does prepared maintainedTabledifferent 1. for surfaceExamples relevant chemistry. of aging common time organic[54]. precursors used to prepare plasma-deposited film with functionalitythe importancefrom non-synthetic retentionPrecursor of carefully to monomerssuit anytuning specific are theChemical a particularly applicationplasma Formula deposition hot[52,53] topic and becausecondition ensure they thatto combinetailor film reactivitythe desirableRef. amount can optical beof and differentTable 1. surfaceExamples chemistry. of common organic precursors used to prepareFunctionality Surfaceplasma-deposited film with maintainedfunctionalityphysical for retention propertiesPrecursorrelevant to aging withsuit anytime biocompatibility specific [54]. Chemical application and Formula environmental [52,53] and ensure sustainability that film [ 50reactivity,51Ref.]. However, can be as the differentTable 1. surfaceExamples chemistry. of common organic precursors used to prepareFunctionalitySurface plasma-deposited film with maintainedcomplexity forAcrylic Precursorrelevant of the acid monomeraging time increases, [54]. Chemical so does Formula the importance ofcarboxylSurface carefully tuning the[55–57]Ref. plasma deposition Tabledifferent 1. surfaceExamplesPrecursor chemistry. of common organicChemical precursors Formula used to prepareFunctionality plasma-deposited Ref.film with conditionAcrylic to tailor acid the amount of functionality retention toFunctionality suitcarboxylSurface any specific application[55–57] [52,53] and different surface chemistry. Table 1. ExamplesPrecursor of common organicChemical precursors Formula used to prepare plasma-deposited Ref.film with ensure thatAcrylic film acid reactivity can be maintained for relevant agingFunctionalitycarboxylSurface time [54 ]. [55–57] different surfacePrecursor chemistry. Chemical Formula Ref. AllylalcoholAcrylic acid FunctionalitycarboxylSurface [55–57] TablePrecursor 1. Examples of common organicChemical precursors Formula used to prepare plasma-deposited filmRef. with different Acrylic acid Functionalitycarboxyl [55–57] Allylalcohol hydroxylSurface [58–60] surfaceAcrylicPrecursor chemistry. acid Chemical Formula carboxyl [55–57]Ref. Allylalcohol Functionality AcrylicEthanlolPrecursor acid Chemical Formula Surfacehydroxylcarboxyl Functionality [58–60][55–57] Ref. Allylalcohol AllylalcoholAcrylicEthanlol acid hydroxylcarboxyl [58–60][55–57]

AllylalcoholAcrylicEthanlolAcrylic acid acid hydroxylcarboxylcarboxyl [58–60][55–57] [55–57] Allylamine Amine,hydroxyl amide [58–60] [61–64]

AllylalcoholEthanlol Ethanlol hydroxyl [58–60] AllylamineAllylalcohol Amine, amide [61–64] Allylalcohol Ethanlol hydroxylhydroxyl [58–60] [58–60] Allylamine Amine, amide [61–64]

Allylalcohol AllylglycidylEthanlol ether hydroxyl [58–60] AllylamineEthanlol Amine, amide [61–64] AllylglycidylAllylamineEthanlol ether Amine,hydroxyl amide [61–64][58–60]

AllylamineAllylamine Amine,Amine,Epoxy amide amide [61–64][65,66] [61–64]

AllylglycidylEthanlol ether

GlycidylAllylglycidylAllylamine methacrylate ether Amine,Epoxy amide [65,66] [61–64]

AllylglycidylAllylglycidyl ether ether Allylamine Amine, amide [61–64]

Epoxy [65,66] Glycidyl methacrylate Allylglycidyl ether Epoxy [65,66]

Allylamine Amine,Epoxy amide [61–64] [65,66] GlycidylAllylglycidyl methacrylate ether Epoxy [65,66]

GlycidylGlycidyl methacrylate methacrylate Oxazoline, AllylglycidylAlkyloxazoline ether Epoxy [41,42][65,66]

Glycidyl methacrylate amine, amide Oxazoline,Epoxy [65,66] GlycidylAllylglycidylAlkyloxazoline methacrylate ether [41,42] amine,Oxazoline,Epoxy amide [65,66] GlycidylAlkyloxazolineAlkyloxazoline methacrylate Oxazoline, amine, amide[41,42] [41,42] Materials 2018, 11, x EthyleneFOR PEER REVIEW amine,Oxazoline, amide 5 of 18 Epoxy [65,66] GlycidylAlkyloxazoline methacrylate Oxazoline, [41,42] Materials 2018, 11Alkyloxazoline, x FORdiamine PEER REVIEW amine, amide [41,42] 5 of 18 EthyleneEthylene [67] Materials 2018Glycidyl, 11, x FOR methacrylate PEER REVIEW Amine,amine,Oxazoline, amideamide 5 of 18 Alkyloxazolinediaminediamine [68–70][41,42] Ethylene amine,Oxazoline,Amine, amide amide [67] [67–70] Materials 2018, 11Alkyloxazoline, x PropanalFOR PEER REVIEW Amine,Aldehyde amide [40,71–73][41,42] 5 of 18 AlkylamineEthylenediamineAlkylamine amine, amide [68–70] Oxazoline, PropanalEthylene Aldehyde [40,71–73][67] Alkyloxazolinediamine [41,42] Alkylamine Amine,amine, amideamide

Propanal Aldehyde [40,71–73][68–70][67] Ethylenediamine Oxazoline, Alkyloxazoline Amine, amide [41,42][67] [68–70] AlkylaminePropanalEthylenediaminePropanal Amine,amine,AldehydeAldehyde amideamide [40,71–73] [40 ,71–73] 1,7-octadiene Alkyl [68–70][67][56] Alkylamine Ethylenediamine Amine, amide 1,7-octadiene Alkyl [56] Alkylamine [68–70][67]

1,7-octadiene1,7-octadienediamine Amine,AlkylAlkyl amide [56] [56] AlkylamineEthylene [68–70][67] 1,7-octadiene Amine,Alkyl amide [56] diamine perfluoroocataneAlkylamine Fluoro [68–70][34] [67] Amine, amide perfluoroocataneperﬂuoroocataneAlkylamine FluoroFluoro [68–70][34] [34]

perfluoroocatane Fluoro [34] Alkylamine perfluoroocatane Fluoro [34] Propanethiol Thiol [74,75] Propanethiol Thiol [74,75] Propanethiol Thiol [74,75] Propanethiol Thiol [74,75]

3. Plasma PolymersPropanethiol in Biomaterial Research Thiol [74,75]

3. Plasma Polymers in Biomaterial Research Plasma polymers are a coating of choice for biomedical applications. The topic has been 3. Plasma Polymers in Biomaterial Research extensivelyPlasma polymersreviewed areelsewhere a coating [76,77]. of choice Plasma for polymer biomedical deposition applications. enables The the topic generation has been of 3. Plasma Polymers in Biomaterial Research extensivelysurfacesPlasma where reviewedpolymers the entire elsewhereare spectruma coating [76,77]. of of surface choicePlasma prop for polymer ertiesbiomedical including deposition applications. chemistry, enables The wettability,the topic generation has stiffness been of surfacesextensivelyand nanotopographyPlasma where reviewed polymers the entire canelsewhere are spectrum be a preciselycoating [76,77]. of surfaceoftailored. choicePlasma prop The forpolymererties techniquebiomedical including deposition is applications.rapid chemistry, andenables reproducible; wettability,The the topicgeneration thus,hasstiffness been itof is andsurfacesextensivelypossible nanotopography whereto reviewedcreate the entirelarge can elsewhere bespectrumquantities precisely [76,77]. of oftailored.surface model Plasma prop The su rfacesertiespolymertechnique includingwith deposition is well-controlledrapid chemistry, and enables reproducible; wettability, propertiesthe generation thus, stiffness for it theisof possibleandsurfacesinvestigation nanotopography towhere create of the many largeentire can complex bequantitiesspectrum precisely processes, ofof tailored. surfacemodel ranging propThesurfaces ertiestechnique from withincluding protein iswell-controlled rapid chemistry,binding, and reproducible; to wettability,properties immune thus, responsestiffnessfor itthe is investigationpossibleandthrough nanotopography to thecreate of fundamentals many large can complex quantitiesbe ofprecisely nano-wetting. processes, of tailored. model ranging They Thesurfaces are techniquefrom also with proteinunderpinning iswell-controlled rapid binding, and ne reproducible; wto biosensing propertiesimmune platformsresponsethus, for theit is throughinvestigationpossible[78] and to novelto the create offundamentals cell many guidancelarge complex quantities ofsurfaces. nano-wetting. processes, ofWe modelused ranging They a capacitivelysu arerfaces from also with underpinningprotein coupled well-controlled binding, parallel new to platebiosensing immuneproperties plasma platformsresponse chamberfor the [78]throughinvestigation[22] and to generate tonovel the fundamentalscellof films many guidance from complex a surfaces. ofvariety nano-wetting. processes, of We organic used rangingThey aprecursors capacitively are fromalso including underpinning proteincoupled allylamine, binding,parallel new plate tobiosensing octadiene, immune plasma platforms aldehyde,chamberresponse [22][78]throughethanol, toand generate novel toacrylic the cell fundamentalsfilms acid guidance fromor even a varietysurfaces. of perfluorooctane. nano-wetting. of We organic used precursors Theya Thcapacitivelye areresulting also including underpinning coupled coatings allylamine, parallel pres neentw plate octadiene, biosensingdistinctive plasma aldehyde, platformschamberchemical ethanol,[22][78]functions, to and generate acrylicnovel namely, cellfilmsacid guidanceamines, fromor even a variety hydroxyls,surfaces. perfluorooctane. of Weorganic carboxylic used precursors Tha capacitivelye acids, resulting includingketones, coupledcoatings etc. allylamine, parallelThesepresent plasma plate octadiene,distinctive plasma polymers aldehyde, chemical chamber have functions,ethanol,[22]been to used generate acrylic namely, as a acidfilmsutility amines, or from to even investig ahydroxyls, variety perfluorooctane.ate of the organiccarboxylic systematic precursorsTh eacids, resulting effect ketones, including of coatingssurf etc.ace allylamine, Thesechemistry present plasma distinctiveoctadiene, on manypolymers aldehyde,biologicalchemical have beenfunctions,ethanol,processes used acrylic namely,asincluding a utility acid amines, the orto eveninvestigbiofunctionality hydroxyls, perfluorooctane.ate the carboxylic systematic of surfac Th acids,e e-adsorbedeffectresulting ketones, of surf coatings proteins aceetc. chemistryThese pres [40] entplasma, the ondistinctive differentiationmany polymers biological chemical have of processesbeenfunctions,embryonic used including asnamely, [79], a utility kidney amines,the to [80],biofunctionalityinvestig hydroxyls, dentalate pulpthe carboxylic systematic of[81], surfac mesenchymal acids,e-adsorbed effect ketones, of surf[82] proteinsace andetc. chemistry Thesehuman [40], plasma theadipose-derived on differentiation many polymers biological havestem of embryonicprocessesbeencells [83,84]used including [79],as as a wellkidneyutility asthe tothe[80], biofunctionality investig deposition dentalate pulp the of collagen[81],systematicof surfac mesenchymal bye-adsorbed effectprimary of [82] surf humanproteins andace humanchemistrydermal [40], adipose-derivedthefibroblasts on differentiation many [85]. biological Usingstem of cellsembryonicprocessesthe reactivity[83,84] including[79], as ofwell kidney the as chemicalthe the [80], biofunctionalitydeposition dental groups pulp created,of collagen [81], of surfacitmesenchymal is by alsoe-adsorbed primary possible [82] human toproteins and bind dermalhuman ligands [40] , fibroblasts adipose-derivedthe and differentiation even [85]. proteins Using stem ofto thecellsembryoniccreate reactivity [83,84] diagnostic [79],as of well the kidney tools chemicalas the [40,86–89]. [80], deposition groupsdental Fine-tuned pulpcreated, of collagen [81], it chemical mesenchymalis byalso primary possible functionality [82]human to bindand facilitateddermal humanligands fibroblasts adipose-derivedand by plasmaeven [85].proteins polymers Using stem to createthecellsalso reactivity [83,84] alloweddiagnostic as of binding wellthe tools chemicalas [40,86–89].theto depositionsurfaces groups Fine-tuned ofcreated, of gold collagen chemicalitand is alsobysilver primary possiblefunctionality nanoparticles human to bind facilitated dermal ligands to generate fibroblasts andby plasma even model proteins[85]. polymers surface Using to alsocreatethenanotopography reactivityallowed diagnostic bindingof the toolsto studychemical [40,86–89].to surfacesbiological groups Fine-tuned of phenomenacreated, gold andchemical it is orsilveralso solve possiblefunctionality nanoparticles environmental to bind facilitated ligandsto challengesgenerate byand plasma even model[25,90–93], proteins polymers surface and to nanotopographyalsocreatenanoengineered allowed diagnostic binding surfacesto tools study to[40,86–89]. withbiologicalsurfaces controlled Fine-tuned ofphenomena gold nanofeatures and chemical orsilver solve size functionalitynanoparticles environmental and density facilitated [94].to challenges generate In thisby plasmamanner, [25,90–93],model polymers uniformsurface and nanoengineerednanotopographyalsoand gradientallowed bindingnanotopography surfaces to study to with biologicalsurfaces controlled can ofphenomena be gold nanofeaturesgenerated and or silver solveus sizeing nanoparticlesenvironmental andelectrostatic density [94]. to bindingchallenges generateIn this ofmanner, [25,90–93],modelgold uniformor surface silver and andnanoengineerednanotopographynanoparticles gradient cappednanotopography surfaces to study with with biologicalmercapto controlled can succinicbephenomena nanofeaturesgenerated acid orto usallylaminesolve sizeing environmentalandelectrostatic densityplasma [94]. polymersbinding challenges In this orof manner, covalent gold[25,90–93], or uniform binding silver and nanoparticlesandnanoengineeredto oxazoline-based gradient cappednanotopography surfaces coatings with with mercapto [95]. controlled can A thin succinicbe layer generatednanofeatures acid of pl toasma allylamineus ingsize polymer electrostaticand plasma density can then polymers [94].binding be In deposited this orof covalentmanner, gold on ortop bindinguniform silverof the tonanoparticlesandsurface oxazoline-based gradient nanotopography capped nanotopography coatings with mercapto [95].to Acontrolcan thin succinic be layer generatedthe acidof outepl toasma allylaminermostus ingpolymer electrostaticsurface plasma can thenchemistry polymers bindingbe deposited or whileof covalent gold on preservingtop orbinding ofsilver the surfacetonanoparticlesnanotopography. oxazoline-based nanotopography capped This coatings with is a mercapto unique[95].to controlA approachthin succinic layerthe thatofacidoute pl canasmatormost allylamine be polymer achieved surface plasma can only thenchemistry polymersby be plasma deposited whileor polymerization covalent onpreserving top binding of the or nanotopography.surfacetoiCVD. oxazoline-based Annanotopography important This coatings applicationis a unique to[95]. control A ofapproach thin this layer approachthe that ofoute plcanasma rmostwas be achievedtopolymer derivesurface can onlyunderstanding chemistrythen by plasma be deposited whilepolymerizationof the oninfluencepreserving top of theor of iCVD.nanotopography.surface An nanotopography nanotopographyimportant This application is a and uniqueto chemistry controlof approach this approachonthe inflammatothat oute can wasrmost be rytoachieved responsesderivesurface understandingonly [96,97].chemistry by plasma Such of polymerizationwhileknowledge the influencepreserving is vital orof surfaceiCVD.nanotopography.for the An nanotopographyutilization important Thisof applicationplasma is and a unique chemistrypolymers of approach this on inapproach implantableinflammato that can was bery devicesto achieved responses derive [98,99]. understanding only [96,97]. byThanks plasma Such to ofknowledge polymerizationthe the wide influence range is vital oforof forsurfaceiCVD.intrinsic the utilizationAnnanotopography surface important chemistry of plasma application and that polymerschemistry can of bethis inachieved, on approachimplantable inflammato th ewas films devicesry to responses createdderive [98,99]. understanding in [96,97]. this Thanks way Such spanto knowledgetheof athe wideuniquely influence range is vitalwide ofof intrinsicforsurfacerange the ofutilization nanotopographysurface wettability, chemistry of plasma generating and that polymers chemistry can wa beter achieved,in contacton implantable inflammato anglesthe films devicesryfrom createdresponses 20° [98,99]. to in 120°[96,97].this Thanks wayon Suchsmooth span to theknowledge a surfaces.uniquelywide range is Whenwide vital of rangeintrinsicforplasma the of utilization surfacewettability,polymers chemistry of aregeneratingplasma combined that polymers can wa beter withachieved, contactin implantablenanotextur angles the films fromdevicesing, created 20°remarkable [98,99]. to in 120° this Thanks on waywetting smooth span to the asurfaces.states uniquely wide suchrange When wide asof plasmarangeintrinsicsuperhydrophobicity of polymerswettability,surface chemistry are generating and combined superhydrophilicity that canwa terbewith achieved,contact nanotextur canangles th bee films achieved ing,from created remarkable20° [100–102]. to in120° this on Wewaywetting smooth nanoengineered span statesasurfaces. uniquely such Whenmodel wide as superhydrophobicityplasmarangegradient of polymerssubstrateswettability, withare andgenerating intrinsic combinedsuperhydrophilicity wawettability terwith contact nanotextur ranging can angles be achieved from ing,from hydrophilic remarkable20° [100–102]. to 120° to We onhydrophobicwetting smoothnanoengineered states surfaces. to investigatesuch model When as gradientsuperhydrophobicityplasmathe mechanisms substratespolymers governing with areand intrinsic superhydrophilicitycombined wetting wettability withat the rangingnanotexturnanoscal can be fromachievede.ing, While hydrophilic remarkable [100–102]. classical to theorieshydrophobicWewetting nanoengineered could states to notinvestigate suchaccount model as thegradientsuperhydrophobicitycorrectly mechanisms substrates for the watergoverning with and contact intrinsic superhydrophilicity wetting angles wettability at measured the nanoscalranging can on be nanorough frome. achieved While hydrophilic classical [100–102].surfaces, to theories wehydrophobic We were nanoengineered could able to tonot investigatedevelop account model an correctlythegradientempirical mechanisms forsubstrates model the water governingthat with 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Materials 2019, 12, 191 5 of 18

3. Plasma Polymers in Biomaterial Research Plasma polymers are a coating of choice for biomedical applications. The topic has been extensively reviewed elsewhere [76,77]. Plasma polymer deposition enables the generation of surfaces where the entire spectrum of surface properties including chemistry, wettability, stiffness and nanotopography can be precisely tailored. The technique is rapid and reproducible; thus, it is possible to create large quantities of model surfaces with well-controlled properties for the investigation of many complex processes, ranging from protein binding, to immune response through to the fundamentals of nano-wetting. They are also underpinning new biosensing platforms [78] and novel cell guidance surfaces. We used a capacitively coupled parallel plate plasma chamber [22] to generate films from a variety of organic precursors including allylamine, octadiene, aldehyde, ethanol, acrylic acid or even perfluorooctane. The resulting coatings present distinctive chemical functions, namely, amines, hydroxyls, carboxylic acids, ketones, etc. These plasma polymers have been used as a utility to investigate the systematic effect of surface chemistry on many biological processes including the biofunctionality of surface-adsorbed proteins [40], the differentiation of embryonic [79], kidney [80], dental pulp [81], mesenchymal [82] and human adipose-derived stem cells [83,84] as well as the deposition of collagen by primary human dermal fibroblasts [85]. Using the reactivity of the chemical groups created, it is also possible to bind ligands and even proteins to create diagnostic tools [40,86–89]. Fine-tuned chemical functionality facilitated by plasma polymers also allowed binding to surfaces of gold and silver nanoparticles to generate model surface nanotopography to study biological phenomena or solve environmental challenges [25,90–93], and nanoengineered surfaces with controlled nanofeatures size and density [94]. In this manner, uniform and gradient nanotopography can be generated using electrostatic binding of gold or silver nanoparticles capped with mercapto succinic acid to allylamine plasma polymers or covalent binding to oxazoline-based coatings [95]. A thin layer of plasma polymer can then be deposited on top of the surface nanotopography to control the outermost surface chemistry while preserving nanotopography. This is a unique approach that can be achieved only by plasma polymerization or iCVD. An important application of this approach was to derive understanding of the influence of surface nanotopography and chemistry on inflammatory responses [96,97]. Such knowledge is vital for the utilization of plasma polymers in implantable devices [98,99]. Thanks to the wide range of intrinsic surface chemistry that can be achieved, the films created in this way span a uniquely wide range of wettability, generating water contact angles from 20◦ to 120◦ on smooth surfaces. When plasma polymers are combined with nanotexturing, remarkable wetting states such as superhydrophobicity and superhydrophilicity can be achieved [100–102]. We nanoengineered model gradient substrates with intrinsic wettability ranging from hydrophilic to hydrophobic to investigate the mechanisms governing wetting at the nanoscale. While classical theories could not account correctly for the water contact angles measured on nanorough surfaces, we were able to develop an empirical model that effectively captures the experimental data. The model, which is now known as the Vasilev-Ramiasa equation [103], further enables us to predict the water contact angle on the nanorough surfaces, using as the only known parameter the number density and size of the spherical nanofeatures and the contact angle on the smooth substrate itself. A range of other biomedical applications have also been facilitated by plasma polymers including in drug delivery allowing to achieve controlled release rate of synthetic therapeutics or biomolecules [104–106]. Another particularly useful application of plasma polymers is in antibacterial technologies [107–109]. Coatings able to protect the surface of medical devices from bacterial adhesion and biofilm formation are used to minimize the risk of infection, and especially hospital acquired infections which are one of this century’s biggest health concerns. Infections are a well-studied subject and it is now well-known that the attachment of individual planktonic bacterial cells to the device surface is just the first step, followed by colonization and infection. It is also well understood that once a biofilm is formed, it protects the bacterial cells from the immune system and enormously (up to 1000 times) increases the dose of antibiotics required to clear the infection. This overuse of antibiotics leads, on the one hand, to development of antibiotic resistance by bacteria and, on the other hand, causes systemic Materials 2019, 12, 191 6 of 18 toxicity to organs such as the kidneys and liver. For these reasons, the purpose of antibacterial coatings is to disturb the initial stage of bacterial adhesion [110,111]. This can be achieved through one of four distinct mechanisms of action: contact killing, bacterial repellence, killing in solution or stimuli responsive killing [109]. Plasma polymers have been used to generate contact killing surfaces on several occasions [112,113]. We conducted a study in which quaternary ammonium compounds were covalently immobilized + to allylamine plasma polymers and found that surface concentration of NR4 groups equivalent to 5 At% nitrogen and surface potential of +120 mV was necessary to damage bacteria. In another study of surface-bacteria interaction, plasma processes were used to generate silicon nanospikes which we coated with different plasma polymer thin films to tailor the substrate chemistry and wettability [114,115]. We found that for hydrophilic substrates, the presence of nanospikes resulted in bacterial death on contact. Arguably, the most efficient way to limit bacterial colonization is to use coatings that release antimicrobial agents either passively or in response to external stimuli. Our group has explored numerous avenues to produce such platforms using plasma polymers, including the ‘sandwiching’ of antibiotics between two plasma polymer layers [106,116], a sacrificial nano-templating approach to create antibiotic reservoirs whose release could be controlled by a plasma polymer overcoating [105] or encapsulation of antibiotic particulates within plasma polymers. As silver is known as a potent antibacterial agent, much work has also been done revolving around the use of silver nanoparticles for the release of silver ions [91,92,117–121]. The application of silver in antibacterial technology is reviewed in much detail elsewhere [122]. Nitric oxide releasing as well as new TEMPO-based coatings capable of delaying biofilm growth but stimulating mammalian cells growth has also been reported [123–125]. The potential of oxazoline-based plasma polymer coatings that we recently developed in antibacterial technologies is discussed later in this review.

4. Plasma Deposited Polyoxazolines—The Importance of Deposition Conditions For most plasma polymers, chemistry, functionality retention and reactivity are highly dependent on the plasma deposition parameters. For instance, it is well accepted that high powers and low flow rates lead to greater monomer fragmentation and crosslinking. The films deposited using these conditions are typically more stable than those generated at low powers and high flow rates [106,126]. In contrast, low flow rate and high powers allow for the retention of the original precursor functionality which results in films that are relatively more reactive. Carefully balancing the precursor flow rate and power is essential to induce film growth, rather than substrate etching [20]. Several studies investigating the growth and adhesion properties of plasma-deposited polymer films have shown that excellent adhesion can be achieved on a variety of substrates [24]. Furthermore, in the film growth regime, increasing deposition time increases film thickness and it was proven that beyond 5 nm in thickness, the nature of the underlying materials does not affect the properties of the polymer films [22–24]. All in all, almost every time a new precursor is used for plasma deposition, optimization is required, even more so when the precursor contains 1 or more heteroatoms.

4.1. PPOx Physico-Chemical Characterization In the case of plasma-deposited oxazoline films, careful optimization of the deposition parameters is paramount [127]. Our research was motivated by the fact that the conventional polyoxazoline polymer (POx) displayed interesting biomaterial properties such as good biocompatibility, low cytotoxicity and excellent stealth properties with stability rates surpassing those of PEG-modified surfaces. The development of the first generation of plasma deposited x oxazolines conducted by our group revealed that, through the plasma process, we could not only produce films with comparable properties but also films with added reactivity. These results illustrate the importance of carefully controlling deposition conditions to tailor the plasma-coating properties [42]. Our group pioneered the field of plasma-deposited oxazolines (PPOx) using various oxazoline precursors (methy, ethyl Materials 2018, 11, x FOR PEER REVIEW 7 of 18 polymer films [22–24]. All in all, almost every time a new precursor is used for plasma deposition, optimization is required, even more so when the precursor contains 1 or more heteroatoms

4.1. PPOx Physico-Chemical Characterization In the case of plasma-deposited oxazoline films, careful optimization of the deposition parameters is paramount [127]. Our research was motivated by the fact that the conventional polyoxazoline polymer (POx) displayed interesting biomaterial properties such as good biocompatibility, low cytotoxicity and excellent stealth properties with stability rates surpassing those of PEG-modified surfaces. The development of the first generation of plasma deposited x oxazolines conducted by our group revealed that, through the plasma process, we could not only produce films with comparable propertiesMaterials 2019 but, 12, 191also films with added reactivity. These results illustrate the importance of carefully7 of 18 controlling deposition conditions to tailor the plasma-coating properties [42]. Our group pioneered theand field isopropylene) of plasma-deposited and a range oxazolines of plasma ignition(PPOx) using powers, various monomer oxazoline flow rates precursors and deposition (methy, timesethyl and(Figure isopropylene)2 and Table 2and). The a range films of were plasma deposited ignition in apowers, custom-made monomer inductively flow rates coupled and deposition glass chamber times (Figureplasma reactor2 and Table described 2). The in detail films elsewhere, were deposited in which in thea custom-m brass electrodesade inductively are set 10 cmcoupled apart glass [128]. chamberThe plasma plasma ignition reactor power described was varied in fromdetail 10 elsewhere, to 50 W. The in incomingwhich the precursor brass electrodes flow rate, are referred set 10 to cm as apartthe chamber [128]. The working plasma pressure, ignition was power adjusted was betweenvaried from 0.10 10 and to 0.30 50 W. mbar. The The incoming deposition precursor time ranged flow rate,from referred 1 to 7 min. to Theas the plasma chamber phase working was characterised pressure, was using adjusted in-situMass between Spectrometry, 0.10 and 0.30 and PPOxmbar. filmsThe depositionwere characterised time ranged via Ellipsometry, from 1 to 7 Watermin. The Contact plasma Angle phase measurement, was characterised X-ray photoelectron, using in-situ Fourier Mass Spectrometry,Transform Infrared and SpectroscopyPPOx films and were Time characte of Flightrised Secondary via Ellipsometry, Ion Mass Spectrometry. Water Contact By tuning Angle the measurement,deposition conditions, X-ray photoelectron, we could produce Fourier plasma-deposited Transform Infrared polyoxazoline Spectroscopy (PPOx) and thinTime films of Flight stable Secondaryunder various Ion pHMass and Spectrometry. salt conditions By that tuning were the biocompatible deposition andconditions, chemically we reactivecould produce [42]. Our plasma- results depositedwere soon polyoxazoline confirmed by other(PPOx) groups thin whofilms specifically stable under studied various films pH formed and salt from conditions 2-ethyl-2-oxazoline, that were biocompatibleFigure2d [129, 130and]. chemically reactive [42]. Our results were soon confirmed by other groups who specifically studied films formed from 2-ethyl-2-oxazoline, Figure 2d [129,130].

Figure 2. PPOx deposition conditions: (a) Effect of monomer chemistry on film thickness, (b) precursor Figure 2. PPOx deposition conditions: (a) Effect of monomer chemistry on film thickness, (b) flow rates on nitrogen content, (c) of plasma ignition powers on films stability for MeOx, EtOx and precursorPiPOx. (d )flow PPEtOX rates Plasmaon nitrogen deposition content, rate (c) as of a plasma function ignition of the Yasundapowers on parameter films stability is defined for MeOx, as the EtOxratio and between PiPOx. plasma (d) PPEtOX power Plasma and monomer deposition flow rate rate, as ina func twotion different of the plasma Yasunda reactors. parameter is defined as the ratio between plasma power and monomer flow rate, in two different plasma reactors. Table 2. Plasma reactor specification and depositions condition ranges for the PPOx deposition studies conducted by Zanini et al. and Vasilev et al.

Reactor and Deposition Parameters Zanini et al. Vasilev et al. Vacuum chamber Stainless steel Glass Chamber Diameter, cm 30 15 Electrode Stainless steel Brass Electrode Diameter, cm 15 10 Separation Distance, cm 4 10 Monomer input Showerhead, 2 mm pinholes Single inlet, 5 mm Radio frequency, MHz 13.56 13.56 Base pressure, Pa 10−3 10−1 Working pressure, Pa 6 1–3 Power range, W 4–80 10–50 Deposition time, min 10–30 1–7 Materials 2018, 11, x FOR PEER REVIEW 8 of 18

Table 2. Plasma reactor specification and depositions condition ranges for the PPOx deposition studies conducted by Zanini et al. and Vasilev et al.

Reactor and Deposition Parameters Zanini et al. Vasilev et al. Vacuum chamber Stainless steel Glass Chamber Diameter, cm 30 15 Electrode Stainless steel Brass Electrode Diameter, cm 15 10 Separation Distance, cm 4 10 Monomer input Showerhead, 2 mm pinholes Single inlet, 5 mm Radio frequency, MHz 13.56 13.56 Base pressure, Pa 10−3 10−1 Working pressure, Pa 6 1–3 Materials 2019, 12, 191Power range, W 4–80 10–50 8 of 18 Deposition time, min 10–30 1–7

The films films produced by Bhatt et al. have have comparab comparablele chemistry, chemistry, but but the the use use of a lower plasma ignitionignition power power resulted resulted in in significant significant film film loss loss after after water water exposure. exposure. Our Our results, results, shown shown in in Figure Figure 22c,c, also show show that that film film loss loss occurred occurred after after 1 h 1immersion h immersion in water in water for the for films the deposited films deposited at the lowest at the powerlowest (10 power W). (10Zanini W). et Zanini al. also et al.used also low used pressu lowre pressure depositions depositions condition condition and investigated and investigated a wider rangea wider of rangeignition of powers, ignition including powers, including some comparable some comparable to the ones to used the onesin our used experiment in our experiment (3.9 sccm, and(3.9 sccm,powers and from powers 5 to 80 from W). 5Table to 80 2 W). summarizes Table2 summarizes side by side side the by reactor side thespecifications reactor specifications and deposition and conditionsdeposition used conditions by these used two by groups. these two Comparing groups. Comparing our results ourand results those of and Zani thoseni et of al. Zanini for 2-ethyl-2- et al. for oxazoline2-ethyl-2-oxazoline films deposited films depositedin two diff inerent two plasma different reactors plasma and reactors using different and using precursor different flow precursor rates, Figureflow rates, 2d, Figurewe found2d, we film found deposition film deposition rates of ratesthe same of the order same of order magnitude of magnitude and comparable and comparable film wettability,film wettability, in the in range the range of approximately of approximately 60 60to to70 70depending depending on on the the nature nature of of the the precursor precursor and deposition conditions, conditions, Figure Figure 33a.a. It is worthworth noting,noting, however,however, thatthat thethe relationshiprelationship betweenbetween thethe filmfilm deposition rate and the power input (W/F) is is complex complex and and will will be be influenced influenced by by the the plasma plasma reactor geometry (e.g., (e.g., deposition deposition area area and and electron electron energy energy distribution distribution function, function, ion iondensity) density) despite despite the fact the thatfact the that deposition the deposition conditions conditions described described in Zanini in Zanini et al. appear et al. appear comparable comparable to those to used those in used our instudy our [27,52,131,132].study [27,52,131 As,132 such,]. As it such, is only it is meaningful only meaningful here to here compare to compare the macroscopic the macroscopic attribute attribute of the offilms the asfilms their as intrinsic their intrinsic chemical chemical nature nature may be may quite be quitedifferent. different.

Figure 3. (a) Advancing water contact angle of water in air on plasma-deposited Methyl, Ethyl, and Figureisopropenyl 3. (a) oxazolineAdvancing deposited water contact at 50 angle W and of 2.3 water mbar. in (airb) FTIRon plasma-deposited spectra of isopropenyl, Methyl, and Ethyl, methyl and isopropenyloxazoline deposited oxazoline under deposited the same at 50 conditions W and 2.3 as mbar. well as (b a) pristineFTIR spectra methyl of oxazolineisopropenyl, precursor. and methyl oxazoline deposited under the same conditions as well as a pristine methyl oxazoline precursor. 4.2. PPOx Unique Reactivity Most importantly, these studies from different research groups demonstrated that under all deposition conditions, the films displayed a rich film chemistry of amine, amide, carbonyl, carboxyl and nitrile functions, as well as intact oxazoline rings [42,130]. Figure3b presents a typical Fourier Transform Infrared Spectroscopy (FTIR) spectrum for oxazoline films deposited from methyl and isopropenyl oxazoline as well as the intact methyl precursor for direct comparison. However, the relative concentration of the surface chemical group, as well as the film wettability and stability, varies with plasma power and the precursor flow rate, as described in details previously [42,127]. Advanced in situ Mass Spectroscopy of the plasma phase correlated with Tof SIMS principal component analysis provided important insights into the physicochemical event occurring in the plasma itself and post deposition [30]. This study revealed that amide groups present in the plasma deposited oxazolines are the result of post deposition reactions in the films while functional groups such as nitrile, isocyanates and oxazoline ring are formed in the plasma process itself and are better retained in the final films Materials 2019, 12, 191 9 of 18 when gentle deposition conditions are used. A schematic representing the resulting chemical group present in the PPOx film is shown in Figure4. Zanini et al. used NMR to estimate the amount of oxazoline ring retention as well as the degree of linear open ring structure in PPOx surfaces. In PEtOX film deposited at 15 W, they achieved 20% ring retention, while the remaining of the surface chemistry resulted from more complex plasma fragmentation and recombination processes, in good agreement with our spectroscopic investigations. The distinctive oxazoline ring functionality of PPOx is a clear advantage over conventional POx because the ring can form covalent bonds with carboxylic acid groups present in biomolecules and in other ligands [42]. This unique reactivity of PPOx with –COOH functionalities, which was also confirmed by Zanini et al., has been used to create surfaces with controlled nanotopography by covalent binding of COOH– functionalised nanoparticles [94]. In a recent study, we created in this way a range of substrates with different nanoparticle sizes and densities to interrogate the effect of nanotopography on protein binding using PPOx as the overlayer [133]. It is well accepted that cell adhesion to biomaterials relies on the initial formation of an adsorbed protein layer [134]. As cells come into contact with the protein film, integrin receptors on the cell membranes recognize favorable binding sites which initiates the adhesion process. It is therefore essential for biomaterials to promote the adsorption of bioactive proteins. Oxygen-rich and nitrogen-rich plasma-derived surfaces have been particularly studied for their application as biomaterials [135]. Oxygen-rich surface chemical functions are known to promote cellular attachment because they contain polar groups such as hydroxyls [136], carboxyls [137,138] and carbonyls [57], which enter ionic interactions with cell adhesion-mediating molecules [139]. Amine-rich plasma polymers, prepared from allylamine [61,62], ethylendiamine [67], propylamine [68], butlyamine [69] and heptylamine [70], also are coatings of choice for biomedical applications [140]. They are positively charged in cell culture conditions and facilitate the electrostatic adsorption of negatively charged proteins. This protein binding ability is thought to confer the amine rich surfaces their biocompatiblity. Plasma-deposited polyoxazolines are both oxygen and nitrogen rich. Surface chemistry analysis indicated that oxygen and nitrogen are, in a PPOx film, engaged in many hydrophilic, H-donor groups which may explain their good ability to support mammalian cell growth, as evidenced in our studies of oxazolines as cell guidance surfaces [41]. We found that mammalian cells such as kidney stem cells and fibroblast do adhere and proliferate on POx coated surfaces just as well as on control tissue culture plate, Figure4, left. Our work on protein adsorption to nanorough PPOx-coated surfaces demonstrated that the amount of protein bound to the surface is determined by nanotopography-induced geometric effects and surface wettability rather than overall surface area. Protein adsorption was hindered on a densely packed array of 16 and 38 nm gold nanoparticles overcoated with PPOx compared to smooth PPOx substrates, while it increased for 68 nm nanoparticles [94,141]. More recently we conducted a one-year aging study of PPOx films which demonstrated that the reactivity of the films towards COOH-functionalised gold nanoparticles [142] was retained above 90% when the films were kept in dark, vacuum-sealed containers [143]. This extended shelf live is a significant asset for future commercial applications of PPOx. From our detailed investigations, we compiled a matrix of the physico-chemical properties of PPOx as a function of the plasma deposition conditions that we used to design PPOx films tailored for cell guidance surfaces, biosensors and low fouling substrates as explained below, and depicted in Figure4. Materials 2018, 11, x FOR PEER REVIEW 10 of 18

compiled a matrix of the physico-chemical properties of PPOx as a function of the plasma deposition Materialsconditions2019, 12that, 191 we used to design PPOx films tailored for cell guidance surfaces, biosensors and10 of low 18 fouling substrates as explained below, and depicted in Figure 4.

Figure 4. Schematic illustrating the PPox deposition process (top) and its applications (bottom) for cellFigure guidance 4. Schematic surfaces, illustrating diagnostic the devices PPox anddeposition low fouling process properties. (top) and The its leftapplications images illustrate (bottom) the for biocompatiblecell guidance naturesurfaces, of PPOxdiagnostic coating devices on which and multiple low fouling cell typesproperties. including Thehuman left images dermal illustrate fibroblast the andbiocompatible kidney stem nature cells proliferateof PPOx ascoating successfully on which as onmultiple tissue culturecell types plate. including The middle human schematic dermal illustratesfibroblast the and reaction kidney occurring stem cells between proliferate PPOx as andsuccessfully biomolecule as on with tissue COOH culture function plate. and The how middle this biofunctionalisationschematic illustrates is the used reaction for the occurring selective between capture PPOx of cancer and cells.biomolecule The right-hand with COOH side function shows theand inhibitedhow this proliferationbiofunctionalisation of biofilm is used on PPOx for the substrates selective as capture well as of the cancer decrease cells. in The pro-inflammatory right-hand side cytokineshows the IL6 inhibited secretion, proliferation which together of makesbiofilm PPOx on PPOx a suitable substrates candidate as forwell implant as the coatings.decrease in pro- inflammatory cytokine IL6 secretion, which together makes PPOx a suitable candidate for implant 4.3. PPOx in Novel Technology coatings. An enormous advantage of plasma polymers for the industrialization of novel technologies is that they4.3. canPPOx be in deposited Novel Technology on any type of substrate from the four classes of materials (i.e., metals, ceramics, polymers and composites) including those featuring complex shapes and topography. The capacity to An enormous advantage of plasma polymers for the industrialization of novel technologies is preserve valuable bulk properties but to alter the properties at the surface contributes substantial added that they can be deposited on any type of substrate from the four classes of materials (i.e., metals, value to numerous products in fields ranging from medicine to membrane filtration and electronics. ceramics, polymers and composites) including those featuring complex shapes and topography. The Oxazoline-derived plasma polymer coatings are a promising candidate in antibacterial capacity to preserve valuable bulk properties but to alter the properties at the surface contributes technologies. Our research demonstrated that, using appropriate deposition conditions, bacteria may substantial added value to numerous products in fields ranging from medicine to membrane attach in small numbers to the PPOx but would not proliferate to form biofilms, Figure4, right [ 144]. filtration and electronics. While the mechanisms underlying these interesting properties are still under investigation, the Oxazoline-derived plasma polymer coatings are a promising candidate in antibacterial simplicity of the method has already attracted industrial interest as it provides excellent opportunities technologies. Our research demonstrated that, using appropriate deposition conditions, bacteria may forattach developing in small medical numbers device-coating to the PPOx but technologies. would not This prol propertyiferate to of form PPOx biofilms, films is Figure interesting 4, right for their[144]. useWhile as low the fouling mechanisms coatings underlying for implantable these devices. interesting For thisproperties reason, weare alsostill investigatedunder investigation, the response the ofsimplicity immune cellsof the to PPOxmethod films. has In thisalready investigation, attracted cytokineindustrial secretion interest from as boneit provides marrow-derived excellent primaryopportunities macrophages for developing (BMDM) medical was measured device-coatingin vitro technologies.. BMDM were This selected property as modelof PPOx immune films is cellsinteresting because for their their function use as low is to fouling mediate coatings early innate for implantable immune inflammatory devices. For this responses reason, [ 41we,141 also]. Comparedinvestigated to otherthe response nitrogen-rich of immune plasma cells polymer to PPOx and tissuefilms. cultureIn this plates,investigation, a marked cytokine reduction secretion in the α expressionfrom bone of marrow-derived TFN- and IL-6 cytokineprimary wasmacrophages observed on(BMDM) the PPOx was substrates, measured Figure in vitro.4, right. BMDM Together, were theseselected results as indicatemodel thatimmune PPOx cells films couldbecause benefit their several function device is typesto mediate such as early prosthetics, innate catheters, immune orinflammatory even wound dressings.responses [41,141]. Compared to other nitrogen-rich plasma polymer and tissue cultureBladder plates, cancer a marked diagnostic reduction devices: in the The expression PPOx capacity of TFN- toα and spontaneously IL-6 cytokine form was covalentobserved bonds on the withPPOx the substrates, carboxylic Figure acid groups 4, right. present Together, in biomolecules these results wasindicate used that togenerate PPOx films immunofunctionalised could benefit several surfacesdevice types for the such selective as prosthetics, capture of cath cancereters, cells or fromeven urinewound [145 dressings.]. Anti-epithelial cell adhesion molecule antibodies were covalently bound to PPOx substrates. Using PPOx to immobilise antibodies for diagnostic purposes is very useful because the strong covalent bond between the substrate and the sensing biomolecule is not disrupted by physiological variations in the composition, pH, and ionic Materials 2019, 12, 191 11 of 18 strength of real body fluid such as urine [146]. The biosensors developed in this way were able to detect cancer cells in model urine and also in real patient urine samples. The outcomes of this work are currently being tested in the clinical setting.

5. Conclusions and Outlook Collectively, this review summarizes the principles at the basis of plasma deposition and highlights recent progress made in understanding the unique chemistry and reactivity of coatings deposited by this method [147]. We then demonstrate how carefully designed plasma polymer films can serve the purpose of fundamental research and biomedical applications. We placed emphasis on relatively recently developed oxazoline precursor-derived plasma polymer coatings which have been demonstrated to offer a number of intriguing and very valuable properties. Some of these properties are unique such as the retention of a population of intact oxazoline rings on the surface of the coatings which opens new opportunities in bio-sensing and medical diagnostics. Other valuable properties such as elimination of biofilm formation and excellent biocompatibility make these coatings good candidates for surface modification of implantable medical devices, tissue engineering constricts, cell and drug delivery vehicles, and many others. However, this is just the beginning of a new era. With more researchers and companies adopting the technology, many new interesting properties will be discovered and new opportunities for commercial applications will be identified.

Funding: This review was supported from funding from ARC DP15104212 and DP180101254, NHMRC Fellowship APP1122825, NHMRC Project grant APP1032738 and the Alexander von Humboldt Foundation for Fellowship for Experienced Researchers. Acknowledgments: K.V. thanks ARC for DP15104212 and DP180101254, NHMRC for fellowship APP1122825 and Project grant APP1032738 and the Alexander von Humboldt Foundation for Fellowship for Experienced Researchers. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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